Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C@@H:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.[H][H]>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C@@H:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [H][H]
Reactant: CCCCCC[C@@H](C)Oc1ccc(C(=O)OCC)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: CCCCCC[C@@H](C)Oc1ccc(C(=O)OCC)cc1N
Yield: 97.3 %

Procedure:
A mixture of 1.7 g of ethyl 3-nitro-4-[(R)-2-octyloxy]benzoate and 50 ml of ethyl alcohol was hydrogenated over 0.1 g of platinum(II) oxide until the uptake of hydrogen had finished. The catalyst was filtered off and the filtrate was concentrated. Chromatography of the residue on silica gel with dichloromethane gave 1.5 g of ethyl 3-amino-4-[(R)-2-octyloxy]benzoate as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[CH:11]=[C:12]([CH:20]=2)[C:13]([O:15]C(C)(C)C)=[O:14])=[N:6][CH:7]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[C:27]([OH:29])([C:26]([F:31])([F:30])[F:25])=[O:28].[CH3:24][O:23][C:21]([C:10]1[CH:11]=[C:12]([CH:20]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:9]=1)[C:13]([OH:15])=[O:14])=[O:22]
Reactant: COC(=O)c1cc(C(=O)OC(C)(C)C)cc(-c2ccc(C)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Reaction time: 16 h

Procedure:
To a solution of tert-butyl methyl 5-(5-methylpyridin-2-yl)isophthalate in dichloromethane (75 mL) was added 25 mL of trifluoroacetic acid. After 16 h, the reaction was concentrated and dried under vacuum to give TFA salt of the title compound (6.5 g). MS 272.1 (M+1).
Reaction SMILES: O[CH:2]([C:7]1[O:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)[CH2:3][CH2:4][CH2:5]O.CS(Cl)(=O)=O.C([N:31]([CH2:34][CH3:35])CC)C>O1CCCC1.C(OCC)(=O)C>[CH2:34]([N:31]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[O:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)[C:35]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: CCN(CC)CC
Reactant: OCCCC(O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(CN2CCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(1,4-dihydroxybutyl)-4,5-diphenyloxazole (1 g) in tetrahydrofuran (10 ml) were added methanesulfonyl chloride (1.6 g) and triethylamine (1.5 ml) at 0° C. The solution was diluted with ethyl acetate and washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated. The residue was dissolved in benzylamine (10 ml). After being stirred for 2 hours at 80° C., the mixture was partitioned between ether and water. The organic layer was washed with water and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to afford 1-benzyl-2-(4,5-diphenyloxazol-2-yl)pyrrolidine (1.3 g). MS (m/z): 381 (M+ +1) IR (Neat): 1600 cm-1NMR (CDCl3, δ): 1.8-2.6 (5H, m), 3.0-3.2 (1H, m), 3.60 (1H, d, J=13 Hz), 3.85 (1H, t, J=7.8 Hz), 3.89 (1H, d, J=13 Hz), 7.0-7.8 (15H, m)
Reaction SMILES: [CH3:1][S:2][C:3](=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O>[CH2:31]([N:4]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[C:3](=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:2][CH3:1])[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CSC(=Nc1ccccc1)NN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C(=Nc1ccccc1)SC)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To 50 ml of dry acetone, 4.0 g (0.013 m) of the product of Example 2, 2.2 g (0.016 m) of powdered anhydrous potassium carbonate, and 1.4 ml (0.016 m) of allyl bromide was added in succession and the mixture stirred overnight at room temperature. The mixture was poured into 300 ml of ice water with stirring. The aqueous layer was decanted and the residue suspended in fresh ice cold water, stirred and filtered to give a yellow semisolid product. This was purified by stirring in hexane to give a yellow powder 1.8 g (39%), m.p. 78°-81°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[NH:8][CH:9]=[C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[C:11](=O)[C:6]=2[S:5][CH:4]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:22])=O>>[C:13]([C:10]1[C:11]([Cl:22])=[C:6]2[S:5][CH:4]=[C:3]([O:2][CH3:1])[C:7]2=[N:8][CH:9]=1)(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)c1c[nH]c2c(OC)csc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCC(=O)c1cnc2c(OC)csc2c1Cl
Reaction time: 0.5 h

