Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:14]2[N:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)=[O:12])=[C:6]([Cl:37])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[CH2:30]([N:13]([C:14]1[N:15]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:16]=[C:17]2[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]2)[C:11](=[O:12])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][C:6]=1[Cl:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(NC(=O)N(Cc2ccccc2)c2c3ccccc3nn2-c2ccc(Cl)cc2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)N(Cc2ccccc2)c2c3ccccc3nn2-c2ccc(Cl)cc2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 2.2, 4-{3-benzyl-3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-ureido}-3-chloro-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 3 days at ambient temperature to give the title compound as colorless oil. MS: m/e=530.0 [M−H−].
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])=[CH:15][CH:14]=1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][S:29]([CH:26]([CH3:28])[CH3:27])(=[O:31])=[O:30])=[CH:17][CH:18]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1ccccc1-c1ccc(Br)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)Nc1ccccc1-c1ccc(Br)cc1
Yield: 97.8 %

Procedure:
Add DBU drop wise (8.76 mL, 56.92 mmol) to a solution of 2-(4-bromophenyl)phenylamine (3.53 g, 14.23 mmol) in methylene chloride (50 ml) at 0° C., followed by isopropylsulfonyl chloride (3.29 mL, 28.46 mmol) also added drop wise and stir the reaction at room temperature for 24 h. Remove solvent under reduce pressure and purify the residue by silica gel chromatography eluting with ethyl acetate:hexane 1:4 to ethyl acetate to provide the title compound (4.93 g, 98%). Mass spectrum (m/e): 355 (M+1); 353 (M−1).
Reaction SMILES: OO.[NH2:3][C:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[C:5]([CH3:9])[C:6]([NH2:8])=[S:7]>CO>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:4]2[C:5]([CH3:9])=[C:6]([NH2:8])[S:7][N:3]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C(N)=C(C)C(N)=S)cc1
Agent: OO
Solvent: CO
Product: COc1ccc(-c2nsc(N)c2C)cc1
Reaction time: 3 h
Yield: 88.2 %

Procedure:
Add hydrogen peroxide (30% by weight, 2.39 g, 70.3 mmol) to a solution of 3-amino-3-(4-methoxyphenyl)-2-methyl-thioacrylamide (7.800 g, 35.135 mmol) in methanol (703 mL). Stir 3 h. Quench the reaction with Na2S2O3 (20% in water) and evaporate to 10 mL. Dilute with EtOAc (500 mL) and wash the organic phase with brine (3×100 mL), evaporate and crystallize from EtOAc/hexane to afford 3-(4-methoxy-phenyl)-4-methylisothiazol-5-ylamine. Yield: 88.2%. ES-MS: m/e 221.0 (m+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:20])[C:9](N2[C@@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)c1ccc(Cl)cc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of (4S)-3-[(2S)-2-(4-chlorophenyl) propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (678 mg, 2.30 mmol) in 45 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (2.1 mL, 18.4 mmol) followed by LiOH (193 mg, 4.6 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (15 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 0.36 g (1.96 mmol, 85%) of (2S)-2-(4-chlorophenyl)propanoic acid; [α]D=+67° (C=1, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–10.8 (br, 1H), 7.32–7.23 (m, 4H), 3.72 (q, 1H, J=7.3 Hz), 1.50 (d, 3H, J=7.3 Hz); ESMS m/e: 183.2 (M−H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:26])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.O>[CH:20]1([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:9]3[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=3)=[O:26])=[CH:15][CH:16]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(COc1ccc(C2CCCCC2)cc1)Nc1cscc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
To a solution of 4-[2-(4-cyclohexyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (75 mg) in 2.5 mL of a mixture of THF:water (1.5:1) was added sodium hydroxide (0.442 mL, 1 M, 2.2 eq) and the reaction mixture was stirred for 24 hours at room temperature. Then the reaction mixture was acidified by addition of a solution of aqueous HCl (0.442 mL, 1N, 2.2 eq). The precipitate was isolated, washed with water and dried in vacuo to yield 4-[2-(4-cyclohexyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid (51 mg, 71%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:36]([C:39]1[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=1)=[C:37]=[O:38]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:37]([NH:36][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=3)=[O:38])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C=Nc1cccc(O)c1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3cccc(O)c3)C2)cc1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-(3-hydroxyphenyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (40 mg, 0.13 mmol) and 3-isocyanatophenol (40.4 mg, 0.15 mmol) according to General Procedure G to give 20 mg (34.4%) of white solid. Anal. Calcd. for C25H31N5O2 m/z 433.2, found: 434.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (s, 1H), 8.66 (m, 1H), 8.52 (s, 1H), 8.41 (m, 1H), 7.41 (d, J=8.9 Hz, 2H), 6.97 (m, 4H), 6.66 (d, J=9.3 Hz, 2H), 6.34 (m, 2H), 3.79 (m, 1H), 3.56 (m, 3H), 3.26 (m, 2H), 3.00 (m, 1H), 2.11 (m, 2H), 1.92 (m, 1H), 1.78 (m, 1H), 1.62 (m, 1H), 1.49 (m, 1H), 1.32 (m, 6H).
