Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].[NH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[NH:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])=[N:21][CH:20]=[C:19]([Br:30])[CH:18]=2>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[Br:30][C:19]1[CH:20]=[N:21][C:22]2[C:23]3[N:24]([CH2:25][C:26]([CH3:27])([OH:28])[CH3:29])[C:1]([CH2:2][CH3:3])=[N:13][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)cnc12
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCc1nc2cnc3cc(Br)cnc3c2n1CC(C)(C)O
Yield: 75 %

Procedure:
Pyridine hydrochloride (0.095 g, 0.82 mmol) and triethyl orthopropionate (6.36 g, 36.1 mmol) were sequentially added to a solution of 1-[(3-amino-7-bromo[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol (10.2 g, 32.8 mmol) in toluene (200 mL), and the resulting mixture was heated at reflux for three hours. Most of the solvent was removed under reduced pressure, and a solid was present. The solid was isolated by filtration and dried to provide 8.59 g of 1-(7-bromo-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-2-methylpropan-2-ol as a light yellow solid. A small portion of the solid was recrystallized from acetonitrile to provide an off-white solid, mp 207-208° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([N:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]([CH3:23])[CH3:22])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:24]([N:20]([CH:21]([CH3:23])[CH3:22])[C:16]1[CH:15]=[N:14][C:13]2[CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][O:11][C:18]=2[N:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)N(Cc1ccccc1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(Cc1ccccc1)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 2-[benzyl({5-[benzyl(1-methylethyl)amino]-3-chloropyrazin-2-yl}methyl)amino]ethanol (3.32 g) in DMF (12 mL) was added potassium tert-butoxide (1.05 g) at 0° C., and the mixture was stirred for 2 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→30% ethyl acetate/hexane) to give the title compound (2.55 g, 84%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21].Cl[CH2:23][C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2CC)[C@H](O)[C@@H]1O>CN.C(O)C>[CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH2:19][CH3:23])[C@H:6]([OH:20])[C@@H:5]1[OH:21]
Reactant: CCc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: CN
Solvent: CCO
Product: CCc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CNC)[C@@H](O)[C@H]1O

Procedure:
The procedure was the same as reported above for 4a using 3b (1.00 g, 3.18 mmol) and 33% methylamine/ethanol solution (30 mL). After column chromatography (elution with 5:1:0.3 chloroform:methanol:NH4OH), a yellow glassy solid was obtained: 498 mg (50%); MS m/z 309 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (bs, 1H, H-2), 7.13 (bs, 2H, 6-NH2), 5.70 (d, 1H, H-1′, J1′,2′=6.6 Hz), 5.30 (d, 1H, 2′-OH, J2′-2′OH=6.4 Hz), 5.16 (d, 1H, 3′-OH, J3′-3′OH=4.5 Hz), 5.08 (ddd, 1H, H-2′, J1′,2′=6.6 Hz, J2′,3′=5.4 Hz, J2′-2′OH=6.4 Hz), 4.14-4.18 (m, 1H, H-3′), 3.96-4.0 (m, 1H, H-4′), 2.88 (q, 2H, 8-CH2CH3), 2.64-2.78 (m, 2H, 5′-CH2), 2.29 (s, 3H, 5′NH—CH3), 1.30 (t, 3H, 8CH2CH3).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]3[N:27]=[C:28]([NH2:30])[N:29]=[C:25]3[CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.NC1C=CC=C(Br)N=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]3[N:27]=[C:28]([NH:30][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[N:6]=5)[CH2:8][CH2:9]4)[N:29]=[C:25]3[CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1nc2cccc(-c3ccc(F)cc3)n2n1
Agent: Nc1cccc(Br)n1
Product: Cc1nsc(N2CCC(Nc3nc4cccc(-c5ccc(F)cc5)n4n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 5-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine. The latter compound can be prepared in analogy to example 1 steps d-f) starting from 2-amino-6-bromo-pyridine. The title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[C:4][CH2:5][OH:6].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.O>[Cl:1][CH2:2][C:3]#[C:4][CH2:5][O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: C1=COCCC1
Reactant: OCC#CCCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: ClCC#CCOC1CCCCO1
Yield: 97.5 %

