Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]=1[C:25]([O:27][CH3:28])=[O:26].[N:29]1[NH:30][C:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)=[CH:32][CH:33]=1>>[CH3:28][O:27][C:25]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13](=[O:14])[C:4]=1[CH2:3][NH:2][C:38](=[O:39])[C:37]1[CH:36]=[CH:35][C:34]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)=[CH:42][CH:41]=1)=[CH:11][CH:10]=[C:9]([C:15]([F:16])([F:17])[F:18])[N:8]=2)=[O:26]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Reactant: O=C(O)c1ccc(-c2ccn[nH]2)cc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc(-c3ccn[nH]3)cc2)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1

Procedure:
4-oxo-1-phenyl-3-{[4-(2H-pyrazol-3-yl)-benzoylamino]-methyl}-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester was prepared starting from intermediate J and 4-(2H-pyrazol-3-yl)-benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.99 (br. s., 1H) 8.90 (d, J=7.85 Hz, 1H) 8.52 (br. s., 1H) 7.97 (d, J=8.15 Hz, 1H) 7.77-7.90 (m, 5H) 7.51-7.60 (m, 3H) 7.43 (dd, J=6.79, 2.87 Hz, 2H) 6.79 (s, 1H) 4.46 (d, J=4.53 Hz, 2 H) 3.38 (s, 3H) LCMS calcd. for C28H20F3N5O4 [(M+H)+] 547.1, obsd. 548.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][O:19][C:20](OCC)=[O:21])=[NH:17])=[CH:12][N:11]3[CH:25]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[NH:17][C:20](=[O:21])[O:19][N:18]=4)=[CH:12][N:11]3[CH:25]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)ONC(=N)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=c1[nH]c(-c2ccc3nc(-c4ccc(F)cc4)cn3c2)no1
Yield: 14 %

Procedure:
The compound was synthesized by treatment of 2-(4-fluoro-phenyl)-N-ethoxycarbonyloxy-imidazo[1,2-a]pyridine-6-carboxamidine (example 60) with aqueous sodium carbonate. Yield: 14%. MS: M+H+=296.95.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC(C)Oc1cc(N2CCCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1cc(N2CCCN(C)CC2)ccc1N
Yield: 91.8 %

Procedure:
A solution of 267 mg of 4-(4-methyl-1,4-diazepan-1-yl)-2-(propan-2-yloxy)nitrobenzene in 90 ml of methanol is hydrogenated using an H-cube, on a cartridge of 10% palladium-on-carbon, at a flow rate of 1 ml/min. The hydrogenated solution is concentrated under reduced pressure, so as to obtain 220 mg of 4-(4-methyl-1,4-diazepan-1-yl)-2-(propan-2-yloxy)aniline in the form of a grey oil.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:18]([F:20])=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:18]([F:20])=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2CC3)cn1
Yield: 100.1 %

Procedure:
To a solution of compound 2B (13.6 mg, 0.036 mmol) in MeOH (5 mL) was added 10% Pd/C (3 mg) and the mixture was stirred under a balloon filled with hydrogen for 1 hour. The reaction was filtered through a 0.45 micron filter membrane and concentrated in vacuo to give the title compound (13.6 mg, 100%). HPLC Rt=2.996 min. (Column: YMC ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA); LCMS Found: (M+H)+=378.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:14][C@H:13]2[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[C:7]1=[O:15])C.[NH3:17]>CO>[O:15]=[C:7]1[C@@H:8]2[C@@H:13]([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:14][N:6]1[CH2:5][C:4]([NH2:17])=[O:3]
Reactant: N
Reactant: CCOC(=O)CN1C[C@@H]2CCCC[C@@H]2C1=O
Solvent: CO
Product: NC(=O)CN1C[C@@H]2CCCC[C@@H]2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of cis-octahydro-1-oxo-2H-isoindole-2acetic acid ethyl ester (17.79 g, 0.079 mole) in methanol (100 ml) is saturated with anhydrous ammonia and the solution is stirred 18 hours at room temperature. The solution is concentrated at reduced pressure to yield a gummy solid. Recrystallization from acetonitrile yields pure cis-octahydro-1-oxo-2H-isoindole-2-acetic acid amide, with mp 142°-144° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[C:9]([O:10]C(=O)C)=[C:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]([CH2:22][O:23]C(=O)C)=[N:6][CH:5]=1.[OH-].[Na+].C(OCC)C.Cl>CO>[CH2:15]([O:14][C:8]1[C:7]([CH2:22][OH:23])=[N:6][CH:5]=[C:4]([C:9]=1[OH:10])[C:3]([OH:27])=[O:2])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cnc(COC(C)=O)c(OCc2ccccc2)c1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: O=C(O)c1cnc(CO)c(OCc2ccccc2)c1O
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 67.7 %