Procedure:
3-Methoxy-6-butyrylthieno[3,2-b]pyridin-7(4H)-one (3 g) and phosphorus oxychloride (10 ml) were heated under reflux for one hour. The reaction mixture was poured onto ice water (100 g) stirred for 30 minutes and then basified with 40% sodium hydroxide solution cooling with ice, then extracted with chloroform (3×100 ml). The chloroform extracts were combined dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a brown solid, 3.1 g, m.p. 76°-78°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[N:7]1[CH2:11][CH2:10][C@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42](O)=[O:43])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[N:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1)=[O:43]
Reactant: Cn1ncc(N)c1N1CC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@H](N)C1
Yield: 17 %

Procedure:
Following the procedures as described in Example 113, (S)-tert-butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 127 as a white solid (20 mg, 17%) over two steps. 1H NMR (400 MHz, DMSO) δ 7.67 (d, J=19.5, 1H), 7.62-7.45 (m, 3H), 7.28 (t, J=8.7, 2H), 3.63 (s, 3H), 3.53 (s, 1H), 3.20 (dt, J=8.9, 4.4, 2H), 2.84 (d, J=10.2, 2H), 2.05-1.84 (m, 2H), 1.75 (s, 2H). ESIMS m/z=420.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1OC)[C:6]([CH2:12]Cl)=[N:7]2.[N:23]1[C:31]([NH2:32])=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[N:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:32][C:31]1[N:23]=[CH:24][N:25]=[C:26]2[C:30]=1[N:29]=[CH:28][N:27]2[CH2:12][C:6]1[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=2)[C:4](=[O:22])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cccc(Cl)c2c(=O)n1-c1ccccc1-c1ccccc1
Yield: 136.5 %

Procedure:
Prepared according to Procedure C using Intermediate 21 (400 mg, 1.05 mmol), adenine (155 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 344 mg of a white solid (68%), mp 299.9-300.1° C. (discolors). 1H NMR (DMSO-d6) δ: 8.08 (s, 1H); 7.89 (s, 1H); 7.58-7.73 (m, 5H); 7.51 (d, J=7.9 Hz, 1H); 7.46 (d, J=7.5 Hz, 2H); 7.27-7.41 (m, 3H); 7.14-7.27 (m, 3H); 5.14 (d, J=17 Hz, 1H); 4.82 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 159.6, 156.2, 152.8, 152.5, 150.0, 149.0, 141.7, 140.2, 137.7, 135.0, 133.3, 133.2, 131.8, 130.7, 130.1, 129.8, 129.5, 128.8, 128.6, 128.4, 127.1, 118.4, 117.6, 45.3. MS (ES): m/z 480.1 (M+). Anal. calcd. for C26H18ClN7O: C, 65.07; H, 3.78; Cl, 7.39; N, 20.43. Found: C, 64.77; H, 3.75; Cl, 7.43; N, 20.35.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:20])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CCOC(C)=O>[CH3:13][C:12]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:3](=[O:21])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:11]1=[O:20]
Reactant: COC(=O)c1ccccc1NC(=O)C(C)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)Nc2ccccc2C1=O
Yield: 65.4 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 2-(2-phenyl-propionyl amino)-benzoic acid methyl ester (1.00 g, 3.53 mmol) and LiHMDS (10.6 mmol, 1M THF solution). After normal workup, the pure objective compound (0.58 g, 65%) was obtained as pale yellow solid by a flash column chromatography (Hex:EtOAc=4:1): 1H NMR (200 MHz, CDCl3) δ 2.05 (s, 3H, CH3), 6.92 (d, J=8.14 Hz, 1H, ArH), 7.11 (t, J=7.73 Hz, 1H, ArH), 7.23-7.37 (m, 5H, ArH), 7.49 (t, J=7.32, 1H, ArH), 7.89 (d, J=7.73 Hz, 1H, ArH), 9.50 (br s, 1H, NH); m.p. 194-196° C.; MS(EI) m/e 251 [M+], 146, 132, 104; HRMS m/e cacld. for C16H13NO2 251.0946, found 251.0944.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[N:27]=[CH:28][S:29][CH:30]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1cscn1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(thiazol-4-yl)propionate hydrochloride (General Procedure H with methanol and HCl on methyl (S)-2-amino-3-(thiazol-4-yl)propyl acid (Synthetech)), the title compound was prepared as a solid (mp=136-139° C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/DCM) and the product was purified by recrystallization from DCM.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11]1)=[O:7])(C)(C)C.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33](C(O)=O)=[C:32]([O:40][CH3:41])[CH:31]=1>>[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:28])[CH2:11]2)=[O:7])=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN(CCCCN1CCC(CNC(=O)OC(C)(C)C)C1)C(=O)c1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN(C)C(=O)c2ccccc2)C1