Procedure:
A solution of 4-chloro-but-2-yn-1-ol (2.16 g, 20.66 mmol), 3,4-dihydro-2H-pyran (2.83 mL, 30.99 mmol, 1.5 eq), and pyridinium p-toluenesulfonate (528.0 mg, 0.21 mmol, 0.10 eq) in anhydrous dichloromethane (50 mL) was stirred at room temperature under N2 for 17 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 3.80 g (97.4%) of the desired product as clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.80 (t, J=4.0 Hz, 1H), 4.39-4.22 (m, 2H), 4.19 (t, J=2.0 Hz, 2H), 3.88-3.80 (m, 1H), 3.57-3.51 (m, 1H), 1.89-1.70 (m, 2H), 1.68-1.50 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH3:24])=[C:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.C(O)C.[BH4-].[Na+]>O>[C:1]1([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH3:24])=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:20][CH:21]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a mixture of 4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzaldehyde (2.40 g), tetrahydrofuran (30 ml) and ethanol (10 mL) was added sodium borohydride (0.28 g) at room temperature and the mixture was stirred at room temperature for 1 hr. To, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.60 g, 66%) of [4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]phenyl]methanol from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 79-80° C.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:29][CH2:30][CH2:31][CH2:32]O.B(F)(F)F.CCOCC>>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][CH2:32][CH2:31][CH2:30][OH:29])=[O:25])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1
Reactant: OCCCO
Agent: FB(F)F
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCCCO)cc1

Procedure:
As in Example 23, the title compound is prepared by the reaction of 4-(hexadecylamino)hydrocinnamic acid with 3-hydroxypropanol and boron trifluoride etherate.
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[C-:21]#[N:22].[Na+]>CN(C)C=O.O>[C:21]([C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1)#[N:22]
Reactant: [C-]#N
Reactant: Cc1cc2c(cc1Br)C(c1ccccn1)=NC(C)(C)O2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1C#N)C(c1ccccn1)=NC(C)(C)O2
Reaction time: 0.25 h
Yield: 20.9 %

Procedure:
Cuprous cyanide (1.1 g) was added to a solution of Compound 46 (2.0 g) in dimethylformamide (5 ml) and the mixture was heated under reflux for 23 hours. The reaction mixture was air-cooled. The mixture was then added to a solution of sodium cyanide (2.2 g) in water (6.5 ml), and the mixture was stirred for 15 minutes. The mixture was extracted with ethyl acetate, successively washed with aqueous 5% sodium cyanide solution and saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off. The resulting crude product was washed with ether/isopropyl ether to obtain 6-cyano-2,2,7-trimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.35 g) (Compound 64).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[CH:9][N:8]=[C:7]([NH2:20])[N:6]=2)[CH2:3][CH2:2]1.Cl.[O:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH2:28])[CH2:23]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:28][CH:24]4[CH2:25][CH2:26][CH2:27][O:22][CH2:23]4)[N:12]=3)=[CH:9][N:8]=[C:7]([NH2:20])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)c1nccc(-c2cnc(N)nc2CC2CC2)n1
Reactant: NC1CCCOC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1ncc(-c2ccnc(NC3CCCOC3)n2)c(CC2CC2)n1
Yield: 13 %

