Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH3:28])=[N:13][C:14]=1[CH2:15][CH3:16].Cl[C:32]1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.ICC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:32])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Solvent: CCI
Product: CCO[C@H]1Cc2ccccc2[C@@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting (1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and iodoethane and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.81, 1.17–1.21, 1.30–1.34, 1.51–1.59, 1.98, 3.90–3.96, 4.02–4.08, 6.71–6.73, 7.04–7.07, 7.19; MS (ESI+) for C25H27Cl2N3O m/z 457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:16](=[O:18])[CH3:17])=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1ccc(O)cc1Cl
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)c1cc(C)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
3-Chloro-4-methylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (747 mg) and acetyl chloride (656 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was dried under the reduced pressure. Scandium trifluoromethanesulfonate (414 mg) was added to the compound thus obtained, and the mixture was suspended in toluene (5 ml) to prepare a suspension which was then heated under reflux overnight. The reaction solution was cooled to room temperature, and the reaction solution was then filtered. The solvent was removed from the filtrate by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give 1-(4-chloro-2-hydroxy-5-methyl-phenyl)-ethanone (193 mg, yield 15%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=3)[C:15]([OH:17])=O)[C:8]2=[O:21])=[CH:4][CH:3]=1.[CH3:24][N:25]1CCOCC1.ClC(OCC(C)C)=O.Cl.CN>O1CCCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=3)[C:15]([NH:25][CH3:24])=[O:17])[C:8]2=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
To a solution of 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid (0.18 g, 0.56 mmol) and 4-methylmorpholine (0.12 g, 1.18 mmol) in anhydrous tetrahydrofuran (15 mL) was added isobutyl chloroformate (0.10 g, 0.69 mmol) at 0° C. The resulting solution was stirred at ambient temperature for 3 hours, followed by the addition of methylamine hydrochloride (0.08 g, 1.12 mmol) and 4-methylmorpholine (0.06 g, 0.56 mmol) at 0° C. The reaction mixture was stirred for 17 hours and concentrated in vacuo. The residue was purified by column chromatography to give 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-methylisonicotinamide as a colorless solid (0.08 g, 43%): mp 118-120° C.; 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.36-8.34 (m, 1H), 7.40-7.37 (m, 1H), 7.29-7.24 (m, 2H), 7.06-6.99 (m, 2H), 6.47 (br s, 1H), 4.44 (s, 2H), 4.07-4.01 (m, 2H), 3.40-3.35 (m, 2H), 2.98 (d, J=4.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.5, 153.0, 148.4, 143.1, 132.1, 129.9, 129.8, 116.1, 115.9, 115.6, 108.8, 47.3, 41.3, 41.0, 26.8; MS (ES+) m/z 329.2 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[CH2:9]([NH:11][CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH3:10]>>[CH2:9]([N:11]([CH2:12][C:13]([OH:18])([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:14]([F:17])([F:16])[F:15])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH3:10]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccsc1
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccsc1

Procedure:
Prepared similarly to Example 11 from 3-thiophenecarboxylic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[NH:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1>>[ClH:2].[ClH:1].[ClH:2].[N:24]1([CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:18]([CH:19]=2)=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][N:24]4[CH:28]=[CH:27][CH:26]=[CH:25]4)[CH:15]=2)[CH:10]=3)[CH:28]=[CH:27][CH:26]=[CH:25]1
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Reactant: c1cc[nH]c1
Agent: Cl
Product: c1ccn(CCOc2ccc3cc4ccc(OCCn5cccc5)cc4nc3c2)c1

Procedure:
The compound is prepared from 3,6-bis(2-chloroethoxy)acridine hydrochloride and pyrrole as described in Example 46.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:28][C:29]1([F:33])[CH2:32][NH:31][CH2:30]1>>[CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:18])([CH3:20])[CH3:19])[C:14]([N:31]3[CH2:32][C:29]([F:33])([F:28])[CH2:30]3)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: FC1(F)CNC1
Reactant: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Agent: Cl
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)N1CC(F)(F)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 194b) and 3,3-Difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials and isolated (31 mg, 53%); MS (ESI, m/z): 450.5 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([O-:23])([O-])=[O:21].[Na+].[Na+].O>CC#N.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])=[O:21])=[CH:16][CH:15]=2)=[N:3][C:4]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1
Reactant: Nc1ncc(Br)nc1-c1noc(-c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)nc1-c1noc(-c2ccccc2)n1
Temperature: 110 °C
Yield: 76 %

