Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](S(C)(=O)=O)=[N:5][N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][N:27]=[C:26]([CH:29]([OH:31])[CH3:30])[N:25]=2)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][N:27]=[C:26]([CH:29]([O:31][C:6]3[N:2]([CH3:1])[C:3]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[N:4][N:5]=3)[CH3:30])[N:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(O)c1noc(-c2cccc(Cl)c2)n1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(Oc1nnc(-c2ccncc2)n1C)c1noc(-c2cccc(Cl)c2)n1
Temperature: 30 °C
Reaction time: 72 h
Yield: 15.5 %

Procedure:
1.45 g (6.08 mmol) 4-[4-Methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine, 1.73 g (7.70 mmol) 1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethanol and 4.03 g (12.3 mmol) cesium carbonate were dissolved under Ar-atmosphere in DMF (25 mL) and stirred at 30° C. for 3 d. After filtration and evaporation to dryness the crude was purified on 4mm silica chromatotron plate (DCM/MeOH=100/0 to 90/10). Further purification on 2 mm silica chromatotron plate (Hep/EA/MeOH=15/15/1) gave 0.36 g (15%) of the title compound. 1H NMR: 8.75 (br s, 2 H), 8.12 (s, 1 H), 8.00 (d, 1 H), 7.64 (d, 2 H), 7.56 (d, 1 H), 7.46 (t, 1 H), 6.39 (q, 1 H), 3.63 (s, 3 H), 1.94 (d, 3 H).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:14]([O:15][CH3:16])=[C:13]([S:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7]>O.C(O)C>[Br:3][C:4]1[C:14]([O:15][CH3:16])=[C:13]([S:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(SCC)c(OC)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCSc1ccc(C(=O)O)c(Br)c1OC

Procedure:
A solution of potassium hydroxide (1.46 g) in water was added to a mixture of ethyl 2-bromo-4-ethylsulphenyl-3-methoxybenzoate (3.98 g) in ethanol with stirring. The mixture was stirred and heated at reflux for 4 hours. It was cooled and evaporated then water was added and the mixture was washed with ethyl acetate then acidified to pH1. It was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-bromo-4-ethylsulphenyl-3-methoxybenzoic acid as an off-white solid NMR (CDCl3) 1.5(t,3H) 3.05(q,2H) 3.9(s,3H) 7.15(d, 1H) 7.6(d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][C:3]=1[F:13].[Cl-].[NH4+].O>C(O)(C)C.[Fe]>[Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: COc1cc(Br)c(F)cc1N
Temperature: 75 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (0.998 g, 3.99 mmol) in isopropanol (20 mL) was added iron (0.7 g, 12 mmol), ammonium chloride (0.64 g, 12 mmol) and water (2 mL). The reaction was stirred at 75° C. for 2 hours, then filtered and concentrated. The residue was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give 4-bromo-5-fluoro-2-methoxyaniline (0.82 g, 93%).
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N(Br)C(=O)C1.[C:17]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30](=[S:32])[NH2:31])[CH2:26][CH2:25]2)=[CH:21][CH:20]=1)#[N:18]>O1CCOCC1.O>[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[S:32][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][N:31]=3)[CH2:26][CH2:25]2)=[CH:33][CH:34]=1)#[N:18]
Reactant: N#Cc1ccc(CN2CCN(C(N)=S)CC2)cc1
Reactant: CO/C=C/C(=O)OC
Agent: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnc(N2CCN(Cc3ccc(C#N)cc3)CC2)s1
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A solution of (E)-methyl 3-methoxyacrylate (290 mg, 280 mL, 2.51 mmol) in 1:1 mixture of dioxane/water (4 mL) was treated with NBS (507 mg, 2.85 mmol) at 0° C. and stirred for 1 hour. The mixture was transferred to a flask containing the thioamide 337 (593 mg, 2.28 mmol) at room temperature and the resulting mixture was refluxed for 1.5 hours. It was cooled down, quenched by adding saturated NH4Cl solution (5 mL) and concentrated. Obtained material was partitioned between EtOAc and water. Organic phase was dried with Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using 60% EtOAc in hexanes as an eluent, to afford the title compound 338 (602 mg, 77% yield). MS: calc: 342.1; found: 343.1 (M+H)
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([CH:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:39]1([CH:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:36]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:37])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)C(c3ccccc3)c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 574.3 (M+H)+.
Reaction SMILES: Cl.[C:2]1([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[N:22]=[C:21]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([NH2:32])=[N:28][NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[C:19](S(C)(=O)=O)[N:18]=1>CN1C(=O)CCC1.CCN(C(C)C)C(C)C>[NH2:16][C:17]1[N:18]=[C:19]([N:13]2[CH2:14][CH2:15][CH:11]([C:9]([NH:8][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:12]2)[CH:20]=[C:21]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([NH2:32])=[N:28][NH:29]3)=[CH:25][CH:24]=2)[N:22]=1
Reactant: O=C(Nc1ccccc1)C1CCNC1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC(C(=O)Nc3ccccc3)C2)n1
Temperature: 160 °C
Yield: 7.5 %