Procedure:
N-(4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butyl)-N-methylbenzamide (0.57 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.30 g) to give 4-amino-N-(1-(4-(N-benzoyl-N-methylamino)butyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:18](=[O:29])[N:19]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[CH3:20])[S:11][C:10]=3[C:9]=2[CH:30]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.C(O)C>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[N:19]([CH3:20])[C:18]([C:12]1[S:11][C:10]2[C:9]3[CH:30]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:29]
Reactant: COC(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(Cl)cc3Cl)cc1CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[(2,4-dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid methyl ester (700 mg) in THF (8 mL) and ethanol (4 mL) was added sodium hydroxide solution (121 mg in 4 mL of water) and the reaction stirred at room temperature for 16 h. The reaction was then acidified with 2 M hydrochloric acid and the resulting solid was filtered and air-dried to give 2-[(2,4-dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:20]1>>[CH3:11][C:7]1[C:5]2[N:6]=[C:2]([N:19]3[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:34])=[O:35])[CH2:20]3)[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Nc1ccccc1OCC1CCNC1)c1ccccn1
Reactant: Cc1cccc2sc(Cl)nc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2sc(N3CCC(COc4ccccc4NS(=O)(=O)c4ccccn4)C3)nc12

Procedure:
Compound 31 is prepared using synthesis method 3 using intermediates 2b and 6b (yield: 28%).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:19])[C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:9]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:9]=1
Reactant: Cc1cncc(Cl)c1-c1nc(-c2ccccn2)no1
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cncc(-c2cccnc2)c1-c1nc(-c2ccccn2)no1
Yield: 6.2 %

Procedure:
A mixture of 5-(3-chloro-5-methyl-pyrid-4-yl)-3-(2-pyridyl)-1,2,4-oxadiazole (75 mg, 0.275 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (75 mg, 0.46 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 30 mg, 0.026 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 40% ethyl acetate in hexane to 100% ethyl acetate afforded 5.4 mg (7.4%) of 5-[3-methyl-5-(3-pyridyl)-pyrid-4-yl]-3-(2-pyridyl)-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 9.32 (s, 1H), 8.87 (d, 1H), 8.70 (d, 1H), 8.30 (m, 2H), 8.25 (s, 1H), 8.00 (s, 1H), 7.90 (d, 1H), 7.47 (m, 2H), 2.77 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[N:17]=[N:16][N:15]=1>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:14]2[N:18]([C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)[N:17]=[N:16][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2Cl)cc1
Reactant: OCCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-n2nnnc2OCCCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Cyclohexylpropyl alcohol (237 mL, 1.56 mol) was added to a suspension of NaH (66.0 g, 1.65 mol) in tetrahydrofuran (1.40 L). A solution of 5-Chloro-1-(4-nitro-phenyl)-1H-tetrazole (320 g, 1.42 mol) in tetrahydrofuran (900 mL) was added dropwise over 1.5 hours. The reaction was allowed to cool to room temperature and stirred overnight. The mixture was concentrated in vacuo to a solid. The solid was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution (2×), dried (Na2SO4), and filtered through silica gel (700 g). The red filtrate was concentrated in vacuo until product began to precipitate from solution. Hexane was added and the slurry filtered to provide a tan solid (320 g, 64%). Mp 82-88° C. (dec); 1H NMR (CDCl3, 300 MHz) δ 8.43 (d, 9.2 Hz, 2 H), 8.04 (d, 9.2 Hz, 2 H), 4.70 (t, 7.0 Hz, 2 H), 1.96 (m, 2 H), 1.75-1.64 (m, 5 H), 1.39-1.13 (m, 6 H), 0.97-0.87 (m, 2 H); MS (CI) m/z 332 (MH+); Anal. calcd for C16H21N5O3 : C, 57.99; H, 6.39; N, 21.13. Found: C, 57.80; H, 6.35; N, 21.02; Rf =0.43 (N).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].N1C=CC=CC=1.[C:13](Cl)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:13]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: OCC(O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
To a mixture of glycerol (30 g, 326 mmol) and pyridine (25 ml) dissolved in DMF (300 ml) was added dropwise stearoyl chloride (10 g, 33 mmol) dissolved in DMF 100 ml 9. The mixture was cooled on an ice bath until addition was complete, whereupon the reaction was maintained under an N2 atmosphere overnight. After 15 hours CH2CL2 (300 ml) and saturated NaHCO3 (aq) was added. The phases were separated and the organic phase washed with water (50 ml) and dried with Na2SO4. The solvent and any pyridine were evaporated under vacuum. The crude product was chromatographed on a silica column (CH2Cl2-MeOH, 20:1) and recrystallised (CH2Cl2-ether) to yield around 7 grams.
Reaction SMILES: CS/[C:3](/[N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)=[O:15])[C@@H:10]([C:27]([O:29][CH3:30])=[O:28])[CH2:9]1)=[CH:4]\[N+:5]([O-:7])=[O:6].C(O)C.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[N+:5](/[CH:4]=[C:3](/[N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)=[O:15])[C@@H:10]([C:27]([O:29][CH3:30])=[O:28])[CH2:9]1)\[N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)([O-:7])=[O:6]
Reactant: COC(=O)[C@H]1CN(/C(=C/[N+](=O)[O-])SC)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Reactant: C1CCNCC1
Solvent: CCO
Product: COC(=O)[C@H]1CN(/C(=C/[N+](=O)[O-])N2CCCCC2)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Temperature: 85 °C
Yield: 70.5 %

