Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH2:10]([C:13]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[NH:15][N:14]=1)[CH2:11][CH3:12]>>[N+:6]([C:17]1[C:13]([CH2:10][CH2:11][CH3:12])=[N:14][NH:15][C:16]=1[C:18]([OH:20])=[O:19])([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: CCCc1cc(C(=O)O)[nH]n1
Agent: O=S(=O)(O)O
Product: CCCc1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
Fuming sulphuric acid (17.8 ml) was added dropwise to stirred, ice-cooled fuming nitric acid (16.0 ml), the resulting solution heated to 50° C., then 3-n-propyl-1H-pyrazole-5-carboxylic acid (Chem. Pharm. Bull., 1984, 32, 1568; 16.4 g, 0.106 mol) added portionwise over 30 minutes whilst maintaining the reaction temperature below 60° C. The resulting solution was heated for 18 hours at 60° C., allowed to cool, then poured onto ice. The white precipitate was collected, washed with water and dried by suction to yield the title compound (15.4 g), m.p. 170-172° C. Found: C, 42.35; H, 4.56; N, 21.07. C7H9N3O4 requires C, 42.21; H, 4.55; N, 21.10%. δ (DMSOd6): 0.90 (3H, t), 1.64 (2H, m), 2.83 (2H, m), 14.00 (1H, s).
Reaction SMILES: CO[N:3](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4]1[NH:5][C:6](=[O:23])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:17][C@H:16]([CH2:18][OH:19])[CH2:15][C@:14]3([C:21]#[CH:22])[F:20])[C:11]=2[N:12]=1>CC(O)=O.C1COCC1.O>[C:21]([C@:14]1([F:20])[CH2:15][C@@H:16]([CH2:18][OH:19])[O:17][C@H:13]1[N:10]1[CH:9]=[N:8][C:7]2[C:6](=[O:23])[NH:5][C:4]([NH2:3])=[N:12][C:11]1=2)#[CH:22]
Reactant: C#C[C@]1(F)C[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C#C[C@]1(F)C[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
15 (0.09 mmol) was stirred in AcOH/THF/H2O (3/6/1) solution at 50° C. for 1 day. The reaction mixture was then concentrated under reduced pressure and purified by silica gel chromatography, C18 (H2O/ACN) Beige lyophilisated powder. Molecular Formula C12H12FN5O5. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 2.57-2.74 (m, 2H), 3.56 (s, 1H), 3.61-3.64 (d, J=12.10 Hz, 1H), 3.79-3.82 (d, J=12.10 Hz, 1H), 3.91-3.93 (d, J=5.40 Hz, 1H), 4.32-4.35 (m, 1H), 5.25 (s, 1H), 6.06-6.10 (d, J=18.20 Hz, 1H), 6.64 (s, 1H), 8.01 (s, 1H), 10.82 (s, 1H) 19F NMR (DMSO-d6, 376 MHz) δ (ppm) −138.4 (s, 1F). Scan ES− 292 (M+H)−, Scan ES+ 316 (M+Na)+, UV λmax 251 nm
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.[Cl:15][CH2:16][CH2:17][CH2:18]I.O>C1COCC1.[Cu]I>[Cl:15][CH2:16][CH2:17][CH2:18][C:10]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=1
Reactant: ClCCCI
Reactant: c1ccc2sccc2c1
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: ClCCCc1cc2ccccc2s1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
n-BuLi in heptanes (0.75 ml, 1.2 mmol, 1.6M) was added drop wise to benzo[b]thiophene (134 mg, 1.0 mmol) in THF (4 ml) at −5° C. under argon. The reaction mixture was stirred at −5° C. for 15 min, then 1-chloro-3-iodopropane (151 μl, 1.2 mmol) and copper (I) iodide (19 mg, 0.1 mmol) were added. The reaction was stirred at −5° C. for 1 h, then at room temperature for 0.5 h. Water (5 ml) was added, the product was extracted with diethyl ether (2×10 ml) and the organic layer was dried (K2CO3), filtered and concentrated in vacuo. The product was purified by column chromatography (0–2% ethyl acetate in heptanes) to give 2-(3-chloro-propyl)-benzo[b]thiophene (93 mg, 44%). 1H NMR (CDCl3): δ 2.22 (tt, 2H), 3.10 (dt, 2H), 3.61 (t, 2H), 7.06 (m, 1H), 7.30 (m, 2H), 7.69 (m, 1H), 7.78 (m, 1H). 2-(3-Chloro-propyl)-benzo[b]thiophene (53 mg, 0.25 mmol), 4-butylpiperidine (36 mg, 0.25 mmol), sodium iodide (75 mg, 0.5 mmol) and sodium carbonate (53 mg, 0.5 mmol) in acetonitrile (2 ml) were shaken at 80° C. for 18 h, then the reaction was cooled to room temperature. Water (5 ml) was added and the product was extracted with ethyl acetate (2×10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was purified by column chromatography (0–15% ethyl acetate in heptanes+0.1% Et3N) to yield the title compound 54. Yield 29 mg (37%). The hydrochloride salt was formed by addition of HCl (4M in dioxane) and recrystallised from methanol-diethyl ether to give a white precipitate that was filtered and dried. 1H NMR (CD3OD): δ 0.91 (t, 3H), 1.32 (m, 6H), 1.39 (m, 2H), 1.55 (m, 1H), 1.96 (br. d, 2H), 2.19 (tt, 2H), 2.93 (m, 2H), 3.04 (t, 2H), 3.14 (m, 2H), 3.53 (m, 2H), 7.14 (br. s, 1H), 7.26 (m, 1H), 7.31 (m, 1H), 7.68 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1.Cl[Si](C)(C)C.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([NH:33][C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[O:17])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19]
Reactant: Cc1sc2nc3ccc(C(=O)O)cn3c(=O)c2c1C
Reactant: Nc1nnn[nH]1
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1sc2nc3ccc(C(=O)Nc4nnn[nH]4)cn3c(=O)c2c1C
Yield: 59.4 %