Procedure:
To a solution of the compound 8 (46.8 g, 125 mmol) in methanol (140 ml) was added a 2N aqueous sodium hydroxide solution (376 ml) under ice-cooling, and this was stirred at 50° C. for 40 minutes. To the reaction solution were added diethyl ether and 2N hydrochloric acid under ice-cooling, and precipitated crystals were filtered. Resulting crystals were washed with water and diethyl ether to obtain 5-benzyloxy-4-hydroxy-6-hydroxymethyl-nicotinic acid 9 (23.3 g, 68%) as a colorless crystal.
Reaction SMILES: F[C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.NC1C=CC=C(OC)C=1[C:17](O)=[O:18]>>[CH3:17][O:18][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(N)c1C(=O)O
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Product: COc1cccc2[nH]c(=O)oc(=O)c12

Procedure:
Prepared analogously to Compound 27E replacing 2-amino-6-fluorobenzoic acid with 2-amino-6-methoxybenzoic acid. 1H NMR (DMSO-d6, 500 MHz) δ 3.87 (s, 3H), 6.64 (d, J=8.6 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 7.65 (m, 1H), 11.59 (br.s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1.[H][H]>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3)oc12
Agent: O=[Pt]=O
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCCN4)cc3)oc12
Yield: 7.3 %

Procedure:
2-(4-(Pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (100 mg, 0.3 mmol) and platinum (IV) oxide monohydrate (55 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by pre-HPLC. 7 mg of 2-(4-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained. Yield: 7%. 1H-NMR (400 MHz, DMSO-d6) δ 1.23 (s, 1H), 1.56-1.70 (m, 4H), 1.87 (brs, 2H), 2.88-2.91 (m, 1H), 4.02-4.04 (m, 1H); 7.48-7.52 (m, 1H); 7.72-7.74 (m, 2H); 7.82-7.98 (m, 4H); 8.30-8.32 (d, J=7.2 Hz, 2H); LC-MS (m/z) 316 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=O.C(O)(=O)C.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:16][C:18]3[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH3:28])[CH3:29])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C)S(=O)(=O)c1ccc(C=O)cc1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (100 mg, 410 μmol) in MeOH (5 mL) was added 4-formyl-N,N-dimethyl-benzenesulfonamide (96.1 mg, 451 μmol) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (65.7 mg, 615 μmol) was added and the stirring was continued for 5 days. The reaction mixture was poured into 0.1N HCl solution (25 ml) to give a suspension, and the suspension was filtered to give an off white solid as desired product (119 mg, 66% yield). MS +m/z: 441 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[NH:5]C(=O)C.[ClH:22]>C(O)(=O)C.C1(C)C=CC=CC=1>[ClH:22].[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([CH2:9][CH:4]([C:3]([OH:21])=[O:2])[NH2:5])(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)C(CS(=O)(=O)c1ccc(OC)cc1)NC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)CC(N)C(=O)O)cc1