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Product: CN(C)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 3-iodoazetidine-1-carboxylate (EP 1176147, prep 18) (5 g, 17.6 mmol) and dimethylamine (27 mL, 33% in ethanol, 176 mmol) was heated to 80° C. for 28 hours in a sealed vessel. The cooled mixture was evaporated in vacuo and the residue pre-adsorbed onto silica gel. This was then purified by column chromatography on silica gel using ethyl acetate:hexane (50:50) as eluant to afford the title compound as a yellow oil, 1.07 g.
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]=[O:8].[CH3:9][Mg]Br.C(O)(C)C>O1CCCC1>[Cl:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]([OH:8])[CH3:9]
Reactant: C[Mg]Br
Reactant: O=CC1=C(Cl)CCC1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(O)C1=C(Cl)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
Under an argon atmosphere, 2-chloro-1-cyclopentenecarbaldehyde (630 mg, 4.82 mmol) was dissolved in anhydrous tetrahydrofuran (19 ml), methylmagnesium bromide (1.4M toluene solution, 4.1 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 30 minutes. Isopropanol (2 ml) was added at 0° C., and the solvent was evaporated under reduced pressure. 1N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1-6:1) to give the title compound (294 mg, 2.01 mmol, 41.6%).
Reaction SMILES: C[O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]([N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20](=[O:22])[CH3:21])[CH2:11][CH:10]2[CH3:29])=[O:8])=[CH:5][CH:4]=1.B(Br)(Br)Br.C(OCC)(=O)C>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([N:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:20](=[O:22])[CH3:21])[CH2:11][C@@H:10]2[CH3:29])=[O:8])=[CH:30][CH:31]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccccc3)CC2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reaction time: 3 h
Yield: 51.8 %

Procedure:
To a solution N-[1-(4-Methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenyl-acetamide (0.1 g) in dichloromethane (2.4 ml) at 0° C., was added boron tribromide (0.265 mmol). After 3 hours, ice and ethyl acetate were added and the solution was washed using water and carbonate potassium. The organic layer was separated and dried over sodium sulfate. The solvent was removed to afford an amorphous materiel. The product was purified by chromatography on silica gel using a mixture of dichloromethane and ethanol (95:5) as eluent to give the title compound (50 mg).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].Cl.CN(C)CCCN=C=NCC.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[C:23]2[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Br:37])[CH:32]=1>CN(C=O)C>[Br:37][C:33]1[CH:32]=[C:31]([NH:30][C:23]2[C:22]3[C:27](=[CH:28][CH:29]=[C:20]([NH:19][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:21]=3)[N:26]=[CH:25][N:24]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC#CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-butynoic acid (196 mg, 2.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (385 mg, 2.0 mmol) in DMF (5 mL) stirring at 25° C. for 20 minutes was added 6-amino-4-[(3-bromophenyl)amino]quinazoline (316 mg, 1.0 mmol). The resulting solution was stirred under N2 at 25° C. for 14 hours further 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (206 mg, 1.0 mmol) and 2-butynic acid (82 mg, 1.0 mmol) were. After another 8 hours further, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 mg, 1.0 mmol) and the acid (93 mg, 1.0 mmol) were added to the reaction. After stirring at 25° C. a further 12 hours, the reaction was quenched with water. The yellow precipitate was collected, sonicated with acetone, treated with triethyl amine and purified by preparative tlc on silica, eluting with 1:1 EtOAc/acetone. The desired product was isolated as a yellow solid (20 mg, 4.7%), mp 281-283° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[OH:37])[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48](O)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH:48]2[CH2:49][CH2:50][N:45]([C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])[CH2:46][CH2:47]2)[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccccc2O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
