Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N+:39]([O-])=O)[CH:27]=2)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:32][C:28]1[CH:27]=[C:26]([C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH2:1])[CH:12]=2)([C:22]([F:23])([F:24])[F:25])[C:18]([F:20])([F:21])[F:19])[CH:31]=[CH:30][CH:29]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1Nc1cccc(C(c2cccc(Nc3ccccc3[N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1Nc1cccc(C(c2cccc(Nc3ccccc3N)c2)(C(F)(F)F)C(F)(F)F)c1
Yield: 94.9 %

Procedure:
20 g (34.7 mmol) of 2,2-bis[N-(2-nitrophenyl)-(3-aminophenyl)]hexafluoropropane synthesized above were dissolved in 200 ml of ethyl acetate. Thereto was added 1 g of 10% palladium carbon as a catalyst, and replacement with hydrogen was carried out. After that, reaction was conducted at room temperature under a hydrogen pressure of 1.01 MPa (10 atm) for 18 hours with stirring vigorously. The obtained reaction solution was filtered with cerite to remove the catalyst, and ethyl acetate was removed under reduced pressure. The residue was recrystallized by using a chloroform-hexane mixed solution, and ethanol-water mixed solution to obtain 17 g of 2,2-bis[N-(2-aminophenyl)-(3-aminophenyl)]hexafluoropropane (hereinafter mNPN-AF) in white solid(yeild: 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Sc2ccc(N)cc2)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid methyl ester (15.0 g, 68 mmol), 4-aminothiophenol (8.8 g, 68 mmol) and K2CO3 (11.8 g, 85 mmol) in DMF (150 mL) was heated at 90° C. for 1.5 hours, cooled to room temperature, and then poured into H2O (450 mL) under stirring. The aqueous mixture was extracted with AcOEt (400 mL). The extract was washed with H2O (3 times) and brine, dried over MgSO4, and evaporated to give the crude product as orange crystal. The crude product was suspended in 150 mL of i-Pr2O and stirred at room temperature for 1 hour. The crystal was collected by filtration, washed with i-Pr2O and dried at 60° C. for 3 days under reduced pressure to give purified title compound as orange crystal (18.6 g, 90%).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([NH:13][CH2:14][NH:15][C:16]([N:18]=[N+]=[N-])=[O:17])=[O:12])[CH2:10][CH:5]2[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[BH4-].[Na+].O>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:18][C:16]([NH:15][CH2:14][NH:13][C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2](=[O:1])[O:3][C:4]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:5]2[CH2:10]1)=[O:12])=[O:17]
Reactant: [N-]=[N+]=NC(=O)NCNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)NCNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
[[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]amino]methyl]carbamic azide (68 mg, 0.16 mmol) was dissolved in methanol (3 mL). Nickel (II) chloride hexahydrate (77 mg, 0.32 mmol) and sodium borohydride (12 mg, 0.32 mmol) were added thereto, and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The precipitated powder was washed with diisopropyl ether and dried to obtain the title compound (52 mg, yield 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20](Br)=[CH:21][N:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:25][O:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1B(O)O.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.N#N>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:32]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[O:26][CH3:25])=[CH:21][N:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cnccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: COc1cnccc1-c1cnc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nn12
Temperature: 85 °C

Procedure:
To a mixture of 4-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester (524.4 mg, 1.4 mmol), 3-methoxypyridine-4-boronic acid hydrate [1072952-50-1] (253.1 mg, 1.7 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (632.2 mg, 2.8 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (117.6 mg, 0.1 mmol) contained in a 50 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (25 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 17 h then cooled and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (CaSO4) and evaporated to afford a brown oil which was purified by preparative RP-HPLC to obtain a white powder, mp. 205-206° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9H) 3.46-3.55 (m, 8H) 4.02 (s, 3H) 7.30 (d, J=10.10 Hz, 1H) 8.00 (d, J=9.85 Hz, 1H) 8.13 (s, 1H) 8.35 (d, J=5.05 Hz, 1H) 8.41 (d, J=5.05 Hz, 1H) 8.51 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 28.04, 45.53, 56.33, 79.10, 111.13, 120.39, 120.75, 124.25, 126.24, 134.48, 135.69, 137.20, 142.26, 151.08, 153.85, 154.60. LRMS (ESI) m/z 411.3 [(M+H)]+, calc'd for C21H26N6O3: 410.48.
Reaction SMILES: [C:1]([C:5]1([OH:17])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[ClH:24]>>[ClH:24].[C:1]([C:5]1([OH:17])[CH2:9][CH2:8][NH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)C1(O)CCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-tert-butyl-3-hydroxypyrrolidine-1-carboxylate (0.60 g, 0.0025 mol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (4N, 0.30 mL, 0.0099 mol) under N2 at rt. The reaction mixture was stirred for 3 h at rt, then concentrated in vacuo. The crude product was used directly in the next step without further purification. (M+H) 144.1
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([N:21]1[CH2:22][C@H:18]2[C@H:17]([C:25]3[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C@@H:16]([O:15][C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH3:14])[O:24][CH2:23][C@@H:19]2[CH2:20]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(I)cc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Product: CC(=O)N1C[C@H]2CO[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3cc(I)ccc3C)[C@@H]2C1

