Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]#[N:8].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[CH2:12]1[CH2:13][CH2:14][C:9]([OH:15])([C:7]#[N:8])[CH2:10][CH2:11]1
Reactant: C#N
Reactant: O=C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#CC1(O)CCCCC1
Temperature: 10 °C

Procedure:
Sodium carbonate (30.0 g., 0.283 mole) was dissolved in 200.2 g. of water, the system was closed and anhydrous liquid HCN (3.46 g., 0.128 mole) was added to the solution. Little, if any, heat was given off in the reaction and the product solution was clear. Cyclohexanone (32.05 g., 0.327 mole) was injected into the system with good mixing. The mixture heated up immediately 10°C. The organic and aqueous phases were mixed for 15 minutes longer and then allowed to separate. The organic layer (35.9 g.) was analyzed for free HCN, showing none, followed by an analysis for both combined and free HCN which showed 3.19 g. (0.118 mole) or 92% of the original HCN injected appearing in the organic phase as cyanohydrin.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>CN(C=O)C>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][CH2:6][N:7]([CH3:22])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(CCNC(=O)OCc1ccccc1)OCC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(CCN(C)C(=O)OCc1ccccc1)OCC
Reaction time: 0.08 h

Procedure:
A solution of phenylmethyl [3,3-bis(ethyloxy)propyl]carbamate (4.17 g, 14.8 mmol, J. Med. Chem. 1998 41, 3919-3922) in anhydrous DMF (15 mL) under nitrogen at ambient temperature was treated LiHMDS (1.0 M in THF, 17.8 mL, 17.8 mmol). After stirring 5 min., methyl iodide (1.11 mL, 17.8 mmol) was added. After stirring an additional 15 min., the reaction mixture was quenched by addition of saturated brine, water and Et2O. After separation of the phases, the aqueous layer was back-extracted with Et2O. The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered, evaporated in vacuo and purified on silica gel eluting with 25% EtOAc in Hexanes to provide the product as an oil: 1H NMR (CDCl3) δ 7.28-7.38 (5H, m), 5.12 (2H, s), 4.45-4.56 (1H, m), 3.29-3.68 (6H, m), 2.92 (3H, s), 1.81-1.90 (2H, m), 1.11-1.23 (6H, m); ES+ MS: 318 (M+Na+).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[CH3:48])=CC=1)([O-])=O>>[CH3:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:32]
Reactant: O=C(NC[C@H]1CCNC1)c1ccc(Cl)s1
Reactant: Cc1cc(-n2ccccc2=O)ccc1NC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-n2ccccc2=O)ccc1NC(=O)N1CC[C@H](CNC(=O)c2ccc(Cl)s2)C1

Procedure:
70.2 Using general method H, 5-chloro-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 471.1 ([M+H]+)
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:43])[N:9]=[C:10](SC)[C:11]([C:28]1[C:29]([F:40])=[C:30]2[C:35](=[C:36]([O:38][CH3:39])[CH:37]=1)[O:34][CH2:33][CH2:32][CH2:31]2)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.Cl.Cl.[CH2:46]([O:48][C:49]([C:51]1[C:52]([NH:56][NH2:57])=[N:53][NH:54][CH:55]=1)=[O:50])[CH3:47]>C(N(CC)CC)C>[CH2:46]([O:48][C:49]([C:51]1[CH:55]=[N:54][NH:53][C:52]=1[N:56]1[C:8](=[O:43])[NH:9][C:10]([CH:11]([C:28]2[C:29]([F:40])=[C:30]3[C:35](=[C:36]([O:38][CH3:39])[CH:37]=2)[O:34][CH2:33][CH2:32][CH2:31]3)[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[O:21][N:20]=3)=[CH:15][CH:14]=2)=[N:57]1)=[O:50])[CH3:47]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C(F)(F)F)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Reactant: CCOC(=O)c1c[nH]nc1NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Temperature: 85 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
To 5 ml of a DMF solution containing 160 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester, 87 mg of 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester bishydrochloride (Example (157b)) and 0.124 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 8 ml of methanol and 0.068 ml of acetic acid, and then 187 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (39 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14][CH2:13]2)Cl.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>ClC1C=CC=CC=1Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14][CH2:13]2
Reactant: Clc1ccccc1C(Cl)c1ccc2c(c1)CCCC2
Reactant: c1c[nH]cn1
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: Clc1ccccc1C(c1ccc2c(c1)CCCC2)n1ccnc1
Temperature: 180 °C
Yield: 55.3 %