Procedure:
From 1 g (0.0036 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 6), 0.83 g (0.0051 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 50 ml of dimethylformamide and 0.41 g (0.004 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company), 1.5 ml (0.012 mol) of chlorotrimethylsilane (Aldrich Chemical Company), 3.0 ml (0.022 mol) of triethylamine in 40 ml of dimethylformamide, following the procedure of Example 11, there is obtained 0.73 g of 2,3-dimethyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide after slurrying in boiling glacial acetic acid, cooling and filtering the precipitate; mp 297°-300° C. (dec).
Reaction SMILES: F[C:2](F)(F)C(O)=O.N[C:9]1([C:15]2[N:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[S:32]([CH3:35])(=[O:34])=[O:33])=[O:22])[C:18]([OH:36])=[C:17]([OH:37])[N:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C.C([O-])(=O)C.[Na+].C=O.[C:52]([BH3-])#[N:53].[Na+].FC(F)(F)C(O)=O>CO>[CH3:2][N:53]([CH3:52])[C:9]1([C:15]2[N:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[S:32]([CH3:35])(=[O:34])=[O:33])=[O:22])[C:18]([OH:36])=[C:17]([OH:37])[N:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=C(O)C(F)(F)F
Reactant: CS(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(C2(N)CCOCC2)nc(O)c1O
Reactant: [BH3-]C#N
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)C1(c2nc(O)c(O)c(C(=O)NCc3ccc(F)cc3S(C)(=O)=O)n2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(4-aminotetrahydro-2H-pyran-4-yl)-N-[4-fluoro-2-(methylsulfonyl)benzyl]-5,6-dihydroxypyrimidine-4-carboxamide trifluoroacetate (C-32) in MeOH was treated with triethylamine (1 eq.), sodium acetate (1.6 eq.), formaldehyde 37% w/w aq. soln. (3 eq.), and sodium cyanoborohydride (1.43 eq.). The mixture was left stirring at room temperature for 1 h. Trifluoroacetic acid (3 eq) and sodium cyanoborohydride (0.5 eq) were added, left stirring overnight. The reaction mixture was concentrated and the title compound (C-33) as trifluoro acetate salt was obtained by preparative HPLC purification (C18, eluting with water and acetonitrile containing 0.1% trifluoroacetic acid in gradient).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][N:24]2[C:30](=[O:31])[CH2:29][C:28]3[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:27]=3[CH:26]=[CH:25]2)[CH2:18]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][N:24]2[C:30](=[O:31])[CH2:29][C:28]3[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:27]=3[CH2:26][CH2:25]2)[CH2:18]1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3cncc4cc(OC)c(OC)cc34)C1)C=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3cncc4cc(OC)c(OC)cc34)C1)CC2