Procedure:
The title compound was prepared from (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(5-iodo-2-methylphenyl)octahydropyrano[3,4-c]pyrrole and acetic anhydride according to the procedures used for example 19. MS: (MH)+642.
Reaction SMILES: ClC1C=C2C(=C(C(O)=O)C=1)NC(C)=C2.C[O:16][C:17]([C:19]1[CH:20]=[C:21]([Cl:30])[CH:22]=[C:23]2[C:27]=1[NH:26][C:25]([CH2:28][CH3:29])=[CH:24]2)=[O:18].[OH-].[Na+]>CO>[Cl:30][C:21]1[CH:22]=[C:23]2[C:27](=[C:19]([C:17]([OH:18])=[O:16])[CH:20]=1)[NH:26][C:25]([CH2:28][CH3:29])=[CH:24]2
Reactant: CCc1cc2cc(Cl)cc(C(=O)OC)c2[nH]1
Agent: Cc1cc2cc(Cl)cc(C(=O)O)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc2cc(Cl)cc(C(=O)O)c2[nH]1
Yield: 97.3 %

Procedure:
The title compound was synthesized in analogy to 5-chloro-2-methyl-1H-indole-7-carboxylic acid (described in example S85) using 5-chloro-2-ethyl-1H-indole-7-carboxylic acid methyl ester (80 mg, 0.34 mmol) and 1N NaOH(aq) (505 μl, 0.51 mmol) in MeOH (5 ml). The desired product (74 mg, 98%) was isolated without further purification. MS (ISP) 222.3 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27]O)=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.CS(Cl)(=O)=O.[CH2:34]([N:36](CC)[CH2:37][CH3:38])[CH3:35].N1CCCC1>C(Cl)Cl>[CH3:15][N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[N:25][C:24]([CH2:27][N:36]4[CH2:37][CH2:38][CH2:35][CH2:34]4)=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:5]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CO)nc3)n2)n1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CN4CCCC4)nc3)n2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
To a solution of [5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-2-yl]methanol (Intermediate 125, 50 mg, 132 μmol) in DCM (10 mL) was added methanesulfonyl chloride (11 μL, 139 μmol) and triethylamine (20 μL, 145 μmol). The reaction mixture was stirred for 90 min at room temperature under an inert atmosphere and then evaporated to dryness. The resulting solid was dissolved in DCM (10 mL), pyrrolidine (24 μL, 333 μmol) and triethylamine (46 μL, 333 μmol) and stirred for a further 3 h at room temperature. Incomplete reaction was observed so the reaction was heated at 35 C for a further 16 h. The reaction mixture was then washed with water (3×25 mL) and combined organics were dried over magnesium sulfate and evaporated to dryness. The resulting crude product was purified by silica chromatography (5% MeOH in DCM) to afford the title compound as a beige solid (25 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH:8]([OH:13])[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:44])[C:23]2[CH:28]=[N:27][C:26](S(C)(=O)=O)=[N:25][C:24]=2[N:33]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[CH2:40][CH2:39][CH2:38]3)[CH:34]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:44])[C:23]2[CH:28]=[N:27][C:26]([NH:1][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH:8]([OH:13])[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=3)=[N:25][C:24]=2[N:33]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[CH2:40][CH2:39][CH2:38]3)[CH:34]=1)=[O:20])[CH3:17]
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(OCC(O)CN(C)C)cc3)ncc2c1=O
Yield: 6.9 %

