Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([OH:9])[C:6]([OH:8])=[O:7].C.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([O:9][CH:5]([CH2:4][CH2:3][S:2][CH3:1])[C:6]([OH:8])=[O:7])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CSCCC(O)C(=O)O
Solvent: CCN(CC)CC
Product: CSCCC(OC(C)=O)C(=O)O
Temperature: 0 °C
Yield: 63.1 %

Procedure:
To a solution of 2-hydroxy-4-(methylthio)butanoic acid (50.74 g, 337.8 mmol, obtained by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap) in dichloromethane (1 L) was added triethylamine (93 mL, 667.3 mmol) and the resulting mixture was cooled to 0° C. To the cooled mixture was added acetyl chloride (26 mL, 365.6 mmol) dropwise. The ice bath was removed and the reaction was allowed to warm to room temperature overnight. The reaction was washed with 1N HCl (2×300 mL), and brine (1×300 mL), dried over magnesium sulfate, filtered and evaporated to give an amber oil (59.82 g, 63.1%). m/z 193 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH3:11][C:12]1([CH3:19])[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:18][C:14]2[O:13][C:12]([CH3:19])([CH3:11])[C:16](=[O:17])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccc(Cl)c(Cl)c2)=CC1=O
Temperature: 60 °C
Yield: 56.4 %

Procedure:
To a solution of 3,4-dichlorobenzaldehyde (2.3 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 60° C. for 4 hours. After the reaction solution cooled, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The crude product was purified by chromatography (silica gel, pet. ether/ethyl acetate) to afford a light yellow solid (2.1 g, 56% yield), m.p. 100°-102° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][C:33](=[O:35])[CH3:34])[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][C:33](=[O:35])[CH3:34])[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1
Reactant: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)C(=O)O
Reaction time: 0.33 h
Yield: 57.6 %

Procedure:
To a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine (14.9 g) in ethyl acetate (150 ml) was added dropwise 4N HCl in ethyl acetate (74.8 ml) for 10 minutes at 0° C. After the mixture was stirred for 1 hour and 20 minutes, a white solid was collected by filtration, and dried in vacuo. The powder was dissolved in water (150 ml), and the solution was neutralized to pH 6.5 with saturated aqueous NaHCO3. The solution was concentrated to about 100 ml, then applied to ODS column (Disogel-120SP®, 1 l), and eluted with 4-6% CH3CN/water. The eluent was concentrated in vacuo, and the residue was dissolved 0.5% aqueous ethanol (200 ml). After the mixture was stirred at room temperature overnight, the resultant solid was collected by filtration, and dried in vacuo to give N-[(R)-1-[3-(4-piperidyl)propionyl]-3-piperidylcarbonyl]-2-(S)-acetylamino-β-alanine (6.85 g) as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:22])[NH:11][CH:12]([CH2:15][CH:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)[C:13]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[CH2:29]([O:14][C:13]1[CH:12]([CH2:15][CH:16]2[CH2:17][CH2:18][S:19][CH2:20][CH2:21]2)[NH:11][C:10](=[O:22])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(C)c(C2=C(O)C(CC3CCSCC3)NC2=O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C)c(C2=C(OCc3ccccc3)C(CC3CCSCC3)NC2=O)c1

