Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:26])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:29](Br)[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>CN(C)C=O>[CH:1]1([NH:7][C:8](=[O:26])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:31])=[CH:21][CH:20]=2)[NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NC1CCCCC1
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCC(=O)c2ccccc2)cc1)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
A mixture of N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine cyclohexylamide (0.68 g) obtained in Example 4, palladium black (0.10 g), cyclohexene (4 ml), and ethanol (20 ml) was allowed to react under reflux of ethanol for one hour, while stirring. After cooling, the solid was filtered off and the filtrate was concentrated under reduced pressure to obtain N-(t-butyloxycarbonyl-4-hydroxy-L-phenylalanine cyclohexylamide (I) (0.54 g). The compound (I) (0.54 g) was dissolved, without purification, in N,N-dimethylformamide (10 ml), followed by adding sodium hydride (0.06 g) thereto. The mixture was stirred at room temperature for 30 minutes. To this solution was added a solution of phenacyl bromide (0.30 g) in N,N-dimethylformamide (5 ml). The reaction was carried out at room temperature for 4 hours, followed by adding ice-water thereto. The resultant oily product was extracted with ethyl acetate. After a conventional post-treatment, N-(t-butyloxycarbonyl)-4-phenacyloxy-L-phenylalanine cyclohexylamide (II) (0.61 g) was obtained. From the compound (II), N-(trans-4-aminomethylcyclohexylcarbonyl)-4-phenacyloxy-L-phenylalanine cyclohexylamide hydrochloride (0.38 g) was obtained, following the procedure of Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]([OH:16])=O.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]([N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1)=[O:16]
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2Cl)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccccc2Cl)s1

Procedure:
prepared by reaction of 5-(2-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1>CN(C)C=O>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][O:6][CH:3]([CH3:5])[CH3:4])=[CH:10][CH:9]=1
Reactant: CC(C)O
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCc1ccc(Br)cc1
Reaction time: 0.42 h
Yield: 85 %

Procedure:
60% Sodium hydride in mineral oil (0.96 g, 24 mmol) was added to a solution of isopropanol (7.59 mL, 36 mmol) in dry N,N-dimethylformamide (30 mL) at 0° to 5° C. under argon atmosphere. After the mixture was stirred for about 25 minutes, 4-bromo-benzyl bromide was added and the mixture stirred at 20° C. for an additional 1 hour. The solution was partitioned between saturated ammonium chloride (50 mL) and diethyl ether (50 mL). The aqueous phase was extracted with diethyl ether (3×20 mL), and the combined organic layers were washed with water, dried (Na2SO4), and evaporated in vacuo. The crude product was filtered over silica gel to give pure 1-bromo-4-isopropoxymethylbenzene (2.33 g, 85%) as clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:32]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33]1.COCCOC>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:34]3[CH:35]=[CH:36][O:32][CH:33]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccoc1
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccoc3)c12
Temperature: 85 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (285 mg, 0.75 mmol) was mixed with K2CO3 (207 mg, 2.2 eq), furan-3-boronic acid (101 mg, 1.2 eq), Pd(Ph3)4 (43 mg, 0.05 eq), 3 mL of 1,2-dimethoxyethane and 0.5 mL of water. The mixture was heated and stirred in a 85° C. oil bath for 2 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography to give 153 mg of 4-furan-3-yl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:7].[NH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(N(CC)CC)C>CO>[F:38][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:10][C@H:9]1[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:7]
Reactant: CS(=O)(=O)OCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: NN1CCOCC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCNN2CCOCC2)C[C@H]1Cc1c[nH]c2ccccc12
Yield: 27.2 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-methylsulfonyloxyethyl)piperazine (200 mg), 4-aminomorpholine (36 mg) and triethylamine (52 mg) in dry methanol (5 ml) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10:1) as an eluent to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[2-(morpholinoamino)ethyl]piperazine (55 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH:17]5[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=4[CH:24]=3)[C:4](=[O:25])[CH:3]=2)=[CH:29][CH:28]=1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (4-fluorophenyl)methanol (74.3 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, filtered through NH silica gel pad, and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was washed with toluene, and recrystallized from IPA-IPE to give the title compound (49.6 mg) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:27][CH2:28][CH:29]=[CH2:30])[CH:12]([CH2:13][CH3:14])[O:11][C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][BH:34][O:33]1>ClCCl.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:1]([O:5][C:6]([C:8]1([CH2:27][CH2:28][CH2:29][CH2:30][B:34]2[O:35][C:36]([CH3:38])([CH3:37])[C:32]([CH3:39])([CH3:31])[O:33]2)[CH:12]([CH2:13][CH3:14])[O:11][C:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC1(C(=O)OC(C)(C)C)NC(c2ccccc2)(c2ccccc2)OC1CC
Reactant: CC1(C)OBOC1(C)C
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC1OC(c2ccccc2)(c2ccccc2)NC1(CCCCB1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 4-but-3-enyl-5-ethyl-2,2-diphenyl-oxazolidine-4-carboxylic acid tert-butyl ester (230 mg, 0.56 mmol) in dichloromethane (2 mL, 0.3 M) was added chlorotris (triphenylphosphine)rhodium(I) (60 mg, 0.065 mmol, 10 mol %) at room temperature. After stirring for 30 min, 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (200 μl, 1.3 mmol, 2 eq) was added to the reaction mixture and stirred overnight. After quenching the reaction with water (3 mL), the resulting solution was diluted with ethyl acetate and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-40% ethyl acetate in heptane) gave 5-Ethyl-2,2-diphenyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-butyl]-oxazolidine-4-carboxylic acid tert-butyl ester (152 mg, 0.28 mmol, 50%).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:8]1[CH2:10][C@@H:9]1[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[CH:1]1([CH2:10][C@@H:9]([OH:8])[C:11]([O:13][CH3:14])=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]C1CCCC1
Reactant: COC(=O)[C@H]1CO1
Solvent: C1CCOC1
Product: COC(=O)[C@H](O)CC1CCCC1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
A solution of Li2CuCl4 (0.2 M in THF, 125 mL, 25.0 mmol) was added slowly to a suspension of cyclopentylmagnesium bromide (2 M in diethyl ether, 135 mL, 270 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) and THF (500 mL) at −50° C. over 2-3 mins. The pale grey/brown suspension was then allowed to warm slowly to −10° C. over 30 mins, by which time the color had developed to a dark grey. The mixture was re-cooled to −78° C. and (R)-methyl oxirane-2-carboxylate (25.0 g, 245 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added neat via syringe over 90 seconds. The reaction was then stirred at −78° C. for 20 mins, before removing the ice-bath and allowing to warm to approximately −50° C. over 30 mins. Saturated NH4Cl (aq, 700 mL) was then added and the mixture stirred for 30 mins. The organic layer was collected and the aqueous layer extracted with diethyl ether (2×250 mL). The combined organics were washed with saturated NH4Cl (aq, 350 mL), dried over MgSO4, and evaporated. Distillation of the crude residue (68-70° C. at 0.8 mbar) yielded 65-70% of (I-1b) as a pale yellow oil. A small amount of less volatile material remained in the still pot. 1H NMR (400 MHz; CDCl3): δ 4.17 (1 H), 3.76 (3 H), 2.67 (1 H), 2.01 (1 H), 1.48-1.88 (8 H), 1.11 (2 H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([NH2:16])=[O:15])[N:2]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[CH3:19][N:20]([CH:22]=[N:16][C:14]([C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:15])[CH3:21]
Reactant: NC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=O)c1cc2c(cn1)[nH]c1ccccc12
Temperature: 115 °C

