Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH2:14][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:12][C:11]2=[O:21])=[CH:6][C:5]=1[CH:22]=[C:23]([Cl:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O.[CH2:31]([OH:33])[CH3:32]>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:21])[CH2:12][CH:13]([C:17]([F:19])([F:20])[F:18])[CH2:14][C:15]([O:33][CH2:31][CH3:32])=[O:16])=[CH:6][C:5]=1[CH:22]=[C:23]([Cl:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(Cl)=Cc1cc(N2C(=O)CC(C(F)(F)F)CC2=O)ccc1Cl
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(CC(=O)Nc1ccc(Cl)c(C=C(Cl)C(=O)OCC)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
0.13 g (34 mmol) of sodium borohydride was added in portions at room temperature to a solution of 4.2 g (10 mmol) of N-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)phenyl]-3-trifluoromethylglutarimide in 100 ml of ethanol. After stirring for 3 hours the reaction mixture was added to 100 ml of water, after which the aqueous phase was extracted twice with dichloromethane. The combined org. phases were dried over sodium sulfate and concentrated. Finally, the residue was purified by triturating with petroleum ether. Yield: 2 g (42%); m.p.: 115°-117° C.
Reaction SMILES: [I-].[K+].CS(O[CH2:8][CH2:9][O:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:23]([F:35])[CH:22]=2)[NH:13][N:12]=1)(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[CH2:41][OH:42]>>[F:35][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([O:10][CH2:9][CH2:8][N:36]4[CH2:40][CH2:39][CH2:38][C@@H:37]4[CH2:41][OH:42])[C:19]=23)[CH:26]=[CH:25][C:24]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCOS(C)(=O)=O)c34)cc2F)cn1
Reactant: OC[C@H]1CCCN1
Agent: [I-]
Agent: [K+]
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC[C@@H]5CO)c34)cc2F)cn1
Yield: 30 %

Procedure:
The procedure described in Example 23 was repeated (except that potassium iodide was not used) using 2-{[4-({3-fluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate (prepared as described in Example 20) and (R)-2-pyrrolidinemethanol to give the title compound in 30% yield; NMR Spectrum: 1.51 (m, 1H), 1.65 (m, 2H), 1.80 (m, 1H), 2.33 (q, 1H), 2.45 (s, 3H), 2.57 (m, 1H), 2.78 (dt, 1H), 3.14 (t, 1H), 3.28 (hidden by DMSO, 2H), 4.41 (t, 2H), 4.47 (br s, 1H), 7.25 (m, 3H), 7.56 (d, 1H), 7.85 (td, 1H), 8.01 (dd, 1H), 8.24 (d, 1H), 8.37 (s, 1H), 8.59 (br s, 1H); Mass Spectrum: 480 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)[CH:3]1[CH2:6][O:5][CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:13][N:12]1[C:8]([CH2:7][N:2]([CH3:1])[CH:3]2[CH2:4][O:5][CH2:6]2)=[CH:9][C:10]([NH2:14])=[N:11]1
Reactant: CN(Cc1cc([N+](=O)[O-])nn1C)C1COC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(Cc1cc(N)nn1C)C1COC1
Temperature: 70 °C
Yield: 83.2 %

Procedure:
To a solution of 320b (1.8 g, 7.96 mmol) in ethanol (20 mL) and water (20 mL), NH4Cl (3.3 g, 63.6 mmol) and iron powder (1.80 g, 31.8 mmol) were added. The reaction mixture was heated at 70° C. for 2 h. After that, the mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue was extracted with methylene chloride (30 mL×3), dried Na2SO4, and concentrated to afford the crude product, which was purified on flash column eluting with 50:1 methylene chloride/methanol containing 0.5% triethylamine to afford 320c as a yellow oil (1.3 g, 83%). LCMS: (M+H)+ 197
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([C:12]2[CH:16]=[C:15]([NH2:17])[NH:14][N:13]=2)[CH2:11][CH2:10]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:15]2[CH:16]=[C:12]([CH:9]3[CH2:11][CH2:10]3)[NH:13][N:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Product: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
The mixture of 2,4-dichloropyrimidine (2.0 g, 13.5 mmol, 1.0 equiv.), EtOH (6 mL) and 3-cyclopropyl-1H-pyrazol-5-amine (20.3 g, 20.3 mmol, 1.5 equiv.) was stirred at room temperature for 8 h. The reaction mixture was filtered to afford compound 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1.4 g, 45%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13](O)[CH3:14])[CH:5]=[C:6]([Br:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10].S([O-])(O)(=O)=O.[K+].C(C1C=C(O)C=CC=1O)(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10])[CH:13]=[CH2:14]
Reactant: CC(=O)Oc1c(Br)cc(C(C)O)cc1Br
Agent: CC(C)(C)c1cc(O)ccc1O
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=Cc1cc(Br)c(OC(C)=O)c(Br)c1