Procedure:
Prepared from 3-[(N-(2-(6,7-dimethoxy-isoquinol-4-yl)-ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3-dihydro-2H-3benzazepine by hydrogenation at 5 bar hydrogen pressure with 10% palladium/charcoal in ethanol at 70° C. analogously to Example 5.
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][C:5]=2[CH:4]=1)=O.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][CH2:1][C:3]2[CH:23]=[CH:22][C:6]3[NH:7][C:8]([C@@H:10]4[CH2:14][CH2:13][CH2:12][N:11]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][C:5]=3[CH:4]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(C=O)ccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CNc3ccc(F)cc3)ccc2[nH]1
Reaction time: 17 h
Yield: 99.6 %

Procedure:
The product from Example 99A (0.50 g, 1.59 mmol), 4-fluoroaniline (0.15 g, 1.59 mmol), and acetic acid (0.09 mL, 1.59 mmol) were combined at ambient temperature in methanol (15 mL) and treated with sodium cyanoborohydride (0.10 g, 1.59 mmol) and stirred 17 hours. The mixture was poured into water, extracted into ethyl acetate, dried over sodium sulfate, filtered, and concentrated to give 0.65 g (100%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Br:9]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:9][C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=C(O)c1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1csc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of thiophene-3-carboxylic acid (18.2 g) in N,N-dimethylformamide (250 mL) was added N-bromosuccinimide (27.8 g) in small amounts on an ice bath. After stirring at room temperature overnight, the reaction solution was poured into water (1.5 L), and the resulting solid was collected by filtration and washed with water. After dissolving in ethyl acetate, and dried with anhydrous magnesium sulfate, the drying agent was removed by filtration, and evaporation in vacuo was carried out. The solid that was generated by dissolving the residue in ethyl acetate, and adding hexane were collected by filtration, and the crude product (16 g) of 5-bromo-thiophene-3-carboxylic acid was obtained as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[NH:24][NH2:25].[OH-].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[C:15]([Cl:23])[C:14]=1[NH:24][NH:25][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)NNc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1
Reaction time: 16 h

Procedure:
A solution of 14.2 g of 4-cyanobenzoyl chloride in 100 ml of methylene chloride is added dropwise with stirring at from 10 to 15° in the course of approximately 30 minutes to 20 g of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 250 ml of dichloromethane, and the mixture is stirred for a further 16 hours. 36 ml of aqueous sodium hydroxide solution (10%) is then run in with vigorous stirring. 100 ml of methylene chloride are added, the organic phase is washed three times using in each case 100 ml of water and dried over sodium sulfate, and the solvent is removed on a rotary evaporator. After the residue has been recrystallized from toluene, the title product of melting point 185-186° is obtained (compound no. 1.6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[OH:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.Cl>C(O)C.[Cl-].[Na+].O>[OH:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: O=Cc1ccccc1O
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCC(=Cc1ccccc1O)C2=O
Yield: 62.9 %

