Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([F:21])=[CH:14][C:15]([N+:18]([O-])=O)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[C:13]([F:21])[C:12]2[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:9]=[N:10][C:11]=2[C:16]=1[CH3:17]
Reactant: Cc1c([N+](=O)[O-])cc(F)c2c1ncn2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(N)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-nitrobenzimidazole (0.776 g) in methanol (100 mL)/ethyl acetate (50 mL) is added palladium-on-carbon (10%, 0.1 g) and ammonium formate (0.663 g). The mixture is stirred at room temperature for 5 hours, then filtered on Celite, with methanol wash of the solids. The filtrate is rotary evaporated and the residue partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 25% ethyl acetate/hexane to afford 5-amino-1-tert-butoxycarbonyl-7-fluoro-4-methylbenzimidazole as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][N:3]=1.[CH2:11](I)[CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH2:11][CH3:12])[N:3]=1
Reactant: Brc1n[nH]c2cccnc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Br)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3-bromo-1H-pyrazolo[4,3-b]pyridine (2.22 g), EtI (1.08 mL), and K2CO3 (2.32 g) in DMF (15 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue purified by basic silica gel column chromatography (hexane/AcOEt) and crystallized from hexane/AcOEt to give the title compound (1.90 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21](Cl)=[C:16]3[CH:15]=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([O:29][C:30](=[O:39])[NH:31][CH:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C>C1COCC1>[C:25]([O:29][C:30](=[O:39])[NH:31][CH:32]1[CH2:33][CH2:34][CH:35]([NH:38][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[N:13]([C:5]4[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[N:14]=[CH:15][C:16]=23)[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: FC(F)(F)c1cc(-n2ncc3c(Cl)ncnc32)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3c2cnn3-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
1-(3,5-Bis-trifluoromethyl-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (147 mg, 0.4 mmol), (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.44 mmole, 1.1 eq) and diisopropylethyl amine (0.44 mmol, 1.1 eq) were dissolved in THF (3 mL) and then stirred at room temperature over night. THF was removed in vacuo and the solid residue was re-dissolved in 30/70 mixture of water and ACN gave yellow solid. The solid was washed with water and dried in vacuo provided compound A44 as creamy green solid (179 mg, 82%). 1H NMR (CDCl3, 400MHz) δ 1.43 (s, 9H), 1.75 (m, 2H), 1.98-1.97 (m, 2H), 2.04 (m, 2H), 2.95 (sb, 2H), 4.12 (q, 1H), 4.62 (m, 1H), 7.80 (s, 1H), 8.09 (s, 1H), 8.50 (s, 1H), 8.94 (s, 2H). Exact mass calculated for C24H26F6N6O2 544.2, Found 545.5 (MH+).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10])=O)C.CC(C)([O-])C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:16]([N:7]1[CH2:8][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:10])[C:4](=[O:3])[CH2:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)CC(C)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CC1=O
Reaction time: 3 h
Yield: 93.7 %

Procedure:
60.2 g (0.196 mole) of N-ethoxycarbonylmethyl-N-(2-ethoxycarbonylpropyl)benzylamine [prepared as described in Step (2) above] were added dropwise to a suspension of 24.2 g (0.22 mole) of potassium t-butoxide in 300 ml of toluene over a period of 3 hours, whilst keeping the temperature below 6° C. The mixture was then stirred at the same temperature for 3 hours, after which 13 g of acetic acid were added to it. The toluene layer was separated, washed with water and dried, and the solvent was removed by evaporation under reduced pressure, to give 48.0 g of 1-benzyl-4-ethoxycarbonyl-4-methyl-3-pyrrolidone as a red oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:11])([F:12])[F:1])[N:10]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccccc1C(F)(F)F
Product: CC(C)(C)c1cc(N)n(-c2ccccc2C(F)(F)F)n1
Yield: 64 %

Procedure:
