Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:24])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)[N:18]=1)[CH3:11].[H-].[Na+].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37](OS(C)(=O)=O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].O>CN(C=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([N:22]2[CH:23]=[C:19]([C:17]3[CH:16]=[N:15][C:14]([NH2:24])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[N:18]=3)[CH:20]=[N:21]2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: C[C@@H](Oc1nc(-c2cn[nH]c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](Oc1nc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-(1H-pyrazol-4-yl)-pyrazin-2-ylamine (295 mg, 0.80 mmol) in anhydrous DMF (4 mL) was added NaH (60% in mineral oil, 30.7 mg, 0.80 mmol). The mixture was stirred at ambient temperature under nitrogen for 0.5 h, and then 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (223.5 mg, 0.80 mmol) was introduced. The reaction mixture was heated to 90° C. oil bath for 0.5 h under nitrogen, and cooled to ambient temperature. Water was added slowly to the mixture, which was extracted with EtOAc, washed with brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (265 mg, 59% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Li]CCCC.[CH3:26][C:27]([S@:30](/[N:32]=[C:33](/[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)\[C:34]([F:37])([F:36])[F:35])=[O:31])([CH3:29])[CH3:28].[NH4+].[Cl-]>C1COCC1>[C:27]([S@:30]([NH:32][C@:33]([C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[C:34]([F:35])([F:36])[F:37])=[O:31])([CH3:29])([CH3:26])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: CC(C)(C)[S@@](=O)/N=C(/c1ccc(F)cc1)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc([C@@](N[S@](=O)C(C)(C)C)(c3ccc(F)cc3)C(F)(F)F)cn2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
tert-Butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (0.242 g, 0.705 mmol) was taken up in THF (3.5 mL) and cooled to −78° C. A solution of nBuLi, 2.5 M in hexanes (0.31 mL, 0.775 mmol) was added at a fast dropwise rate from a syringe. The resulting mixture was stirred at −78° C. for 15 minutes. A solution of (R,Z)-2-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethylidene)propane-2-sulfinamide (0.225 g, 0.762 mmol) in THF (0.5 mL) was added at a fast dropwise rate from a syringe. The reaction mixture was stirred at −78° C. for 5 minutes before warming to room temperature. After 45 minutes, saturated NH4Cl was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by MPLC (0-80% EtOAc-hexanes) gave tert-butyl 4-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (304 mg, 0.543 mmol, 77% yield) as a pale yellow gum. The absolute stereochemistry was assigned randomly.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[O:37](S(C1C=CC(C)=CC=1)(=O)=O)[S:38]([C:41]1[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=1)(=O)=[O:39]>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH:27]([CH2:29][O:30][S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:39])=[O:37])[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c(C3CC(CO)C3)nc(-c3cccc(OCc4ccccc4)c3)c12
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CC(c3nc(-c4cccc(OCc5ccccc5)c4)c4c(N)nccn34)C2)cc1
Temperature: 25 °C

Procedure:
A solution of {3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol (23 mg, 0.057 mmol) in dry methylene chloride (3 mL) was charged with pyridine (0.1 mL) and Ts2O (21 mg, 0.063 mmol) at −20° C. under N2 atmosphere. The mixture was slowly warmed to rt overnight. The reaction was quenched with water (1 mL), diluted with ethyl acetate (20 mL), washed with sat. aq. NaHCO3 (10 mL) and brine (2×10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (eluting with EtOAc:MeOH=98:2→96:4), yielding the title compound as a white solid. Partial trans isomer was removed by chromatography and the ratio of cis and trans isomers raised to 8:1; MS (ES, Pos.): m/z 555 [MH+]. 1H NMR (CDCl3, 400 MHz) δ 2.27-2.35 (m, 2H), 2.41 (s, 3H), 2.55-2.62 (m, 2H), 2.80 (m, 1H), 3.66 (m, 1H), 4.07 (d, J=6.7 Hz, 2H), 5.01 (br s, 2H, NH2), 5.15 (s, 2H), 7.02-7.85 (m, 15H). Anal. Calcd for C31H30N4O4S.1/3H2O: C, 66.41; H, 5.51; N, 9.99. Found: C, 66.43; H, 5.44; N, 10.07.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][C:14]([N+:22]([O-])=O)=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H].Cl.[Sn](Cl)Cl>>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][C:14]([NH2:22])=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nc3ccc([N+](=O)[O-])cc3c(C)c2CC1
Reactant: [H][H]
Agent: Cl
Agent: Cl[Sn]Cl
Product: CCOC(=O)N1CCc2nc3ccc(N)cc3c(C)c2CC1
Yield: 95 %