Procedure:
To a solution of 6-methoxy-1-tetralone (30 g) and 2-hydroxybenzaldehyde (25 g) in ethanol (200 ml) was added concentrated hydrochloric acid (10 ml), and the solution was refluxed for one day and one night. To the reaction solution was added brine, the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 2-(2-hydroxybenzylidene)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (30 g). To a solution of a portion thereof (15 g) in ethanol (200 ml) was added platinum(IV) oxide (0.1 g), and the solution was stirred overnight under a hydrogen atmosphere at ambient pressure. The reaction solution was filtered, and the solvent was evaporated in vacuo. To a solution of a portion of the resulting 2-(2-hydroxybenzyl)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one crude product (1.0 g) in ethylene glycol (15 ml) was added potassium hydroxide (1.2 g) and hydrazine hydrate (2 ml), and the solution was refluxed overnight. To the reaction solution was added 5N hydrochloric acid, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by silica gel column chromatography (hexane-ethyl acetate system), 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenol (810 mg) was used according to an analogous synthetic method to Preparation Example 80 to provide the title compound (1.1 g).
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.CS[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][N:14]([C:25]4[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=4)[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: CSc1ncc(C#N)cn1
Reactant: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1CN(c2ncc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (from Step 2 of Example 302, 200 mg, 0.415 mmol) in N,N-dimethylformamide (1 mL), was added 2-(methylthio)pyrimidine-5-carbonitrile (75 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.25 mmol). The mixture was heated at 80° C. for 5 h. The mixture was added water, stirred at rt for 2 h, filtered and rinsed with water to give 6-bromo-4-((3R,4S)-1-(5-cyanopyrimidin-2-yl)-4-methoxypyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (162 mg, 80% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.38 (d, J=2.0 Hz, 1H), 8.17 (s, 1H), 7.73 (dd, J=8.9, 2.3 Hz, 1H), 7.10 (s, 1H), 6.59 (s, 1H), 5.10-5.01 (m, 1H), 4.25 (d, J=3.7 Hz, 1H), 4.09 (br. s., 1H), 3.85-3.74 (m, 2H), 3.61-3.46 (m, 5H), 1.28 (d, J=6.4 Hz, 2H); MS (ES+) m/z: 372.26 (M+H); LC retention time: 1.92 min (analytical HPLC Method H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[CH3:13].Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:13]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCOC(=O)c1ccc(N)c(C)c1
Product: Cc1cc(C(=O)O)ccc1N1CCCS1(=O)=O

Procedure:
Using ethyl 4-amino-3-methylbenzoate (1.0 g) and 3-chloropropane-1-sulfonyl chloride (0.9 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (463 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:7][CH:8]=1.[Li]CCCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[S:7][C:8]=1[Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COCc1csc(NC(=O)OC(C)(C)C)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1sc(NC(=O)OC(C)(C)C)nc1COC
Temperature: -78 °C
Yield: 65.1 %