The title compound was prepared from 2-(trifluoromethyl)-phenylhydrazine (1.41 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedure in Example 161A Step 3 to give 3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.45 g, 5.12 mmol, 64%). 1H NMR (300 MHz, DMSO-d6) δ 7.86 (d, 1H), 7.75 (t, 1H), 7.65 (t, 1H), 7.49 (d, 1H), 5.27 (s, 1H), 4.97 (s, 1H), 1.18 (s, 9H); LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(NC(C)C)(C)C.C(OCC)(=O)C.[Cu]I>[N:14]1([C:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1ccc(C(=O)N2CCCC2)c(C#C[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
18 g (57.7 mmol) of methyl 3-bromo-4-(pyrrolidin-1-ylcarbonyl)benzoate is placed under a nitrogen atmosphere together with 6.66 g (5.77 mmol) of tetrakis-triphenylphosphinepalladium(0) and 0.439 g (2.31 mmol) of copper(1) iodide in 150 mL of N,N-diisopropylamine, the mixture is heated to 80° C. and 16.6 mL (115 mmol) trimethylsilylethyne is added. The reaction mixture is stirred for 8 hours at 80° C. and then for 16 hours at ambient temperature. Then volatile constituents are eliminated in vacuo, the residue is taken up in ethyl acetate, insoluble matter is filtered off, and the solvent is eliminated in vacuo. The residue is purified by chromatography on silica gel (gradient: dichloromethane/ethanol 100:0□95:5). Yield: 7.7 g (41%); Rf value: 0.44 (silica gel; dichloromethane/ethanol=95:5); C18H23NO3Si (329.48); mass spectrum: (M+H)+=330.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.N12CCN(CC1)CC2.[NH2:15][C:16]1[C:25](I)=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:27])[N:17]=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[C:25]2[CH:4]=[C:2]([C:1]([OH:6])=[O:5])[NH:15][C:16]2=[N:17][C:18]=1[CH3:27])=[O:21]
Reactant: CC(=O)C(=O)O
Reactant: COC(=O)c1cc(I)c(N)nc1C
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(C(=O)O)[nH]c2nc1C
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
Under argon, pyruvic acid (6.90 ml, 100.1 mmol) and 1,4-diazabicyclo[2.2.2]octane (11.2 g, 100.1 mmol) were added to a solution of methyl 6-amino-5-iodo-2-methylnicotinate (9.00 g, 30.8 mmol) in N,N-dimethylformamide (88 ml), and the flask was evacuated and flushed with argon. Argon was subsequently passed through the solution for 5 min, palladium(II) acetate (0.345 g, 1.54 mmol) was then added and the mixture was heated at 100° C. for 2 h. The cooled solution was filtered through Celite and the dimethylformamide was distilled off. The residue was then taken up in water and acidified with hydrochloric acid, giving a solid (6.3 g, 86% of theory). HPLC-MS: log P=1.26; mass (m/z): 235.0 (M+H)+; 1H-NMR (DMSO) 2.79 (s, 3H), 3.85 (s, 3H), 7.19 (s, 1H), 8.62 (s, 1H), 12.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10](C=O)=[C:9]2[CH3:21])=[O:7])=[CH:4][CH:3]=1.[C:24]([BH3-])#[N:25].[Na+].C(=O)(O)[O-:29].[Na+]>C(O)(=O)C.C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:24][NH:25][OH:29])=[C:9]2[CH3:21])=[O:7])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)c(C=O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-carboxaldehyde, oxime (1.0 g, 2.9 mmol) in 15 ml of acetic acid is added 0.9 g (14.6 mmol) of sodium cyanoborohydride (0.9 g, 14.6 mmol). The reaction mixture is stirred vigorously for three hours whereupon an additional 0.35 g (5.6 mmol) of the reducing agent is added. After an additional 45 minutes the reaction mixture is diluted with ethyl acetate and methylene chloride, cooled to 0° C., and 300 ml of a saturated solution of sodium bicarbonate is added dropwise while continuing to stir vigorously. This mixture is diluted further with 400 ml of ethyl acetate and separated from the aqueous phase (pH=9). The organic phase is washed again with a saturated solution of sodium bicarbonate, water, and finally a saturated solution of sodium chloride. It is dried over magnesium sulfate, filtered, and concentrated to a yellow oil which is crude 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine and is used without further purification in the subsequent reaction. Mass balance is quantitative. A sample recrystallized from methylene chloride has a mp of 164°-165° C. (dec).