Procedure:
Part A: A solution of (18.13 g, 57 mmol) of N-acetyl-β-(4-methoxyphenylsulfonyl)-D,L-alanine methyl ester in 125 mL concentrated hydrochloric acid and 125 mL of glacial acetic acid was refluxed for several hours under nitrogen atmosphere. The contents were concentrated by rotory evaporation to yield a crude solid which was slurried in dry toluene and filtered to yield 14.3 g of β-(4-methoxyphenylsulfonyl)-D,L-alanine hydrochloride as a white crystalline solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][NH:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.BrC1C=CC=CC=1[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[O:33]>CC#N>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C:32](=[O:33])[CH2:31][N:15]2[CH2:16][CH:13]([CH2:12][S:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:14]2)=[CH:35][CH:36]=1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Reactant: O=C(Cc1ccccc1Br)c1ccc(F)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CN1CC(CS(=O)(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A mixture of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (75 mg, 0.28 mmol) in MeCN (5 mL) was treated with Et3N (97 μL, 0.7 mmol) and 2-bromo-4′-fluorophenylacetophenone (68 mg, 0.31 mmol) and stirred for 30 min at room temperature. The reaction was evaporated and the residue dissolved in DCM and purified using silica chromatography. The column was eluted with 1% MeOH/DCM to give the title compound as a white solid (70 mg, 68%). 1H NMR (500 MHz, CDCl3) δ 2.94–2.99 (1H, m), 3.10 (2H, t, J=7.4 Hz), 3.42 (2H, d, J=7.4 Hz), 3.62 (2H, t, J=7.4 Hz), 3.87 (2H, s), 7.12 (2H, t, J=8.8 Hz), 7.25 (2H, t, J=8.6 Hz), 7.90–7.94 (4H, m). m/z (ES+) 366 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[OH:6][C:7]1[CH:17]=[CH:16][C:10]([CH:11]([OH:15])[C:12]([OH:14])=[O:13])=[CH:9][C:8]=1[CH3:18].[OH-].[Na+].Cl>O>[C:3]([CH2:2][O:6][C:7]1[CH:17]=[CH:16][C:10]([CH:11]([OH:15])[C:12]([OH:14])=[O:13])=[CH:9][C:8]=1[CH3:18])([OH:5])=[O:4]
Reactant: O=C(O)CCl
Reactant: Cc1cc(C(O)C(=O)O)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(O)C(=O)O)ccc1OCC(=O)O
Temperature: 80 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
4.7 g (0.05 mol) of chloroacetic acid is added to a solution of 9.11 g (0.05 mol) of 4-hydroxy-3-methylmandelic acid and 6.0 g (0.15 mol) of sodium hydroxide in 25 ml of water, and the mixture is then stirred at 80° C. for 3 hours. The reaction mixture is acidified with concentrated hydrochloric acid, cooled with ice/water, and the precipitated product is filtered, washed with water and dried in a high vacuum, giving 5.65 g (62%) of 4-carboxymethoxy-3-methylmandelic acid, melting point 95°-100° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:9]=[C:10]2[C:15](=O)[O:14][C:12](=[O:13])[C:11]2=[CH:17][CH:18]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[CH3:7][C:8]1[CH:18]=[CH:17][C:11]([CH2:12][OH:13])=[C:10]([CH2:15][OH:14])[CH:9]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CO)c(CO)c1
Yield: 95.7 %

Procedure:
To tetrahydrofuran (200 ml) was added lithium aluminum hydride (4.91 g, 129 mmol), and the mixture was stirred under ice-cooling. Then, a solution (100 ml) of 4-methylphthalic anhydride (10.4 g, 64.1 mmol) in tetrahydrofuran was added and the mixture was heated under reflux for 90 min. The reaction mixture was ice-cooled, and water (4.91 ml), 15% aqueous sodium hydroxide solution (4.91 ml), water (14.7 ml) and anhydrous magnesium sulfate were successively added with stirring. The insoluble material was filtered off through celite, and the solution was concentrated under reduced pressure to give the title compound (9.34 g, yield 96%) as a colorless oil.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([OH:12])[CH2:2]1.O[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C@:24]1([CH3:30])[CH2:28][O:27][C:26](=[O:29])[NH:25]1)[CH:18]=[CH:17]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:30][C@@:24]1([C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([O:12][CH:3]4[CH2:2][CH2:1][C:6]5([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]5)[CH2:5][CH2:4]4)[CH:15]=3)[CH:20]=2)[CH2:28][O:27][C:26](=[O:29])[NH:25]1
Reactant: OC1CCC2(CCCCC2)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@]1(c2ccc3cc(OC4CCC5(CCCCC5)CC4)ccc3c2)COC(=O)N1
Yield: 100.1 %

Procedure:
The mixture of spiro[5.5]undecan-3-ol (166.0 mg, 0.0009866 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (200.0 mg, 0.0008222 mol), and triphenylphosphine (259 mg, 0.000987 mol) in tetrahydrofuran (7 mL, 0.08 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.194 mL, 0.000987 mol) was added dropwise and was stirred and refluxed for overnight. The mixture was taken up into methylene chloride and subjected to chromatography purification with EtOAc/hexane (10:90 to 80:20) to give product (4R)-4-methyl-4-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)oxazolidin-2-one as a white solid (324 mg, 100%). LCMS Rf=2.34 min 394.45 ([M+1]+, 100%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])=[CH:14][CH:13]=1)(=[O:10])[CH3:9].[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(Cl)Cl.C(OCC)(=O)C>[C:8]([O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[N:19]([C:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:18]2=[O:23])=[CH:14][CH:13]=1)(=[O:10])[CH3:9]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Oc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
3.43 g of triethylamine were added to a solution of 9.0 g of 5-(4-acetoxybenzyl)thiazolidine-2,4-dione [prepared as described in step (b) above] in 70 ml of methylene chloride, and a solution of 9.45 g of triphenylmethyl chloride in 30 ml of methylene chloride was added dropwise to the resulting mixture. The mixture was then stirred at room temperature for one hour, after which it was allowed to stand overnight at the same temperature. At the end of this time, the reaction mixture was mixed with water and ethyl acetate, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the crystals which separated were washed with a mixture of hexane and ethyl acetate and dried, to give 7.86 g of the title compound, melting at between 152° C. and 156° C. 11(d) 5-(4-Hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[O:26]1[CH2:27][CH2:28][CH:23]([CH2:22][O:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]4[C:15](=[N:16][CH:17]=3)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]4)[CH:5]=[N:6][CH:7]=2)[CH2:24][CH2:25]1
Reactant: BrCC1CCOCC1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(O)c3)cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NC(=O)N1CCCc2cc(-c3cncc(OCC4CCOCC4)c3)cnc21
Yield: 50.2 %