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 1-(4-amino-phenoxy)-3-dimethylamino-propan-2-ol (18 mg, 0.083 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 34 mg, 0.083 mmol). 3.1 mg of 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a yellow solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.38 (s, 1H), 8.52 (s, 1H), 7.50 (br, 1H), 7.40 (d, 2H), 7.28 (m, 3H), 7.19 (d, 1H), 6.66 (br, 2H), 4.40 (q, 2H), 4.05 (m, 1H), 3.90 (d, 2H), 3.10 (m, 4H), 2.52 (dd, 1H), 2.33 (m, 7H), 2.22 (m, 2H), 1.40 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H33N5O5: 544.25 (M+H), Found: 544.4.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)([CH2:14][CH2:15]S(C)(=O)=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:53]=[CH:52][C:34]([CH2:35][N:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=[C:37]2[C:45]2([OH:51])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CO>O1CCCC1.O.ClCCl>[C:1]([N:9]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][N:48]2[CH2:49][CH2:50][C:45]([C:37]3[N:36]([CH2:35][C:34]4[CH:52]=[CH:53][C:31]([F:30])=[CH:32][CH:33]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)([OH:51])[CH2:46][CH2:47]2)([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Reactant: COc1ccc(C2(CCS(C)(=O)=O)CCN(C(=O)c3ccccc3)C2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C2(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)CCN(C(=O)c3ccccc3)C2)cc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Combine 1-benzoyl-3-(3,4-dimethoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.48 g, 1.1 mmol) and 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazol-2-yl]-4-hydroxy-piperidine (0.54 g, 1.7 mmol), and sodium bicarbonate (0.235 g, 2.22 mmol) in tetrahydrofuran/water (15/4) (50 mL). Heat to reflux. After 72 hours, cool to ambient temperature and evaporate in vacuo to obtain a residue. Partition the residue between dichloromethane and 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5/1 ethyl acetate/methanol to give a solid. Combine the solid with dichloromethane and extract with 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a solid residue. Dry the residue in vacuo at 82° C. to give the title compound: Rf=0.32 (silica gel, 5/1 ethyl acetate/methanol); mp; 111-114° C. HRMS (FAB+): calculated 663.334502. Found 663.334660.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].[C:17](=O)([O:19]CC)[NH2:18]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][CH:5]=[CH:6][C:7]=2[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:18][C:17]1=[O:19]
Reactant: CNc1sccc1C(=O)c1ccccc1F
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: Cn1c(=O)nc(-c2ccccc2F)c2ccsc21
Temperature: 200 °C

Procedure:
A mixture of 500 mg of 2-methylamino-3-(o-fluorobenzoyl)thiophene, 716 mg of ethyl carbamate and 44 mg of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure and, the residue is recrystallized from ethanol to give 1-methyl-4-(o-fluorophenyl)-1,2-dihyrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 221.5° - 222°C.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]#[N:32])[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:29]2[CH:30]=[C:31]([NH2:32])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: N#CC=Cc1cc(Cl)cc(Cl)c1
Product: Nc1cc(-c2cc(Cl)cc(Cl)c2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, mp. 257-260° C. and MS m/e (%): 345 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(3,5-dichloro-phenyl)-acrylonitrile
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=[O:37])[CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:31]5[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=[O:37])[CH2:32]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: O=C(O)C1CCNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-3-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and pyrrolidine-3-carboxylic acid following General Procedure B.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH2:17][OH:18])[CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].O1CCOCC1>CO>[ClH:19].[NH:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH2:17][OH:18])[CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(CO)CO)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: OCC(CO)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidine-4-ol, triethylamine, benzenesulfonyl chloride and methylene chloride was stirred for two days at room temperature to give 1-tert-butoxycarbonylpiperidine-4-ylbenzenesulfonate. A mixture of the obtained 1-tert-butoxycarbonylpiperidine-4-ylbenzenesulfonate, diethyl malonate, 20% sodium ethoxide-EtOH solution and EtOH was stirred for 22 hours heated to reflux to give diethyl[1-(tert-butoxycarbonyl)piperidine-4-yl]malonate. A mixture of the obtained diethyl[1-(tert-butoxycarbonyl)piperidine-4-yl]malonate, lithium borohydride, toluene and THF was stirred for 18 hours at 60° C. to give 2-(1-tert-butoxycarbonylpiperidine-4-yl)propane-1,3-diol. A mixture of the obtained 2-(1-tert-butoxycarbonylpiperidine-4-yl)propane-1,3-diol, 4M HCl-dioxane solution and MeOH was stirred for one hour at room temperature to give 2-piperidine-4-ylpropane-1,3-diol hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH:12]=[O:13])=[C:7]([OH:14])[CH:6]=[CH:5][C:4]=2[N:3]=1.OC1C=C2C(C(C)=C([C:27]3[CH:43]=[CH:42][C:30]([C:31]([NH:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40]OC[CH2:37]4)=[O:32])=[CH:29][CH:28]=3)C(=O)O2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C.O>[OH:14][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([C:28]3[CH:27]=[CH:43][CH:42]=[C:30]([C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH3:37])[CH2:41][CH2:40]4)=[O:32])[CH:29]=3)[CH:11]=[CH:10][C:9]=2[C:8]=1[CH:12]=[O:13]
Reactant: O=Cc1c(O)ccc2nc(Cl)ccc12
Reactant: Cc1c(-c2ccc(C(=O)NCCN3CCOCC3)cc2)c(=O)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CN1CCN(C(=O)c2cccc(-c3ccc4c(C=O)c(O)ccc4n3)c2)CC1