Reaction SMILES: Cl.C[O:3][C:4]([C:8]1[S:9][C:10]([C:13]2([OH:22])[CH2:18][CH2:17][CH2:16][N:15]3[CH:19]=[N:20][CH:21]=[C:14]23)=[CH:11][N:12]=1)(OC)[CH3:5].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[OH:22][C:13]1([C:10]2[S:9][C:8]([C:4](=[O:3])[CH3:5])=[N:12][CH:11]=2)[CH2:18][CH2:17][CH2:16][N:15]2[CH:19]=[N:20][CH:21]=[C:14]12
Reactant: COC(C)(OC)c1ncc(C2(O)CCCn3cncc32)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ncc(C2(O)CCCn3cncc32)s1
Reaction time: 2 h

Procedure:
5 ml of conc. HCl are added dropwise to a solution of 0.31 g of 8-[2-(1,1-dimethoxyethyl)thiazol-5-yl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol and 20 ml of 1:1 acetone/water at room temperature, and the mixture is stirred for 2 hours. The reaction mixture is evaporated—the residue is mixed with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (3×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO2 60F) on the basis of the Rf.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.P(Br)(Br)[Br:27].C([O-])(O)=O.[Na+].CCOC(C)=O>COCCOC>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][Br:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To (2′-hydroxymethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (1.855 g, 5.23 mmol) in DME (19 mL) was added phosphorus tribromide (0.74 mL, 7.85 mmol), and the reaction was stirred at room temperature for 1.5 hours. The mixture was cooled to 0° C., and saturated aqueous NaHCO3 and EtOAc were added. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH:19]([CH3:24])[C:18]=3[CH:25]=2)=[CH:4][CH:3]=1.[OH:26]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:26])=[CH:6][CH:7]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)OC(=O)N3)cc1
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methylphenylmercapto)-butoxy]-4-methyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: CO.[CH3:3][NH2:4].C(O[C:8]([C:10]1[C:11]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[CH:22]3)=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1)=[O:9])C>O>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:11]3[C:10]([C:8]([NH:4][CH3:3])=[O:9])=[CH:15][N:14]=[C:13]([S:16][CH3:17])[N:12]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: CN
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Solvent: CO
Solvent: O
Product: CNC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To the solution of methanol with 40% methylamine (30 ml) was added 4-(1H-5-indazolylamino)-2-methylthio-5-pyrimidine carboxylic acid ethyl ester (1.5 g) obtained by by preparation example 1, and the solution was reacted at 25-30° C. for 1 hr. The reaction mixture was cooled at 20-25° C., added H2O (90 ml) and stirred for 0.5hr. The reaction mixture was filtered, washed with 25% aqueous methanol solution (10 ml), obtained a solid product. The solid product was dried in vacuo to obtain the desired compound (1.26 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([Br:12])[CH:3]=1.[CH:13](OCC)(OCC)OCC.[N-:23]=[N+:24]=[N-:25].[Na+]>CC(O)=O>[Br:12][C:4]1[CH:3]=[C:2]([N:1]2[CH:13]=[N:25][N:24]=[N:23]2)[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(CC(=O)O)c(Br)c1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(-n2cnnn2)cc1Br
Temperature: 100 °C

Procedure:
A solution of (4-amino-2-bromophenyl)acetic acid (230 mg, 1 mmol) and triethyl orthoformate (444 mg, 3 mmol) in 8 mL of HOAc was added sodium azide (80 mg, 1.2 mmol), and the mixture was heated to 100° C. for 3 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed under vacuum. The residue was dissolved in EtOAc, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to afford [2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetic acid. 1H-NMR (300 MHz, MeOD) δ ppm 9.78 (s, 1H), 8.16 (s, 1H), 7.83˜7.87 (m, 1H), 7.60˜7.63 (m, 1H), 3.89 (s, 2H).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:27])=[C:22]([C:25]#[N:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[NH:28][C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30].C(=O)([O-])[O-].[K+].[K+].O.[C:42]([O:45][CH2:46][CH3:47])(=O)C>>[C:25]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH2:47][C@H:46]1[CH2:42][O:45]1)[N:18]=[CH:17][CH:16]=[C:15]2[O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:28][C:29]([NH:31][CH:32]2[CH2:33][CH2:34]2)=[O:30])=[C:7]([CH3:6])[C:12]=1[CH3:13])#[N:26]
