Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([CH:8]([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[C:9]([F:12])([F:11])[F:10])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[F:1][C:2]1([CH:8]([O:13][Si:14]([CH2:17][CH3:18])([CH2:19][CH3:20])[CH2:15][CH3:16])[C:9]([F:11])([F:12])[F:10])[CH2:3][CH2:4][N:5]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:6][CH2:7]1
Reactant: CC[Si](CC)(CC)OC(C(F)(F)F)C1(F)CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC[Si](CC)(CC)OC(C(F)(F)F)C1(F)CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
4-Fluoro-4-[2,2,2-trifluoro-1-(triethylsiloxy)ethyl]-piperidine (300 mg, 0.951 mmol) was dissolved in dichloromethane (6 mL). To this, triethylamine (0.199 mL, 1.43 mmol) and methanesulfonyl chloride (0.140 mL, 1.43 mmol) were added and the mixture was stirred at room temperature for 30 minutes. The reaction was stopped by addition of water to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 4-fluoro-1-methanesulfonyl-4-[2,2,2-trifluoro-1-(triethyl-siloxy)ethyl]piperidine (309 mg, yield: 83%).
Reaction SMILES: [C:1](Cl)(=[O:3])C.C[OH:6].[CH3:7][O:8][N:9]=[C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][C:11]1=NO>O>[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:10](=[N:9][O:8][CH3:7])[C:11]([O:3][CH3:1])=[O:6]
Reactant: CO
Reactant: CON=C1C(=NO)Oc2ccccc21
Reactant: CC(=O)Cl
Solvent: O
Product: CON=C(C(=O)OC)c1ccccc1O
Temperature: 25 °C

Procedure:
5 g of acetyl chloride (0.064 mol) are added dropwise to 50 ml of methanol. 4.8 g (0.025 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime are dissolved in this mixture, and the reaction mixture is then heated under reflux for 12 hours. After cooling to room temperature, the mixture is poured into water and the product is extracted with diethyl ether. The organic phase is washed with aqueous sodium bicarbonate solution and dried over sodium sulphate, and the solvent is distilled off under reduced pressure. This gives 4.33 g of crude product which, according to HPLC, contains 27.4% methyl E-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=1.48 and 56% methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.37.
Reaction SMILES: C(OC([N:8]([CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]2[C:19]([CH3:25])=[C:20]([C:22]([OH:24])=O)[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.[NH2:33][NH2:34].[C:35]([OH:43])(=O)[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>>[CH3:25][C:19]1[C:18]2[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:14][CH:15]=[CH:16][C:17]=2[O:21][C:20]=1[C:22]([NH:33][NH:34][C:35](=[O:43])[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)=[O:24]
Reactant: Cc1c(C(=O)O)oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c12
Reactant: NN
Reactant: O=C(O)c1ccncc1
Product: Cc1c(C(=O)NNC(=O)c2ccncc2)oc2cccc(OCCCNCc3cccnc3)c12

Procedure:
This compound was prepared from 4-[3-(tert-butoxycarbonyl-pyridin-3-ylmethyl-amino)-propoxy]-3-methyl-benzofuran-2-carboxylic acid (Example 139-a) and isonicotinic acid hydrazine in a similar manner to Example 139-b and 139-c. Yellow solid. ESI-MS: m/z 460 (MH+), 1H-NMR (CD3OD) δ: 2.11 (2H, tt, J=5.8, 7.3 Hz), 2.66 (3H, s), 2.90 (2H, t, J=7.3 Hz), 3.89 (2H, s), 4.21 (2H, t, J=5.8 Hz), 6.78 (1H, d, J=7.9 Hz), 7.13 (1H, d, J=8.6 Hz), 7.37 (2H, m), 7.86 (1H, m), 7.89 (2H, dd, J=1.7, 4.5 Hz), 8.43 (1H, m), 8.54 (1H, m), 8.74 (2H, dd, J=1.7, 4.5 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[C:5]([NH2:8])=[N:6][N:7]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.C(OCC)(=O)C>CN(C=O)C>[NH2:8][C:5]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[C:3]([CH2:2][NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)=[N:7][N:6]=1
Reactant: NCC1=NN=C(N)C1=NNc1ccc(F)c(F)c1
Reactant: O=C(Cl)c1cccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC1=NN=C(CNC(=O)c2cccnc2)C1=NNc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a solution of 5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (245 mg, 0.97 mmole) and triethylamine (202 mg, 2 mmole) in 10 mL of anhydrous DMF was added nicotinoyl chloride (178 mg, 1.0 mmol) in 7 mL of anhydrous DMF. The reaction was stirred at ambient temperature for 1 hour, and then mixed with saline and ethyl acetate. The title compound was purified by column chromatography (CH2Cl2:CH3OH=13:1) to yield 119 mg of the title compound as a yellow powder. MS (m/z, ES−): 356 (M−1, 20%); 1H NMR (ppm, 400 MHz, DMSO-d6) □δ 11.86 (br s, 1H), 9.04 (brs, 1H), 9.01 (s, 1H), 8.67 (d, 1H), 8.19 (d, 1H), 7.71 (dd, 1H), 7.57 (m, 1H), 7.47 (m, 2H), 7.11 (br s, 2H), 4.69 (s, 2H).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH2:19]([O:21][C:22](=[O:35])[CH:23]([O:32][CH2:33][CH3:34])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[CH3:20].[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51]O)=[CH:46][CH:45]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:19]([O:21][C:22](=[O:35])[CH:23]([O:32][CH2:33][CH3:34])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:51][CH2:50][C:47]2[CH:48]=[CH:49][C:44]([O:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:45][CH:46]=2)=[CH:29][CH:30]=1)[CH3:20]