Procedure:
A mixture of 2-chloro-6-hydroxyquinolin-5-carbaldehyde (3) (104 mg, 0.5 mmol), 3-(4-methylpiperazine-1-carbonyl)phenylboronic acid (6) (198 mg, 0.7 mmol) and K2CO3 (174 mg, 1.25 mmol) in a mixture of i-PrOH and water (6 mL 10:1) was purged with Argon for five minutes in a microwave vessel. A tablet of PdOAc2(Sphos)4 (Aldrich, Cat, No. 694088) was added under an Argon atmosphere then the vessel was sealed and irradiated for 45 min at 165° C. Upon cooling, the reaction mixture was filtered through a silica plug using MeOH. The solution was evaporated and purified by Flash chromatography using 0-5% MeOH in CH2Cl2. The product was recrystallized from CH2Cl2/hexanes to afford the title compound, MS (ESI): 376 (M+H)+. 1H NMR (δ, DMSO (2.5 ppm)): 10.74 (s, 1H), 9.44 (d, 1H), 8.30 (dd, 1H), 8.27 (d, 1H), 8.24 (s, 1H), 8.23 (d, 1H), 7.61 (t, 1H), 7.49 (d, 1H), 7.47 (dd, 1H), 3.60, 3.40, 2.40 and 2.30 (4 broad s, 4×2H), 2.23 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:16]2[C@@H:17]3[C@@H:22]([C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18]3)[CH2:13][CH2:14][CH2:15]2)=[O:7])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1N
Yield: 63 %

Procedure:
The title compound is prepared from 3-amino-4-methoxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 63% of theory; LC (method 4): tR=1.79 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:17]([O:21][C:22]([N:24]1[CH2:30][C@H:29]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:28][C@H:25]1[CH:26]=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(OCC)C.O1CCCC1.O>[C:17]([O:21][C:22]([N:24]1[CH2:30][C@H:29]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:28][C@H:25]1[CH:26]([OH:27])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Brc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
Magnesium (3.4 g) and a solution of 1,2-dibromoethane (5.3 ml, 60.8 mmol) in diethyl ether (40 ml) were successively added to a solution of 2-bromonaphthalene (12.6 g, 60.8 mmol) in diethyl ether (160 ml) at room temperature in a nitrogen stream and this reaction solution was refluxed under heating for 2.5 hours. The reaction solution was gradually cooled and a solution of (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (10 g, 30.4 mmol) in tetrahydrofuran (50 ml) was added dropwise thereto under cooling with ice. Then, the reaction solution was stirred at room temperature for 1 hour. After addition of water, the reaction solution was concentrated in vacuo and was poured into a liquid mixture of ethyl acetate with water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting oily residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=4:1) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[hydroxy(2-naphthyl)methyl]pyrrolidine (9.38 g, yield: 67.5%) as a yellow oily substance.