Procedure:
5-bromo-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyrazin-2-amine (200 mg, 0.6287 mmol) 4-carboxyphenylboronic acid (104.3 mg, 0.6287 mmol) and Na2CO3 (133.2 mg, 1.257 mmol) were suspended in MeCN (3.314 mL)/water (3.314 mL) and the mixture de-gassed (×5) and treated with Pd(PPh3)4 (72.65 mg, 0.06287 mmol). The reaction was de-gassed again and heated at 110° C. in the microwave for 30 minutes. The mixture was concentrated to half its original volume and washed with DCM. The aqueous phase was acidified to pH4 (2M HCl) and resulting precipitate collected, washed with water and dried under vacuum (172 mg, 76% Yield). 1H NMR (400.0 MHz, DMSO) d 7.41 (2H, br s), 7.69 (2H, m), 7.76 (1H, m), 7.98 (2H, m), 8.09 (2H, m), 8.29 (2H, m), 8.94 (1H, s); MS (ES+) 360.98
Reaction SMILES: C[O:2][C:3](=[O:16])[C@@H:4]([NH:11][C:12]([O:14][CH3:15])=[O:13])[C@H:5]([O:7][CH:8]([F:10])[F:9])[CH3:6].[OH-].C[Sn+](C)C>ClC(Cl)C.C(OCC)(=O)C>[F:9][CH:8]([F:10])[O:7][C@H:5]([CH3:6])[C@H:4]([NH:11][C:12]([O:14][CH3:15])=[O:13])[C:3]([OH:16])=[O:2]
Reactant: COC(=O)N[C@H](C(=O)OC)[C@@H](C)OC(F)F
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC(F)F
Temperature: 80 °C

Procedure:
To a solution of (2S,3R)-methyl-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoate (265 mg, 1.1 mmol) in dichloroethane (10 mL) was added trimethyltin hydroxide (1 g, 5.5 mmol) and the resulting mixture was heated to 80° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate, washed twice with 5% aqueous HCl solution and brine, dried (MgSO4) and concentrated. The resulting crude material (209 mg, 84%) was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2.C(=O)(O)[O-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([O:22][C:21]([C:6]1[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)=[O:23])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc2cc(Br)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1cc2cc(Br)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 83.9 %

Procedure:
To a mixture of 5-bromo-1-(4-nitro-benzyl)-1-H-indole-2-carboxylic acid (1.66 g, 4.43 mmol) and sodium bicarbonate (0.93 g, 11.1 mmol) in dry dimethylformamide at room temperature under nitrogen was added benzyl bromide (2.275 g, 1.58 ml, 13.3 mmol). The reaction mixture was warmed to about 60° C. for about 16 hours and then the mixture was cooled, diluted with ethyl acetate, washed with dilute sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was flash chromatographed on silica (60 g) with 20% ethyl acetate/hexanes. The purified product was taken up in hot toluene/heptane and allowed to crystallize slowly. The light brown solid was washed with heptane and dried in air, then under vacuum to give the title compound (1.73 g).
Reaction SMILES: [C:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CCOCC>CCOC(C)=O>[C:27]([O:26][C:24](=[O:25])[CH2:23][N:13]1[C:12](=[O:21])[CH2:11][C:10]2[N:16]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]1=2)([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1Cc2nnc(-c3ccccc3)n2-c2ccccc2N1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 44.3 %