Procedure:
44 g (0.15 mol) of 2-chlorophenyl-1,2,3,4-tetrahydronaphth-6-yl-chloromethane, dissolved in 50 ml of 1,2-dichlorobenzene, are added dropwise to a suspension of 51 g (0.75 mol) of imidazole in 100 ml of 1,2-dichlorobenzene at 180° C. The reaction mixture is heated to 180° C. for 2 hours and, after cooling, is poured onto water and the organic phase is diluted with methylene chloride and washed with water. After drying the solution over sodium sulphate, it is evaporated in vacuo. 26.8 g (55% of theory) of 2-chlorophenyl-imidazol-1-yl-1,2,3,4-tetrahydronaphth-6-yl-methane of refractive index nD20 =1.6000 are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl-].[CH3:38][O:39][C:40]([C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45][NH3+:46])=[O:41]>ClCCl.CN(C=O)C>[CH3:38][O:39][C:40](=[O:41])[C:42]1[CH:49]=[CH:48][CH:47]=[C:44]([CH2:45][NH:46][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:43]=1
Reactant: COC(=O)c1cccc(C[NH3+])c1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CNC(=O)c2ccc(OC)c(OC)c2)c1
Reaction time: 1 h
Yield: 103.2 %

Procedure:
3,4-Dimethoxybenzoic acid (400.8 mg, 2.2 mmol), EDC (479 mg, 2.5 mmol) and HOBt (338 mg, 2.5 mmol) were combined in a reaction vial. DMF (2 mL) was added followed by Hunig's base (0.79 mL, 4.5 mmol). The resulting mixture was agitated for 1 hour. Subsequently, 3-methoxycarbonyl-benzyl-ammonium chloride (403.3 mg, 2 mmol) was added and the mixture was agitated 16 h. The reaction mixture was diluted with 10 mL dichloromethane, and the resulting mixture was washed with 1N HCl (2×10 mL), NaHCO3 (satd. aq., 2×10 mL), and brine (1×10 mL), dried, and the solvents were evaporated to give 3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoic acid methyl ester (680 mg) as an oil which was used without purification. The ester was then dissolved in a mixture of methanol (6 mL) and DMF (1 mL) and treated with Amberlyst® A26 (OH− form) (3730 mg, 5 mmol), and the resulting mixture was agitated for 36 h. The resin was then filtered and washed with 2×4 mL methanol, 1×4 mL DMF and 2×4 mL methanol. The product acid was eluted with a solution of 20% formic acid in methanol. The eluant solvents were evaporated, and the resulting solid was triturated in diethylether. 3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoic acid was isolated by filtration (386 mg, 61%-2 steps) and carried forward. This intermediate (80 mg, 0.254 mmol) was combined with EDC (57.5 mg, 0.3 mmol) and HOBt (40.5 mg, 0.3 mmol) in a reaction vial, and N-methyl morpholine (0.034 mL, 0.3 mmol) was added. The resulting mixture was agitated for 30 min, after which time, 3-(2-amino-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (64 mg, 0.28 mmol) was added and the resulting mixture was agitated overnight. The reaction mixture was diluted with 3 mL dichloromethane, and the resulting mixture was washed with 1N HCl (2×1 mL), NaHCO3 (satd. aq., 2×1 mL), and brine (1×1 mL), dried, and the solvents were evaporated to 140 mg of the intermediate, 3-(2-{3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoylamino}-ethyl)-piperidine-1-carboxylic acid tert-butyl ester, which was redissolved in dichloromethane (2 mL). SCX (681 mg, 0.6 mmol) was added and the resulting mixture was agitated overnight. The reaction mixture was filtered and the solids were washed with dichloromethane (2×2 mL) and methanol (2×2 mL). The product was eluted with NH3 in methanol (7N, 3×1 mL). The solvents were evaporated to provide 80 mg (74.3%-2 steps) of the title compound, MS analysis electrospray, 426 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[C:18]2[N:19]=[C:20]([CH3:22])[S:21][C:17]=2[CH:16]=[CH:15][C:14]=1[NH2:23].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:23][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH3:22])=[N:19][C:18]=2[C:13]=1[Cl:12])=[O:6]
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)c(NC(=O)c3cc(Cl)ccc3Cl)ccc2s1
Yield: 52 %

