Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=[O:9].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10][C:13]1[CH:14]=[C:15]([Cl:19])[C:16]([Cl:18])=[CH:17][C:12]=1[Cl:11])=[O:9]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C(O)CN1CCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CN1CCCC1=O)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
84.8 g of 2-oxo-1-pyrrolidineacetic acid and 128.5 g of 2,4,5-trichlorophenol are dissolved in 1,500 ml of methylene chloride, 138.75 g of dicyclohexylcarbodiimide are slowly added at 0° C. and the mixture is stirred at 20° C. for three hours. The urea which has precipitated is then filtered off, the solvent is evaporated off and the residue is recrystallised from ethyl acetate.
Reaction SMILES: [C:1]([NH:4][C:5](=[S:22])[NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])(=[O:3])[CH3:2].[C:23]([N:27]=[C:28]=[S:29])([O:25][CH3:26])=[O:24]>CC(C)=O>[C:1]([NH:4][C:5](=[S:22])[NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[NH:21][C:28]([NH:27][C:23]([O:25][CH3:26])=[O:24])=[S:29])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)N=C=S
Reactant: CC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(C(=O)c2ccccc2)cc1NC(=S)NC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a suspension of 3-(3-acetylthioureido)-4-aminobenzophenone (1.1 g.) in acetone (15 ml.) is added carbomethoxy isothiocyanate (0.41 g.). The mixture is heated to reflux and then is stirred at room temperature for 18 hours. The crude product is collected by filtration, washed with acetone and ether and then dried to afford 0.6 g. (40% yield) of 3-(3-acetylthioureido)-4-(3-carbomethoxythioureido)benzophenone, m.p. 203°-204° C., dec.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35]>C1COCC1.O>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:11]=[C:10]3[C:5]([N:6]=[CH:7][C:8]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35]
Reactant: Brc1ccc2ncc(N3CCOCC3)nc2c1
Reactant: O=[N+]([O-])c1cc(B(O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(-c2ccc3ncc(N4CCOCC4)nc3c2)ccc1F
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a suspension of 7-bromo-2-morpholin-4-yl-quinoxaline (1 g, 3.4 mmol), potassium carbonate (0.56 g, 4.1 mmol) and [1,1,-Bis(diphenlyphosphino)ferrocene]palladium(II)chloride (0.83 g, 1.0 mmol) in THF (38 mL) and water (3.8 mL) was added (4-fluoro-3-nitrophenyl)boronic acid (1.26 g, 6.8 mmol). The reaction mixture was allowed to reflux for 6 h. After cooling to room temperature, the solvent was removed and the residue was purified by chromatography (silica gel, Hexane/EtOAc: 20%->100% EtOAc) giving rise to 1.1 g (92%) of the desired product.
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][C:3]1=2.Cl.O>C1(C)C=CC=CC=1>[CH:16]1[C:3]2[CH2:2][CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH:13]=[C:14]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:15]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)Oc1ccccc1CC2=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(C)c1ccc2c(c1)Oc1ccccc1CC2
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To 95 mg of methyl 2-(10,11-dihydro-11-oxo dibenzo[b,f]-oxepin-3-yl)-propionate in 1 ml of toluene were added a small amount of zinc-amalgam, 0.3 ml of conc. hydochloric acid and 0.2 ml of water, and the mixture was refluxed with stirring for 1 hour. After cooling, the mixture was filtered and the filtrate was extracted with benzene. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain pale yellow oil, which was subjected to thin-layer chromatography to give 30 mg of methyl 2-(10,11-dihydro dibenzo[b,f]oxepin-3-yl)-propionate as pale yellow oil.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1.Cl.[OH:30][CH:31](COC1C=CC=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl>C(OCC)C>[ClH:1].[OH:2][CH:3]([CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)[CH2:4][NH:5][C:6]([CH3:15])([CH3:16])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:30][CH3:31])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2)cc1
Reactant: CC(C)(Cc1ccc(F)cc1)NCC(O)COc1cccc2ccccc12
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc3ccccc3c2)cc1