Procedure:
A mixture of N-phenyl-3-pyrrolidinecarboxamide hydrochloride (500 mg, 2.21 mmol), 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (500 mg, 1.6 mmol) in NMP (3 mL) and Hunig's base (1.5 mL) was heated at 160° C. for 1 hour under microwave conditions. The reaction mixture was concentrated and purified by SiO2 chromatography (eluent: 4.5:4.5:1 EtOAc:THF:NH4OH) to afford the title compound (50 mg) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 2.05 (m, 2H), 3.30 (m, 1H), 3.4-3.7 (m, 4H), 5.36 (s, 2H), 6.03 (s, 2H), 6.31 (s, 1H), 7.03 (m, 1H), 7.31 (m, 2H), 7.57-7.74 (m, 4H), 7.94 (s, 1H), 10.10 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH:10]([Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C>C(OCC)C>[ClH:1].[CH3:20][Si:18]([CH3:19])([CH3:21])[CH:10]([NH2:9])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)[Si](C)(C)C
Agent: Cl
Solvent: CCOCC
Product: C[Si](C)(C)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 3N solution of HCl in diethyl ether (3 ml) was added at room temperature to a mixture of N-tertbutoxycarbonyl-α-(trimethylsilyl)benzeneethanamine (0.150g, 0.51 mmol) in diethyl ether (3 ml). The mixture was stirred at room temperature for 48 hours. The resulting solid was filtered off and dried, in vacuo, to yield 0.106 g of the expected α-(trimethylsilyl)-benzeneethanamine hydrochloride,
Reaction SMILES: [C:1]([C:6](=[CH2:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:1]([C:6](=[CH:12][O:15][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C(=O)OCC)C(=O)C(C)C
Product: CCOC=C(C(=O)OCC)C(=O)C(C)C

Procedure:
A mixture of ethyl isobutyrylacrylate (60.5 g, 0.38 mol) triethyl orthoformate (126 ml, 0.76 mol) and acetic anhydride (36 ml, 0.38 mol) was heated at reflux for 24 hours, then the volatile components removed in vacuo, finally at 100°/0.5 mm. The residue consisted mainly of ethyl 2-isobutyryl-3-ethoxyacrylate as a mixture of E/Z isomers, and was used without further purification.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([N:5]([CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)[C:16]([O:17][CH2:18][CH3:19])=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCN(C(=O)OCC)C1CC(C)(C)NC(C)(C)C1

Procedure:
The N-butyl-N-ethoxycarbonyl-2,2,6,6-tetramethyl-4-piperidylamine is prepared by reacting N-butyl-2,2,6,6-tetramethyl-4-piperidylamine with ethyl chlorocarbonate at 15°-25° C. in toluene in the presence of an aqueous solution of K2CO3. The product obtained, which is 99.2% pure, is employed directly, without any purification.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[NH2:13].[CH:14]1([NH:19][C:20]2[C:25]([CH:26]=O)=[CH:24][N:23]=[C:22]([S:28][CH3:29])[N:21]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH:14]1([NH:19][C:20]2[C:25]([CH:26]=[N:13][C:3]3[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[F:12])=[CH:24][N:23]=[C:22]([S:28][CH3:29])[N:21]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COc1cc(OC)c(F)c(N)c1F
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(F)c(N=Cc2cnc(SC)nc2NC2CCCC2)c1F

Procedure:
In a 1-L round bottom flask, 10.00 g (0.0528 mol) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 12.42 g (0.0523 mol) of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 500 mL of toluene with 3.65 g (0.0157 mol) of camphorsulfonic acid was fitted with a Dean Stark trap and heated at reflux. During the day, the toluene was drained three times from the finger and continued heating at reflux under nitrogen atmosphere overnight. The toluene was concentrated in vacuo and dried to give 25.30 g (quantitative) of the title compound. No further purification was necessary. MS (APCI) (m+1)/z 409.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].FC(F)(F)C(O)=O.[CH2:19]([O:26][C:27](=[O:40])[CH2:28][CH2:29][NH:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:40])[CH2:28][CH2:29][NH:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:33]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Reactant: N#Cc1cccc(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C(=O)Nc2cccc(C(=O)NCCC(=O)OCc3ccccc3)c2)c1

