Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:14](=[O:16])[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:17])=[CH:30][CH:29]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.9 %

Procedure:
A mixture of 0.64 g (2.4 mmol) of [4-(4-fluoro-benzyl)piperidin-1-yl]-oxo-acetic acid, 0.34 ml (2.4 mmol) of triethylamine, 0.35 g (2 mmol) of 4-bromo-aniline (Aldrich), 0.91 g (2.4 mmol) of HBTU and 10 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is concentrated. Then 30 ml of 8% sodium hydrogencarbonate solution and 30 ml of chloroform is added to the mixture. The organic layer is separated and the water phase is extracted three times with 20 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated. The residue is treated with diethylether and the crystals are filtered off to yield 0.36 g (43%) of the title compound. Melting Point: 156-158° C. (diethylether)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(Cl)Cl.[C:14](Cl)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(N(CC)CC)C>[C:14]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2cc[nH]c2c1
Reaction time: 1 h

Procedure:
A solution of 4.24 g. 6-aminoindole in 300 ml. methylene chloride was stirred at 0° C. and 5.4 ml triethylamine followed by 4.2 ml. hexanoyl chloride was then added. The dark mixture was stirred for 1 hour and then filtered to remove a white precipitate. The filtrate was diluted with methylene chloride; washed sequentially with 10% w/v sodium hydrogen sulphate water, and brine; dried (MgSO4); and evaporated. The residue was crystallized from ethyl acetate and hexane to give 6-hexanamidoindole (E) as a white solid. Partial evaporation of the mother liquor gave a second crop of solid giving a combined yield of 4.5 g. (65%); NMR: 0.9 (t, 3H, CH3), 1.4 (m, 4H, CH3CH2CH2), 1.8 (m, 2H, CO.CH2CH2), 2.4 (t, 2H, CO.CH2), 6.5 (m, 1H, H3), 6.8 (dd, 1H, H 5), 7.2 (m, 2H, CO.NH+H2), 7.5 (d, 1H, H4), 8.1 (bs, 1H, H7), 8.3 (br, 1H, NH).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]([O:19]CC)=O.[NH3:22]>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]([NH2:22])=[O:19]
Reactant: CCOC(=O)c1cnc(-c2ccccc2OCC)[nH]c1=O
Reactant: N
Product: CCOc1ccccc1-c1ncc(C(N)=O)c(=O)[nH]1
Yield: 77 %

Procedure:
A mixture of ethyl 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carboxylate (10.0 g.) and aqueous ammonia (120 ml., d = 0.90) was heated in a sealed vessel on a steam bath for 4.5 hours. The solution was partially evaporated and then acidified to pH 3 with 6N hydrochloric acid. The collected solid was washed with water, dried, and recrystallized from N,N-dimethylformamide to give the title compound (6.93 g., 77% yield), m.p. 236°-238°.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([C@H:12]3[C@H:19]4[C@H:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]4)[CH2:14][CH2:13]3)=[CH:10][N:11]=2)[CH:6]=[CH:7][N:8]=1>C(O)(C)C>[CH3:20][C:17]1([CH3:21])[O:16][C@@H:15]2[CH2:14][CH2:13][C@@H:12]([C:9]3[N:5]4[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]4=[N:11][CH:10]=3)[C@@H:19]2[O:18]1
Reactant: CC1(C)O[C@@H]2[C@@H](CC[C@H]2c2cnc3c(Cl)nccn23)O1
Reactant: N
Solvent: CC(C)O
Product: CC1(C)O[C@@H]2[C@@H](CC[C@H]2c2cnc3c(N)nccn23)O1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Liquid ammonia (50 mL) was added to 8-chloro-3-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazine (2-9) (1.5 g, 5.1 mmol, 1 equiv) in isopropanol (50 mL). The resulting solution was placed in a high pressure vessel and heated to 100° C. After 16 hours, no more starting material was present, the amber solution was concentrated to afford desired 3-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazin-8-amine (2-10) as a tan solid that was carried to the next step without further purification. 