Procedure:
A mixture of 1.0 g of beta-carboline-3-carboxamide and 3 ml of dimethyl-formamide-dimethylacetal is heated for 3 h at about 115° C. in an oil bath. After cooling, the crystals are collected on a glass frit and washed with 1 ml of dimethylformamide and then with 20 ml of ether. 1.2 g of N-[(dimethylamino)methylene]-beta-carboline-3-carboxamide with a m.p. of 307°-317° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][S:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:8])=[O:7]>C(O)C.O1CCCC1.[Pd]>[NH2:21][C:19]1[CH:18]=[CH:17][C:3]([CH2:4][NH:5][S:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:8])=[O:7])=[C:2]([F:1])[CH:20]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc(N)cc1F
Reaction time: 6 h
Yield: 102.9 %

Procedure:
10% Pd/C (42 mg) was added to a solution of tert-butyl N-(2-fluoro-4-nitrobenzyl)sulfamoylcarbamate (135 mg) in ethanol and tetrahydrofuran. The mixture was charged with H2 and stirred for 6 h. The reaction mixture was filtered using celite and evaporated in vacuo to obtain tert-butyl N-(4-amino-2-fluorobenzyl)sulfamoylcarbamate (127 mg, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:38])[CH3:37])=[CH:31][CH:30]=2)[N:28]=1>>[C:36]([NH:35][C:32]1[CH:33]=[CH:34][C:29]([C:27]2[N:28]=[C:24]([NH:23][C:17](=[O:19])[C:16]3[CH:15]=[CH:14][C:13]([S:10](=[O:12])(=[O:11])[N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH3:22])=[CH:21][CH:20]=3)[S:25][CH:26]=2)=[CH:30][CH:31]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3nc(-c4ccc(NC(C)=O)cc4)cs3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with N-(4-(2-aminothiazol-4-yl)phenyl)acetamide (61 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 30-90% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(4-(4-acetamidophenyl)thiazol-2-yl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide as a yellow solid. Yield: 68 mg (49%). 1H-NMR: 10.03 (s, 1H), 8.27 (d, J=9.0 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.68-7.63 (m, 4H), 7.60 (s, 1H), 7.01 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 3.75 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[N:2]1.[ClH:18].[CH3:19][NH:20][CH3:21].[BH4-].[Na+]>CO.C(OCC)(=O)C>[ClH:18].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][N:20]([CH3:21])[CH3:19])=[N:2]1
Reactant: O=Cc1ccccc1-c1noc2ccccc12
Reactant: CNC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)Cc1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
In one portion, a total of 2.0 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde was added to a solution of 8.0 g of dimethylamine hydrochloride in 70 ml of methanol. The reaction mixture was stirred at room temperature for 16 h, after which 2.0 g of sodium borohydride were added. After stirring at room temperature for another 24 h, the solids were filtered off, and the residue was washed with dichloromethane. The combined filtrate was dried over magnesium sulphate and evaporated to dryness under reduced pressure. The resulting solid was purified by chromatography on silica gel, eluting with ethyl acetate, affording 0.89 g. This solid was dissolved in ethyl acetate, and triturated with a solution of hydrogen chloride in methanol. This solution was evaporated to dryness under reduced pressure and the residue was crystallised from ethanol/diethyl ether/hexane, yielding 0.54 g of pure 2-(1,2-benzisoxazol-3-yl)-N,N-dimethyl-benzenemethanamine hydrochloride, melting at 190° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:22]#[N:23])[CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:22]#[N:23])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCNCC1
Yield: 88.5 %