Procedure:
For the preparation of the starting material, m.p. 182°-183° C., 3-cyanobenzoic acid and N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate are coupled to give N-[m-(m-cyanobenzamido)benzoyl]-β-alanine benzyl ester, MS: 428 (100, M+H), and this is converted with hydrogen sulphide and triethylamine in pyridine into N-[m-[m-(thiocarbamoyl)benzamido]benzoyl]-β-alanine benzyl ester, m.p. 128°-131° C. The latter is then reacted with methyl iodide in acetone and subsequently with ammonium acetate in methanol and treated with benzyl chloroformate and triethylamine in THF.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C@:10]3([C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](O)=[O:26])[C@@H:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:38].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([F:38])=[O:26])[CH:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[C@H]1N(CC(=O)O)C(=O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(hydroxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.24 mmol) prepared in example 31 in dichloromethane (40 mL) at 0° C. was added cyanuric fluoride (48 mg, 0.35 mmol) (Alfa) and pyridine (37 mg, 0.48 mmol). After the mixture was stirred at 0° C. for 2 h, the mixture was partitioned between H2O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4, concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow gum and used for the next step without further purification (Yield: 0.12 g, 98%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[I:12]N1C(=O)CCC1=O>C(#N)C>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[I:12]
Reactant: ClCc1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: ClCc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
5 g (30 mmol) of 2-(chloromethyl)imidazo[1,2-a]pyridine were solubilised in 60 ml of acetonitrile with magnetic stirring, 7.31 g (31.5 mmol) of N-iodosuccinimide were added and the mixture was stirred at r.t. for 15 min. The solid formed was isolated by filtration, washed with 30 ml of water and dried in a vacuum bell jar. 8.46 g (yield=95%) of 2-(chloromethyl)-3-iodoimidazo[1,2-a]pyridine were obtained as a white solid. LC-MS: m/z=293 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.31 (d, J=6.9 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.46-7.29 (m, 1H), 7.07 (td, J=6.8, 1.0 Hz, 1H), 4.81 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)=[O:26])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CCNCc1ncc[nH]1
Product: CCN(Cc1ncc[nH]1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-(1H-imidazol-2-ylmethyl)-amine
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[Br:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(N(CC)CC)C>[Br:18][CH2:19][CH2:20][C:21]([N:9]1[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][CH2:10]1)=[O:22]
Reactant: c1ccc(C2CNCO2)cc1
Reactant: O=C(Cl)CCBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCBr)N1COC(c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Four and five tenths (4.5) grams of 5-phenyl oxazolidine contained in 44.7 g. of benzene solution was mixed with 3.1 g. of triethylamine and stirred in a room temperature water bath, while 5.2 g. of 3-bromopropionyl chloride was added dropwise. After standing for about 30 minutes, the solution was washed with water, separated, dried over magnesium sulfate and the solvent stripped under vacuum. There was obtained a yield of 6 g. of an oil, the title compound, ND30 =1.5591.
Reaction SMILES: CC([O-])=O.[NH4+].[BH3-][C:7]#[N:8].[Na+].[Br:10][C:11]1[C:12]2[CH2:19][CH2:18]C(=O)[C:13]=2[CH:14]=[N:15][CH:16]=1>CCO>[Br:10][C:11]1[C:12]2[CH2:19][CH2:18][CH:7]([NH2:8])[C:13]=2[CH:14]=[N:15][CH:16]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCc2c(Br)cncc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: NC1CCc2c(Br)cncc21
Reaction time: 0.07 h
Yield: 90.5 %

Procedure:
CH3COONH4 (4.8 g, 62 mmol), NaCNBH3 (315 mg, 5 mmol) and 4-bromo-5H-cyclopenta[c]pyridin-7(6H)-one (1.0 g, 4.15 mmol) in EtOH (10 mL) was added to a sealed microwave vial. The mixture was subject to microwave radiation at 130° C. for 4 min. After the majority of EtOH was evaporated under reduced pressure, it was treated with aq. 2 N NaOH until pH>10 and extracted with EtOAc (50 mL x2). The combined organic layers were dried over anhy. Na2SO4, filtered, and concentrated under reduced pressure to give a crude title product (800 mg) which was used in the next step reaction without further purification. MS: 212.9 (M+H+, 1Br).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([CH3:28])=[CH2:27])[CH:23]=[CH:22][C:21]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([CH:26]([CH3:27])[CH3:28])[CH:23]=[CH:22][C:21]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C=C(C)c1ccc(-c2cc(C(C)C)c(F)cc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Solvent: CO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(C)C)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′-fluoro-4-isopropenyl-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (15 mg, 0.025 mmol) in methanol (1 mL) was subject to H2 (ballon atmosphere) at 20° C. overnight. The crude mixture was filtered through a syringe filter. The filtrate was evaporated in vacuo and purified by preparative TLC plates developed by 20% EtOAc in hexanes to give the titled compound. LC-MS: 612 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 7.84 (s, 1H), 7.64-7.68 (m, 2H), 7.30 (s, 0.5), 7.20-7.27 (m, 1.5H), 7.13-7.17 (m, 1H), 7.02 (d, J=8.5 Hz, 0.5H), 6.99 (d, J=8.0 Hz, 0.5H), 6.65 (d, J=6.0 Hz, 0.5H), 6.63 (d, J=6.0 Hz, 0.5H), 5.52 (d, J=8.0 Hz, 0.5H), 5.25 (d, J=8.0 Hz, 1H), 4.87 (d, J=15.5 Hz, 0.5H), 4.82 (d, J=15.5 Hz, 0.5H), 4.03 (d, J=15.0 Hz, 0.5H), 3.81 (d, J=15.0 Hz, 0.5H), 3.69-3.77 (m, 4H), 3.14-3.24 (m, 1H), 2.92-3.02 (m, 1H), 1.14-1.33 (m, 12H), 0.48 (d, J=6.5 Hz, 1.5H), 0.30 (d, J=7.0 Hz, 1.5H).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O:13]/[C:14](/[CH3:21])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>P(=O)(O)(O)O.C(O)C>[C:14]([CH:15]([CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:1])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:21]
Reactant: CCOC(=O)/C=C(/C)OCC
Reactant: OCC=Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: CCO
Product: C=CC(c1ccccc1)C(C(C)=O)C(=O)OCC
Temperature: 150 °C
Yield: 85.4 %

