Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:40])[C@:4](C1C=CC(C2C=CC=CC=2)=CC=1)([NH:6][C:7]([C:9]1[CH:14]=[N:13][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)=[CH:11][N:10]=1)=[O:8])[CH3:5].[Li+].[OH-].[CH2:43]1[CH2:47]O[CH2:45][CH2:44]1.CO>O>[C:43]1([C:47]2[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][C:3]([CH2:5][C@H:4]([NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:26])([F:27])[F:25])[CH:18]=3)=[CH:11][N:10]=2)=[O:8])[C:3]([OH:2])=[O:40])=[CH:45][CH:44]=1
Reactant: COC(=O)[C@@](C)(NC(=O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1)c1ccc(-c2ccccc2)cc1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1

Procedure:
A solution of biphenyl-4-yl-2(S)-{[5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carbonyl]-amino}-propionic acid methyl ester (0.170 g, 0.308 mmol) in THF:MeOH (4:1, 5 mL) was treated with LiOH (0.064 g, 1.54 mmol) in 1.5 mL of water by the general procedure C to give 0.140 g of pure 3-biphenyl-4-yl-2(S)-{[5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carbonyl]-amino}-propionic acid as a white solid. LCMS: 539 (M+2)+
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CO[C:11](=[O:27])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[C:13]=1[N:22]=[CH:23]N(C)C.C(O)(=O)C>O1CCCC1.O>[OH:27][C:11]1[C:12]2[C:13](=[C:14]([O:20][CH3:21])[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[N:22]=[CH:23][C:7]=1[C:6]#[N:8]
Reactant: CC#N
Reactant: COC(=O)c1c(OC)ccc(OC)c1N=CN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(OC)c2c(O)c(C#N)cnc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To 12.5 ml of tetrahydrofuran at -78° C. was added 8.8 ml of 2.5M n-butyllithium in hexanes. Then 1.18 ml of acetonitrile in 25 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -78° C. for 15 minutes. Then a solution of 2-(dimethylamino-methyleneamino)-3,6-dimethoxy-benzoic acid methylester in 62 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -78° C. for 10 minutes, then warmed to room temperature in 15 minutes. Acetic acid (3 ml) was added, followed by 200 ml of water. The product was collected, washed with water, and dried to give 1.57 g of 4-hydroxy-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 300-305° C.; mass spectrum (EI, m/e): M 230.0685.
Reaction SMILES: [C:1]([O:6][OH:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[OH-].[Na+].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>O>[C:12]([O:7][O:6][C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCC(C)(C)OO
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(C)OOC(=O)C(C)(C)C

Procedure:
The reaction is effected in a reactor arrangement of a first reactor of type E with a downstream reactor of type C. Before the start of the reaction, the first reactor is filled with a solution of 23.1% by weight of tert-amyl hydroperoxide, 9.9% by weight of potassium hydroxide and 8.3% by weight of sodium hydroxide in water. 20.2 kg/h of a solution of 88% by weight of tert-amyl hydroperoxide in water, 15.8 kg/h of a solution of 45% by weight of potassium hydroxide in water, 12.2 kg/h of a solution of 50% by weight of sodium hydroxide in water, 24.4 kg/h of water and 18.0 kg/h of pivaloyl chloride are then fed to the first reactor. Cooling with cooling water keeps the internal temperature in the first reactor at 18° C. and in the second reactor at 10° C. The reaction mixture withdrawn from the second reactor is mixed with 8.8 kg/h of isododecane and the organic phase is removed. The organic phase is washed successively with an 8% by weight solution of sodium hydroxide in water, with a solution of 10% by weight of sodium sulphite in water comprising acetic acid and with a 1% by weight solution of sodium hydrogencarbonate in water, and then dried by stripping in a packed column at 20° C. and 45 mbar. 35.0 kg/h of a 75% by weight solution of tert-amyl peroxypivalate in isododecane are obtained (93.5% based on pivaloyl chloride). The space-time yield is 2.82 kg/l·h.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)[CH3:10].Cl>CCO.O>[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][C:12]([O:11][CH2:9][CH3:10])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1)[CH3:10]