Procedure:
A mixture of 67.6 g (0.02 mole) 1-(3',5'-dibromo-4'-acetoxyphenyl)ethanol, 0.35 g freshly melted and then finely pulverized potassium hydrogen sulfate, and 0.5 g t-butylhydroquinone are heated at 20 Torr to 170°-190° C. The resulting product is distilled off (under vacuum) at a temperature of 140° to 160° C. It is taken up in ether, the ether solution is washed with Na2CO3, dried, and concentrated under vacuum. The remaining product is distilled at 0.02 mbar; the boiling point is 116° C. The isolated product, which is a highly viscous oil or a white, waxy solid, has a melting point of approximately 75° C. The reaction yield is 27 g.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:22]=[N:21][C:7]2[N:8]([CH2:19][CH3:20])[C:9]3[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1.O.[CH3:24]N(C=O)C>>[Br:3][C:4]1[CH:22]=[N:21][C:7]2[N:8]([CH2:19][CH3:20])[C:9]3[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=3[N:11]([CH3:24])[C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: CCN1c2nc(Cl)ccc2NC(=O)c2cc(Br)cnc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Solid NaH (60% oil dispersion, 3.46 g, 86.1 mmol) was added over 30 min to a solution of 8-bromo-2-chloro-5,11-dihydro-11-ethyl-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (23.4 g, 66.3 mmol) in DMF (220 mL) at 50° C. The mixture was stirred at 50° C. for 1 h then was allow to cool to room temperature. The mixture was poured into water (1 L) and the resulting suspension was filtered. The solid was successively washed with water and hexane then dried under reduced pressure to give the title compound (23.0 g, 94% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:13])=[N:3]1.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:14][N:15]([CH3:16])[C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:13])[C:5]=1[N+:10]([O-:12])=[O:11])=[O:8]
Reactant: CNC
Reactant: Cc1nn(C)c(C(=O)Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1nn(C)c(C(=O)N(C)C)c1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
A solution of 40 g of 1,3-dimethyl-4-nitropyrazole--5-carboxylic acid chloride in 50 ml of methylene chloride is added dropwise at from 10° to 20° C., while cooling, to 43 g of a 40% strength aqueous solution of dimethylamine; stirring is continued for a further 20 minutes. The resulting mixture is rendered alkaline with potassium carbonate; the organic layer is separated off, and the aqueous phase is extracted by shaking it with methylene chloride. The organic solution is dried and concentrated, and the residue is triturated with petroleum ether (bp 40° to 70° C.) to yield 38.3 g of N,N,1,3-tetramethyl-4-nitropyrazole-5-carboxamide, mp 57° to 59.5° C., which is converted into a product of mp 114° to 115.5° C. on recrystallization from cyclohexane.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8]CC)=[O:7])[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[OH-].[K+]>CC(C)=O.CCO>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:2]2[CH:3]=[C:4]([C:6]([OH:8])=[O:7])[CH:5]=[N:1]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Temperature: 50 °C