Diisopropyl azodicarboxylate (0.70 mL, 3.55 mmol) was added dropwise to a stirred solution of 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid benzyl ester (0.74 g, 2.4 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.48 g, 2.4 mmol) and triphenylphosphine (0.93 g, 3.6 mmol) in THF (25 mL) cooled to 0° C. The resulting solution was warmed to r.t. and stirred for about 16 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (20% ethyl acetate in hexanes) to afford the final compound (0.50 g, 43%) as a clear oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:28])[O:22][C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:28])[O:22][C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)O[C@H]2CCOC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CCNC1)O[C@H]1CCOC1
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
TFA (1 mL) was added to a solution of (S)-tetrahydrofuran-3-yl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (490 mg, 1.63 mmol) in 5 mL CH2Cl2. After stirring for 30 min, the reaction was quenched with NaOH and extracted twice with EtOAc. The organic extracts were combined, dried over MgSO4, filtered, and concentrated to yield (S)-tetrahydrofuran-3-yl(R)-pyrrolidin-3-ylcarbamate (230 mg) which was used without further purification. LC/MS: m/z 201.3 (M+H)+ at 0.59 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][NH2:28])([CH3:19])([CH3:18])[CH3:17].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C:13]([NH:28][CH2:27][C@@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24][CH2:23][NH:22][C:21]([O:20][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:37])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 79A from 92 mg (0.44 mmol) of N-[(benzyloxy)carbonyl]glycine and 181 mg (0.57 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) in 6 ml of dimethylformamide with the addition of 110 mg (0.57 mmol) of EDC and 18 mg (0.13 mmol) of HOBt. The product is purified by preparative RP-HPLC (mobile phase water/acetonitrile gradient: 90:10→5:95).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][C:14]([CH:16]1[CH2:20][CH2:19][N:18]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:17]1)=[O:15])[CH3:12].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCCC1>[CH2:11]([O:13][C:14]([C:16]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:20][CH2:19][N:18]([C:21](=[O:30])[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1CCN(C(=O)c2ccc(OC)cc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (1000 mL of a 1.0M solution in tetrahydrofuran, 1.0 mol) was added to a stirred solution of 1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (±) (268 g, 0.97 mol) (see Preparation 2) in THF (1600 mL) at −70° C. The mixture was stirred for 20 mins at −70° C. then ethyl chloroformate (104 mL, 1.09 mol) was added over 15 minutes. The resulting mixture was stirred at −60° C. for 1 hour. The reaction mixture was quenched with 10% citric acid aqueous solution (1200 mL) at −50° C. then warmed to room temperature. The organic layer was separated, washed with saturated aqueous NaHCO3 (1200 mL) and water (1200 mL) then concentrated under reduced pressure to afford the title compound as an orange oil (316.0 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C)cc3)sc2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2cc3c(s2)CCCC(C(=O)O)=C3)cc1
Reaction time: 120 h
Yield: 84.9 %

Procedure:
To a solution of methyl 2-(4-methylphenyl)-7,8-dihydro-6H-cyclohepta[b]thiophene-5-carboxylate (803 mg) in ethanol-tetrahydrofuran (5-10 ml) was added 2N sodium hydroxide (2 ml) at room temperature, and the mixture was stirred for 5 days and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to precipitate crystals, which were collected by filtration and washed with diisopropylether to give 2-(4methylphenyl)-7,8-dihydro-6H-cyclohepta[b]thiophene-5-carboxylic acid (650 mg) as pale yellow crystals.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH3:9])[CH3:2].[CH2:10]([O:12][P:13](Cl)(Cl)=[O:14])[CH3:11]>>[CH2:1]([N:3]1[CH2:4][CH2:5][CH2:6][N:7]([CH2:8][CH3:9])[P:13]1([O:12][CH2:10][CH3:11])=[O:14])[CH3:2]