1H NMR (500 MHz, CDCl2): δ 7.50 (d, J=4.7 Hz, 1H); 7.36 (t, J=4.6 Hz, 1H); 7.23 (s, 1H); 5.60 (s, 2H); 4.78 (s, 1H); 4.64 (d, J=5.7 Hz, 1H); 3.44 (d, J=6.9 Hz, 1H); 2.43-2.33 (m, 1H); 2.04-1.93 (m, 3H); 1.55 (s, 3H); 1.34 (s, 3H). LRMS m/z (M+H) 275.0 found, 275.1 required.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH3:19])[C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:5][C:6](=[O:20])[N:7]([C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[Cl:21])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(-c2cccnc2)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Cl
Temperature: 45 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of methyl-(2-pyridin-3-yl-thiazol-5-yl)-carbamic acid tert-butyl ester (3.0 g, 10.29 mmol) in acetonitrile (60 mL) was added N-chlorosuccinimide (2.75 g, 20.58 mmol) in one portion and the reaction mixture was stirred at 45° C. for 16 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a yellow solid (2.10 g, 62%): mp 119-122° C.; IR (KBr) 1718 cm−; 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.67 (d, J=4.2 Hz, 1H), 8.22-8.16 (m, 1H), 7.39 (dd, J=7.9, 5.0 Hz, 1H), 3.26 (s, 3H), 1.46 (s, 9H); ESIMS m/z 326 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([CH:12]1[CH2:21][NH:20][CH2:19][CH2:18][C:13]21[O:17][CH2:16][CH2:15][O:14]2)=[O:11].[C:22]([O:30][C:31](Cl)=[O:32])(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:8][O:9][C:10]([CH:12]1[CH2:21][N:20]([C:31]([O:30][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:32])[CH2:19][CH2:18][C:13]21[O:17][CH2:16][CH2:15][O:14]2)=[O:11]
Reactant: O=C(Cl)OC(=O)c1ccccc1
Reactant: COC(=O)C1CNCCC12OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCC12OCCO2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 84.7 %

Procedure:
Triethylamine (29.0 mL, 208 mmol) was added to a solution of 1,4-dioxa-8-aza-spiro[4.5]-decane-6-carboxylic acid methyl ester (91) (16.6, 82.5 mmol) in CH2Cl2 (159 mL, 0.5 M). The solution was cooled to 0° C. in an ice bath, then benzoylchloroformate (12.8 mL, 89.9 mmol) was added dropwise, with stirring, over 40 minutes. When the reaction was judged complete by TLC (0.75 h), the solution was concentrated in vacuo and purified by silica gel chromatography (10:3 Hexanes:EtOAc) to provide pure 8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-carboxylic acid methyl ester (92) (23.43 g, 85%). 1H NMR (CDCl3): 7.41-7.25 (5H, m), 5.10 (2H, broad s), 4.02-3.50 (11H, m), 2.80-2.62 (1H, broad s), 2.20-2.00 (1H, broad s), 1.70-1.50 (1H, broad s) ppm. 13C NMR (CDCl3): 170.26, 154.88, 136.47, 128.32, 127.86, 127.74, 106.78, 67.09, 64.90, 64.59, 51.71, 48.63, 43.94, 41.76, 33.15 ppm.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH3:37])=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[H][H]>C(#N)C>[Si:1]([O:8][CH2:9][CH:10]([C@@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH3:37])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@@H]2C(C)CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
To a solution of (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (20 g) in acetonitrile (200 ml), there were added 5% platinium on activated carbon (4.0 g) and water (4 ml) under nitrogen atmosphere. The mixture was stirred at 10° C. in a hydrogen gas flow until 2.2 equivalents of hydrogen had been taken up. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate and the washings were combined together and concentrated in vacuo to give (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di-(p-anisyl)methyl-2-azetidinone as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.I[CH2:12][CH:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>C1COCC1>[CH2:22]([CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCC(CI)CCCCCC