Procedure:
A mixture of ethyl 1H-pyrazole-4-carboxylate (400 mg, 2.85 mmol), K2CO3 (1.97 g, 14.3 mmol) and 4-methoxybenzyl bromide (0.453 ml, 3.14 mmol) in dry acetone (10 ml) was heated to 50° C. for 3 h. The reaction mixture was filtered, and the filtrate was concentrated. EtOH (10 mL) and KOH (320 mg, 5.71 mmol) were added and the mixture was heated to 65° C. for 6 h, before it was concentrated again. The crude product was dissolved in water (5 ml), washed with EA (2×10 ml) and acidified with 1N HCl. The resulting precipitate was collected by filtration, washed with water and dried in vacuo affording the title compound. LCMS RtL=0.86 min, [M+H]+=233.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:37]=[CH:36][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:29])[CH2:11]2)=[CH:6][CH:5]=1.[N+:38]([C:41]1[CH:53]=[CH:52][C:44]([CH2:45][O:46][C:47]([NH:49][CH:50]=N)=[O:48])=[CH:43][CH:42]=1)([O-:40])=[O:39]>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:35][CH2:34][N:33]([CH:50]=[N:49][C:47]([O:46][CH2:45][C:44]4[CH:52]=[CH:53][C:41]([N+:38]([O-:40])=[O:39])=[CH:42][CH:43]=4)=[O:48])[CH2:32][CH2:31]3)=[O:29])[CH2:11]2)=[CH:36][CH:37]=1
Reactant: N=CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCNCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 2 h
Yield: 76 %

Procedure:
A suspension of 5.51 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in Preparation 1(ii)] and 2.45 g of N-(4-nitrobenzyloxycarbonyl)formamidine in 10 ml of dry acetonitrile was stirred for 2 hours on a water-bath kept at 50° C. At the end of this time, the reaction mixture was freed from impurities by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 6:4 by volume mixture of ethyl acetate and acetonitrile as the eluent, to give 5.48 g of the title compound, as a powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[Ba+2:34].[OH-]>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ba:34]
Reactant: [Ba+2]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [OH-]
Solvent: CC#N
Product: [Ba]
Temperature: 62.5 °C
Reaction time: 18 h

Procedure:
Raltegravir (100 gm) was suspended in acetonitrile (400 ml) and then added barium hydroxide (42 gm) at 25 to 30° C. The contents were heated to 60 to 65° C. to obtain a solution. The solution was cooled to 25 to 30° C. and stirred for 18 hours at 25 to 30° C. The solid obtained was collected by filtration and dried to obtain 105 gm of raltegravir barium.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[O:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=3[F:36])[CH:18]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][Cl:16].[NH4+].[Cl-]>CO.O.C(OCC)(=O)C.[Fe]>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[O:26][C:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=3[F:36])[CH:18]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][Cl:16]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(OCCCCl)c(OCCCCl)c4)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCCCl)c(OCCCCl)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 8.4 %