Reactant: CCOc1ccc(N)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOc1ccc(Nc2ccnc(Nc3ccc(OCC)cc3)n2)cc1

Procedure:
To a solution of 2,4-dichloropyrimidine (0.015 g, 0.1 mmol) in EtOH (1 mL) was added 4-ethoxyaniline (0.034 g, 0.025 mmol) and heated in a sealed tube at 70–80° C. for 24 h. Upon cooling the reaction was diluted with H2O (10 mL), acidified with 2N HCl, the solid obtained was filtered, washed with H2O and dried to give N2,N4-bis(4-ethoxyphenyl)-2,4-pyrimidinediamine (R926069). 1H NMR (CD3OD): δ 7.63 (d, 1H), 7.45 (d, 2H), J=9 Hz), 7.32 (d, 2H, J=9.3 Hz), 6.95 (d, 2H, J=6.9 Hz), 6.87 (d, 2H, J=8.7 Hz), 6.23 (d, 1H, J=7.2 Hz), 4.04 (m, 4H), 1.38 (m, 6H); LCMS: ret. time: 25.91 min.; purity: 99.5%; MS (m/e): 351 (MH+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([C:38]#[N:39])[C:21]=1[C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[F:37]>>[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([C:38]#[N:39])[C:21]=1[C:22]1[CH:27]=[C:26]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)[CH:25]=[CH:24][C:23]=1[F:37]
Reactant: CC1(C)OB(c2ccc(F)c(-c3c(F)cccc3C#N)c2)OC1(C)C
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1cccc(F)c1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 6,2′-difluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 6,2′-difluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white solid: δH (400 MHz, CDCl3) 7.29 (1H, d, J 7), 7.44-7.71 (6H, m), 8.11 (1H, s), 9.00 (1H, d, J 7); m/z (ES+) 401 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](Cl)=[O:7].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1)=[O:7]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of the product of Example 39A (13 mmol) in dichloromethane (100 mL) at 0° C. was added slowly tert-butyl piperazine-1-carboxylate (1.06 g, 13 mmol) and triethylamine (3.6 mL). After stirring for 2 hours, water was added slowly and the mixture was extracted with dichloromethane (3×200 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography on silica gel (200-300 mesh) eluting with 100/1 dichloromethane/methanol to provide the title compound. MS: 388 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=2[C:13]#[N:14].C(N(CC)CC)C.N1C=CC=CC=1.[SH2:28]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=2[C:13](=[S:28])[NH2:14]
Reactant: S
Reactant: N#Cc1cc(Cl)cc2cc(Cl)cnc12
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=S)c1cc(Cl)cc2cc(Cl)cnc12
Temperature: 40 °C

Procedure:
22 parts of 3,6-dichloro-8-cyanoquinoline (prepared by a method similar to that in Example 8) in 80 parts of triethylamine and 80 parts of pyridine were heated at 40° C., and H2S gas was slowly passed in for 4 hours. Water was then added and the solid was filtered off with suction, washed with water and acetone and recrystallized from ethyl acetate. 17 parts of 3,6-dichloroquinoline-8-thiocarboxylic acid amide of melting point 226° C. were obtained. The yield corresponds to 66% of theory.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[S:11]1[CH:15]=[CH:14][C:13]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C:17]2=O)=[CH:12]1>ClCCl.N1C=CC=CC=1>[Cl:3][C:17]1[N:16]([C:13]2[CH:14]=[CH:15][S:11][CH:12]=2)[C:24]2[C:19]([C:18]=1[CH:8]=[O:9])=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: O=C1Cc2ccccc2N1c1ccsc1
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1c(Cl)n(-c2ccsc2)c2ccccc12
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