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCC(CCCCCC)Cc1cccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A solution of thiophene (46.4 g, 551 mmol., 2.50 equiv.) and THF (300 mL) was cooled to −78° C. n-Butyllithium (2.5 M in hexanes, 212 mL, 528 mmol., 2.40 equiv.) was added over 1 hour. The mixture was stirred for an additional 30 minutes at −78° C. before a solution of 1-iodo-2-hexyldecane (90.0 g, 220 mmol., 1.00 equiv) in THF (200 mL) was added slowly over 1 hour. After stirring for 1 hour at −78° C., the reaction mixture was warmed to ambient temperature and stirred for 18 hours. Water (200 mL) was added and the organic material was extracted with Et2O (3×250 mL), washed with additional water, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting brown residue was purified by silica gel column chromatography (hexanes) to give a pale yellow oil (52.03 g, 77% yield). 1H NMR (500 MHz, CDCl3) δ 7.12 (dd, J=5.2, 1.2 Hz, 1H), 6.92 (m, 1H), 6.76 (dd, J=3.4, 0.9 Hz, 1H), 2.76 (d, J=6.7, 2H), 1.62 (b, 1H), 1.33-1.21 (m, 24H), 0.91-0.87 (m, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:19])([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:7]([O:20][CH2:21][O:22][CH3:23])[CH:6]=1.[Li]CCCC.[B:29](OC)([O:32]C)[O:30]C.Cl>C1COCC1.O>[CH3:23][O:22][CH2:21][O:20][C:7]1[CH:8]=[C:9]([C:11]([CH3:18])([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[B:29]([OH:32])[OH:30]
Reactant: CCCCCCC(C)(C)c1cc(OCOC)cc(OCOC)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC(C)(C)c1cc(OCOC)c(B(O)O)c(OCOC)c1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
1,3-Bis(methoxymethoxy)-5-(1,1-dimethylheptyl)-benzene (50) (1 equiv.) was dissolved in dry THF (10 mL). The solution was cooled to −10° C. and n-BuLi (1.1 equiv. using 1.6 solution in hexanes) was added dropwise. The mixture was stirred for an additional 1.5 h, then it was cooled to −78° C. and (MeO)3B (5 equiv.) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with water, stirred for 30 min and the pH was adjusted to 4 with dilute aqueous HCl. The mixture was extracted with EtOAc, the organic layer was dried (MgSO4) and the solvent was evaporated. Purification by flash column chromatography (hexane-acetone) gave the title compound in 81% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:4]([CH3:16])[CH:3]=1.CCN(C(C)C)C(C)C.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:31](=[O:32])[C:30]2[CH:29]=[C:28]([C:27]([F:42])([F:41])[F:26])[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: CNc1cnccc1-c1ccc(F)cc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
To a solution of 4-(4-fluoro-2-methylphenyl)-N-methylpyridin-3-amine (47 mg, 0.22 mmol) and DIPEA (57 μL, 0.33 mmol) was added 3,5-bis(trifluoromethyl)benzoyl chloride (78 mg, 0.28 mmol, CAS RN 1271-19-8) in CH2Cl2 (2 mL). After stirring for 16 hours, the reaction mixture was loaded directly onto a silica gel column and elution with EtOAc gave the title compound as a waxy oil which solidified upon standing (56 mg, 56%). MS (ESI): m/z=457.0 [M+H]+.
Reaction SMILES: C(OC([NH:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:17][C:11]=2[N:10]=1)=O)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:20])=[O:21])=[CH:17][C:11]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.45 g of 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-1H-benzoimidazol-5-yl ester were combined with 15 ml trifluoroacetic acid in 60 ml dichloromethane. The reaction mixture was stirred overnight at room temperature. Solvents were evaporated under reduced pressure. The residue was washed with ethyl ether and dried on glass frit yielding 6.58 g of 4-fluoro-benzenesulfonic acid 2-amino-1H-benzoimidazol-5-yl ester trifluoroacetic acid salt.