Procedure:
To a stirred suspension of nitro compound 333 (32 mg, 0.57 mmol) in a mixture of MeOH (2 mL) and water (1 mL) were added iron powder (16 mg, 0.29 mmol) and NH4Cl (2.8 mg, 0.05 mmol). The reaction mixture was heated to reflux for 2.5 hrs, cooled to room temperature, diluted with ethyl acetate, filtered, and rinsed with AcOEt. The filtrate was successively washed with sat. ammonium chloride, sat. NaHCO3, water, dried over anhydrous MgSO4, filtered, and concentrated to afford title compound 334 (25 mg, 83% yield) as a pale yellow solid. MS (m/z): 521.0 and 523.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH2:10][NH:11][C:12](=[O:29])[C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC1C(O[C:46](=[O:64])[C@H:47]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([OH:63])=[CH:59][CH:58]=2)[NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=C(Cl)C(Cl)=C(Cl)C=1Cl>C(OCC)(=O)C.Cl>[CH2:1]([O:8][C:9](=[O:30])[CH2:10][NH:11][C:12](=[O:29])[C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:14][C:46](=[O:64])[C@H:47]([CH2:56][C:57]1[CH:58]=[CH:59][C:60]([OH:63])=[CH:61][CH:62]=1)[NH:48][C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
18.55 g (45 mmoles) of the protected dipeptide ester obtained in Step 1 above are dissolved in 60 ml of ethyl acetate containing 11-15% of hydrochloric acid. After 0.5 hours of standing the solution is evaporated, and the residue is dried in a vacuum desiccator above potassium hydroxide. The resulting substance, Rf3 =0.4-0.5, is dissolved in 40 ml of dimethyl formamide, and 5.0 ml (45 mmoles) of N-methylmorpholine and 26.2 g (49.5 mmoles) of tert.-butoxycarbonyl-L-tyrosine pentachlorophenyl ester are added. The reaction mixture is stirred for 16-20 hours. During the first two hours 5.5 ml (49.5 mmoles) of N-methylmorpholine are added to the mixture in five portions. The reaction mixture is evaporated under reduced pressure, the residue is dissolved in a mixture of 300 ml of ethyl acetate and 50 ml of water, the ethyl acetate phase is separated, washed twice with 50 ml of 1 n aqueous hydrochloric acid cooled with ice water and then twice with 50 ml of water, each, dried over sodium sulfate, decolourized with carbon, filtered, and the filtrate is evaporated under reduced pressure. The crystalline residue is suspended in diisopropyl ether, the solid is filtered off, washed with diisopropyl ether, and dried in a vacuum desiccator. 23.5 g (90.8%) of tert.-butoxycarbonyl-L-tyrosyl-D-phenylalanyl-glycine benzyl ester are obtained; m.p.: 169° C., Rf10 =0.45-0.55, [α]D20 +16.3° (c=1%, in dimethyl formamide).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15]CC)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].IC>CS(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH3:15])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCCSc1cc2c(cc1Br)N(C(C)=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: CSc1cc2c(cc1Br)N(C(C)=O)CC2
Yield: 92.1 %

Procedure:
The thiol (D79) (0.35 g, 1.29 mmol) was treated with K2CO3 (0.20 g, 1.45 mmol) and iodomethane (0.24 ml, 3.85 mmol) in DMSO (15 ml) at 50° C. as in the method of Description 80 to afford the title compound (0.34 g, 92%) as an off-white solid.
Reaction SMILES: [NH:1]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][C:11](O)=O)[N:6]=1)[C:2]([NH2:4])=[S:3].BrC[C:16]([O:18]C(C)(C)C)=[O:17].C(OC(=O)CCBr)(C)(C)C>>[NH:1]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][CH2:11][C:16]([OH:18])=[O:17])[N:6]=1)[C:2]([NH2:4])=[S:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=S)Nc1ccn(CC(=O)O)n1
Agent: CC(C)(C)OC(=O)CCBr
Product: NC(=S)Nc1ccn(CCC(=O)O)n1

Procedure:
This material is prepared by an analogous procedure to (3-thioureido-pyrazol-1-yl)-acetic acid (intermediate DD) by replacing tert-butyl bromoacetate in step 2 with 3-bromo-propionic acid tert-butyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:35]([O:37][C:38]([CH3:44])([CH3:43])[C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36]>>[Cl:40][C:39]([Cl:42])([Cl:41])[C:38]([O:37][C:35]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:36])([CH3:44])[CH3:43]
Reactant: CC(C)(OC(=O)Cl)C(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1)C(Cl)(Cl)Cl