Procedure:
The starting material was prepared as follows. To a mixture of 4.02 g of cinnamyl alcohol and 6.6 g of ethyl β-ethoxycrotonate was added 10 mg of phosphoric acid. The resulting mixture was heated to a temperature of 150° C. over a period of about 40 minutes and then heated at 150° C. for 4 hours with stirring while the ethanol formed during the reaction was distilled off. Thereafter, the reaction mixture was distilled to give 6.3 g (81% yield) of ethyl 2-acetyl-3-phenyl-4-pentenoate, boiling point 170°-174° C./20 mmHg.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:8]3=2)[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22]COC(C)=O>>[CH3:22][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:8]3=2)[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1cc2ccc3oc4ccccc4c3c2[nH]1
Product: CCOC(=O)c1cc2ccc3oc4ccccc4c3c2n1C
Yield: 86.3 %

Procedure:
Using the procedure outlined in Example 34A, ethyl 1H-benzofuro[2,3-g]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 86.3% yield of ethyl 1-methyl-1H-benzofuro[2,3-g]indole-2-carboxylate, mp 114°-116°, (EtOAc), (C,H,N).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[C:17]([O:19]C)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)/C=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(/C=C/C(=O)O)cc1OC1CCCC1

Procedure:
To a stirring solution of 0.8 g (2.9 mmol) of methyl 3-(3-cyclopentoxy-4-methoxyphenyl)-E-propenoate in 20 mL of methanol was added dropwise 25 mL of a 1.0N solution of potassium hydroxide in water over a 5 minute period. The mixture precipitated immediately, but returned to a solution after a 16-hour period at which time the solution was concentrated, diluted with 20 mL of water and neutralized to pH 1.0 with concentrated hydrochloric acid. The analytically pure white solid which formed was collected, washed several times with cold water, and dried in vacuo.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[C:16]3[NH:23][C:24]([NH:26][C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)=[O:25])[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CC(O)C>[N:28]1[CH:29]=[CH:30][N:31]=[CH:32][C:27]=1[NH:26][C:24]([NH:23][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)[CH:14]=2)[N:19]=[CH:18][CH:17]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3nccc(NC(=O)Nc4cnccn4)c3c2)C1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(Nc1cnccn1)Nc1ccnc2ccc(C3CCNC3)cc12
Temperature: 25 °C
Yield: 124.6 %

Procedure:
To a solution of 50 mg of tert-butyl-3-[4-(3-pyrazin-2-yl-ureido)-quinolin-6-yl]-pyrrolidine-1-carboxylate (example 43) (0.120 mmol) in 5 ml of DCM was added 1 ml of 6M HCl solution in propanol-2 with stirring at room temperature. After reaction over night the solvent and excess HCl was removed in vacuum, and the residue was co-distilled at least three times with propanol-2. 50 mg of the desired product were obtained as powder as the di-hydrochloride salt (yield: quant.).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH2:8].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>C(O)C>[CH3:1][NH:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH:8][CH2:24][CH2:23][C:22]([O:26][CH3:27])=[O:25]
Reactant: C=CC(=O)OC
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NCCC(=O)OC
Temperature: 70 °C

Procedure:
A solution of L-leucyl-L-phenylalanine N-methylamide (1.09 g) in ethanol (20 ml) was treated with methyl acrylate (0.33 ml). The resulting colourless solution was heated to 70° C. over 7.5 h. The crude product was purified by flash silica chromatography, eluting with ethyl acetate/methanol (9:1) to provide the title compound was isolated as a white solid (0.482 g).