Reaction SMILES: I.CS[C:4]([C:6]1[S:7][C:8]2[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)=[NH:5].[CH2:23]([N:30]1[CH2:35][CH2:34][C:33](OCC)(OCC)[CH:32]([NH2:42])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.B(F)(F)F.CCOCC>O1CCCC1>[CH2:23]([N:30]1[CH2:35][CH2:34][C:33]2[N:5]=[C:4]([C:6]3[S:7][C:8]4[C:14]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=4[N:10]=3)[NH:42][C:32]=2[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC1(OCC)CCN(Cc2ccccc2)CC1N
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=N)SC)nc12
Agent: FB(F)F
Agent: I
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CN(Cc3ccccc3)CC4)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1 %

Procedure:
To a suspension of 0.04 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboximidothioic acid methyl ester hydroiodide in 1.8 ml tetrahydrofurane were added 0.1 g 1-benzyl-4,4-diethoxy-piperidin-3-ylamine in 1.8 ml tetrahydrofurane and the mixture was stirred at room temperature for 16 hours. Then 0.015 ml boron trifluoride etherate was added and the solvent was distilled off under vacuum. Again 0.015 ml boron trifluoride etherate was added and the mixture was dissolved in 1.5 ml dimethylformamide and heated for 15 minutes at 125° C. The solvent was distilled off and the residue was dissolved in dichloromethane and extracted with water. The organic layer was dried with sodium sulfate, filtered and the solvent was evaporated. Chromatography on silicagel with ethylacatate/heptane 1:1 to 2:1 yielded 0.4 mg (1%) 5-benzyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine as an amorphous solid; m/e=462 (M+H+).
Reaction SMILES: CO[C:3]1[C:8]([C:9]([C:11](=[C:17](SC)SC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:7][N:6]=[C:5]([S:22][CH3:23])[N:4]=1.[NH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28].[H-].[Na+]>C(Cl)Cl.O>[CH2:15]([O:14][C:12]([C:11]1[C:9](=[O:10])[C:8]2[CH:7]=[N:6][C:5]([S:22][CH3:23])=[N:4][C:3]=2[N:24]2[C:17]=1[NH:29][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]2=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(C(=O)c1cnc(SC)nc1OC)=C(SC)SC
Reactant: NC(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(=O)c2cnc(SC)nc2n2c1[nH]c(=O)c1ccccc12
Temperature: 140 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
A solution of ethyl 2-(4-methoxy-2-(methylthio)pyrimidine-5-carbonyl)-3,3-bis(methylthio)acrylate (250 mg, 0.668 mmol) and 2-aminobenzamide (118 mg, 0.867 mmol) in DCM (5 mL) was heated over stream of nitrogen allowing DCM to evaporate and continued heating as neat at 140° C. for over night. The residue was dissolved in DMF (7 mL) after cooling to rt and treated with NaH (60 mg, 1.500 mmol). The reaction was stirred at rt for 1 h and diluted with DCM (20 mL) and H2O (20 mL). The layers were separated and DCM was removed under reduced pressure. Trituration of the crude in Et2O (10 mL) afforded the desired product as a yellow solid (50 mg, 20%). MS (m/z): 383 (MH+). 1H NMR (CDCl3) δ: 13.58 (br s, 1H), 9.43 (s, 1H), 8.60 (d, 1H), 8.33 (dd, 1H), 7.79 (m, 1H), 7.59 (m, 1H), 4.48 (q, 2H), 2.62 (s, 3H), 1.46 (t, 3H).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>COCCOC>[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[S:27]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(NC(=O)c2ccc(F)cc2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(NC(=S)c2ccc(F)cc2)c(OC)c1
Temperature: 85 °C
Reaction time: 4 h
Yield: 48.8 %

Procedure:
