Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]([O:16][CH2:17][CH3:18])[CH3:15])[CH:13]=2)[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[C:4]([C:26](=O)[CH3:27])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]([O:16][CH2:17][CH3:18])[CH3:15])[CH:13]=2)[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[C:4]([CH:26]([NH2:35])[CH3:27])[CH:3]=1
Reactant: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2-c2cccc(F)c2)cn1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)N)c2-c2cccc(F)c2)cn1
Temperature: 25 °C

Procedure:
A mixture of 1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′-fluoro-5-methylbiphenyl-2-yl}ethanone (37 mg, 0.092 mmol), ammonium acetate (71 mg, 0.92 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.23 mL, 0.23 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to give the desired product (35 mg). LCMS calculated for C22H26ClFN3O (M+H)+: m/z=402.2. found: 402.2.
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.O[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: OCCc1ccccn1
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: c1ccccc1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)OCCc1ccccn1

Procedure:
2-(2-Pyridyl)ethyl Tributylstannyl Ether is prepared from 59.6 gm (0.1 mole) of bis(tributyltin) oxide and 24.6 gm (0.2 mole) 2-(β-hydroxyethyl)pyridine in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After 30 minutes refluxing water began to collect in the Dean-Starke tube and after refluxing 22 hours a total of 2.0 ml of water (theory 1.8 ml) had collected. This is evaporated on a rotating evaporator to provide 82.6 gm of straw colored liquid, which fractionated at reduced pressure. 66.4 gm. of a straw colored liquid are collected at 155°-158° C. at 0.5 mm. (Percent yield - 80.6). Infrared spectral analysis shows this to be the desired ether.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[C:10]([SH:21])=[N:9][CH:8]=1)=[O:6].Cl>O>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=1)[CH2:12][N:11]1[C:7]([C:5]([OH:6])=[O:4])=[CH:8][N:9]=[C:10]1[SH:21]
Reactant: COC(=O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Reaction time: 2 h

Procedure:
A solution of sodium hydroxide (2.70 g, 0.674 mole) in water (110 ml) was added to 1-(3,5-difluorobenzyl)-2-mercaptoimidazole-5-carboxylic acid methyl ester prepared as above (6.39 g, 0.0225 mole) and the resulting solution was stirred for 2 hours. The solution was cooled in ice, acidified to pH 2 with 3N hydrochloric acid, and the product was filtered and dried. The product was recrystallized from ethanol-water and dried to give 1-(3,5-difluorobenzyl)-2-mercapto-imidazole-5-carboxylic acid, m.p.: 240°-241° C. (5.66 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:31](=[O:32])[CH2:30][C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: O=C(O)Cc1ccncc1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)Cc4ccncc4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 6 from rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine and 4-pyridine-acetic acid; MS: m/e=425.3 (M+H+).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:23]([F:26])([F:25])[F:24])=[C:18]([CH:22]=1)[C:19](Cl)=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:19]([C:18]1[CH:22]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=1[C:23]([F:26])([F:24])[F:25])=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: CCCC[n+]1c(C)csc1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCN1C(C)=CS/C1=C\C(=O)c1cc(F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 5-fluoro-2-(trifluoromethyl)benzoyl chloride (36.2 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR, MS and LC/MS. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.90 (t, 3 H) 1.29-1.38 (m, 2H) 1.56-1.69 (m, 2 H) 2.28-2.32 (m, 3 H) 3.91-4.00 (m, 2 H) 6.00-6.05 (m, 1 H) 6.58-6.62 (m, 1 H) 7.37-7.45 (m, 2 H) 7.77-7.86 (m, 1 H); MS (ESI) positive ion 360 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6]1.[OH-].[Na+]>CO>[C:11]([CH:8]1[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:15])=[O:2])[CH2:6][CH2:7]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)CC1CCC(C(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C1CCC(CC(=O)O)CC1
Temperature: 25 °C