Procedure:
Using the method of Example 4, supra, 2-naphthyl glycidyl ether (400 mg, 2 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (358 mg, 2 mmol) were used to prepare the free base of the title compound: GC/EI-MS, m/z (rel. int.) 364 (M−15, 1), 258 (100), 183 (2), 163 (3), 144 (4), 127 (10), 121 (22), 115 (20), 71 (11). The free base in diethyl ether was treated with excess 1M HCl (diethyl ether). The resulting solid was recrystallized from hot acetonitrile to afford 496 mg of the hydrochloride product as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.Cl[C:46]([O:48][CH2:49][CH3:50])=[O:47]>C(Cl)Cl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:46](=[O:47])[O:48][CH2:49][CH3:50])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)NC[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (18 mg, 0.032 mmol) and triethylamine (22 μL, 0.16 mmol) in methylene chloride (1 mL) was added ethyl chloroformate (3.7 μL, 0.039 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.9 mg, 7%). LCMS calculated for C20H27N4O3S (M+H)+: m/z=403.2. Found: 402.9.
Reaction SMILES: BrBr.[CH2:3]([O:5][C:6]([CH:8]1[CH2:19][N:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[C:9]1=[O:25])=[O:7])[CH3:4].C(N(CC)CC)C>C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[C:9](=[O:25])[C:10]2[CH:15]=[N:14][C:13]([S:16][CH3:17])=[N:12][C:11]=2[N:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[CH:19]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1CN(C2CCCC2)c2nc(SC)ncc2C1=O
Agent: BrBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CCCC2)c2nc(SC)ncc2c1=O
Reaction time: 0.25 h

Procedure:
Bromine (0.13 g, 0.82 mmol) was added to a solution of 8-Cyclopentyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.34 g, 0.82 mmol) in DCM (5 mL). After 15 min, the solution was concentrated and the crude residue was redissolved in DCM (5 mL) and triethylamine (0.16 mL, 0.24 mmol) was added. After 15 h, the reaction mixture was partitioned between water and DCM, the organic layer was separated, dried (MgSO4) and concentrated to provide the title compound. Mass Spectrum (LCMS, ESI pos.) Calcd. For C16H19N3O3S: 333.11, found: (M+H) 334.1.
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][C:14]([CH3:18])=[C:15](Br)[CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)=O.CC(C)=O.[Li]CCCC.C([O:42][B:43](OC(C)C)[O:44]C(C)C)(C)C>C1COCC1.CCCCCC>[C:1]12([C:11]3[C:12]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][C:14]([CH3:18])=[C:15]([B:43]([OH:44])[OH:42])[CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
To a solution of 5-(1-adamantyl)-4-benzyloxy-2-methylphenyl bromide (2.66 g, 6.47 mmol) in THF (10 mL) at −78° C. (dry ice/acetone bath) under argon was added 1.6 M n-BuLi (11.64 mmol) in hexane (7.3 mL) in one portion. This mixture was stirred at −78° C. for 15 min. Tri(isopropyl)borate (4.5 mL, 19.40 mmol) was added, and the resulting solution was stirred at −78° C. for 20 min before being allowed to warm to room temperature with stirring overnight. The reaction mixture was quenched with 1 N HCl (40 mL) and then extracted with EtOAc (100 and 60 mL). The combined organic extracts were washed with brine and dried. Solvents were removed at reduced pressure, and the residue was washed with hexane to give 1.47 g (60%) of 5-(1-adamantyl)-4-benzyloxy-2-methylphenylboronic acid as a white solid, mp 243-247° C. IR 3226, 2903, 2848, 1328 cm−1; 1H NMR (CDCl3) δ 1.74 (bs, 6H, AdCH2), 2.05 (bs, 3H, AdCH), 2.20 (bs, 6H, AdCH2), 2.82 (s, 3H, CH3), 5.19 (s, 2H, C6H5CH2), 6.85 (s, 1H, 3-ArH), 7.31-7.54 (m, 5H, C6H5), 8.19 ppm (s, 1H, 6-ArH).
Reaction SMILES: C(OCC)(=O)C.Cl.[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][NH:22][CH2:21][C@H:20]2[O:25][CH2:26][CH3:27])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15].B(F)(F)[O:29][C:30]([C:32]1[C:41](=[O:42])[C:40]2[C:35](=[C:36]([O:44][CH3:45])[C:37](F)=[CH:38][CH:39]=2)[N:34]([CH:46]2[CH2:48][CH2:47]2)[CH:33]=1)=[O:31]>CS(C)=O.C(N(CC)CC)C.O.C(O)C>[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:37]3[C:36]([O:44][CH3:45])=[C:35]4[C:40]([C:41](=[O:42])[C:32]([C:30]([OH:31])=[O:29])=[CH:33][N:34]4[CH:46]4[CH2:47][CH2:48]4)=[CH:39][CH:38]=3)[CH2:21][C@H:20]2[O:25][CH2:26][CH3:27])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)OB(F)F)cn(C3CC3)c12
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCO[C@@H]1CN(c2ccc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 40 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
Ethyl acetate was added to cis(±)-4-chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), and the organic layer was washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue and (1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl difluoroborate obtained in Example (146a) (82 mg, 0.30 mmol) were dissolved in DMSO (0.6 mL). Triethylamine (0.100 mL, 0.721 mmol) was added, and the mixture was stirred at 40° C. overnight. Ethanol (3 mL), water (0.3 mL) and triethylamine (0.3 mL) were added to the reaction solution, and the mixture was stirred at 80° C. for six hours. The reaction solution was cooled to room temperature. The resulting solid was collected by filtration and washed with ethanol to obtain 102.5 mg of the title compound as a pale yellow solid (62%).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]3)=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH3:23])[C:5]1=[O:6])[CH2:2][CH3:3]>C(O)C>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]3)=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH3:23])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2[nH]c(C3CCC(=O)C3)nc2n(CCC)c1=O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(C3CCC(O)C3)nc2n(CCC)c1=O
Yield: 78 %