Phosphorous oxychloride (1.9 mL, 20.9 mmol) is added slowly to a stirred solution of dimethylformamide (2 mL) and dichloromethane (2 mL) cooled to 0-5° C. After 5 min, a solution of the above 1-(thien-3-yl)-1H-indol-2-one (1.0 g, 2.65 mmol), pyridine (1 mL) and dichloromethane (4 mL) is added and the reaction is stirred at room temperature for 48 hr. The reaction mixture is poured into ice/water and extracted with ethyl acetate. Some solids are removed by filtration and the organic layer is separated, dried, filtered and concentrated. The residue is purified by chromatography eluting with pentane-10% ethyl acetate. Product containing fraction are combined and concentrated to afford 2-chloro-1-(thien-3-yl)-1H-indole-3-carboxaldehyde (694 mg, 57%) as a light orange solid. MS 262 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6](O)=[O:7].B.CO>O1CCCC1>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([CH2:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[CH2:5][CH2:6][OH:7]
Reactant: COC(=O)[C@H](CC(=O)O)CC1CCCCC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H](CCO)CC1CCCCC1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of (S)-2-cyclohexylmethyl-succinic acid 1-methyl ester (60.0 g, 263 mmol) and tetrahydrofuran (600 mL) was stirred at room temperature and then cooled to −5° C. over 30 min. To the reaction mixture was added 1.0 M borane in tetrahydrofuran (520 mL) dropwise over 45 min, keeping the internal temperature below 0° C. To the reaction mixture was added MeOH (100 mL) dropwise to quench the reaction. The reaction mixture was concentrated to about 100 mL by rotary evaporation. (Trifluoromethyl)benzene (200 mL) was added and volume was reduced to 25 mL by rotary evaporation. (Trifluoromethyl)benzene (100 mL) was added to the resulting thick oil and the volume was reduced to ˜25 mL to provide crude title product (56.3 g).
Reaction SMILES: Cl([O-])(=O)=O.[N:5]1[C:14]2[C:9](=CC=CC=2)[CH:8]=[CH:7][C:6]=1[C:15]([O-:17])=[O:16].[Cu+2:18].N1C2C(=CC=CC=2)C=CC=1[C:29]([O-:31])=[O:30]>>[Cu:18].[N:5]1[CH:14]=[CH:9][CH:8]=[C:7]([C:29]([OH:31])=[O:30])[C:6]=1[C:15]([OH:17])=[O:16]
Reactant: O=C([O-])c1ccc2ccccc2n1
Reactant: [Cu+2]
Agent: [O-][Cl+2]([O-])[O-]
Product: O=C(O)c1cccnc1C(=O)O
Product: [Cu]
Reaction time: 11 h

Procedure:
In another example of a preferred embodiment of the process, a sodium chlorate solution is added in small increments to a mixture of the other components, including copper oxide, which has been previously mixed and heated to reaction temperature (99°-101° C.). The acid concentration in the mixture is about 5 equivalents of acid per liter. The total chlorate addition will provide a chlorate molar excess of about 18% relative to the quinoline present. An exotherm becomes apparent after 6-8% of the chlorate has been added, and soon thereafter a suspension of copper quinolinate develops. Total chlorate addition is completed in 2-4 hours with total reaction time of 10-12 hours. The product, crude copper salt of pyridine-2,3-dicarboxylic acid, is isolated by filtration.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:26](=[O:29])[NH:27][CH3:28])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:10][CH:9]1[CH2:30][CH2:31][OH:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:26](=[O:29])[NH:27][CH3:28])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:10][CH:9]1[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)OC(C)(C)C)C(CCOC(C)=O)C1

Procedure:
A solution of 2-(2-hydroxyethyl)-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)piperazine-1-carboxylic acid tert-butyl ester, 60, (4.4 g, 10 mmol), acetic anhydride (13 mL), pyridine (1 mL) and N,N-dimethylaminopyridine (0.25 g) in dichloromethane (50 mL) is stirred for 1.5 hours. The solution is then extracted with water and 1 n HCl. The organic phase is dried, concentrated in vacuo, and the resulting crude product purified over silica gel (EtOAc/hexane 1:3 then 1:1) to afford the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])C)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[CH3:15].[CH2:16](OB(C=C)OCCCC)[CH2:17]CC.[C:29](=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[CH3:15][C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([O:8][CH2:9][CH2:11][CH3:29])=[CH:7][C:2]=1[CH:16]=[CH2:17]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1Cl
Reactant: C=CB(OCCCC)OCCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(OCCC)c([N+](=O)[O-])cc1C
Temperature: 90 °C

Procedure:
To a mixture of 1-chloro-2-methyl-4-nitro-5-isopropoxy-benzene (Intermediate 4, 870 mg, 3.77 mmol), vinylboronic acid dibutyl ester (1.24 mL, 5.6 mmol), and sodium carbonate (2.8 g, 26.4 mmol) in THF/H2O (20/5 mL) is added dichlorobis(triphenylphospine) palladium (II) (132 mg, 5% mmol). The reaction tube is sealed, the mixture is purged with N2 for 3 min and then heated at 90° C. under N2 for overnight. The reaction is cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The crude reaction mixture is extracted with ethyl acetate (3×100 mL). The organic extracts are combined, washed with brine and concentrated. The crude product is purified with silica gel column chromatography (10% ethyl acetate in hexanes) to afford 1-methyl-5-nitro-4-propoxy-2-vinyl-benzene as a yellow solid. 1-Methyl-5-nitro-4-propoxy-2-vinyl-benzene obtained from the previous step (360 mg, 1.63 mmol) is dissolved in DCM (20 mL) and is cooled to −78° C. O3 (g) is bubbled into the solution until the solution's color turns blue/gray. The solution is then purged with N2 (g) until the blue color disappears. The solution is warmed to room temperature and treated with triphenylphospine resin (2 g) pre-swelled in DCM (30 mL). After 30 min, the mixture is filtered, and the filtrate is concentrated to afford 2-methyl-4-nitro-5-propoxy-benzaldehyde as yellow solid.
Reaction SMILES: [O:1]=[C:2]([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:15]OC(OC)N(C)C.[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=1>C1C=CC=CC=1.O1CCCC1>[C:40]([O:39][C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][NH:23][CH:15]=[C:3]([C:2](=[O:1])[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:26][CH:27]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCCCC=CC(=O)CC(=O)OCC
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCCCC=CC(=O)C(=CNCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of ethyl 3-oxo-4-nonenate (1.00 g, 5.04 mmol) and N,N-dimethylformamide dimethyl acetal (0.94 ml, 7.08 mmol) in benzene (10 ml) was stirred at 70° C. for 1.5 hours under nitrogen stream. After cooling, a solution of 4-aminomethyl-2'-t-butoxycarbonylbiphenyl (2.86 g, ca. 10.1 mmol) in tetrahydrofuran (15 ml) was added to the reaction solution and the solution was stirred at room temperature for 2 hours and then concentrated to dryness. The resulting residue was purified by column chromatography on silica gel. The column was eluted with dichloromethane-ethyl acetate (1% to 5%) to give 1.65 g (66.6%) of the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH2:4]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>ClCCl>[CH3:23][S:24]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH2:4]1)(=[O:26])=[O:25]
Reactant: O=C1CC(CO)CCN1c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCN(c2ccccc2)C(=O)C1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
4-(Hydroxymethyl)-1-phenylpiperidin-2-one (0.27 g, 1.3 mmol) was dissolved in dichloromethane (15 mL), cooled to 0° C. and treated with triethylamine (1.0 mL, 7.2 mmol, 5.5 equiv). To the mixture was added methanesulfonyl chloride (0.10 mL, 1.3 mmol, 1 equiv), the mixture was warmed to ambient temperature and stirred for an additional 15 hours. The mixture was poured into water (25 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: N1C=CN=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:64][C:65]1[CH:73]=[CH:72][C:68]([CH2:69]NC)=[CH:67][CH:66]=1>CN(C=O)C>[F:64][C:65]1[CH:73]=[CH:72][C:68]([CH2:69][N:6]([CH3:2])[C:7]([C:9]2[C:17]3[NH:16][C:15]([NH:18][C:19]([C:21]4[N:22]=[CH:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:20])=[N:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:67][CH:66]=1
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccccc2cn1
Reactant: CNCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccc(F)cc1)C(=O)c1cccc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 66.2 %

Procedure:
To a solution of 100 mg (0.3 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (from Example 58) in DMF (2 mL) was added 200 mg (0.53 mmol) of HBTU and DIEA (0.5 mL). The mixture was stirred for 5 min then 140 mg (1.0 mmol) of N-(4-fluoro-benzyl)-N-methyl-amine was added. The resulted reaction mixture was heated at 70° C. for 1 h. After usual workup as described in general procedure A, the residue was purified by column chromatography eluting with DCM/EtOAc (v/v=1:1) to afford the 90 mg (66%) of isoquinoline-3-carboxylic acid {7-[(4-fluoro-benzyl)-methyl-carbamoyl]-1H-benzoimidazol-2-yl}-amide. LCMS: 454 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21](O)=[O:22])=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([NH2:27])=[O:22])=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(N)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) in DMF (2 mL) was added 1,1′-carbonyldiimidazole (39 mg, 0.24 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (308 L, 2.0 mmol) and stirred for 2 h at room temperature. The reaction mixture was then evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:1 to 0:1) afforded the title compound (33 mg, 48%) as a white solid after trituration from dichloromethane. MS: m/e=345.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH2:10][CH:11]=C)([CH3:9])[C:5]([O:7][CH3:8])=[O:6].CSC.C(Cl)Cl.C[OH:21]>>[CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:9])([CH2:10][CH:11]=[O:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=CCC(C)(C(=O)OC)C(=O)OC
Reactant: CO
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)C(C)(CC=O)C(=O)OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of the product of Example 31A (1.1 gm, 5.9 mmol) was dissolved in CH2Cl2/MeOH 10:1 (15 mL) and cooled to −78° C. To the solution was bubbled O3 over 20 minutes. The reaction solution was purged with N2 for a further 10 minutes and dimethyl sulfide (DMS) (3.6 gm, 59 mmol) was added and the reaction warmed to ambient temperature and stirred for a further 2 hours. The solvent was evaporated in vacuo and product purified by flash column chromatography (hexane/EtOAc 100:0 to 70:30) to collect Example 31B as an oil.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]([CH:18]1[CH:23]([CH3:24])[CH2:22][CH2:21][NH:20][CH2:19]1)[C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCl>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:23]([CH3:24])[CH:18]([N:8]([CH3:7])[C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:19]2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: CC1CCNCC1N(C)c1ncnc2[nH]ccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCC(C)C(N(C)c3ncnc4[nH]ccc34)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a stirred solution of 1 mL of pyridine and 9 ml of dichloromethane was added 40 mg (0.163 mmol) of the product from Method H and 20 L of 4-methoxy-benzenesulfonyl chloride and the resulting mixture stirred at room temperature for 18 hours. The reaction was then quenched upon addition of saturated NaHCO3 (aq), the organic layer was removed and the aqueous layer extracted with dichloromethane. The dichloromethane layer was dried over Na2SO4 and concentrated to dryness in vacuo. The residue was purified by PTLC (silica; 10:1 dichloromethane/methanol) affording 22 mg (32%) of the title compound as a light yellow solid. LRMS: 416.5 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)#[N:2].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1>C1C=CC=CC=1>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[O:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CCc1ccc(N=C=O)cc1
Reactant: OCc1cccnc1
Solvent: c1ccccc1
Product: N#CCc1ccc(NC(=O)OCc2cccnc2)cc1
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of p-cyanomethylphenyl isocyanate (3.75 g., 0.0237 mole) in 100 ml. of benzene was added 3-pyridyl carbinol (2.59 g., 0.0237 mole). An exothermic reaction occurred and a precipitate formed. The reaction mixture was heated to reflux then allowed to stand at ambient temperatures for 3 hrs. The solid was filtered off and dried to give 5.8 g. melting at 157°-161.5° C. The product is a 92% yield of 3-pyridylmethyl N-(4-cyanomethylphenyl)carbamate. Recrystallization from methanol gave a solid melting at 162°-163.5° C.