Procedure:
A solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-5-(tetrahydro-thiopyran-4-ylmethyl)-1,5-dihydro-pyrrol-2-one (compound P2.5) (1.0 g, 3.15 mmol), potassium carbonate (0.87 g, 6.3 mmol) and benzyl bromide (0.81 g, 4.7 mmol) in 10 ml of acetone was refluxed for 2 h. Then, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel. Yield: 640 mg of 4-benzyloxy-3-(2,5-dimethyl-phenyl)-5-(tetrahydro-thiopyran-4-ylmethyl)-1,5-dihydro-pyrrol-2-one as a solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:30])([CH2:27][CH2:28][OH:29])[CH2:25][OH:26])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:30])([CH2:25][O:26][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:27][CH2:28][O:29][S:40]([CH3:39])(=[O:42])=[O:41])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CO)CCO)cc2OCC3)n(C(C)C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CCOS(C)(=O)=O)COS(C)(=O)=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylbutane-1,4-diol (14 mg, 0.0318 mmol) and Et3N (13 uL, 0.095 mmol) in DCM (2 mL) at 0° C. was added methanesulfonyl chloride (6.0 uL, 0.080 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording Methanesulfonic acid 3-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-4-methanesulfonyloxy-3-methylbutyl ester as a colorless gum (23 mg, quantitative). LCMS: RT 2.99 min [M+H]+ 584.1
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:7]2.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O>[C:19]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[CH:8]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:7]3)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1c2c(Cl)cccc2CC1CC1CCCCC1
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: O=C1c2c(cccc2-c2cccc3ccccc23)CC1CC1CCCCC1
Temperature: 125 °C
Yield: 96.2 %

Procedure:
18.5 g (70.4 mmole) 7-Chloro-2-cyclohexylmethyl-indan-1-one, 14.5 g (1.2 eq.) naphthyl boronic acid, 16.4 g sodium carbonate, 230 ml ethylene glycol and 45 ml water were placed in a 1 l-roundbottom flask equipped with a mechanical stirrer and a reflux condenser. The mixture was degassed three times by slight evacuation and recharging with argon. A premixed catalyst solution consisting of 32 mg (0.2 mole %) palladium acetate, 0.94 ml NaTPPTS (2.6 M in water, 0.8 mole %) and 3 ml of water was added and the mixture was refluxed at 125° C. until complete conversion (approx. 5 h). 100 ml of water were added and the mixture was extracted three times with 100 ml of toluene each. The combined organic layers were washed twice with 100 ml water and once with 100 ml of a saturated sodium chloride solution. Drying over magnesium sulphate and evaporation of the solvent in vacuo yielded 24 g (96%) of the desired product as a yellow sticky oil. 1H-NMR (400 MHz, CDCl3): δ=7.86 (d, 2 h, aromatic), 7.63 (m, 1H, aromatic), 7.52 (m, 2H, aromatic), 7.43 (m, 2H, aromatic), 7.33 (m, 3H, aromatic), 2.39 (m, 1H, (C═O)CH), 2.85, 2.67 (2×m, 2H, benzylic), 1.90-0.80 (m, 13H, aliphatic) ppm.
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[N:17][C:2]([O:27][C:24]2[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[CH:22][CH:23]=2)=[C:3]([CH:14]=1)[C:4]([NH:6][C:7]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1(CO)CCCC1)c1cc(F)cnc1Cl
Reactant: CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ncc(F)cc2C(=O)NC2(CO)CCCC2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
2-Chloro-5-fluoro-N-(1-hydroxymethyl-1-cyclopentyl)-nicotinamide (100 mg, 0.367 mmol), 4-methylsulfanyl phenol (51 mg, 0.367 mmol) and caesium carbonate (131 mg, 0.403 mmol) were suspended in DMF (1.5 ml) and the reaction was heated to 50° C. and stirred at this temperature under nitrogen for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was removed and washed with brine (25 ml) followed by water (25 ml). The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 95:5, by volume) to give 5-Fluoro-N-(1-hydroxymethyl-cyclopentyl)-2-(4-methylsulfanyl-phenoxy)-nicotinamide (27 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28]CC)=[CH2:27])=[CH:22][C:21]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][C:21]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: C=C(OCC)c1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)c(OCC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(C)=O)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reaction time: 1 h