11 g (131 mmol; 4 equivalents) of NaHCO3 is added to 9 g (32.7 mmol) of N-(2,4-dimethoxyphenyl)-4-fluorobenzamide dissolved in 350 ml of 1,2-dimethoxyethane. 29 g (65.2 mmol; 2 equivalents) of phosphorus pentasulphide (P2S5) is then added by parts to the reaction medium which is maintained under stirring under an inert atmosphere of argon at 85° C. for 4 hours. 250 ml of a saturated solution of NaHCO3 are then added to the medium then the product is extracted with 3 times 200 ml of ethyl acetate. The combined organic phases are washed with twice 200 ml of a saturated solution of NaCl, then dried over sodium sulphate. The solvents are evaporated off under reduced pressure and the residue purified on a silica column (eluent: ethyl acetate/heptane mixture 1:4) in order to provide 4.65 g (yield=49%) of expected product.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][OH:15].CCCCCC>O1CCCC1>[CH2:16]([C:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:11])([CH2:14][OH:15])[CH2:18][CH3:19])[CH3:17]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCC(N)(CC)CO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)(CO)NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
Benzoyl isothiocyanate (4.28 mL, 31.8 mmol) was added under nitrogen to a solution of 2-amino-2-ethylbutan-1-ol (3.7315 g, 31.8 mmol), prepared in the previous step, in 100 mL of anhydrous tetrahydrofuran (exotherm on addition). After the addition, the reaction was refluxed for 2.5 h. After cooling to room temperature, 100 mL of hexane was added. The solid that formed was collected by filtration and dried under reduced pressure to give N-({[1-ethyl-1-(hydroxymethyl)propyl]amino}carbonothioyl)benzamide (7.1406 g, 80%) as a white solid, mp 161-163° C.; MS (ESI) m/z 281 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][C:17]3C4C(=CC=CC=4)N[CH:18]=3)[CH2:10]2)=[CH:5][CH:4]=1.[C:30]1([C:40]2[CH:45]=CC=[CH:42][CH:41]=2)[CH:35]=[CH:34][C:33](CC(O)=O)=[CH:32][CH:31]=1>>[C:40]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:45]=[CH:18][C:17]([CH2:16][CH2:15][N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([CH2:8][O:7][C:6]3[CH:26]=[CH:27][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=3)[CH2:10]2)=[CH:42][CH:41]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: FC(F)(F)c1ccc(OCC2CCCN(CCc3c[nH]c4ccccc34)C2)cc1
Product: FC(F)(F)c1ccc(OCC2CCCN(CCc3ccc(-c4ccccc4)cc3)C2)cc1

Procedure:
Following exactly the same two step procedure used in the previous example for the preparation of 3-{2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethyl}-1H-indole but using biphenyl-4-yl-acetic acid in place of (1H-Indol-3-yl)-acetic acid, 1-(2-Biphenyl-4-yl-ethyl)-3-(4-trifluoromethyl-phenoxymethyl)-piperidine was obtained in 54% overall yield from 0.19 mmol of 3-(4-Trifluoromethyl-phenoxymethyl)-piperidine, 181. Data for this compound: MS 440 (M++1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[Cl:17][C:16]1[C:11]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC1CCOCC1
Reactant: Clc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cccnc1OC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrahydro-2H-pyran-4-ol (1.03 g, 10.1 mmol) was added slowly over 1 min to a suspension of NaH (60% in mineral oil) (0.41 g, 10.16 mmol) in anhydrous THF (20 mL) at 5° C. (ice bath). The suspension was then warmed to room temperature. After 30 mins, 2,3-dichloropyridine (1.00 g, 6.76 mmol) was added, and the reaction heated at 70° C. for 18 hours. The reaction was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organics were then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as a yellow oil, which was taken onto the next step without further purification (1.40 g, 98%):
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]/[CH:28]=[C:29]1/[C:30]2[CH:43]=[C:42]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:31]=2[O:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][C:35]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:13]2)[CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(N(CC(N)=O)Cc3ccc(Cl)cc3)C1)c1cccnc1CO2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]acetamide (0.21 g, 0.8 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.6 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by HPLC. 1H-NMR (CDCl3) δ: 1.35 (6H, s), 1.55-1.75 (1H, m), 1.80-2.00 (1H, m), 2.20-2.85 (8H, m), 2.90-3.10 (2H, d), 3.30-3.50 (1H, m), 3.60 (1H, d), 4.80-5.30 (2H, br, s), 6.10 (1H, t), 6.70 (1H, dd), 7.00-7.45 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 562 (M+1), UV retention time: 1.31 min.