Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[CH2:20].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1/[CH:19]=[CH:20]/[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: O=Cc1ccc2c(I)nn(C3CCCCO3)c2c1
Reactant: C=Cc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc2c(/C=C/c3ccccn3)nn(C3CCCCO3)c2c1
Temperature: 100 °C
Yield: 75.8 %

Procedure:
In a scintillation vial a solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (24 mg, 0.0673 mmol), 2-vinylpyridine (9.4 uL, 0.0875 mmol), DIPEA (24 uL, 0.135 mmol) and DMF (1.0 mL) was purged with Ar for 20 min. Pd(OAc)2 (1.5 mg, 0.0067 mmol) and P(o-tolyl)3 (6.1 mg, 0.0202 mmol) were then added and the vial was capped and heated to 100° C. overnight. The solution was cooled to room temperature and extracted with EtOAc, washing with NH4Cl(sat.), H2O, and brine. The organic layer was dried over MgSO4, the solvent removed in vacuo, and the residue purified by column chromatography (silica gel, 96:4 CH2Cl2/MeOH) to give 17 mg, 77% of a yellow oil which was 70% pure by NMR. This crude material was used for the subsequent synthetic step. 1H NMR (400 MHz, CD3OD) δ 10.16 (s, 1H), 8.59 (s, 1H), 8.34 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.95-7.83 (m, 4H), 7.75 (m, 1H), 7.68 (d, J=16.0 Hz, 1H), 6.00 (d, J=9.6 Hz, 1H), 4.05-4.01 (m, 1H), 3.93-3.86 (m, 1H), 2.65-2.56 (m, 1H), 2.27-2.10 (m, 2H), 1.92-1.66 (m, 3H); MS ESI 334.1 [M+H]+, calcd for [C20H19N3O2+H]+ 334.16.
Reaction SMILES: [NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:7]3[C:8]4([CH2:13][CH2:12][CH2:11]4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:23].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:7]3[C:8]4([CH2:13][CH2:12][CH2:11]4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:33][CH2:32][CH2:31][NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[C:3]=1[F:23]
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCC1)CO2
Reactant: NCCNc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3C1(CCC1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
A solution of 8′-amino-9′,10′-difluoro-7′-oxospiro[cyclobutane-1,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylic acid (360 mg, 1.12 mmol), N-2-pyridinyl-1,2-ethanediamine (230 mg, 1.68 mmol) and triethylamine (0.234 mL, 1.68 mmol) in DMSO (5 mL) was stirred for 3 hours at 100° C. The reaction mixture was poured into ice-water and stirred for 30 minutes. The resulting precipitate was collected by filtration, washed with water, suspended in EtOH (10 mL) and stirred at reflux for 1 hour. The suspension was cooled to room temperature, and the resulting precipitate was collected by filtration and dried to yield the title compound (459 mg, 93%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.91-2.03 (2H, m), 2.08-2.17 (2H, m), 2.61-2.69 (2H, m), 3.44-3.48 (2H, m), 3.58-3.66 (2H, m), 6.35-6.40 (1H, m), 6.45-6.49 (2H, m), 6.71 (1H, t, J=5.5 Hz), 6.88 (2H, brs), 7.35 (1H, td, J=6.7, 1.8 Hz), 7.97 (1H, dd, J=4.9, 1.2 Hz), 8.71 (1H, s), 15.30 (1H, s). HRESIMS (+): 440.17267 (−0.74 mmu).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][Zn]C.C1(C)C=CC=CC=1.CO>O1CCOCC1>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn]C
Solvent: CO
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (21.54 g, 40 mmol) in 1,4-dioxane (300 mL) was bubble with argon for 10 min. The reaction mixture was treated with 2N dimethylzinc in toluene (40 mL, 80 mmol) under argon. The reaction mixture was treated with PdCl2(dppf)CH2Cl2 adduct (0.326 g, 0.400 mmol) and heated to 80° C. After 2 h, the reaction was check by HPLC. The reaction was cooled to room temperature and slowly added MeOH until reaction was quenched. After quenched, the reaction mixture was diluted with NaHCO3 (sat'd) (200 mL) and extracted with EtOAc (3×, 200 mL). The EtOAc layers were stirred with activated carbon (darco G-60, 100 mesh, powder) for 1 h. The reaction mixture was filtered through pad of SiO2 (3″×3″) and washed with EtOAc. The reaction mixture was concentrated. IPA (350 mL) was to the reaction mixture and heated to reflux. After 2 h, the reaction mixture was cooled to room temperature and filtered and washed with IPA and water (200 mL). The product was dried under vacuum at 60° C. for 2 days. Title compound was obtained as an off-white solid (17.5 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.47 (d, J=5.3 Hz, 1H), 7.52-7.58 (m, 1H), 7.40-7.50 (m, 4H), 7.29 (t, J=7.8 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 2.58 (s, 3H), 1.42 (s, 9H). MS (ESI): 519 [M+H]+.