Procedure:
4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2,2,2-trichloro-1,1-dimethyl-ethyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 2,2,2-trichloro-1,1-dimethylethyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.87-1.89 (m, 6H), 2.02-2.08 (m, 4H), 3.00-3.10 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.10-4.16 (m, 2H), 5.05-5.09 (m, 1H), 7.62-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.40 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=576.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]([F:20])([F:19])[F:18])=[C:13]([CH:16]=1)[C:14]#[N:15].[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:24][CH2:25][C:26]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]([F:18])([F:19])[F:20])=[C:13]([C:14]#[N:15])[CH:16]=1)=[O:27])(=[O:23])[CH3:22]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#Cc1cc(N)ccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc(C(F)(F)F)c(C#N)c1
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
Triethylamine (1.09 g, 10.8 mmol) was added to a stirred solution of 5-amino-2-(trifluoromethyl)benzonitrile (Intermediate 37, 1.0 g, 5.37 mmol) in DCM (40 mL), at 0° C., and the mixture was stirred for 15 min. Chloro-2-oxoethyl acetate (1.10 g, 8.06 mmol) was added at 0° C. and the mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with DCM and washed with ice water, and saturated brine solution. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude compound. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% EtOAc/pet.ether to give the title compound (1.1 g).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])[CH:2]=1.C(O)C.[OH-].[K+].Cl>O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])[CH:2]=1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)Sc1ccccc1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc2c(c1)Sc1ccccc1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
the mixture of 26 mg of ethyl 2-(10,11-dihydro dibenzo[b,f]thiepin-3-yl)-propionate, 1 ml of ethanol, 200 mg of potassium hydroxide and 1 ml of water was stirred at room temperature for 1 hour. The solvent was distilled off to obtain the residue, which was acidified with hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 24 ml of 2-(10,11-dihydro dibenzo[b,f]thiepin-3-yl)-propionic acid as pale yellow oil.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([C@H:16]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@H:17]2[CH2:30][CH2:31][CH3:32])[C:12]1=[O:33])C1C=CC=CC=1>CO.[Pd]>[C:26]([O:25][C:23](=[O:24])[NH:22][C@@H:19]1[CH2:20][CH2:21][C@H:16]([N:13]2[CH2:14][CH2:15][C@H:11]([NH2:10])[C:12]2=[O:33])[C@H:17]([CH2:30][CH2:31][CH3:32])[CH2:18]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reaction time: 12 h

Procedure:
A solution of {(3S)-1-[(1S,2R,4R)-4-tert-butoxycarbonylamino-2-propyl-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid benzyl ester (185 mg, 0.54 mmol) in MeOH (8 mL) was charged with 5% Pd/C, Degussa (180 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 1 atm of H2 for 12 h and then filtered and concentrated in vacuo to afford (1R,3R,4S)-{4-[(3S)-3-amino-2-oxo-pyrrolidin-1-yl]-3-propyl-cyclohexyl}-carbamic acid tert-butyl ester. MS found: (M+H)+=340.3.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C=CC=CC=1C=C.Cl[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.P(=O)(O)(O)O>>[CH3:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1]1
Reactant: C=Cc1ccccc1
Reactant: ClCCc1ccccc1
Agent: C=Cc1ccccc1Cl
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: CC1CC(c2ccccc2)c2ccccc21
Reaction time: 1 h

Procedure:
A mixture of 90 parts of styrene, 182 parts of o-chlorostyrene, 118 parts of o-chloroethylbenzene and 0.5 part of phenothiazine is added to 600 parts of 100 per cent strength by weight phosphoric acid at 35° to 40° C over 5 hours. After completion of the addition, the mixture is stirred for one hour at 35° to 40° C. The organic phase is separated off, washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution and fractionated at 10 mm Hg. 19 parts of 1-methyl-3-phenylindan, 120 parts of 1-methyl-3-(o-chloro)-phenylindan (b.p. 165° to 168° C (10 mm), nD25 : 1.5890) and 22 parts of 1-methyl-3-(o-chloro)-phenyl-7-chloroindan (b.p. 195° to 200° C (10 mm)) are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([N:26]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:16]([O:15][CH3:14])[CH:17]=1)[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:8])=[O:5]
Reactant: COC(=O)c1ccc(NNC(=O)OC(C)(C)C)cc1OC
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(Cl)cccc2Cl)cc1OC
Yield: 86.6 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2,6-dichlorobenzoyl isocyanate (1.0 g, 3.38 mmol), tert-butyl 2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (Intermediate-14, 0.805 g, 3.72 mmol) and DCM (20 mL) to afford 1.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.42 (s, 9H), 3.76 (s, 6H), 6.99 (d, J=6.0 Hz, 1H), 7.10 (s, 1H), 7.60-7.37 (m, 3H), 7.67 (d, J=7.8 Hz, 1H), 9.86 (br s, 1H), 11.30 (br s, 1H).