Reactant: CCNCCCNCC
Reactant: CCOP(=O)(Cl)Cl
Product: CCOP1(=O)N(CC)CCCN1CC
Yield: 24.7 %

Procedure:
Substantially the same procedure was followed as in Example 1, with 4.00 grams (30.7 mmol) N,N'-diethyl-1,3-diaminopropane and 5.0 grams (30.7 mmol) ethyldichlorophosphate, to produce 1.67 grams of 1,3-diethyl-2-ethoxy-2-oxo-1,3-diaza-2-phosphacyclohexane, ##STR24## as a phosphorus amide catalyst.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[CH2:17]([O:19][C:20](=[O:27])[C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[CH3:18]>C1CCCCC1.C(OCC)(=O)C>[CH2:17]([O:19][C:20](=[O:27])[C:21]([CH3:26])([CH3:25])[C:22]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:23])[CH3:18]
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: CCOC(=O)C(C)(C)C(=O)O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 2, starting from 4-(3-fluoro-benzyloxy)-phenylamine and 2,2-dimethyl-malonic acid monoethyl ester (Holmes et al., J. Amer Chem. Soc. 1984, 106, 2353). Yield after flash-chromatography with cyclohexane/ethyl acetate 7:3: 79%. Colorless oil. MS: m/e=359 (M+).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C@@H:6]1[C@@:10]2([CH3:28])[CH2:11][CH2:12][C@@H:13]3[C@@:18]4([CH3:27])[CH2:19][CH2:20][C@H:21]([O:23][C:24]([CH3:26])=[O:25])[CH2:22][C:17]4=[CH:16][CH2:15][C@H:14]3[C@@H:9]2[CH2:8][CH2:7]1)=[O:5]>C(O)C.C(Cl)Cl>[C:24]([O:23][CH:21]1[CH2:20][CH2:19][C@@:18]2([CH3:27])[C:17](=[CH:16][CH2:15][C@@H:14]3[C@@H:13]2[CH2:12][CH2:11][C@@:10]2([CH3:28])[C@H:9]3[CH2:8][CH2:7][C@@H:6]2[CH:4]([OH:5])[CH3:3])[CH2:22]1)(=[O:25])[CH3:26]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (21 gm) was added to a solution of pregnenolone acetate (100 g, 0.28 mol) in absolute ethanol (1 L) and methylene chloride (0.4 L) at -10° C. After stirring overnight at 4° C., another amount of sodium borohydride (10.5 gm) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched by pouring into 5% sodium phosphate monobasic (2 L) and extracted with methylene chloride. The organic extracts were dried over anhydrous magnesium sulfate and filtered through a pad of anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the title compound.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=1.[OH-].[K+]>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1
Reactant: COc1cccc(OC)c1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(OC)c1-c1c[nH]c2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Methanol (1 mL) was added to crude (3-(3-(2,6-dimethoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone from step 1 and potassium hydroxide (50% w/v, 0.038 mL, 0.34 mmol) was added to the resulting solution. The mixture was stirred for 30 minutes at room temperature before being diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography afforded (3-(3-(2,6-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (7) (31% yield from (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone) as light yellow solids. 1H NMR (500 MHz, CD3OD) δ 3.65 (m, br, 8H), 3.75 (s, 6H), 6.77 (d, J=8.5 Hz, 2H), 7.31 (t, J=8.5 Hz, 1H), 7.39 (m, 1H), 7.46 (s, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.67 (m, 1H), 7.74 (m, 1H), 7.91 (d, J=2.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H). MS: m/z 444.1 (M+H+).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[C:5]#[N:6])[CH2:2][CH3:3].S(=O)(=O)(O)[OH:11]>>[CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[C:5]([NH2:6])=[O:11])[CH2:2][CH3:3]
Reactant: O=S(=O)(O)O
Reactant: CCCC(C#N)CCC
Product: CCCC(CCC)C(N)=O

Procedure:
Process according to claim 1, whereby the di-n-propyl acetonitrile is hydrolysed by means of 75% aqueous sulphuric acid in the proportion of 1.7 g of dilute acid/g of nitrile at the temperature of 140° C. and then the crude di-n-propyl acetamide thus obtained is hydrolysed in the same aqueous sulphuric acid medium in the presence of 1.4 to 1.5 mol of sodium nitrite/mol of nitrile at a temperature of 50°-60° C.