Reaction SMILES: Cl.[O:2]1CCO[CH2:4][CH2:3]1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:22][CH2:23][N:24]2[CH2:31][CH:30]3[CH:26]([CH2:27][N:28]([C:32]([C:34]4[C:35]([CH3:41])=[N:36][CH:37]=[N:38][C:39]=4[CH3:40])=[O:33])[CH2:29]3)[CH2:25]2)[CH2:17][CH2:16]1)=[O:14])(C)([CH3:10])[CH3:9].C1(O)CCC(O)C1>CC#N>[OH:2][CH:3]1[CH2:4][CH2:10][CH:8]([O:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH:21]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:22][CH2:23][N:24]3[CH2:31][CH:30]4[CH:26]([CH2:27][N:28]([C:32]([C:34]5[C:35]([CH3:41])=[N:36][CH:37]=[N:38][C:39]=5[CH3:40])=[O:33])[CH2:29]4)[CH2:25]3)[CH2:17][CH2:16]2)=[O:14])[CH2:9]1
Reactant: C1COCCO1
Reactant: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC(c3ccccc3)C3CCN(C(=O)OC(C)(C)C)CC3)CC2C1
Agent: Cl
Agent: OC1CCC(O)C1
Solvent: CC#N
Product: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC(c3ccccc3)C3CCN(C(=O)OC4CCC(O)C4)CC3)CC2C1
Reaction time: 4 h

Procedure:
A solution of HCl-dioxane (1 mL, 4.0 M) and 78a (35 mg, 0.064 mmol) was stirred at RT for 90 min. The solvent was removed, and the residue was dried in vacuo. Cyclopentane-1,3-diol (cis/trans, 9 μL, 0.096 mmol) was added to a solution of N,N′-disuccimidylcarbonate (30 mg, 0.12 mmol) and TEA (44 μL, 0.32 mmol) in MeCN (0.47 mL) and the solution was stirred for 4 h. A solution of the above residue from the Boc deprotection in MeCN was added and the reaction mixture was stirred for 3 h. The solvent was evaporated and the crude product was purified on a preparative TLC plate developed with a mixture of 45% DCM and 55% of DCM/MeOH/NH4OH (60/10/1) to afford 0.011 g (30%) of V-6.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.CO[C:10]([CH:12]([NH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1)[CH2:13][CH:14]=[CH2:15])=[O:11]>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:13]([CH:12]1[N:16]([CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:21][CH2:22]2)[C:6](=[O:7])[NH:5][C:10]1=[O:11])[CH:14]=[CH2:15]
Reactant: C[Si](C)(C)N=C=O
Reactant: C=CCC(NC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C=CCC1C(=O)NC(=O)N1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Yield: 80.5 %

Procedure:
Trimethylsilyl isocyanate (1.66 g, 14.4 mmol) was added to a solution of benzyl 4-{[1-(methoxycarbonyl)but-3-en-1-yl]amino}piperidine-1-carboxylate (2.00 g, 5.77 mmol) and DMAP (71 mg, 0.57 mmol) in THF (30 mL) at room temperature. The reaction was heated at 50° C. for 48 h. The reaction was quenched with saturated aqueous sodium bicarbonate, extracted with methylene chloride (3×), dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by chromatography (silica gel, 0 to 20% methanol in methylene chloride gradient elution), which gave the title compound (1.66 g). MS 358.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:11])[CH:17]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-n2nccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 480 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[C:17]([N:21]1[C:25]([CH:26]=O)=[CH:24][C:23]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N:22]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([N:21]1[C:25]([CH2:26][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12]2)=[CH:24][C:23]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: NCCN1CCN(c2ccccc2F)CC1
Reactant: CC(C)Cc1cc(C=O)n(C(C)(C)C)n1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccccc3F)CC2)n(C(C)(C)C)n1
Yield: 60.2 %

Procedure:
Compound 65 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 2-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH2:4]1.C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C>[ClH:1].[NH2:2][C@@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([Br:20])[CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH2:4]1
Reactant: COc1cccc2c1CC[C@@H](N)C2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Br)c2c1CC[C@@H](N)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(R)-2-Amino-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (5.0 g, 23 mmol) was dissolved in acetic acid (300 mL) under nitrogen atmosphere. Sodium acetate (5.5 g, 70 mmol) was added and bromine (3.5 g, 23 mmol) was then added in one portion. The mixture was stirred for 5 minutes at room temperature. The solvent was removed in vacuo to give a solid residue which was partitioned between ethyl acetate and NaOH (2 M). The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic layers were combined and dried (Na2SO4). The solvent was removed in vacuo to give a brown oily residue. The HCl salt was precipitated from diethyl ether/methylene chloride by the addition of HCl in diethyl ether (3 M): yield 7.7 g (94%). Recrystallization from methanol gave the title compound as needle crystals: mp 264-265° C.; [α]21D+54° (c 1, MeOH); EIMS (70 eV) m/z (relative intensity) 257 (30, M+, 81Br), 255 (31, M+, 79Br).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH:7]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10]>C(O)C>[C:1]([S:3][CH:7]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])(=[O:4])[CH3:2]