Procedure:
(4-tert-Butylcyclohexyl)acetic acid methyl ester (9.81 g, 46.5 mmol) was dissolved in methanol 950 ml) and cooled on an ice bath. 2M Sodium hydroxide solution (50 ml, 100 mmol) was added with stirring. When addition was complete the reaction mixture was allowed to warm to room temperature and was stirred overnight. The methanol was evaporated in vacuo and the remaining aqueous phase was acidified to pH1 with 1M hydrochloric acid. The aqueous phase was then extracted with ethyl acetate(3x). The organic extracts were combined, dried over magnesium sulphate, filtered and evaporated to give a white solid, (8.66 g, 94%). 1H-NMR δ (CDCl3) (as a mixture of cis-trans isomers), 2.43 (0.1 H, d, J=8Hz), 2.24 (0.9H, d, J =7 Hz), 1.92-1.47 (5H, m), 1.18-0.90 (5H, m) and 0.87 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].[CH:13](OCC)(OCC)OCC>C(O)C.C(OCC)(=O)C.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(N)cc1F
Reactant: CCOC(OCC)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To a solution of 2-fluoro-4-aminobenzonitrile [Ind. Chim. Belg., 39, 490-500 (1974)] (3.8 g, 28 mmol) in anhydrous triethyl orthoformate (50 mL) was added trifluoroacetic acid (0.16 g, 1.4 mmol). The solution was heated to reflux 45 min, cooled and concentrated to give a yellow crystalline solid. To a solution of this solid in absolute ethanol (60 mL) at 0° C. was added sodium borohydride (3.2 g, 84 mmol). The resulting suspension was stirred at RT for 20 min, heated at reflux for 1 h, cooled and concentrated to give a colorless solid. This residue was partitioned between ether and water and the aqueous layer was extracted with ether. The organic phases were combined, washed with brine and dried (sodium sulfate). Concentration gave a white solid which was slurried in 35% ethyl acetate:hexane (200 mL) and filtered to give the title compound (3.7 g, 88%). mp 110-112° C.; 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 1H), 6.4 (dd, 1H), 6.3 (dd, 1H), 2.9 (s, 3H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH:30]=[CH2:1])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CCCC1CCC(CCc2ccc(C3CCC(C=O)CC3)cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(c2ccc(CCC3CCC(CCC)CC3)cc2)CC1
Yield: 80.1 %

Procedure:
Potassium tert-butoxide (0.86 g, 7.01 mmol) was added slowly with stirring for 3 minutes to 32 ml of solution including methyltriphenylphosphonium bromide (3 g, 8.41 mmol) dissolved in THF. Then, the solution was stirred for 30 minutes at a room temperature and THF solution (25 ml) of 4-{4-[2-(4-propyl-cyclohexyl)ethyl]phenyl}cyclohexane carbaldehyde (2.39 g, 7.01 mmol) was added slowly dropwise to reaction mixture, and then was stirred at a room temperature for 24 hours. The precipitate was filtered under reduced pressure and the filtrate was washed by water (100 ml) and extracted with ether (20 ml×1 time). The aqueous layer was extracted by chloroform (20 ml×3 times). The organic layer was collected, washed by NaCl solution, dried by anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane, Rf=0.36) and was recrystallized by addition of chloroform and ethanol to obtain 1.9 g (80%) of 1-[2-(4-propyl-cyclohexyl)ethyl]-4-(4-vinyl-cyclohexyl)benzene.
Reaction SMILES: C(S)C.[H-].[Na+].C[O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=2[CH:18]=1.O>CN(C)C=O>[CH3:16][C:13]1([CH3:17])[C:12]2[CH:18]=[C:8]([OH:7])[CH:9]=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: COc1ccc2c(c1)C(C)(C)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCS
Product: CC1(C)COc2ccc(O)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of ethanethiol (12.6 parts) in dimethyl formamide (60 parts) was added with stirring under nitrogen over a period of 20 minutes to a mixture of sodium hydride (6.6 parts of 80% dispersion in oil) and dry dimethyl formamide (60 parts) cooled to 0° C. After 10 minutes, a solution of 2,3-dihydro-5-methoxy-3,3-dimethylbenzofuran (18 parts) in dimethyl formamide (40 parts) was added and the mixture boiled under reflux in a nitrogen atmosphere for 3 hours. The mixture was then added to water and the aqueous phase washed with chloroform, acidified with hydrochloric acid and extracted into ether. The ether was evaporated off to yield 2,3-dihydro-3,3-dimethyl-benzofuran-5-ol (5.4 parts) as a brown oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=1.[C:34]1([NH:40][CH2:41][CH2:42][NH2:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH:40]([CH2:41][CH2:42][NH:43][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[CH:33][CH:32]=1)=[O:18])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: NCCNc1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCCNc2ccccc2)N(C(=O)c2ccc(-c3ccccn3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(2-pyridinyl)benzoic acid, and N1-phenyl-1,2-ethanediamine, the title compound was obtained in 67% purity by HPLC. MS(ESI+): m/z=458.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:24]=[CH:23][C:17](C(OCC)=O)=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1.[CH3:30][Mg]I.CC[O:35][CH2:36][CH3:37]>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:24]=[CH:23][C:17]([C:36]([OH:35])([CH3:37])[CH3:30])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1
Reactant: C[Mg]I
Reactant: CCOCC
Reactant: CCOC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)(C)O)cc3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)benzoate (from Example 70) (1.0 eq.) in DCM at 0° C. was added 3.0 M methyl magnesium iodide (10 eq.) in ether and warmed to room temperature overnight. The reaction was cooled to 0° C. and quenched with 1N HCl aqueous solution and ether. After stirring for 15 minutes, the reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution. The two phases were separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by RP-HPLC using a 10-50% MeCN in water gradient followed by extraction in DCM to give 2-(4-(2-(5-amino-8 methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)propan-2-ol. 1H NMR (Acetone-d6): δ 8.73 (m, 2H), 8.22 (d, 1H), 7.40-7.44 (m, 3H), 7.20 (d, 2H), 7.12 (d, 1H), 6.5 (br, 2H), 3.94 (s, 1H), 3.21 (t, 2H), 3.08 (t, 2H), 2.44 (s, 3H), 1.47 (s, 6H). LRMS [M+H]=372.2
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:4]=1)=O.[NH:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>>[OH:31][CH:29]1[CH2:30][N:27]([CH2:1][C:3]2[N:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[N:6]=[C:5]([O:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH:4]=2)[CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C=O)nc(C(F)(F)F)n2)CC1
Reactant: OC1CNC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CN3CC(O)C3)nc(C(F)(F)F)n2)CC1