Procedure:
0.5 g (1.6 mmol) of 1,3-dipropyl-8-(1-oxo-3-cyclopentyl)xanthine, 10 ml of ethanol and 0.1 g (2.6 mmol) of sodium tetrahydridoboranate are stirred for 21/2 days at ambient temperature. The mixture is evaporated down in vacuo and mixed with water and methylene chloride then the aqueous phase is acidified and extracted. The combined organic extracts are dried and evaporated down in vacuo. The residue is separated into the isomers by chromatography on silica gel (CH2Cl2 /CH3OH 95:5). From the 1st fraction, 0.4 g of the title compound are obtained in the form of white crystals (39% of theory), m.p. 174°-176° C. and from the 2nd fraction 0.4 g of the title compound are obtained in the form of white crystals (39% of theory), m.p. 191°-193° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.Cl.[CH3:20][NH:21][O:22][CH3:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:23][O:22][N:21]([CH3:20])[C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]2)=[CH:17][CH:16]=1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (10.05 g), N,O-dimethylhydroxylamine hydrochloride (4.35 g), WSC (9.32 g), HOBt (6.57 g), and TEA (6.21 ml) in DMF (80 ml) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) and crystallized from hexane to give the title compound (7.60 g).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:4]=1[O:5][CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:2].[BH4-].[Na+].Cl>O1CCCC1.O.O>[OH:2][CH2:1][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:4]=1[O:5][CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C)Oc1c(C=O)cccc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Oc1c(CO)cccc1OC
Reaction time: 2 h
Yield: 70.6 %

Procedure:
A solution ethyl 2-(2-formyl-6-methoxyphenoxy)propionate (2.60 g) in tetrahydrofuran-water (9:1) was ice-cooled and sodium borohydride (185 mg) was added. The mixture was stirred at the same temperature for two hours. Diluted hydrochloric acid (1N, 5 ml) was added to the solution and the mixture was stirred for an hour. The mixture was diluted with water and was extracted with ethyl acetate. The organic layer was separated and washed with brine and dried over magnesium sulfate. After concentration, the crude product was purified on a column of silica gel (29 g) eluting with a mixed solvent of toluene and ethyl acetate (7:1) to give ethyl 2-(2-hydroxymethyl-6-methoxyphenoxy)propionate (1.85 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:14][OH:15].CC([O-])=O.[Na+]>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:11])[O:15][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC(=O)c1cccc(Br)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2cccc(Br)c2)no1

Procedure:
To a solution of 3-(3-bromophenyl)-3-oxopropanenitrile (1.12 g; 5.00 mmol; Note 1) in EtOH (20 mL) was added a solution of hydroxylamine hydrochloride (1.74 g; 25 mmol) and NaOAc (2.46 g; 30 mmol) in water (20 mL). The mixture was heated under reflux for 1 h, cooled and concentrated in vacuo. The residue was slurried in 1N NaOH and extracted with Et2O (×1). The organic layer was washed (water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound as a pale yellow solid which was used without further purification. LC/MS (method B) 2.21 min, m/z 239, 241 (Br isotopes).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([N:10]([CH3:20])[C:11]1([C:18]#[N:19])[CH2:14][N:13]([C:15]([O-:17])=[O:16])[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.OO>C(O)C>[NH2:19][C:18]([C:11]1([N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:20])[CH2:14][N:13]([C:15]([O:17][C:4]([CH3:9])([CH3:5])[CH3:3])=[O:16])[CH2:12]1)=[O:1]
Reactant: [OH-]
Reactant: CN(Cc1ccccc1)C1(C#N)CN(C(=O)[O-])C1
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CN(Cc1ccccc1)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 165.3 %