Reactant: O=C(c1ccccc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 1.25 g. of potassium thioacetate in 20 ml. of ethanol is added a solution of 3.54 g. of 1-(3-bromo-3-benzoylpropionyl)-L-proline (Example 20) in 20 ml. of ethanol. The mixture is stirred at room temperature for 2 hours. The mixture is concentrated to dryness under vacuum and the residue partitioned between dichloromethane and water. The dichloromethane layer is washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed under vacuum to give 2.9 g. of product as a glass. A 2.3 g. sample is chromatographed over silica gel with solvent system, ethyl acetate-hexane-acetic acid (75:25:2) to give 1.07 g. of product as a pale yellow glass.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[Cl:12].CCN(C(C)C)C(C)C.[O:22]1[CH2:26][CH2:25][CH:24]([C:27](Cl)=[O:28])[CH2:23]1>C(Cl)Cl>[Cl:12][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:1][C:27]([CH:24]1[CH2:25][CH2:26][O:22][CH2:23]1)=[O:28]
Reactant: Nc1c(Cl)cc(O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1c(Cl)cc(O)cc1[N+](=O)[O-])C1CCOC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.40 g (2.12 mmol) 4-amino-3-chloro-5-nitrophenol were placed in 5 mL DCM. 0.44 mL DIPEA and 0.34 g tetrahydrofuran-3-carbonyl chloride were added and the mixture was stirred for 2 h at RT. A further 0.34 g tetrahydrofuran-3-carbonyl chloride was added and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and washed with water. The organic phase was evaporated down i.vac.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH:40]=[CH:41][C:42](O)=[O:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].ClC(OCC)=O.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=3)[C:22]([CH:40]=[CH:41][CH2:42][OH:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C=CC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C=CCO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-carboxyvinyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in tetrahydrofuran (4 ml), then thereto are added ethyl chloroformate (0.04 ml) and triethylamine (0.06 ml) under ice-cooling, and the mixture is stirred for 30 minutes. The reaction solution is filtered, then thereto is added sodium borohydride (58 mg), and the mixture is stirred for 1 hour and 30 minutes under ice-cooling. 1N-Hydrochloric acid is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with water, a saturated aqueous sodium hydrogen carbonate solution and a saturated brine successively, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→3:2) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-hydroxypropenyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (155 mg). MS (m/z): 640 [M+H]+
Reaction SMILES: [C:1]1(=[O:12])[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].CN1CCOCC1.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22].C1(C)C=CC=CC=1>O1CCCC1.O>[CH3:20][Si:21]([CH3:23])([CH3:22])[O:3][CH:2]1[CH:4]([O:5][Si:21]([CH3:23])([CH3:22])[CH3:20])[CH:6]([O:7][Si:21]([CH3:23])([CH3:22])[CH3:20])[CH:8]([CH2:9][O:10][Si:21]([CH3:23])([CH3:22])[CH3:20])[O:11][C:1]1=[O:12]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)OCC1OC(=O)C(O[Si](C)(C)C)C(O[Si](C)(C)C)C1O[Si](C)(C)C
Temperature: 17 °C
Reaction time: 4 h

Procedure:
To a solution of D-(+)-glucono-1,5-lactone (21.6 kg) and N-methylmorpholine (98.2 kg) in tetrahydrofuran (192 kg) was added trimethylsilyl chloride (79.1 kg) at 40° C. or below, and then the mixture was stirred at a temperature from 30° C. to 40° C. for 4 hours. After the mixture was cooled to 17° C., toluene (93.6 kg) and water (109 kg) were added thereto. The organic layer was separated and washed with an aqueous solution of 5% sodium dihydrogen phosphate (108 kg×2) and water (108 kg×1). The solvent was evaporated under reduced pressure. To the resulting residue was added tetrahydrofuran (154 kg) and the solvent was evaporated under reduced pressure. Again tetrahydrofuran (154 kg) was added thereto and evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (253 kg) to give a solution of the titled compound in tetrahydrofuran. The purity of the product was 99.0% (conversion rate: 99.1%), which was calculated based on the area ratio measured by HPLC.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:35]=[CH:34][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:33])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]2[CH:35]=[CH:34][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:33])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:2][CH2:3]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCNCC2)cc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCN(C(=O)c3ccccc3)CC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and benzoyl chloride Rf value: 0.7 (silica gel, methylene chloride/methanol=10:1) C35H32N4O4
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[N:3]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1Br
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a stirred solution of methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (2.85 g, 8.50 mmol) in mixed solvents (THF/MeOH/water; 2:2:1; 50 mL) was added LiOH H2O (1.07 g, 25.5 mmol) at 0° C. The cold bath was removed and stirring was continued for 2 h. The reaction mixture was concentrated in vacuo, diluted with water and washed with MTBE. The aqueous layer was neutralized with 1.5N HCl and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound (2.4 g, 88%) as a white solid. 1H NMR (CDCl3) δ 12.54 (br s, 1H), 8.14 (s, 1H), 5.33 (s, 2H), 3.54 (t, J=8.0 Hz, 2H), 0.85 (t, J=8.0 Hz, 2H), 0.01 (s, 9H); MS(ESI+) m/z 323.0 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:8][C:7]=2[CH:21]=1)=[O:2].Cl([O-])=[O:23].[Na+].S(=O)(=O)(O)N>C1COCC1.C(O)(C)(C)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:8][C:7]=2[CH:21]=1)([OH:23])=[O:2]
Reactant: O=Cc1ccc2oc(C(=O)OCc3ccccc3)cc2c1
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc2oc(C(=O)OCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
To a solution of benzyl 5-formylbenzofuran-2-carboxylate (0.380 g, 0.1.36 mmol) in THF (5 mL) and t-butanol (1 mL) was added slowly a solution of sodium chlorite (0.245 g 2.71 mmol) and sulfamic acid (0.277 g, 2.86 mmol) in water (2 mL). After stirring at room temperature for 3 h, the solution was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate, and brine then collected, dried (MgSO4), filtered and concentrated to yield the title compound as an off-white solid (0.272 g, 68%). 1 H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.23 (d, 1H), 7.67 (m, 2H), 7.49 (m, 2H), 7.41 (m, 3H), 5.46 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:13]=[CH:12][C:6]2[S:7][C:8]([CH2:10][OH:11])=[CH:9][C:5]=2[CH:4]=1.C(N(CC)CC)C.C1C=CN=CC=1.O=S(=O)=O.O>CS(C)=O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:14])[C:3]1[CH:13]=[CH:12][C:6]2[S:7][C:8]([CH:10]=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: CN(C)c1ccc2sc(CO)cc2c1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)c1ccc2sc(C=O)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of (5-dimethylamino-benzo[b]thiophen-2-yl)-methanol (790 mg, 3.8 mmol) and triethylamine (4.9 mL, 35.1 mmol) in dimethyl sulfoxide (20 mL) was added a solution of pyridine-sulfur trioxide (1.8 g, 11.2 mmol) in dimethyl sulfoxide (20 mL). The mixture was stirred for 1 hour at room temperature followed by addition of water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with water (3×50 mL) and brine (2×50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a colourless oil that was purified by flash chromatography (10:90:1 to 50:50:1 ethyl acetate:40-60° C. petroleum ether:triethylamine) to give a solid that was recrystallised from ethanol to give the title compound (743 mg, 95%) as a solid, mp 105-106° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:27]=[C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCOP(=O)(CCc1cccc(C#N)n1)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCc1cccc(-c2nc(=O)c3ccccc3s2)n1)OCC
Yield: 52 %

Procedure:
Diethyl 2-(6-cyano-2-pyridyl)ethylphosphonate (0.80 g, 2.9 mmol) and methyl thiosalicylate (1.00 g, 5.9 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 5 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from diisopropyl ether-ethanol to give the titled compound (0.61 g, 50%) as white crystals.