Procedure:
To a 250 mL flame-dried 3-neck round-bottomed flask was added tert-butyl 4-(methoxymethyl)thiazol-2-ylcarbamate (1.75 g, 7.2 mmol) and 200 mL of dry THF. The resulting solution was stirred at −78° C. and treated dropwise with 1.6 M n-BuLi in THF (9.4 mL, 15 mmol) over 15 minutes. The resulting pale yellow solution was stirred at −78° C. for 30 minutes and was then treated dropwise with tributyltin chloride (2.1 mL, 7.9 mmol). The reaction mixture was stirred at −78° C. for 30 minutes. The bath was then removed, and the mixture was allowed to warm to room temperature and was stirred at room temperature for 2.5 hours. The reaction was quenched by the addition of saturated NH4Cl (150 mL). The layers were separated, and the aqueous layer was washed with Et2O (3×100 mL). The organic phases were combined and washed with NaCl (100 mL) dried over MgSO4, filtered, and concentrated in vacuo to provide the crude produce as a viscous oil which was then purified by column chromatography using a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 10% to 20% EtOAc in hexane, to provide tert-butyl 4-(methoxymethyl)-5-(tributylstannyl)thiazol-2-ylcarbamate (2.5 g, 65% yield) as waxy oil. MS m/z: 535 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][CH:16]=1)[C:7]=2[CH3:29])=O.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CN1CCCC1=O.C(O)(=O)C>[OH:37][C@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]1[NH:30][CH2:1][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13][C:14](=[O:28])[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:19][CH:20]=1)[C:7]=2[CH3:29]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Cc1c(NC(=O)c2ccc(OCC3CCCO3)cc2)ccc2cc(C=O)cnc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: Cc1c(NC(=O)c2ccc(OCC3CCCO3)cc2)ccc2cc(CN[C@H]3CCCC[C@@H]3O)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
N-(3-Formyl-8-methylquinolin-7-yl)-4-(tetrahydrofuran-2-ylmethoxy)benzamide (1.0 g) obtained in Reference Example 2% and trans-2-aminocyclohexanol (546 mg) were suspended in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL) and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (2.35 g) was added and the mixture was stirred at room temperature for 3 hr. 1N Aqueous sodium hydroxide solution was added to quench the reaction and basify the mixture. The mixture was partitioned and extracted with ethyl acetate, the organic layer was added to a solution of citric acid (4.0 g) in water (40 mL)-dimethyl sulfoxide (20 mL), and the mixture was washed with ethyl acetate. 1N Aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was partitioned and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (395 mg, yield 32%) as a colorless solid.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH:9]2[C:21]([CH:26]2[CH2:28][CH2:27]2)([CH:23]2[CH2:25][CH2:24]2)[OH:22])C=CC=CC=1.[C:29](=[O:32])([O-:31])O.[Na+].[C:34](Cl)(=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)C.O.[C].[Pd]>[C:37]1([CH2:36][O:31][C:29]([N:8]2[CH2:13][CH2:12][N:11]([C:34]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:43])[CH2:10][CH:9]2[C:21]([CH:26]2[CH2:28][CH2:27]2)([CH:23]2[CH2:25][CH2:24]2)[OH:22])=[O:32])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C([O-])O
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC(C1CC1)(C1CC1)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)C(C(O)(C2CC2)C2CC2)C1
Temperature: 25 °C

Procedure:
1,4-Bis(phenylmethyl)-α,α-dicyclopropyl-2-piperazinemethanol (1.2 g, 3.1 mmol) was dissolved in ethanol/water (40 mL/4 mL). 10% Palladium carbon (0.12 g) was added thereto, and the mixture was stirred under hydrogen pressure (3.6 bar) at room temperature one whole day and night. The reaction solution was filtered through a Celite, the Celite was washed with ethanol, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml). A 0.5 M aqueous sodium hydrogen carbonate solution (50 mL) and benzyl chlorocarbonate (1.8 mL, 12 mmol) were added thereto. The resulting mixture was stirred at room temperature for 4 hours and the reaction solution was extracted with ethyl acetate (100 mL). The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Then, the residue was purified with silica gel column chromatography (hexane:ethyl acetate=21:1 to 4:1) to obtain the title compound (1.4 g, quantitative) as an oily matter.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[C:11]1([O:17][C:18]([N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH2:21]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])=O.[K+]>ClCCl.O>[C:11]1([O:17][C:18]([N:20]2[CH:25]=[C:24]([CH:9]=[O:10])[CH:23]=[C:22]([Cl:26])[CH2:21]2)=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Oc1ccccc1)N1C=CC=C(Cl)C1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=CC1=CN(C(=O)Oc2ccccc2)CC(Cl)=C1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 96.6 %

Procedure:
Phosphorus oxychloride (5.4 g, 57.9 mmol) was added slowly to a stirred solution of DMF (8.9 mL, 116 mmol) in dichloromethane (10 mL) at 0° C. After addition, the solution was stirred at same temperature for 25 min., then transferred a solution of 3-chloro-2H-pyridine-1-carboxylic acid phenyl ester (5.67 g, 26.3 mmol) in anhydrous dichloromethane (50 mL) at 0° C. The ice bath was removed and stirring was continued at r.t. for 2 h, then the mixture was refluxed for 40 min. After the mixture was cooled to 0° C., an aqueous solution of KOAc (15 g, 153 mmol) in water (50 mL) was added slowly. The mixture was refluxed for 20 min., organic layer was separated, and aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined, washed with saturated NaHCO3, water and brine then dried over MgSO4, concentrated to give the crude product (Yield: 6.7 g).