Procedure:
A 1M solution of sodium hydroxide (12.5 ml, 12.5 mmol) at 0° C. was added dropwise to a solution of 3-[benzyl(methyl)amino]-3-cyanoazetidine-1-carboxylate (800 mg, 2.66 mmol) in ethanol (25 ml). Hydrogen peroxide 30% wt (1 ml) was then added and the reaction mixture was allowed to stir at room temperature overnight. After removal of solvent under reduced pressure, the remaining aqueous layer was extracted with ethyl acetate (×2) and the combined organic layers washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 3-(aminocarbonyl)-3-[benzyl(methyl)amino]azetidine-1-carboxylate (702 mg, 87%) as a white solid, used without any further purification in the next step; 1H NMR Spectrum: (CDCl3) 1.45 (s, 9H), 2.27 (s, 3H), 3.61 (s, 2H), 4.07 (d, 2H), 4.22 (brd, 2H), 5.51 (brs, 1H), 6.70 (brs, 1H), 7.26-7.36 (m, 5H); Mass Spectrum: (M+H)+ 320.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH:19]=[O:20])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[BH4-].[Na+]>C(OCC)(=O)C>[OH:20][CH2:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:9]
Reactant: CN1CCN(C(=O)c2[nH]c3ccccc3c2C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)c2[nH]c3ccccc3c2CO)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
2-(4-Methyl-piperazine-1-carbonyl)-1H-indole-3-carbaldehyde (Example 51, 0.094 g) in ethyl acetate (1.5 mL) was treated with sodium borohydride (0.024 g) and stirred at ambient temperature for 3 h. The solvent was removed under reduced pressure, and the residue treated with saturated sodium hydrogencarbonate solution and extracted with dichloromethane. The organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography, eluting with 1-8% methanol/dichloromethane, to afford the title compound (0.042 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][OH:11])[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]=1.C(N(CC)CC)C.ClCCl.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([O:11][CH2:10][CH2:9][CH2:8][N:7]1[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]=[C:3]1[S:2][CH3:1])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1nc2ccccc2n1CCCO
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1nc2ccccc2n1CCCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a stirred mixture of 19 parts of 2-(methylthio)-1H-benzimidazole-1-propanol, 15.2 parts of N,N-diethylethanamine and 195 parts of dichloromethane are added dropwise 11.5 parts of methanesulfonyl chloride. Upon completion, stirring is continued for one hour at reflux. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated, yielding 3-[2-(methylthio)-1H-benzimidazol-1-yl]propyl methanesulfonate as an oily residue.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[H-].[Na+].Br[CH2:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[O:22])[CH2:15][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2)[CH3:21]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: CCOC(=O)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CN1CCCCc2ccccc21

Procedure:
Add 2,3,4,5-tetrahydro-1H-benzo[b]azepine in small portions to a 0° C. suspension of 60% sodium hydride (3.0 g, 0.12 mol) in 300 mL of dimethylformamide. Upon complete addition of the amine, remove the ice bath and stir the reaction at 20-24° C. for 40 minutes. Add ethyl bromopyruvate (22.6 mL, 0.16 mol) and stir the resulting mixture at 20-24° C. for 6 hours. Add an additional 5 mL of ethyl bromopyruvate and stir the mixture for 1 hour. Quench by adding 50 mL of water then dilute with 1.5 L of dichloromethane. Separate the layers, wash the organic layer sequentially with water (2×500 mL) and saturated aqueous sodium chloride (500 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure at 60° C. Dissolve the residue in ethyl acetate (500 ml), wash sequentially with water (3×100 mL) and saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 5-10% EtOAc/hexanes to provide the desired compound as an off white solid (7.0 g, 40%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[N:12][CH:11]=[CH:10]3)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[CH:13]1[C:14]2[C:9](=[CH:8][C:7]([C:4]3[O:3][C:2]([NH:17][C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)=[N:6][CH:5]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: Clc1ncc(-c2ccc3cnccc3c2)o1
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc4cnccc4c3)o2)c1
Temperature: 80 °C
Yield: 36.5 %

Procedure:
A mixture of 2-chloro-5-(isoquinolin-6-yl)oxazole 14 (0.15 g, 0.652 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.121 g, 0.649 mmol) in 2-propanol (20 mL) was heated to 80° C. for 12 h with stirring. Additional one more equivalent of N-(3-aminophenyl)methanesulfonamide 6 (0.121 g, 0.649 mmol) was added to reaction mixture and heated to 80° C. for further 12 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(isoquinolin-6-yl)oxazol-2-yl)amino)phenyl)methane sulfonamide 59 (0.09 g, 38% yield) as pale yellow solid. MS (ES) m/z 381 (M+H+).