Procedure:
To a solution of 6-(5-hydroxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (25 mg, 0.092 mmol) in DMA (1 mL) is added 4-(bromomethyl)tetrahydropyran (20 mg, 0.11 mmol) and cesium carbonate (36 mg, 0.11 mmol). The resultant mixture is stirred at 70° C. for 16 h. Water is added and the mixture is extracted with EtOAc. The organic layers are combined, washed with brine and dried (Na2SO4). The solvent is evaporated and the crude product is purified by silica gel column eluting (0-10% MeOH in DCM) to afford the title compound (17 mg).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26].C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[N:28]([CH3:29])[CH3:30])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CN(C)S(=O)(=O)c1ccc(Cl)cc1CN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
(Step 3) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.50 g) in methanol (10 ml) was added a solution of 2-(aminomethyl)-4-chloro-N,N-dimethylbenzenesulfonamide hydrochloride obtained in Step 2 (0.85 g) and triethylamine (0.58 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (1 ml) was added. The mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.43 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](OC)=O)[CH2:3][CH2:2]1.[CH3:11][NH2:12].Cl.CN.[OH-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:11][NH:12][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C1CCOCC1
Reactant: CN
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCC1CCOCC1
Temperature: 110 °C

Procedure:
Methyl tetrahydro-2H-pyran-4-carboxylate (5 ml, 40.0 mmol) was added to a solution of methylamine (generated by heating a mixture of methylamine hydrochloride and sodium hydroxide pellets) in THF (30 ml) and the mixture heated at 110° C. in a bomb reactor overnight. The solvents were evaporated, the residue dissolved in THF (100 ml), and LiAlH4 (4.6 g, 121 mmol) added, and the mixture heated at 70° C. for 1 h. The mixture was cooled to 0° C., concentrated NaOH solution added and the THF evaporated. Chloroform (100 ml) was added to the residue and the resulting solid was filtered off and the filtrate concentrated under vacuum to give N-methyl-N-tetrahydro-2H-pyran-4-ylmethylamine as a pale brown oil. The preceding amine (1 g, 7.8 mmol) was dissolved in dichloromethane (50 ml), and triethylamine (4 ml) and [2,1,3]-benzoxadiazole-5-carbonylchloride (1.7 g, 9.3 mmol), as a solution in dichloromethane (20 ml), were added, slowly. The mixture was stirred at room temperature for 1 h, the mixture washed with 1N HCl (20 ml), and saturated sodium bicarbonate solution (20 ml), dried (MgSO4) and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate/chloroform (3:1) to give the title compound as a pale brown oil. 1H NMR (300 MHz, CDCl3, 2-rotamers) δ 7.93 (d, J=9.3 Hz, 1H), 7.83 (br s, 1H), 7.38-7.45 (m, 1H), 4.10-3.90 (m, 2H), 3.52-3.20 (m, 4H), 3.13 and 3.05 (both s, total 3H), 2.18-1.80 (m, 1H), 1.73-1.40 ppm (m, 4H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:19]=[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])[C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:24][C:25](=[N:31][NH2:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:24][C:25](=[N:31][NH:32][C:15](=[O:17])[C:14]1[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)=[N:12][CH:13]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(N)=NN
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(N)=NNC(=O)c1cnc(Nc2ccc3ncsc3c2)cc1NC(C)C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinic acid (4) (500 mg, 3.8 mmol) and ethyl 2-amino-2-hydrazonoacetate (6) (3.8 mmol, 1 equiv.) in DMF (10 mL), HATU (7.63 mmol, 2 equiv.) and DIPEA (15.2 mmol, 4 equiv.) were added and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to remove excess of DMF. The residue obtained was partitioned between water and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent to afford the title compound.