Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27](O)[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][Si](C(C)(C)C)(C)C)[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:7]([CH3:62])[CH:6]([O:63][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:71])[CH3:2].C(N(S(F)(F)[F:78])CC)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:78])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:7]([CH3:62])[CH:6]([OH:63])[CH2:5][C:4]1=[O:71])[CH3:2]
Reactant: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a stirred solution of 17-Ethyl-1,20-di-hydroxy-12-[2'-(4"-t-butyldimethylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in methylene chloride cooled to -78° C. was added diethylaminosulfur trifluoride. After 3 min., saturated sodium bicarbonate solution was added followed by ethyl acetate and the reaction mixture was allowed to warm to room temperature. The reaction mixture was extracted with ethyl acetate, the organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The product was purified by chromatography (silica, ethyl acetate:hexanes 1:2+1% methanol. To a solution of this material (10 mg) in THF (0.6 ml) in a polypropylene vial was added 40 μL of HF-pyridine solution in THF. After stirring for 28 hours at rt, the mixture was added to a saturated solution of sodium bicarbonate. This mixture was extracted with ethyl acetate and the organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The product was purified by chromatography (silica, ethyl acetate:hexanes 2:1+1% methanol) to give the title compound. Mass Spectrum (FAB): 832 (M+Na)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[O:29].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:12](=[O:15])[CH2:13][CH2:14][C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[O:29])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=Cc1ccccn1
Reactant: C=CC(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)CCC(=O)c2ccccn2)cc1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydrofuran-3-yl)pent-1-en-3-one (229 mg) in ethanol (3.6 mL) were added pyridine-2-carbaldehyde (84.8 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (22.0 mg) and triethylamine (44.5 μL), and the mixture was stirred with heating under reflux for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (43.5 mg, yield 14%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: COc1ccccc1I
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Product: COc1ccccc1CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.5 g, 8.55 mmol) and 9-borabicyclo[3.3.1]nonane (68.4 mL, 34.20 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hours, add 1-iodo-2-methoxy-benzene (3.0 g, 12.82 mmol), triphenylphosphine (358.8 mg, 1.37 mmol), tetrakis(triphenylphosphine) palladium(0) (197.5 mg, 0.17 mmol), and 3N NaOH (7.0 mL) and stir at 60° C. After 22 hours, remove the THF under vacuum, stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H2SO4 then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using ethyl acetate/hexanes (5:95) to give (2.21 g, 65%) of the title compound: mp 58–61 C°; mass spectrum (ion spray): m/z=401.3 (M+1); Analysis for C27H32N2O: calcd: C, 80.96; H, 8.05; N, 6.99; found: C, 81.08; H, 7.99; N, 7.10.
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([C:27]1[O:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1)[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:25]([C:27]1[O:31][C:30]([C:32]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[N:16]=[CH:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:13][N:14]=3)=[CH:23][CH:22]=2)=[O:33])=[CH:29][CH:28]=1)[CH3:26]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCc1ccc(C(=O)O)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc(CC)o3)cc2)nc1

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 1.4 g of 5-ethyl-2-furancarboxylic acid (prepared as described by Perry et al., Appl. Organomet. Chem. 10, 389–392 (1996) from furan-2-carboxylic acid; m.p. 90° C.) and 2.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound as colorless crystals having the phase sequence X 80 (N62) I.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].[Cl-].[CH3:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([NH:22][C:23]2[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:22][C:23]2[C:24]([NH:29][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:12][CH:11]=3)=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: CCOc1ccc(C(=O)O)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