Procedure:
9-Amino-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared from 9-nitro-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester by reduction with nascent hydrogen, generated in situ by concentrated hydrochloric acid and tin(II)chloride, at a temperature of 60°-80° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]([F:9])([CH3:8])[CH3:7])[CH2:3][OH:4].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CN(C)C1C=CN=CC=1>[Si:10]([O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][C:6]([F:9])([CH3:8])[CH3:7])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(F)C[C@H](N)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(F)C[C@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The amino alcohol (21.0 g) from Step 11 was dissolved in dichloromethane (300 mL) and the solution was cooled to 0° C. 4-(dimethylamino) pyridine (0.051 g) and tert-butyldimethylsilyl chloride (21 g) were added followed by triethylamine (25 mL). The mixture was stirred at room temperature overnight. The reaction mixture was slowly poured into 0° C. saturated aqueous ammonium chloride and extracted with dichloromethane (3×300 mL). The organic layer was washed with brine, dried with sodium sulfate and the solvents were removed in vacuo to yield (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-fluoro-4-methylpentan-2-amine.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1.S(Cl)(Cl)=O>C(Cl)Cl>[N:27]1([C:18](=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)[N:4]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1
Reactant: O=C(Nc1ccccc1)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: c1ccc2[nH]nnc2c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1C(=Nc1ccccc1)n1nnc2ccccc21
Yield: 58.1 %