Procedure:
4-(4-Nitro-phenyl)-1-(2,2,2-trifluoro-acetyl)-piperidine-4-carbonitrile (1.28 g, 3.91 mmol) was suspended in Methanol (50.0 mL) and treated with 2.00 M of Sodium carbonate in Water (20.0 mL, 40.0 mmol) at rt overnight. Water was added to the heterogenous mixture to achieve a solution, then the mixture was partitioned between DCM and brine (50 mL each). Ext. of the aq. with DCM (3×50 mL), followed by washing the org. with brine (50 mL), drying and conc. in vacuo afforded 4-(4-Nitro-phenyl)-piperidine-4-carbonitrile (0.800 g; Yield=88.4) as a white solid. 1H-NMR (DMSO-d6): 8.30 (d, 2H, J=8.8 Hz), 7.83 (d, 2H, J=8.8 Hz), 3.07 (m, 2H), 2.82 (m, 2H), 2.36 (br s, 1H), 2.05 (m, 2H), 1.92 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[S:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)=[O:22])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(O)c1ccc(Cl)s1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2ccc(Cl)s2)C1

Procedure:
50.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-chlorothiophene-2-carboxylic acid to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Brown oil. MS 345.0 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:27]=1)([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[N:28]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)C)nn4-c4ccccc4)c3)c2cc1OC
Yield: 71.2 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (125 mg, 0.4 mmol), prepared as described in Example 115B, in THF (2 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-isopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (129 mg, 0.4 mmol) described in Example 324A. The suspension was filtered and triturated with anhydrous diethyl ether to afford 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea (154 mg, 71%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, J=7.2 Hz, 6H), 2.88 (m, 1H), 3.99 (s, 6H), 6.32 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.25-7.53 (m, 10H), 7.79 (m, 1H), 8.47 (s, 1H), 8.69 (s, 1H), 9.21 (s, 1H); LC-MS (ESI) m/z 541 (M+H)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1.[CH3:11][Si:12](Cl)([CH3:14])[CH3:13].[NH4+].[Cl-]>C1COCC1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:4][CH:5]=1)[CH3:10]
Reactant: CCc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc([Si](C)(C)C)cc1
Temperature: 30 °C
Yield: 93.5 %

Procedure:
Magnesium(9.5 g, 0.39 mole) was suspended in THF (60 mL) at room temperature. A solution of 4-bromo-1-ethylbenzene (49 mL, 0.36 mole) in 300 mL of THF was added dropwise at such a rate as to maintain the temperature between 30° and 60° C. When the addition was complete the reaction mixture was stirred for an additional hour and then cooled to 30° C. Trimethylsilyl chloride (49 mL, 0.39 mole) was added dropwise at such a rate as to maintain the temperature between 30° and 40° C. The thin suspension was stirred overnight at room temperature. Saturated aqueous NH4Cl was added and the reaction mixture partitioned. The aqueous phase was extracted three times with ether, and the combined organic phases were dried (MgSO4) and concentrated. The resultant oil (60 g, 93% yield) was used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[N:19]1([C:25]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=2[C:27](O)=[O:28])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:27]([C:26]3[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:25]=3[N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:28])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 2-morpholin-4-yl-5-nitro-benzoic acid (Example 2.1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid. MS (m/e): 482.2 (M+H+; 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
Procedure D may also be used to couple 4-chloro-3-(pyridin-2-yl)aniline and 2-chloro-4-(methylsulfonyl)benzoyl chloride to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide which is collected by suction filtration and the HCl salt is washed with Et2O (or alternatively with MTBE). This material is freebased using EtOAc/aq NaHCO3 and the organics are dried and concentrated to the solid freebase. This material is then crystallized from acetone:EtOAc (80:20, approx 10 mL/g) which is then finally recrystallized from hot slurry of iPrOAc. 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide HCl salt may also be dissolved in distilled water followed by freebasing with 0.5 N NaOH solution (pH to 11) and filtering and vacuum drying the precipitate.