Procedure:
Reaction of 2,5-dichlorobenzoic acid (145 mg, 0.76 mmol) in thionyl chloride (5 mL) then with 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in presence of triethylamine (0.5 mL) in THF (2 mL) according to method B gave 2,5-dichloro-N-(4-chloro-2-methyl-benzothiazol-5-yl)-benzamide (50 mg, 0.13 mmol, 52% yield) as a white powder after purification by chromatography on silica gel(eluent: DCM).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C@H:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7].[ClH:24]>O1CCOCC1.CO.O=[Pt]=O>[ClH:24].[CH3:1][O:2][C:3](=[O:23])[CH2:4][C@H:5]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7]
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCNC1
Reaction time: 2 h

Procedure:
A mixture of N-(3-pyridyl)-3(S)-(tert-butoxycarbonylamino)succinamic acid methyl ester (3.91 g) and 4N HCl in dioxane (3.36 ml) and PtO2 (0.39 g) in methanol (40 ml) was hydrogenated at atmospheric pressure for 2 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo. The residue was recrystallized from diethyl ether to give N-(3-piperidyl)-3(S)-(tert-butoxycarbonylamino)succinamic acid methyl ester hydrochloride (3.67 g).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[CH:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[CH2:12][CH:6]1[C:5]2[C:10](=[N:11][CH:2]=[CH:3][CH:4]=2)[NH:9][CH2:8][CH2:7]1
Reactant: Fc1ccc(F)c(C=C2CCNc3nc(Br)ccc32)c1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(F)c(CC2CCNc3ncccc32)c1
Reaction time: 1.5 h

Procedure:
7-Bromo-4-[1-(2,5-difluorophenyl)methylidene]-1,2,3,4-tetrahydro-[1,8]naphthyridine (200 mg) was dissolved in methanol (20 mL) and Pd/C (20 mg) was added. The reaction was hydrogenated at atmospheric pressure for 1.5 hours, filtered through Celite, and then concentrated under reduced pressure to give the title compound as a clear colorless oil (near quantitative yield). LCMS: m/z=261.11 (M+H+), 1H-NMR (MeOH-d4, 400 MHz) δ 1.68-1.86 (m, 2H), 2.80 (dd, J=9.0 and 13.3, 1H), 2.96 (dd, J=10.0 and 13.3 Hz, 1H), 3.02-3.12 (m, 1H), 3.34-3.41 (m, 1H), 3.46-3.55 (m, 1H), 6.44 (dd, J=5.2 and 7.2 Hz, 1H), 6.93-7.03 (m, 2H), 7.03-7.11 (m, 2H), 7.72 (dd, J=1.0 and 5.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.O.S(=O)(=O)(O)O>CCOCC.[O-2].[Cr+6].[O-2].[O-2].C(O)(C)C>[O:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Yield: 56.5 %

Procedure:
Methyl (2S,4R)—N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (2.00 g, 0.00815 mol) was dissolved in acetone (50.0 mL, 0.681 mol) and ether (50 mL). To the solution with stirring, was added a solution of chromium(VI) oxide (1.90 g, 0.0190 mol) in water (5.50 mL, 0.305 mol) and sulfuric acid (1.60 mL, 0.0294 mol) over 15 minutes with the presence of an ice-water bath to maintain the reaction temperature at about room temperature. The mixture was stirred at rt for 10 minutes and then iso-propanol (10 mL) was added. The mixture was stirred for an additional 5 min. The mixture was filtered through a pad of silica gel plus potassium carbonate. The filtrated was concentrated and the residue was purified by Combiflash with ethyl acetate/hexane (25%) to give the desired product (1.12 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:23]O>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]3[C:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)=[N:23][O:12][C:11]3=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1ncc2c(O)c(C(=O)c3cccc(F)c3)cnc21
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4cccc(F)c4)c3cnc21