Procedure:
A solution of 4-oxo-N-phenyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (0.153 g, 0.426 mmol), 1H-benzo[d][1,2,3]triazole (0.201 g, 1.69 mmol) and thionyl chloride (0.06 mL, 0.82 mmol) in methylene chloride (2 mL) was heated under microwave heating conditions at 80 watts of power for 10 min. After that time, the reaction was concentrated and the crude product purified by flash column chromatography (silica gel, hexanes to ethyl acetate) to give 0.114 g (58%) of 3-[1H-benzotriazol-1-yl(phenylimino)methyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale red solid that was used without further characterization.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:51][O:52][C:53]1[CH:61]=[CH:60][C:59]([N:62]2[CH:66]=[N:65][N:64]=[N:63]2)=[CH:58][C:54]=1[C:55](Cl)=[O:56]>C(OCC)(=O)C.O>[CH3:51][O:52][C:53]1[CH:61]=[CH:60][C:59]([N:62]2[CH:66]=[N:65][N:64]=[N:63]2)=[CH:58][C:54]=1[C:55]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)=[O:56]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Reactant: OCCC1(c2ccccc2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (56.0 g, 92.1 mmol), sodium carbonate (19.5 g, 184 mmol) in ethyl acetate (2 L) and water (2 L). Cool to about 0° C. in an ice bath. After 30 minutes, slowly add portionwise 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (92.1 mmol). After the addition is complete, warm to ambient temperature. After 1 hour, dilute the reaction mixture ethyl acetate and extract with water, 1M aqueous hydrochloric acid solution, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound. Rf =0.48 (9/1 dichloromethane/methanol).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C)n(CC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (1.82 g), 1-iodo-2,2-dimethylpropane (0.74 mL) and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O:13][CH3:14])=[O:12].ClCCl>C(Cl)CCC>[C:8]([C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:23])=[O:22])=[O:26])[N:7]=1)#[CH:9]
Reactant: C=Cc1cc(C)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CCCCCl
Solvent: ClCCl
Product: C#Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
In a dry flask under a nitrogen atmosphere was mixed 0.24 g of 2-amino-4-ethenyl-6-methylpyrimidine, 0.61 g of 2-carbomethoxybenzenesulfonylisocyanate and 25 ml of dry dichloromethane. The solution was heated to reflux for five minutes and allowed to stir at room temperature overnight. A precipitate formed. The reaction mixture was stripped, titurated with butyl chloride to give 0.56 g of the title compound as a solid, m.p. 185°-190° (dec); IR(nujol) 2111 (C≡C), 3250 (NH), 3321 (NH), 1716 (CO) and 1725 (CO) cm-1.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[NH2:9][C:10]1[C:15]([N:16]([CH3:18])[CH3:17])=[N:14][C:13]([Br:19])=[CH:12][N:11]=1.[CH3:20][N:21]([CH3:36])[C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32](Cl)(=[O:34])=[O:33].CCOCC>O1CCCC1>[CH3:20][N:21]([CH3:36])[C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32]([NH:9][C:10]1[C:15]([N:16]([CH3:17])[CH3:18])=[N:14][C:13]([Br:19])=[CH:12][N:11]=1)(=[O:34])=[O:33]
Reactant: CN(C)c1nc(Br)cnc1N
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)c1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: -60 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
A 2M solution of lithium diisopropylamide in tetrahydrofuran (THF)/heptane (1:1 v/v; 2.3 ml) was added over 10 minutes to a stirred solution of 2-amino-5-bromo-3-dimethylaminopyrazine (0.45 g) in dry THF (25 ml) at -60° C. The solution was stirred at -60° C. for 1 hour and then 5-dimethylamino-1-naphthalenesulphonyl chloride (0.62 g) was added portionwise over 5 minutes. The solution was allowed to warm to ambient temperature and then stirred for 18 hours. Ether (20 ml) was added and the solution was extracted with water (2×20 ml). The aqueous extracts were neutralised to pH 7 with 10% citric acid solution and extracted with ethyl acetate (2×20 ml). The organic extracts were combined and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column. The resulting solid was further purified by elution with dichloromethane through a fresh silica gel Mega Bond Elut column to give 5-dimethylamino-N-(5-bromo-3-dimethylamino-2-pyrazinyl)-1-naphthalenesulphonamide (0.125 g), m.p. 180°-182° C. (after trituration with ether); mass spectrum (+ve FAB, methanol/dichloromethane/DMSO/NBA): 450 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(N(CC)CC)C.[S:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>CN(C)C=O>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:28]3[CH2:29][CH2:30][S:26][CH2:27]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: C1CSCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSC3)nc21
Yield: 50.2 %

Procedure:
A solution of 1.0 g (3.7 mmol) of 7-chloro-1,4-dihydro-1-ethyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.8 g (8.0 mmol) of triethylamine, 1.1 g (12.0 mmol) of 97% thiazolidine in 30 ml of N,N-dimethylformamide was stirred at room temperature for 18 hours. The solvent was removed at reduced pressure and the residue dissolved in water using 1.0N sodium hydroxide to adjust to pH 12.0. The solution was filtered to remove a trace of insoluble material and the filtrate was acidified to pH=3.0 with 6.0N hydrochloric acid. The precipitate was removed by filtration, washed with water and the wet filter cake recrystallized from ethanol clarifying with charcoal to give 0.6 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(3-thiazolidinyl)-1,8-naphthyridine-3-carboxylic acid; mp 288°-289° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[NH2:13][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:5]=1[O:4][C:3]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=1[Cl:1])[C:9]#[N:10]
Reactant: N#Cc1ccc(Oc2cc(Cl)ccc2Cl)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Oc2cc(Cl)ccc2Cl)c(N)c1
Yield: 103.7 %