Procedure:
To a stirred solution of methyl (3R,4S)-1-[(Z)-1-(methylthio)-2-nitrovinyl]-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxylate (81.0 mg, 0.000187 mol) in ethanol (3.0 mL, 0.051 mol) was added piperidine (92.8 uL, 0.000934 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 17 h 45 min. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 0-8% MeOH/CH2Cl2 to give the product as a yellow solid (62 mg, 71% in yield). MS (ESI): (M+H)+=471.1.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:16]([N:24]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]2[N:26]([CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:25]1=[O:38])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]([N:24]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]2[N:26]([CH2:33][CH2:34][CH2:35][CH2:36][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[S:9][N:8]=3)[CH2:2][CH2:3]2)[C:25]1=[O:38])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(c1ccccc1)N1C(=O)N(CCCCBr)C2CCCCC21
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1C(=O)N(CCCCN2CCN(c3nsc4ccccc34)CC2)C2CCCCC21
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A suspension of 3-(1-piperazinyl)-1,2-benzisothiazole (0.44 g, 2.0 mmoles), 3-benzoyl-1-(4-bromobutyl)perhydrobenzimidazol-2-one (0.76 g, 2.0 mmoles) and potassium carbonate (0.33 g, 2.4 mmoles) in 4 ml of dimethylformamide was stirred at 60° C. for 2 hours. Insolubles were removed by filtration, and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform and washed with water, and the solvent was evaporated. The residue was purified by chromatography on a silica gel column to give 1.0 g of the title compound as an oil.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[C:25]([CH2:24][CH2:23][CH2:22][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][CH:2]1[CH3:1])#[N:26]
Reactant: N#CCCCBr
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1CCCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
To the stirred solution of tert-butyl 3-methylpiperazine-1-carboxylate (prepared according to procedure reported in US200876758A1, 2008, 5 g, 24.97 mmol) in N,N-dimethylformamide (50 ml) were added potassium carbonate (17.25 g, 125 mmol) and 4-bromobutanenitrile (2.98 ml, 30.0 mmol) at 25° C. The resulting solution was stirred at 25° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction water (100 ml) was added and extracted with dichloromethane (3×60 ml). The combined extract was washed with brine (25 ml) and dried over sodium sulphate, filtered and concentrated to give crude compound. The crude compound was purified by column chromatography over silica gel (100-200) using 15% ethyl acetate in hexane to obtain the title compound (5 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I:12]I>FC(F)(F)S([O-])(=O)=O.[Ag+].C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([I:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(C#N)c(Br)c1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Br)c(C#N)cc1I
Reaction time: 48 h
Yield: 57.1 %

Procedure:
A RBF was charged with 2-bromo-4-methoxybenzonitrile (891 mg, 4.20 mmol, Matrix Scientific) and DCM (1.68E+04 μl) to give a clear solution. silver trifluoromethanesulfonate (1188 mg, 4.62 mmol) and iodine (1173 mg, 4.62 mmol) were added in sequence. The resulting mixture was stirred for 2 d. Additional portions of silver trifluoromethanesulfonate (1188 mg, 4.62 mmol) and iodine (1173 mg, 4.62 mmol) were added, and the mixture was stirred for another 5 h. The reaction mixture was then filtered through celite with the aid of DCM. The filtrate was shaken with saturated aq. sodium thiosulfate until the color disappeared. The biphasic mixture was diluted with water then the layers were separated. The aq. layer was extracted with DCM (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel column, 5-30% EtOAc/Heptane) give 2-bromo-5-iodo-4-methoxybenzonitrile (811 mg, 2.400 mmol, 57.1% yield) as an off-white solid. m/z (ESI) 337.8 (M+H)+.