Procedure:
An aqueous solution of hydrochloric acid (2 M, 18 mL) was sparged for 10 min with nitrogen and then used to slurry 4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-ethoxyvinyl)phenyl]-4,5-dihydro-1H-imidazole (0.638 g, 1.33 mmol). Tetrahydrofuran (18 mL) was added to create a homogeneous solution. After stirring 1 h, the reaction mixture was poured into a mixture of 2 M sodium hydroxide (16 mL) and 10% sodium carbonate solution (50 mL) and extracted with methylene chloride (2×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1-3% methanol in chloroform) to give 1-{4-[4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}ethanone as a faintly yellow foam (0.392 g, 65%). LC-MS: 453.3 [(M+H)+].
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:13])[CH2:8][CH2:7]1)C.[Li+].[OH-]>C1COCC1.O>[Cl:40][C:36]1[C:35]([F:41])=[C:34]([C@@H:15]2[C@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:18][N:14]2[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:42])=[O:3])[CH2:11][CH2:10]2)=[O:13])[CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)CC1CCN(C(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)N2CCC(CC(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.9 %

Procedure:
To a mixture of rac-{1-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-piperidin-4-yl}-acetic acid ethyl ester (33.0 mg, 0.053 mmol) in THF (3 mL) was added a solution of LiOH (Aldrich, 15.7 mg, 0.374 mmol) in water (1.5 mL) and the reaction mixture was stirred at rt for 24 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 6-7), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-{1-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-piperidin-4-yl}-acetic acid (29.5 mg, 93.6%). HRMS (ES+) m/z Calcd for C30H33Cl2F2N3O3+H [(M+H)+]: 592.1940; Found: 592.1940.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N.O>ClCCl>[Br:23][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 47.5 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(4-methylphenyl)benzonitrile [MPB] 23 g, NBS 22 g and 2,2′-azobis(2,4-dimethylvaleronitrile) 47 mg was suspended in dichloromethane 44 ml and the mixture was stirred at 45-50° C. for about 5 hours. To the reaction mixture was added water 46 ml and the organic layer was separated. This operation was conducted three times. The organic layer was concentrated and acetonitrile 50 ml was added to the concentrate. The solution was again concentrated and acetonitrile 50 ml was added to the concentrate to give acetonitrile solution of 2-(4-bromomethylphenyl)benzonitrile [BMB] (116 g; Yield based on the theoretical amount of (2-(4-bromomethylphenyl)benzonitrile: 84%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:27][CH3:28])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.CO>[ClH:38].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:27][CH3:28])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:46])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2CC)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2CC)c1ccccn1
Yield: 85 %