To a mixture of 4-ethoxybenzoic acid (0.332 g, 2.00 mmol) and a few drops of N,N-dimethylformamide in methylene chloride (50 mL) cooled to 0° C. was added oxayl chloride (0.21 mL, 2.2 mmole). After 30 min reaction the mixture was warmed to room temperature and stirred for an additional 10 min. The mixture was concentrated in vacuo, and the residue dissolved in methylene chloride (10 mL), and the resulting solution added in two portions to a mixture of N1-(4-methoxybenzoyl)-1,2-benzenediamine (0.455 g, 2.00 mmol) and triethylamine (0.281 mL, 2.00 mmol) in methylene chloride (40 mL) cooled to 0° C. After 4 h, the mixture was allowed to warm to room temperature and stirred for an additional 12 h. The reaction was quenched with cold dilute aqueous hydrochloric acid (50 mL), diluted with hexane, and shaken in a separatory funnel. The organic layer was washed with cold dilute aqueous hydrochloric acid and saturated aqueous sodium bicarbonate solution. The solution was dried (magnesium sulfate), filtered, and concentrated in vacuo. Recrystallization of the residue from methylene chloride/hexane provided 317 mg (41%) of title compound.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[C:14]([C:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=1[NH:28][C@@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:36][CH:35]=1)[C:30]([OH:32])=[O:31])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O1CCOCC1.O.[OH-].[Li+].P(=O)(O)(O)O>O>[C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH:29]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:39]=1)[C:30]([OH:32])=[O:31])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(C1=C(N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O)CCCC1)c1ccccc1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=P(O)(O)O
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccccc1NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 50 °C
Reaction time: 5 h
Yield: 47.5 %

Procedure:
To a solution of 185 mg (0.62 mmol) of Intermediate 2 in 8 mL (1:1; dioxane:water) was added 500 mg (11.9 mmol) lithium hydroxide monohydrate. The resulting suspension was stirred at 50° C. for 5 h and then cooled to RT. A 1M phosphoric acid solution was added until pH was 5.5 was reached where upon the resulting suspension was extracted with EtOAc (2×25 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated and chromatographed on silica gel using CH2Cl2/MeOH (9:1) to yield 133 mg of the title compound. 1H NMR (CDCl3) δ 8.87 (bs, 1H) 7.60-7.58 (d, 2H, J=6) 7.94-7.32 m (10H), 7.23-7.21 (d, 2H, J=3.9), 6.90-6.88 (m, 2H) 6.67-6.56 (m, 2H), 4.98 (s, 2H), 4.39 (m, 1H), 3.30-3.10 (m, 2H); low resolution MS (FAB+) m/e (MH+) 452.1.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.[CH:33]1([CH2:36][N:37]2[C:45]([N:46]3[CH2:51][CH2:50][NH:49][C@H:48]([CH3:52])[CH2:47]3)=[N:44][C:43]3[C:38]2=[N:39][C:40]([C:59]2[CH:60]=[N:61][C:62]([NH2:65])=[N:63][CH:64]=2)=[N:41][C:42]=3[N:53]2[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)[CH2:35][CH2:34]1.[C:66](O)(=[O:70])[C@@H:67]([CH3:69])[OH:68]>C(Cl)Cl.CO.C(Cl)Cl.CN(C)C=O>[NH2:65][C:62]1[N:63]=[CH:64][C:59]([C:40]2[N:39]=[C:38]3[C:43]([N:44]=[C:45]([N:46]4[CH2:51][CH2:50][N:49]([C:66](=[O:70])[C@H:67]([OH:68])[CH3:69])[C@H:48]([CH3:52])[CH2:47]4)[N:37]3[CH2:36][CH:33]3[CH2:35][CH2:34]3)=[C:42]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[N:41]=2)=[CH:60][N:61]=1
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CCN1
Reactant: C[C@@H](O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CCN1C(=O)[C@@H](C)O
Reaction time: 18.5 h
Yield: 75.1 %

Procedure:
1-Hydroxybenzotriazole (33.2 mg, 0.25 mmol), N,N′-dicyclohexylcarbodiimide (76.1 mg, 0.37 mmol), and triethylamine (102.8 μl, 0.75 mmol) were added to an N,N-dimethylformamide (3.0 ml)-methylene chloride (3.0 ml) mixture solution of 5-{9-(cyclopropylmethyl)-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (110.8 mg, 0.25 mmol) and D-lactic acid (26.9 mg, 0.30 mmol) at room temperature. The resulting mixture was stirred for 18.5 hours followed by the addition of N,N′-dicyclohexylcarbodiimide (76.1 mg, 0.37 mmol) and the resulting mixture stirred at 40° C. for 22 hours. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (98.1 mg, 76%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1([O:7][CH3:8])[CH2:5][NH:4][C:3]1=[O:6].[C:9]1([CH2:15][C:16](O)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[C:9]1([CH2:15][C:16]([NH:1][C:2]2([O:7][CH3:8])[CH2:5][NH:4][C:3]2=[O:6])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COC1(N)CNC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC1(NC(=O)Cc2ccccc2)CNC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of 61 mg of 3-amino-3-methoxy-2-oxoazetidine in 2 ml of THF are added 72 mg of phenylacetic acid, 71.3 mg of 1-hydroxybenzotriazole and 130 mg of dicyclohexylcarbodiimide, and the mixture is stirred at room temperature for 3 hours. The dicyclohexylurea is filtered off, and the filtrate is concentrated. The residue is chromatographed on a column of silica gel [eluted with n-hexane-ethyl acetate (1:2)] to obtain 86 mg of 3-phenylacetamido-3-methoxy-2-oxoazetidine.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>>[CH3:36][O:35][C:31](=[O:34])[CH2:32][CH2:33][N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([Cl:13])[CH:23]=2)[CH:18]=[C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:24]
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c2cc(Cl)ccc2cc1-c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: COC(=O)CCn1c(=O)c(-c2ccccc2)cc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
1 ml of benzyltrimethylammonium hydroxide is added to a suspension of 8 g of 7-chloro-1,2-dihydro-2-oxo-3-phenylquinoline in 21.3 ml of methyl acrylate at 40° to 50° C., under nitrogen, the mixture is stirred at this temperature for 31/2 hours and the excess methyl acrylate is then distilled off in vacuo. The solid residue is dissolved in 100 ml of methylene chloride and the solution is washed with 2 N acetic acid, sodium bicarbonate solution and water. After drying the organic phase over sodium sulphate and distilling off the solvent, the residue is recrystallised from cyclohexane. 8.0 g of the title compound of m. 122°-124° C. are obtained.
Reaction SMILES: [Cl-].[NH4+].O.[CH:4]1([O:10][C:11]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:12]=2[C:13]#[N:14])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>[Fe].C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:11]([O:10][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[C:12]([CH:15]=1)[C:13]#[N:14]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1OC1CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)ccc1OC1CCCCC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Subsequently, ammonium chloride (1.8 g) and iron powder (9.2 g) were added to a mixed solvent of water (32 ml) and ethanol (130 ml), and the mixture was heated to 65° C. Then, ethanol solution (4 ml) containing 2-cyclohexyloxy-5-nitrobenzonitrile (11.6 g) was added dropwise over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of diisopropyl ether-n-hexane to give the title compound (9.5 g), melting point: 59° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH:22]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]([CH3:40])=[C:35]([CH2:37][CH2:38]O)[N:36]=2)=[CH:28][CH:27]=1)([CH3:24])[CH3:23]>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:38][CH2:37][C:35]2[N:36]=[C:32]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH:22]([CH3:23])[CH3:24])=[CH:27][CH:28]=3)[O:33][C:34]=2[CH3:40])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Product: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
Intermediate 51 was prepared from 598 mg of N-(Boc)-L-Tyrosine methyl ester and 530 mg of Intermediate 14 to yield 540 mg (63% overall yield) of the title compound as a solid. 1H NMR (DMSO-d6, 400 MHz) δ7.77 (d, 2H, J=8.7), 7.12 (d, 2H, J=8.6), 6.9 (d, 2H, J=8.9), 6.82 (d, 2H, J=8.5), 4.65 (hept, 1H, J=6.0), 4.13 (t, 2H, J=6.6), 3.0 (dd, 1H, J=14.4, 4.5), 2.85 (t, 2H, J=6.4), 2.76 (dd, 1H, J=14.4, 8.0), 2.31 (s, 3H), 1.25 (d, 6H, J=6.0); low resolution MS (ES+)m/e 425.2 (MH+).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[C:14]1([S:20]([NH:23][C:24](=[O:46])[C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:36][CH:35]=3)[CH:26]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([S:20]([NH:23][C:24](=[O:46])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[C:27]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:36][CH:35]=3)[CH:26]=2)(=[O:21])=[O:22])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