Procedure:
This compound was prepared according to the method of Example 41, Step 2 using tert-butyl 4-{[6-formyl-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate and azetidin-3-ol as starting materials. LCMS (M+H)+: 433.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:11])[CH3:10].[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:11])[CH2:10][C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(=O)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)CC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2′,6′-dichloroacetophenone (12.5 g, 66 mmol) and diethyl oxalate (14.6 g, 100 mmol) in 450 mL of anhydrous toluene, cautiously add sodium hydride (60% dispersion in mineral oil, 2.8 g, 70 mmol). Cautiously heat the reaction mixture to reflux under N2 for 1 h, cool to ambient temperature and pow onto ice-cold 1M HCl. Separate the layers and extract the aqueous phase with EtOAc (2×200 mL). Wash the combined organic extracts with brine, dry over MgSO4 and evaporate to obtain the title compound which is used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH2:23]([N:25]([CH2:31][CH3:32])[C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:24]>>[CH2:23]([N:25]([CH2:31][CH3:32])[C@@H:26]1[CH2:30][CH2:29][N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27]1)[CH3:24]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CCN(CC)[C@@H]1CCNC1
Product: CCN(CC)[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-N,N-diethylpyrrolidin-3-amine (1.2 equiv) to give 202 (M+1 438.0)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([NH2:17])=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[N:14]=[N:13]1.B(Br)(Br)Br.CO.[OH-].[Na+]>ClCCl.O>[NH2:17][C:16]1[N:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[F:1])[N:13]=[N:14][C:15]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3F)c2N)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Nc1c(-c2ccc(O)cc2)nnn1-c1ccc(C(F)(F)F)cc1F
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a stirred solution of 3-(2-fluoro-4-trifluoromethyl-phenyl)-5-(4-methoxy-phenyl)-3H-[1,2,3]triazol-4-ylamine (14) (0.400 g, 1.1354 mmol) in anhydrous dichloromethane (25 ml), cooled to −78° C. and under a nitrogen flow, a solution of boron tribromide (1.991 g, ˜0.75 ml, 7.9478 mmol) in 5 ml of anhydrous dichloromethane is added drop-wise. The mixture is allowed to reach room temperature spontaneously overnight and it is then cooled again in an ice-salt bath and the excess of the reagent is decomposed upon drop-wise addition of 10 ml of methanol and 10 ml of water. After 5 min stirring, 10% sodium hydroxide solution (10 ml) is added and the aqueous layer, once separated, is acidified with 10% hydrochloric acid solution and extracted with chloroform (3×70 ml). The combined organic layers are dried over MgSO4, filtered and evaporated to afford a solid residue (0.350 g). This is purified by column chromatography over silica gel (60-120 mesh) eluting with 16% ethyl acetate in hexane (0.150 g, 40% yield). M.p. 163.5-165.2° C. LC-ESI-HRMS of [M+H]+ shows 339.0853 Da. Calc. 339.086898 Da, dev. −4.7 ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[C:4]([CH3:22])[CH:3]=1.[C:23]1(B(O)O)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>C(OCC)(=O)C>[C:23]1([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[O:10])=[C:4]([CH3:22])[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: Cc1cc(Br)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Reactant: OB(O)C1=CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(C2=CCCCC2)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 150 °C
Yield: 69.7 %