Procedure:
Following the procedure described for Preparation 13(A), 1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(A)) (5.0 g, 18.1 mmol) was alkylated with tert-butyl bromoacetate (2.94 mL, 19.9 mmol). Trituration with Et2O (100 mL), hexanes (30 mL) and EtOAc (10 mL) provided 3.13 g of (5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetic acid tert-butyl ester. 1H NMR (CD3OD) δ 7.68 (d, 1H), 7.60-7.51 (m, 4H), 7.43 (m, 2H), 7.23 (t, 1H), 6.99 (d, 1H), 4.86 (d, 1H), 4.44 (d, 1H), 3.99 (d, 1H), 3.83 (d, 1H), 1.36 (s, 9H); MS 391.4 (M+1), 389.3 (M−1).
Reaction SMILES: [CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([OH:21])[CH2:16]1.[H-].[Na+].I[CH3:28]>CN(C=O)C>[CH3:28][O:21][CH:15]1[CH2:16][C:17]2[C:12]([CH3:22])([CH:11]3[CH:20]([CH2:19][CH:18]=2)[CH:7]2[CH2:6][CH2:5][CH:4]4[CH:3]([CH3:24])[N:2]([CH3:1])[CH2:23][C:8]24[CH2:9][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CC1C2CCC3C4CC=C5CC(O)CCC5(C)C4CCC32CN1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reaction time: 8 h
Yield: 38.4 %

Procedure:
Compound 130A (30 mg, 0.091 mmol) was dissolved in 1.5 mL anhydrous DMF. Sodium hydride (60% dispersion in mineral oil, 6 mg, 0.137 mmol) was added and the mixture was stirred at room temperature for 1 hour before iodomethane (39 mg, 0.274 mmol) was added. The reaction mixture and stirred overnight, quenched with water and extracted with dichloromethane to give the crude product, which was purified on silica gel column eluted with 0.3% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (12 mg, 38% yield).
Reaction SMILES: [Br:1][CH2:2][C@H:3]([CH3:6])[CH2:4][OH:5].[C:7](OC(=O)C)(=[O:9])[CH3:8].O.C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([O:5][CH2:4][C@@H:3]([CH3:6])[CH2:2][Br:1])(=[O:9])[CH3:8]
Reactant: C[C@H](CO)CBr
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OC[C@@H](C)CBr
Temperature: 70 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
6 g of (R)-(−)-3-bromo-2-methyl-1-propanol (39.2 mmol) were stirred in 6 ml of pyridine at room temperature. 4.08 g of acetic anhydride (43.1 mmol) were added and the reaction mixture was stirred for 4 h at 70° C. Stirring was continued for 16 h at room temperature. 40 ml of water and 60 ml of ethyl acetate were added to the reaction mixture. The organic layer was separated and washed with a further portion of water, then dried over magnesium sulfate, filtered, and evaporated under vacuum, whereby 6.03 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:23]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([O:19][CH2:21][C:22](=[O:23])[C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)COC1
Product: O=C(CC1(NC(=O)OCc2ccccc2)COC1)OCC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared by Method E using (3-{[(benzyloxy)carbonyl]amino}oxetan-3-yl)acetic acid (Preparation 25, 0.3 g, 1.13 mmol) and 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone (0.317 g, 1.19 mmol) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]([CH:26](O)[CH2:27][CH3:28])[C:10]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:9](=[CH:26][CH2:27][CH3:28])[C:10]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:7]1
Reactant: CCC(O)C1C(N2CCN(C)CC2)=Nc2ccccc2N=C1N1CCN(C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCC=C1C(N2CCN(C)CC2)=Nc2ccccc2N=C1N1CCN(C)CC1
Temperature: 0 °C
Yield: 75.9 %