Triethylamine (0.060 g) and 0.084 g of butyryl chloride were added to a solution of 0.300 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 2 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was directly purified through silica-gel column chromatography to obtain 0.250 g of N-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-butyrylaminobenzamide. To this compound were added 5 ml of methanol and 0.50 g of 35% hydrochloric acid, and the mixture was stirred at 60° C. for 3 hours. Then, 20% potassium hydrogencarbonate was added thereto to stop the reaction, and the reaction solution was extracted with ethyl acetate and with water. The organic layer was concentrated, and the product was dissolved in a small amount of chloroform. Ether was added thereto for crystallization. The crystals precipitated were separated through filtration, and were dried to give 0.157 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylbenzimidazole potassium salt (232).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][Si](C)(C)C)[C:5]([NH2:8])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].[Cl-].[Na+]>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]2[CH:9]=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cc(F)cnc1N
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Fc1cnc2[nH]ccc2c1
Reaction time: 4 h
Yield: 94.6 %

Procedure:
A mixture of 3.8 g of 5-fluoro-3-trimethylsilanylethynylpyridin-2-ylamine and 3.4 g of potassium tert-butoxide in 100 ml of 1-methylpyrrolidin-2-one is brought to around 130° C. for approximately 4 hours. After returning to a temperature in the region of 20° C., the mixture is run into 1000 ml of a saturated aqueous sodium chloride solution and extracted with five times 250 ml of diethyl ether. The organic phases are combined, washed with five times 100 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (13 kPa). 2.35 g of 5-fluoro-1H-pyrrolo[2,3-b]pyridine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10]C)=O)#[N:2].[C-]#N.[Na+].CO.[CH:19]([NH2:22])([CH3:21])[CH3:20]>CS(C)=O>[CH:19]([NH:22][C:8](=[O:10])[C:7]1[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[OH:13])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: CC(C)N
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)NC(=O)c1cc(C#N)ccc1O
Temperature: 60 °C
Yield: 93 %

Procedure:
Methyl 5-cyano-2-hydroxybenzoate (8.85 g; 50 mmol; see Example 10(b) above) and NaCN (250 mg; 5 mmol) were dissolved in DMSO (10 mL) and MeOH (50 mL) and iso-propyl amine (25 mL) was added. The reaction mixture was heated (60° C. ) in a sealed steel vessel for 10 h, the MeOH was removed under reduced pressure and H2O (500 mL) was added. The solution was acidified with HCl (pH 1), filtered and the precipitate was washed with H2O giving the sub-title compound in a 93% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1>C(NCC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:18][C:6]=4[C:7](=[O:17])[N:8]([CH3:16])[CH2:9][C:10]=23)=[CH:22][CH:21]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: CN1Cc2c(C#Cc3ccc(Cl)cc3)ncn2-c2ccc(F)cc2C1=O

Procedure:
3.6 g (10 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature for 16 hours with 1.5 g (11 mmol) of p-chlorophenylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 15 mg of copper(I) iodide in 35 ml of diethylamine. The reaction mixture was diluted with 175 ml of methylene chloride and washed three times with water. The organic phase was dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel and subsequent recrystallization from methylene chloride and ethyl acetate there was obtained 3-[(p-chlorophenyl)ethynyl]-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 221°-222°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[S:27][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[C:9]=2[CH:8]=1>>[N:1]1([C:12]2[N:13]=[C:14]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[C:9]3[CH:8]=[CH:7][S:27][C:10]=3[N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Clc1cc2c(NCCc3ccc4c(c3)OCO4)ncnc2s1
Product: c1cnn(-c2nc(NCCc3ccc4c(c3)OCO4)c3ccsc3n2)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 6-chloro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.