Procedure:
To a solution of 4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (5-2) (50 mg, 0.173 mmol) in DMSO (1 ml), was added Tetrahydro-pyran-3-ylamine HCl (119 mg, 0.864 mmol) and triethylamine (0.120 ml, 0.864 mmol) and the reaction was microwaved for 45 min at 160° C. The reaction was purified directly by reverse phase HPLC with a gradient of 10-90% acetonitrile in water over 15 minutes and then further purified by flash chromatography with a gradient of 25-100% ethyl acetate in heptane to give the desired product as a white solid (7.36 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25]([OH:27])=[O:26]>CC(O)C.CCN(C(C)C)C(C)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=2[C:25]([OH:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A slurry of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (50 g, 146 mmol) and 2-amino-6-fluorobenzoic acid (27.2 g, 175 mmol) (for instance from Acros Organics, Belgium) in iPrOH (1200 mL) and 30 mL of DIEA was heated to reflux. After 1 h, the solution turned a clear brown color, at which time about 450 mL of solvent were removed via distillation. The remaining mixture was treated with DIEA (90 mL) and heated to reflux for 16 hours. The reaction mixture was then further concentrated by distilling more solvent off (400 mL over 4 hours), then continued heating at reflux overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to obtain a thick oil which was diluted with EtOAc (1.3 L), then sequentially washed with a 1N HCl solution (2×500 mL), and a saturated NaHCO3 solution (500 mL). Further dilution of the separated organic layer with a saturated NaCl solution (500 mL) led to the formation of a thick precipitate. The entire mixture was filtered and the solid was washed with Et2O. The solid was dried overnight in a vacuum oven at 60° C. to obtain 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid as a yellow solid (61.63 g, 92%). 1H NMR (400 MHz, DMSO-d5) δ ppm 2.37 (s, 3H), 6.67 (d, J=3.85 Hz, 1H), 6.71-6.81 (m, 1H), 7.31 (td, J=8.33, 6.04 Hz, 1H), 7.48 (d, J=8.24 Hz, 2H), 7.74 (d, J=4.03 Hz, 1H), 7.98 (d, J=8.42 Hz, 2H), 8.36 (d, J=8.24 Hz, 1H); ESIMS (M+H)+=461.06.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[CH:7]=[CH:8]/[C:9]([OH:11])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:35][C:36]1([C:42]2[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:45]=[CH:46][CH:47]=2)[CH:41]2[CH:37]1[CH2:38][NH:39][CH2:40]2.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:35][C:36]1([C:42]2[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:45]=[CH:46][CH:47]=2)[CH:41]2[CH:37]1[CH2:38][N:39]([C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH2:40]2
Reactant: Cc1ccsc1/C=C/C(=O)O
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccsc1/C=C/C(=O)N1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
To a solution of (E)-3-(3-methyl-2-thienyl)-2-propenoic acid (200 mg, 1.00 mmol) in N,N-dimethylformamide (20 ml) was added 1-hydroxybenzotriazole monohydrate (212 mg, 1.39 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (352 mg, 1.84 mmol). After stirring at room temperature for 10 min, the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 414 mg, 1.36 mmol) and sodium hydrogen carbonate (225 mg, 2.68 mmol). The reaction mixture was stirred at room temperature for 7 d and then concentrated in vacuo. Attempted partition between water (15 ml) and ethyl acetate (20 ml) produced a buff solid which was collected by filtration. Sonication for 5 min at room temperature in dichloromethane (5 ml) followed by filtration afforded the title compound as an off-white solid (280 mg, 67%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:15][CH2:16][S:17][CH3:18])[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.[NH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][CH2:20][NH:19][C:11](=[O:13])[CH:10]([OH:14])[C@H:9]([NH2:8])[CH2:15][CH2:16][S:17][CH3:18])[CH:23]=1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Reactant: NCCc1cccnc1
Product: CSCC[C@@H](N)C(O)C(=O)NCCc1cccnc1

Procedure:
The product of example 3A and 1-amino-2-(3-pyridyl)ethane were processed as in example 2 to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH:12]([OH:14])[C@@H:11]([OH:15])[C@H:10]([OH:16])[C@H:9]2[OH:17])=[CH:4][C:3]=1[CH2:18][C:19]1[CH:28]=[CH:27][C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1.C(O[C:33](=[O:35])[CH3:34])(=O)C>N1C=CC=CC=1>[C:12]([O:15][C@H:11]1[C@H:10]([O:16][C:10](=[O:16])[CH3:9])[C@@H:9]([O:17][C:22](=[O:23])[CH3:21])[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]4[O:23][CH2:24][CH2:25][O:26][C:21]=4[CH:20]=3)[CH:4]=2)[O:13][CH:12]1[O:14][C:33](=[O:35])[CH3:34])(=[O:13])[CH3:11]
Reactant: OC1O[C@@H](c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1O[C@@H](c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.8 %

Procedure:
To a cooled solution of (3S,4R,5R,6S)-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2,3,4,5-tetraol (4.7 g, 9.9 mmol) in pyridine (20 ml) was added acetic anhydride (8.1 g, 79.5 mmol) at 0° C. After complete addition reaction mixture was stirred at room temperature for 2 h. Pyridine was evaporated under reduced pressure. The resulting residue was taken in ethyl acetate and washed with aqueous 1 N sodium bisulfate solution followed by brine, dried over sodium sulfate, concentrated to give 3.5 g of acetic acid (3S,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-yl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[NH:30]([CH2:34][CH2:35]O)[CH2:31][CH2:32][OH:33]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][CH2:34][NH:30][CH2:31][CH2:32][OH:33])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OCCNCCO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCNCCO

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{2-[(2-hydroxyethyl)amino]ethyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and diethanolamine following General Procedure K.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([CH2:31][N:32]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[N:33]2)[CH2:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH:27]1([CH2:31][N:32]2[CH:36]=[C:35]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:34]=[N:33]2)[CH2:30][CH2:29][CH2:28]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CC3CCC3)c2)OC1(C)C
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: CO
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(CC4CCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(cyclobutylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.9 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. It was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (6.2 mg). LCMS (M+H)+: m/z=473.3.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C[O:16][C:17](=[O:30])[CH2:18][CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[CH2:18][C:17]([OH:30])=[O:16])=[CH:23][C:24]=3[F:29])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)CC1CC1c1ccc(O)c(F)c1
Reactant: ClCc1cccc(SC2CCCC2)n1
Product: O=C(O)CC1CC1c1ccc(OCc2cccc(SC3CCCC3)n2)c(F)c1
Yield: 90.6 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.026 g, 0.11 mmol) obtained in Step C of Preparation Example 27 and [2-(3-fluoro-4-hydroxy-phenyl)-cyclopropyl]-acetic acid methyl ester (0.026 g, 0.11 mmol) obtained in Step F of Preparation Example 53 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.040 g, 87%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:20][O:21][N:22]=[C:23]1[C:27]2([CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[CH2:26][NH:25][CH2:24]1>C(#N)C>[C:34]([O:33][C:31]([N:29]1[CH2:30][C:27]2([C:23](=[N:22][O:21][CH3:20])[CH2:24][N:25]([C:11]3[N:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:26]2)[CH2:28]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Product: CON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 47.5 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
400 mg of 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid and 84 g of t-butyl 8-(methoxyimino)-2,6diazaspiro[3,4]octane-2-carboxylate were added to 10 ml of acetonitrile and the resulting mixture was stirred for 3 hours at 45-50° C. Then the precipitated solid was filtered and dried to give 650 mg of the titled compound(yield: 93.9%).
Reaction SMILES: CNCCO.BrC1SC(C=O)=CC=1.[OH:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:31][C:32]#[N:33]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30](/[C:31](=[CH:23]/[C:21]2[S:22][C:18]([N:17]([CH2:16][CH2:15][OH:14])[CH3:25])=[CH:19][CH:20]=2)/[C:32]#[N:33])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CN(CCO)c1ccc(C=O)s1
Agent: CNCCO
Agent: O=Cc1ccc(Br)s1
Product: COc1ccc(/C(C#N)=C/c2ccc(N(C)CCO)s2)cc1OC
Yield: 23.6 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from N-methylethanolamine (2.25 g) was introduced into 5-bromothiophene-2-carboxaldehyde (1.91 g), to thereby yield 5-[(2-hydroxy-ethyl)-methyl-amino]-thiophene-2-carbaldehyde (yield: 991 mg, 53%). The produced 5-[(2-hydroxy-ethyl)-methyl-amino]-thiophene-2-carbaldehyde (682 mg) was condensed with 3,4-dimethoxybenzyl cyanide (654 mg) through Method A (production step 2), to thereby yield the target product (yield: 300 mg, 24%).
Reaction SMILES: C([CH2:3][C:4]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1)([CH3:8])[C:5]([OH:7])=[O:6])C.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25]>CO>[S:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:16]1[C:13]1[CH:12]=[CH:11][C:10]([O:9][C:4]([CH3:3])([CH3:8])[C:5]([OH:7])=[O:6])=[CH:15][CH:14]=1
Reactant: Nc1ccccc1S
Reactant: CCCC(C)(Oc1ccc(C=O)cc1)C(=O)O
Solvent: CO
Product: CC(C)(Oc1ccc(-c2nc3ccccc3s2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
In a methanol solvent, a solution including Compound 97c (1.0 eq.) and 2-aminothiophenol (1.0 eq.) was stirred at room temperature. After methanol was removed, the precipitate was filtered, and washed with cold methanol to obtain a solid target product.