Procedure:
The coupled product 34 was reduced with sodium hydrosulfite ((49.76 g, 268.56 mmol) in a mixture of THF (200 mL) and water (100 mL). After the reaction was complete, THF was removed in vacuo. The product was precipitated out from the remaining reaction mixture, and was collected via vacuum filtration to yield compound 35 (12.961 g, 103.7% yield, 97.3% pure). 1H NMR (500 MHz, DMSO-d6): δ 7.64 (d, J=9 Hz, 1H), 7.31 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.13 (d, J=2 Hz, 1H), 7.08 (d, J=2 Hz, 1H), 6.93 (dd, J1=8 Hz, J2=2 Hz, 1H), 6.74 (d, J=8 Hz, 1H), 5.63 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([CH3:10])[CH:4]=1.[Br:11][C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[CH3:10][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:17]([C:15]2[S:16][C:12]([Br:11])=[CH:13][CH:14]=2)(=[O:19])=[O:18])[CH:8]=[C:7]([CH3:9])[N:6]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: Cc1cc(CN)cc(C)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CNS(=O)(=O)c2ccc(Br)s2)cc(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
To a stirred solution of commercially available 4-aminomethyl-2,6-dimethyl-pyridine [CAS-No. 324571-98-4] (0.24 g, 1.76 mmol) in THF (8 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (0.46 g, 1.76 mmol) dissolved in THF (8 ml) and triethylamine (0.27 ml, 1.94 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) and crystallization from dichloromethane/hexane to yield the title compound (0.33 g, 52%) as a light red solid. MS (ISN) 359.0 [(M−H)−], mp 138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:17][CH3:18])=[O:8]
Reactant: CCO
Reactant: Cc1ccc(Cl)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Cl)ccc1C
Temperature: 25 °C

Procedure:
5-chloro-2-methylbenzoic acid (5.04 g, 29.5 mmol) was dissolved in 100 mL ethanol in a 250 mL round bottom flask fitted with a water condenser. 0.5 mL concentrated sulfuric acid was added and the solution heated to reflux. The solution was heated for 48 h and cooled to ambient temperature. The ethanol was removed under reduced pressure. The resultant oil was taken up in 300 mL diethyl ether and washed with saturated aqueous sodium bicarbonate (2×300 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield 5.12 (87%) of ethyl 5-chloro-2-methylbenzoate as a clear oil.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[N:25][C:26](Cl)=[CH:27][C:28]=2[C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[C:18]([C:36]#[N:37])[CH:17]=1)(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:36]([C:18]1[CH:17]=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:14])=[O:15])[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:24]=[N:25][C:26]([C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=2)=[CH:27][C:28]=1[C:29]1[CH:34]=[N:33][CH:32]=[N:31][CH:30]=1)#[N:37]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2cnc(Cl)cc2-c2cncnc2)c(C#N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1cncnc1
Reaction time: 0.17 h
Yield: 753.9 %

Procedure:
10 mg (0.02 mmol) of tert-butyl((4-((6-chloro-4-(pyrimidin-5-yl)pyridin-3-yl)oxy)-3-cyanophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 3.7 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2 mg (10 mol %) of Pd(PPh3)4, 5.5 mg (0.05 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 80 mg (70% yield) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:13][NH2:14])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[C:22]1([CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][C:30](Cl)=[O:31]>O1CCCC1>[Cl:2][C:3]1[C:4]([CH2:13][NH:14][C:30](=[O:31])[CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH3:33])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1ccccc1CCC(=O)Cl
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1CCC(=O)NCc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (1 mmol, 0.247 g) in tetrahydrofuran (5 ml) was added triethylamine (2 mmol, 0.202 g) at room temperature and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate added to a solution of 3-(2-tolyl)propionyl chloride (1.1 mmol, 0.2 g) in tetrahydrofuran (5 ml) at room temperature. After 4 hours stirring at room temperature the solvent was evaporated and the residue washed with water. The solid was filtered and washed with diethyl ether/light petroleum (1:20) to give the title product, m.p. 152-3° C.