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OCc3ccccc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
Azodicarbonyl dipiperidine (7.5 g; 30 mmole) was added to 2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) (7 g; 30 mmole), 2-(4-benzyloxyphenyl)ethanol (6.8 g; 30 mmole) and triphenylphosphine (7.8 g; 30 mmole) dissolved i dichloromethane. After stirring at room temperature overnight the solvent was evaporated in vacuo and diethyl ether was added. The solid material was filtered off after 1 hour and the filtrate was evaporated in vacuo. Purification by chromatography on silica gel using ethyl acetate:dichloromethane as eluant gave 10 g (yield 75%) of 3-{4-[2-(4-benzyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13]=2[CH:14]=1.Br[CH:17]=[C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([CH3:19])=[CH:17][N:6]2[C:5]3[N:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:13]=3[C:12]3[CH2:11][N:10]([CH3:15])[CH2:9][CH2:8][C:7]2=3)=[CH:21][CH:22]=1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(C)cnc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a degassed solution of 3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene (201 mg, 1.0 mmol), 1-(2-bromo-1-methyl-vinyl)-4-fluoro-benzene (279 mg, 1.3 mmol), potassium phosphate (530 mg, 2.5 mmol) in DMF (4 mL), L-proline (28 mg, 0.25 mmol) and cuprous iodide (47 mg, 0.25 mmol) were added. The reaction mixture was stirred at 120° C. for 8 h. The reaction mixture was cooled to RT, diluted with water (20 mL) and extracted with EtOAc (4×20 mL). The organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by silica gel flash chromatography to yield 9-[2-(4-fluoro-phenyl)-propenyl]-3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene. 1H NMR (CDCl3, freebase) δ (ppm): 8.1 (s, 1H), 7.57 (m, 3H), 7.07 (t, 2H), 6.92 (s, 1H), 3.62 (s, 2H), 2.8 (s, 4H), 2.6 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH:5]=O)[CH2:4][CH2:3]1.[CH3:7][O:8][C:9](=[O:13])[CH:10](Cl)Cl.[Na].[NH2:15][C:16]([NH2:18])=[S:17]>C(OCC)C.CO>[CH3:7][O:8][C:9]([C:10]1[N:15]=[C:16]([NH2:18])[S:17][C:5]=1[C:2]1([CH3:1])[CH2:3][CH2:4]1)=[O:13]
Reactant: CC1(C=O)CC1
Reactant: NC(N)=S
Reactant: COC(=O)C(Cl)Cl
Agent: [Na]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1nc(N)sc1C1(C)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Combine 1-Methyl-cyclopropanecarbaldehyde (4.88 g, 58.01 mmol) and methyldichloroacetate (5.46 mL, 52.74 mmol) in diethyl ether (20 mL); cool to 0° C. Add dropwise a solution of sodium (1.21 g, 52.74 mmol) in methanol (20 mL). Stir the reaction mixture for 4 hours at 0° C. under N2. Extract the mixture with diethyl ether versus water. Dry the resulting organics over magnesium sulfate, filter, and concentrate to a clear liquid. Combine the liquid with thiourea (4.42 g, 58.01 mmol) in methanol (25 mL). Heat the reaction mixture for 14 hours at 60° C. under N2. Concentrate in vacuo and purify on a plug of silica gel, eluting with hexanes→3% methanol in dichloromethane→5% methanol in dichloromethane to afford product (5.10 g, 46% over two steps). MS (ES), m/z 213 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)[C:17]([O:19]C)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:23][CH:22]=2)[C:17]([OH:19])=[O:18])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)O)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A mixture of methyl ({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate (2.52 g, 5.19 mmol) and 5N NaOH (5.18 mL) in THF (32 mL) and methanol (32 mL) was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in water and neutralized with HCl to pH˜6. The precipitated solid was filtered to provide 1.61 g of ({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetic acid as a white solid. Yield 66%. mp 245-247° C. Electrospray Mass Spec 473.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14](=[O:25])[N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[O:25]=[C:14]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)[CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:5](=[O:26])[C:4]([OH:27])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCc3ccccc3C2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCC(=O)N2CCc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.1 %