Procedure:
To a suspension of 1-[2,4-bis(4-methyl-1-piperazinyl)-3H-[1,5]benzodiazepin-3-yl]-1-propanol (19.93 g, 50 mmol) and triethylamine (45 ml, 325 mmol) in dichloromethane (100 ml) under constant flow of argon, at 0° C., a solution of trifluoroacetic anhydride (21 ml, 150 mmol) in dichloromethane (50 ml) was added dropwise. The reaction mixture was stirred for another hour at 0° C. The solution was allowed to warm to room temperature. Methanol (66 ml) and tetrabutylammonium bromide (1.61 g, 5 mmol) were added successively. While strongly agitated NaOH (1 M, 660 ml) was added dropwise. Two phase system was agitated for two hours. The phases were separated and the water phase was extracted with dichloromethane (2×100 ml). The organic phase was dried over anhydrous Na2SO4 and the solvent was evaporated at reduced pressure. The crude product was suspended in isopropyl ether (150 ml) and filtered off the filtrate was evaporated at reduced pressure to give 14.44 g (76%) of the title compound as a brown resin.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([C:26](=[O:30])[C:27]([OH:29])=O)[CH:23]=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)C(Cl)=O.[NH:37]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:37]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:27](=[O:29])[C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=1)=[O:30])[CH3:43]
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)C(=O)O)c1
Reactant: CCOC(=O)CNCC(=O)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of 1.0 g (2.4 mmol) of 3-(octadecyloxy)-alpha-oxobenzeneacetic acid in 50 ml of anhydrous methylene chloride and 2 drops of DMF stirred in an ice bath was added 1.1 ml (11.9 mmol) of oxalyl chloride. The cooling bath was removed and stirring was continued at room temperature for 2 hours. The solvent was removed at reduced pressure and the residual acid chloride was dissolved in 40 ml of anhydrous methylene chloride and added dropwise to a stirred, ice bath cooled solution of 0.6 ml (3.6 mmol) of diethyl iminodiacetate and 0.66 ml (4.8 mmol) of triethylamine in 10 ml of methylene chloride. The mixture was stirred for 30 minutes in the ice bath and then at room temperature for 19 hours when it was washed with NaHCO3 solution, dried and concentrated to an oil which was purified by chromatography on 35 g of 230-400 mesh silica gel using 20% ethyl acetate-hexane to give 1.3 g (93% yield, mp 27°-29°) of N-(2-ethoxy-2-oxoethyl)-N-[2-[3-(octadecyloxy)phenyl]-1,2-dioxoethyl]glycine ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:17]([NH:20][NH2:21])([NH2:19])=[NH:18].[ClH:22].Cl.O>C(O)C>[ClH:22].[NH:20]([N:21]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:8]1)[C:17]([NH2:19])=[NH:18]
Reactant: Cc1coc2c1C(=O)CC(c1cccs1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1coc2c1C(=NNC(=N)N)CC(c1cccs1)C2
Yield: 85.8 %

Procedure:
A mixture of 3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.30 g), aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.065 ml), water (0.065 ml) and ethanol (30 ml) was refluxed for 2.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 48) (0.36 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1>C(Cl)Cl.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:9])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Br)cc1)C1CCCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-bromophenyl)(cyclohexyl)methanol (3.45 g, 12.82 mmol) in DCM (100 ml) was added manganese dioxide (11.14 g, 128 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with aqueous NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound as slightly orange solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([CH3:26])[NH:7][C:8](=[O:25])[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1.[H-].[Na+].CN(C)C=O.Br[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([CH3:26])[N:7]([CH2:35][C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[C:8](=[O:25])[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1
Reactant: COCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1nc(C)n(Cc2cccs2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
A mixture of 4′-{[4-(methoxymethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-(bromomethyl)thiophene (4.5 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.68 g, 53%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].C(=O)(O)[O-].[Na+].[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[N:7]=[C:6]1[N:25]1[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(Cl)nc2nc(Cl)nc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
A mixture of 2.4 g of 7-(2-butynyl)-2,6,8-trichloro-7H-purine, 1.46 g of sodium bicarbonate, 2.43 g of t-butyl piperazine-1-carboxylate, and 45 ml of acetonitrile was stirred at room temperature for 2 hours and 20 minutes. Then, 0.73 g of sodium bicarbonate and 1.21 g of t-butyl piperazine-1-carboxylate were added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was triturated with diethyl ether. The crystals were collected by filtration, and washed with diethyl ether. Thus, 3.0 g of the title compound was obtained as a white solid.