Procedure:
To N-(4-bromo-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (50 mg, 0.14 mmol), cyclohexen-1-ylboronic acid (35 mg, 0.28), and Pd(dppf)C12-DCM (11 mg, 0.01 mmol) was added Na2CO3 (980 μL of 2 M, 1.96 mmol) and acetonitrile (2 mL). The reaction mixture was heated under microwave irradiation for 10 min at 150° C. under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel column chromatography (30-100% ethyl acetate/hexane) to obtain N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide as a white solid (35 mg, 70%). N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (35 mg, 0.10 mmol) was stirred vigorously with 10% Pd/C (wet) (30 mg, 0.01 mmol) under an atmosphere of H2 for 30 min at 50° C. The reaction mixture was filtered, concentrated in vacuo, and purified by HPLC (30-95% CH3CN/5 mM HCl) to yield N-(4-cyclohexyl-2-methylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (20 mg, 57% yield). LC/MS m/z 361.4 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 12.94 (d, J=6.0 Hz, 1H), 12.24 (s, 1H), 8.89 (d, J=6.5 Hz, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.55-7.51 (m, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 2.45 (m, 1H), 2.38 (s, 3H), 1.80-1.69 (m, 5H), 1.42-1.21 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[N:5]([N:23]([C:27]([O:29]C(C)C)=O)[C:24](=[O:26])[CH:25]=2)[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10]C(C)C)=[O:9].[CH2:33]([N:36]=C=O)[CH2:34][CH3:35].O1C[CH2:42][CH2:41][CH2:40]1>N1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]2[N:5]([N:23]([C:27]([NH:36][CH2:33][CH2:34][CH3:35])=[O:29])[C:24](=[O:26])[CH:25]=2)[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH:41]([CH3:42])[CH3:40])=[O:9]
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)n2c(cc(=O)n2C(=O)OC(C)C)N1
Reactant: CCCN=C=O
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: CCCNC(=O)n1c(=O)cc2n1C(c1cccc([N+](=O)[O-])c1)C(C(=O)OC(C)C)=C(C)N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The suspension of the title A compound from Example 1 (0.75 g, 2.0 mmol) in tetrahydrofuran (10 mL) and pyridine (1 mL) was treatetd at 0° C. under argon with n-propylisocyanate (0.24 mL, 2.5 mmol). After the addition was finished, the cooling bath was removed and the reaction was allowed to stir at room temperature for 5 hours. The resulting solution was diluted with ethyl acetate and was washed with 1N hydrochloric acid, water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed and the residue was crystallized from ether-hexanes to yield 701 mg of a colorless solid. The product was recrystallized from dichloromethane-isopropyl ether to yield 601 mg of the title compound, m.p. 160°-163° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6]C=C[CH:9]=2)[N:4]=CC=1.C[O:12][P:13]([O:16][CH3:17])[O:14][CH3:15].[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:15][O:14][P:13]([CH2:6][C:5]1[C:10]([CH2:9][P:13](=[O:12])([O:16][CH3:17])[O:14][CH3:15])=[N:1][C:18]2[C:19]([N:4]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:12])[O:16][CH3:17]
Reactant: c1ccc2nccnc2c1
Reactant: COP(OC)OC
Reactant: Cc1ccccc1
Product: COP(=O)(Cc1nc2ccccc2nc1CP(=O)(OC)OC)OC

Procedure:
This known compound is prepared by making a solution of quinoxaline (3.16 g, 10 mmol) in hot toluene (20 ml) and treating with trimethylphosphite (2.73 g, 22 mmol). The mixture is heated at reflux temperature for 24 hours. The cooled solution deposits [2,3-quinoxalindiyl]bis(methylene) bisphosphonic acid tetramethyl ester (2.70 g, m.p. 113°-114° C.) after recrystallization from toluene. V. A. Arbuzov et al. Izvest Acad. Nauk SSSR, 1961, 1016; 1954, E 868; (Chem Abstracts (CA) 55:27352b; CA 49:13222e) report a m.p. 115°-116° C.