Procedure:
4-[2-Oxo-2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.3 g) in methanol (10 mL) was treated with sodium carbonate (0.113 g) in water (3 mL), and the mixture was stirred at room temperature for 20 minutes. After the solvents were removed in vacuo, water (10 mL) was added and the solution acidified with 3N hydrochloric acid, then the aqueous layer was extracted with dichloromethane-tetrahydrofuran (1:1). The organic layer was dried (MgSO4), evaporated and the residual solid was crystallized from acetone-tetrahydrofuran-hexane to yield 0.078 g of 4-[2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethoxy]-alpha-oxobenzeneacetic acid, mp 218°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(I)ccc1Cl
Temperature: 12.5 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
A 1 L 4-necked flask equipped with thermometer and mechanical stirrer (operating at 150 RPM) was charged with 2-chloro-5-iodobenzoic acid (14.1 g, 0.05 mol), DCM (70.5 mL) and oxalyl chloride (5.5 mL, 0.06 mol). After stirring for 10 min, the mixture was cooled to 10 to 15° C. and DMF (0.15 mL, 1.92 mmol) was added by syringe over 10 min in two bolus of 0.1 and 0.05 mL while keeping the reaction temperature below 20° C. After the addition was completed, the mixture was warmed to 25° C. and stirred for 16 h. The mixture was concentrated and the residue was dried under vacuum at 30° C. for 5 h to give 15.0 g of product as a white solid. Yield: 100%. LCMS-0013: 99% Purity. 1H NMR (CDCl3, 400 MHz): 8.33 (d, J=2.4 Hz, 1H), 7.81˜7.84 (dd, J=2.4 Hz, 8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([Cl:12])[N:3]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([Cl:12])[N:3]=1
Reactant: O=c1[nH]c2cc(Cl)nc(Cl)c2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c(Cl)nc(Cl)c([N+](=O)[O-])c2[nH]1
Temperature: 125 °C

Procedure:
To a solution of 4,6-dichloro-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.6 g, 2.94 mmol) from Step C in conc. H2SO4 (15 mL) was added KNO3 (2.97 g, 29.4 mmol) and the reaction mixture was heated at 125° C. for 2 h. After cooling, the reaction was mixed with ice and the solid precipitate was isolated by filtration and washed with cold 1420 to give the title compound. MS: m/z=250 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16]2[N:17]=[N:18][N:19]([CH3:21])[N:20]=2)[C:10]2[CH:37]=[C:38]3[C:43](=[CH:44][C:9]1=2)[CH2:42][CH2:41][CH2:40][CH2:39]3)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:36][C:33]([F:34])([F:35])[C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=1)[CH2:22][N:15]([C:16]1[N:17]=[N:18][N:19]([CH3:21])[N:20]=1)[C@H:11]1[CH2:12][CH2:13][CH2:14][NH:8][C:9]2[CH:44]=[C:43]3[C:38](=[CH:37][C:10]1=2)[CH2:39][CH2:40][CH2:41][CH2:42]3
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc4c(cc32)CCCC4)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)CCCC4)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3,4,5,7,8,9,10-octahydro-naphtho[2,3-b]azepine-1-carboxylic acid tert-butyl ester (0.67 mmol) in dichloromethane (18 mL) add trifluoroacetic acid (2 mL). After stirring at room temperature for 1 h, quench with concentrated sodium carbonate (10 mL) and dilute with dichloromethane (20 mL) and water (20 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel eluting with ethyl acetate/hexane (5-30%) to afford the title compound as a colorless foam. MS (ES+): 525 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25](F)[C:22]=1[C:23]#[N:24].O>CN(C=O)C>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([O:15][CH2:14][CH:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[O:4][CH3:3])[CH2:13][CH2:12]2)[C:22]=1[C:23]#[N:24]
Reactant: COc1ccccc1CC1CCC(CO)CC1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1CC1CCC(COc2cccc(F)c2C#N)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
To a cold (ice water) suspension of sodium hydride (0.043 g; 1.1 mmol) in anhydrous DMF (1.4 mL) is added a solution of [4-(2-methoxybenzyl)cyclohexyl]methanol (0.21 g, 0.9 mmol) in anhydrous DMF (1.4 mL) over 11 minutes. After allowing to room temperature over 2 hours, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (0.14 g; 0.99 mmol) in anhydrous DMF (1.4 mL), and allowed to room temperature over 18 hours. The mixture was poured into a water (40 mL) solution and extracted with ethyl acetate (EtOAc) (4×10 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to purify by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain 2-fluoro-6-[4-(2-methoxybenzyl)cyclohexylmethoxy]benzonitrile (0.09 g, 28% yield).