Procedure:
1-Ethyl-5-(3-fluorobenzoyl)-4-hydroxy-1H-pyrazolo[3,4-b]pyridine (2.85 g) was refluxed overnight in 50 ml of pyridine containing 3.0 g of hydroxylamine hydrochloride. The pyridine was evaporated and the residue triturated with 5% hydrochloric acid. The product thus obtained was filtered off and recrystallized from methanol to give 2.21 g of analytically pure product, mp 136°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:21]2)[CH:12]=[CH:11]1>>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)[CH:12]=[CH:11]1
Reactant: Clc1cccc(I)c1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4cc[nH]c34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4ccn(-c5cccc(Cl)c5Cl)c34)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1,2-dichloro-3-iodobenzene and N-{3-[1-(1H-indol-7-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:15]O>N1C=CC=CC=1.C(O)C>[CH2:1]([C:7]1[CH:8]=[C:9]([C:12]#[N:15])[S:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NO
Reactant: CCCCCCc1csc(C=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCCCc1csc(C#N)c1
Yield: 84.5 %

Procedure:
A mixture solution of 4-hexylthiophene-2-carbaldehyde (11.8 g, 60.0 mmol) and hydroxylamine hydrochloride salt (6.3 g, 90 mmol) in pyridine/ethanol (60 mL, 1/1 v/v) was stirred at 80° C. overnight. Then the solvent was removed and the residue was dissolved in chloroform (100 mL). The solution was washed with distilled water (2×50 mL) and dried over anhydrous magnesium sulphate. The solvent was removed and the viscous liquid residue was refluxed in acetic anhydride (30 mL) containing potassium acetate (0.2 g) for 3 h. Then the mixture was poured into distilled water (100 mL) and extracted with hexanes (3×50 mL). The combined organic phase was washed three times with water (50 mL), dried over anhydrous magnesium sulfate before the solvent was removed by rotary evaporation. The yellow liquid residue was purified by silica-gel column chromatography (EtOAc/hexane=7/93, v/v, Rf=0.4) to yield a clear light yellow liquid product. (9.8 g, 84.5% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.43 (d, 1H, J=1.4 Hz); 7.17 (d, 1H, J=1.4 Hz); 2.60 (t, 2H, J=8.0 Hz); 1.59 (m, 2H); 1.22-1.36 (m, 6H); 0.87 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 144.04, 138.22, 127.41, 114.48, 109.28, 31.45, 30.18, 29.86, 28.67, 22.46, 13.96. HRMS EI calcd for C11H15S 193.0925, found 193.0915.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>>[NH2:32][C:11]1[N:12]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([CH:26]4[CH2:27][CH2:28][N:29]([C:35]([N:34]([CH3:38])[CH3:33])=[O:36])[CH2:30][CH2:31]4)=[CH:20][CH:21]=3)[CH2:16]2)[CH:14]=[C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]2)[N:10]=1
Reactant: CN(C)C(=O)Cl
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(C3CCN(C(=O)N(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 138 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine HCl salt and N,N-dimethylcarbamoyl chloride. LCMS (M+H)+: m/z=493.2.
Reaction SMILES: [F:1][CH:2]([F:30])[CH:3]([N:19]1C(=O)C2=CC=CC=C2C1=O)[CH2:4][C:5](=[CH2:18])[CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O.O.NN.O.[ClH:35]>C(O)C>[ClH:35].[ClH:35].[F:1][CH:2]([F:30])[CH:3]([NH2:19])[CH2:4][C:5](=[CH2:18])[CH2:6][NH2:7]
Reactant: C=C(CC(C(F)F)N1C(=O)c2ccccc2C1=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: C=C(CN)CC(N)C(F)F
Temperature: 90 °C