Procedure:
Prepared analogously to Example 25d from 1-ethyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 85% of theory, C28H31N7O3 (513.6) Rf value: 0.21 (silica gel; dichloromethane/methanol=5:1) ##EQU55##
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Br:13])[CH:3]=1.C([N:22]=[C:23]=[S:24])(=O)C1C=CC=CC=1.[OH-].[Na+].[NH4+].[Cl-]>C1COCC1>[Br:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[C:2]([NH:1][C:23]([NH2:22])=[S:24])[NH:6][N:5]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(-c2ccccc2Br)n[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(-c2ccccc2Br)n[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 5-amino-3-(2-bromophenyl)pyrazole (1.3 g, 5.46 mmol) in THF (20 mL) was added dropwise benzoyl isothiocyanate (0.81 mL, 6.0 mmol). The reaction mixture was stirred at room temperature for 3 hours, then 4 N aqueous solution of NaOH (4 mL) was added, and the reaction mixture was further stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, neutralized to pH 7 with a saturated solution of NH4Cl, and extracted with EtOAc (3×). The combined organic layers were directly purified on silica gel with 0-10% MeOH in CH2Cl2 as eluent to provide 1.62 g (quant.) of [5-(2-bromo-phenyl)-2H-pyrazol-3-yl]-thiourea as a yellowish foam. 1H-NMR (d6-DMSO) δ: 12.8 (broad s, 1H), 10.4 (broad s, 1H), 8.99 (broad s, 1H), 8.52 (broad s, 1H), 7.76 (d, 1H), 7.50 (m, 2H), 7.36 (t, 1H), 6.24 (broad s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH:15]2[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][CH:14]12)#[CH:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.O>[CH3:27][N:24]1[CH2:25][CH2:26][C:14]2[N:13]([C:11]#[C:12][C:2]3[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=3)[N:8]([CH3:10])[CH3:9])[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: CN(C)c1cccc(Br)c1
Reactant: C#CN1c2ccc(C)cc2C2CN(C)CCC21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2cccc(N(C)C)c2)CCN(C)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
(3-Bromo-phenyl)-dimethylamine (100 mg, 0.5 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido[4,3-b]indole (123 mg, 0.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (17 mg, 0.25 mmol) and TBAF.3H2O (275 mg, 1.5 mmol) were mixed and stirred at 80° C. for 30 min under nitrogen. The progress of reaction was monitored by TLC and LCMS. The mixture was cooled to RT, water was added, and extracted with EtOAc. The organic layer was washed with water (1×10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using silica gel (100-200 mesh), neutralizing the silica gel with aq. Ammonia, and using 0-2% MeOH:DCM as eluent. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.50 (d, 1H), 7.30 (m, 1H), 7.18 (d, 2H), 7.05 (d, 2H), 6.90 (m, 1H), 4.78 (m, 1H), 4.10 (m, 1H), 3.90 (m, 1H), 3.40 (m, 2H), 3.20 (m, 1H), 3.0 (s, 9H), 2.42 (s, 3H),
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[C:13]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:20][C:16]=1[C:17](Cl)=[O:18])#[N:14].O>CN(C)C=O>[C:13]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:20][C:16]=1[C:17]([N:8]1[C:9](=[O:10])[C:4]2=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=[C:5]2[C:6]1=[O:7])=[O:18])#[N:14]
Reactant: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)Cl
Reactant: O=C1NC(=O)c2cc(Cl)ccc21
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)N1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of 4-chlorophthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-cyano-5-(2,4-dichlorophenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-cyano-5-(2,4-dichlorophenoxy)benzoyl]-4-chlorophthalimide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH:23]3[CH2:25][CH2:24]3)(=[O:22])=[O:21])=[C:16]([F:26])[C:15]=2[F:27])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[CH:23]1([S:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[C:15]([F:27])[C:16]=2[F:26])(=[O:21])=[O:22])[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(S(=O)(=O)C3CC3)c(F)c2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(N2CCNCC2)c(F)c1F)C1CC1
Temperature: 80 °C

Procedure:
To 3.7 mmol 4-(4-Cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 100 ml dioxane was added 14.9 mmol HCl (as a 4 M solution in dioxane), and the mixture was heated at 80° C. for 1 h. The mixture was then cooled to room temperature, and the ensuing white crystals were collected by filtration, washing twice with ether, to afford the title compound. MS (m/e): 303.2 (M+H+, 100%)
Reaction SMILES: [C:1]([C:3]1[C:8]([OH:9])=[C:7]([N+:10]([O-])=O)[CH:6]=[CH:5][CH:4]=1)#[N:2].[Sn](Cl)Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:10][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[C:8]=1[OH:9]
Reactant: N#Cc1cccc([N+](=O)[O-])c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#Cc1cccc(N)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 272.1 %

Procedure:
A mixture of 6-cyano-2-nitrophenol(600 mg, 1.0 mmol) and tin (II) chloride (3.2 g, 14.4 mmol) in acetic acid(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(365 mg, 75%). 1H NMR (CD3OD): δ 6.92 (d, 1H), 6.85-6.69 (m,2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][O:11][P:12](=[O:39])([OH:38])[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>N1CCCCC1>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][P:12]([O:11][CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])([OH:39])=[O:38]
Reactant: CC(C)(C)OC(=O)NC(COP(=O)(O)OCCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NC(COP(=O)(O)OCCCCCCN)C(=O)OC(C)(C)C

Procedure:
3 g of tert-butyl 15-[(tert-butoxycarbonyl)amino]-1-(9H-fluoren-9-yl)-12-hydroxy-3-oxo-2,11,13-trioxa-4-aza-12-phosphahexadecan-16-oate 12-oxide are stirred in 0.62 ml of piperidine and 3 ml of water for 12 hours at ambient temperature. The reaction medium is filtered and the crystals obtained are washed twice with 50 ml of acetonitrile and then recrystallized from 100 ml of acetonitrile.