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.N1C=CC(C(O)=O)=N1.N1C=CC=CC=1.[NH2:36][C:37]1[C:45]([CH3:46])=[CH:44][C:43]([Cl:47])=[CH:42][C:38]=1[C:39](O)=[O:40]>C(#N)C.O>[Br:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:39](=[O:40])[C:38]3[CH:42]=[C:43]([Cl:47])[CH:44]=[C:45]([CH3:46])[C:37]=3[N:36]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Agent: O=C(O)c1cc[nH]n1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 mL), and the mixture was cooled to −5° C. A solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Example 5, Step 1D) (3.02 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then a mixture of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of Example 1 Step A) (1.86 g, mmol) and pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added, rinsing with more acetonitrile (5 mL). The mixture was stirred 15 minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise over 5 minutes at a temperature of −5 to 0° C. The reaction mixture was stirred minutes more at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (20 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile (2×3 mL), and dried under nitrogen to afford the title product as a light yellow powder, 4.07 g (90.2% crude yield), melting at 203-205° C. HPLC of the product using a Zorbax® RX-C8 chromatography column (4.6 mm×25 cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 95.7% of total chromatogram peak area.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[CH2:21][CH2:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)nc1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(Cc3ccccn3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-[(2-pyridyl)-methyl]-piperazine (0.097 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.163 g, 83%); 1H-NMR (500 MHz, DMSO-d6) 2.57 (br s, 4H, piperazine N(CH2)2), 3.08 (br s, 4H, piperazine N(CH2)2), 3.65 (s, 2H, NCH2), 6.97 (s, 2H, NH2), 7.26 (ddd, J=7.45, 4.80, 1.00 Hz, 1H), 7.46 (d, J=7.80 Hz, 1H), 7.77 (td, J=7.66, 1.80 Hz, 1H) and 8.48 (dm, J=4.09 Hz, 1H) (pyrid-2-yl protons), 8.16 (s, 1H, 6-H);
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:22])(=[O:21])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5][N:4]=[N:3]1.Br[CH2:25][C:26]([O:28]CC)=[O:27]>C(O)C>[C:26]([CH2:25][N:4]1[N:3]=[N:2][C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:21])(=[O:22])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5]1)([OH:28])=[O:27]
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: O=C(O)Cn1nnc(-c2ccc3c(c2)S(=O)(=O)c2ccccc2C3=O)n1
Reaction time: 2 h

Procedure:
Sodium (0.46 g) was dissolved in ethanol (20 ml) and 3-(5-tetrazolyl)thioxanthone-10,10-dioxide (6.24g) was added. Ethyl bromoacetate (3.34 g) was added to the mixture, which was boiled under reflux for 1.5 hr. The ester intermediate was deposited during this time, and after cooling was filtered off, washed with water and dried, m.p. 194°-195° C. The ester was boiled with concentrated hydrochloric acid (40 ml) and acetic acid (120 ml) for 2 hr. On cooling 3-(2-carboxymethyl-5-tetrazolyl)thioxanthone-10,10-dioxide crystallised out, and was filtered off, recrystallised from acetic acid, and dried, m.p. 252° C. with decomposition.
Reaction SMILES: O1CCCC1.N.[C:7](#[N:16])[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[H][H]>[Co].O>[C:8]1([CH2:7][NH2:16])[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Co]
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(CN)cc1
Temperature: 120 °C

Procedure:
A stirred autoclave was charged with 400 ml. tetrahydrofuran (THF), 100 ml. ammonia, 50 g. terephthalonitrile (TPN) and 6.0 g. cobalt supported catalyst and various amounts of water. The autoclave was heated to 120° C. Hydrogen was introduced rapidly until the selected pressure was reached. The absorption of hydrogen started immediately and additional hydrogen was added to keep the pressure at the selected level. The course of the reaction was monitored by measuring the volume of hydrogen consumed and by periodic withdrawal of a small sample of the reaction mixture for analysis. When the analysis indicated that all of the terephthalonitrile had reacted, the agitation was stopped and the reactor was cooled rapidly and vented. The reaction mixture was filtered to recover the catalyst and then was flash evaporated to remove solvent. The residual oil was flash distilled at about 100° C. and 0.5 mm Hg. to give practically pure p-xylylene diamine. A small amount of high boiling residue remained in the distillation pot. Results of experiments conducted with various amounts of water and at 1500 and 2500 psig are listed in Table I.