Procedure:
A mixture of 1,1-difluoro-2,5-diphthalimido-4-methylene-pentane (7.77 g, 19 mmoles) prepared as in Step D above, and hydrazine hydrate (38 mL of a 1 M solution in ethanol) is heated for 5 hours at 90° C. After addition of water (30 mL) and concentrated hydrochloric acid (60 mL) heating is continued for one more hour at 90° C. After filtration, and evaporation to dryness, the residue is dissolved in water, and the remaining phthalhydrazide is elimated by filtration. Concentration under vacuum affords an oil which is used without further purification.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:29][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCCC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (10 g, 29.6 mmol), cyclohexyl amine (3.4 ml, 30.0 mmol), diisopropylethylamine (11 ml, 65.0 mmol) in propan-2-ol (150 ml) was heated at 80° C. for 14 h. The mixture was then cooled to 25° C. and stirred for 6 h. The resulting yellow solid was collected by vacuum filtration, washed with propan-2-ol (1×30 ml), and was air-dried to afford (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-cyclohexyl-amine (10.45 g, 90%). LCMS (Method G, ESI): RT=1.33 min, m+H=401.2; 1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.91 (s, 1H), 8.13 (d, J=7.6 Hz, 2H), 7.82 (d, J=4.1 Hz, 1H), 7.77 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.8 Hz, 2H), 6.99 (d, J=4.2 Hz, 1H), 4.12-4.01 (m, 1H), 2.02-1.93 (m, 2H), 1.76-1.54 (m, 3H), 1.55-1.38 (m, 4H), 1.33-1.20 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8](=[O:35])[C:9]([C:20]([C:22]2[CH:26]=[C:25]([CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[S:24][C:23]=2Cl)=[O:21])=[CH:10][NH:11][CH2:12][CH2:13]N2CCOCC2)=[CH:4][CH:3]=1.[C:38]([O-:41])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:9]2[C:20](=[O:21])[C:22]3[CH:26]=[C:25]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[S:24][C:23]=3[N:11]([CH2:12][CH2:13][CH:6]3[NH:7][CH2:8][CH2:38][O:41][CH2:5]3)[CH:10]=2)=[O:35])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)C(=CNCCN1CCOCC1)C(=O)c1cc(CN2CCOCC2)sc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCC2COCCN2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-((2-chloro-5-(morpholin-4-ylmethyl)thien-3-yl)carbonyl)-3-((2-morpholin-4-ylethyl)amino)acrylamide (Preparation 6, 4.3 g) and K2CO3 (1.6 g) in DMF (75 mL) is stirred at 100° C. for 5 h. The mixture is allowed to cool to room temperature and is concentrated in vacuo. The crude product is triturated with EtOAc and filtered to afford 1.4 g of the title compound as a yellow solid Physical characteristics. 1H NMR (300 MHz, DMSO-d6) δ 10.57, 8.71, 7.42-7.32, 4.55, 4.37, 3.74, 3.59, 3.50, 2.73, 2.44; MS (ESI+) m/z 531 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:14])([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])[C:3](O)=[O:4].[NH2:15][C@@H]1C(=O)N(CC(F)(F)F)C2C=C(F)C=CC=2O[C@@H]1CC>>[OH:1][C:2]([CH3:14])([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])[C:3]([NH2:15])=[O:4]
Reactant: CC(O)(C(=O)O)C(=O)NCC(F)(F)F
Reactant: CC[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1N
Product: CC(O)(C(N)=O)C(=O)NCC(F)(F)F

Procedure:
N-[(6R,7S)-6-Ethyl-2-fluoro-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-(R or S)-2-hydroxy-2-methyl-N′-(2,2,2-trifluoro-ethyl)-malonamide, entity A, was obtained according to the procedures described for example 2b using (S or R)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid, entity B (example 72), and (6R,7S)-7-amino-6-ethyl-2-fluoro-9-(2,2,2-trifluoro-ethyl)-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one, MS m/e (%): 504.0 (M+H+, 100). N-[(6R,7S)-6-Ethyl-2-fluoro-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-(R or S)-2-hydroxy-2-methyl-N′-(2,2,2-trifluoro-ethyl)-malonamide, entitiy B, was obtained according to the procedures described for example 2b using (S or R)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid, entity A (example 72), and (6R,7S)-7-amino-6-ethyl-2-fluoro-9-(2,2,2-trifluoro-ethyl)-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one, MS m/e (%): 504.0 (M+H+, 100).