Reactant: CCOC(C)=O
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(O)c(C#N)cc23)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)c1C
Temperature: 50 °C

Procedure:
Dimethylformamide (4 ml) was added to N-(2,3-dimethyl-4-(6-cyano-7-hydroxy-quinolin-4-yloxy)-phenyl)-N′-cyclopropylurea (476 mg), and then p-toluenesulfonic acid (2R)-glycidyl ester (365 mg) and potassium carbonate (340 mg) were further added and the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was washed with ethyl acetate to obtain the title compound (270 mg) as light yellow crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([OH:24])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=3)[N:14]=[CH:13][C:12]=2[F:23])[CH2:5]1.[O:25]=[C:26]1[NH:31][C:30]2[N:32]=[C:33]([CH:36]=O)[CH:34]=[CH:35][C:29]=2[S:28][CH2:27]1.CCN(CC)CC.[BH4-].[Na+]>C(Cl)Cl.CCO>[F:23][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[CH2:10][CH2:9][N:6]1[CH2:7][CH2:8][C:4]([CH2:3][NH:2][CH2:36][C:33]3[CH:34]=[CH:35][C:29]4[S:28][CH2:27][C:26](=[O:25])[NH:31][C:30]=4[N:32]=3)([OH:24])[CH2:5]1)=[N:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2
Reactant: COc1ccc2ncc(F)c(CCN3CCC(O)(CN)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3CCC(O)(CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a stirred solution of 3-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol hydrochloride salt (0.21 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (20 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.04 g, 0.21 mmole) and Et3N (0.06 mL, 0.42 mmole). After 24 h at RT was added NaBH4 (0.01 g, 0.23 mmole). After 2 h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.075 g, 72%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 4.38 (s, 2H), 4.03 (s, 3H), 3.81 (m, 2H), 3.37 (m, 4H), 3.12 (m, 4H), 2.72 (m, 2H), 2.54 (m, 2H), 1.92 (m, 2H). LC-MS (ES) m/e 499 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([OH:5])#N.[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[CH2:6]([O:5][CH2:3][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a slurry of 1.1 g of sodium hydride (21 mmole, 50% oil dispersion in 25 ml of dry DMF at 0° C. was added a solution of 3.34 g of title F cyanoalcohol (20 mmole) in 10 ml of DMF over a period of 10 minutes. After stirring for an additional 15 minutes, 3.6 g of benzyl bromide was added dropwise. The reaction mixture was stirred for 30 minutes at 0° C. and 3 hours at 25° C. then quenched with a saturated ammonium chloride solution, and diluted with ether. The organic layer was washed with brine. The combined aqueous layer was re-extracted with ether. The combined organic layer was dried over anhydrous MgSO4 and concentrated to leave an oil. The crude oil was chromatographed on a silica gel column, eluting with 10-20% ethyl acetate in hexanes to give 4.43 g of the title G benzyl ether.
Reaction SMILES: [CH2:1](O)[CH:2]([OH:6])[CH2:3][CH2:4][OH:5].C[O:9][C:10](OC)([CH3:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:11][C:10]1([CH3:12])[O:9][CH:3]([CH:2]([OH:6])[CH3:1])[CH2:4][O:5]1
Reactant: OCCC(O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(O)C1COC(C)(C)O1
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
To a vigorously stirring suspension of 1,2,4-butanetriol (5.8 g, 54.6 mmol) in dichloromethane (20 mL) was added 2,2-dimethoxypropane (6.8 mL, 54.6 mmol) and catalytic p-toluenesulfonic acid. After 5 minutes, the solution became homogenous and was allowed to stir for an additional 30 minutes. The reaction mixture was then concentrated in vacuo to afford (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (7.72 g, 96.7%). To a stirring solution of (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (6.95 g, 47.5 mmol), triphenylphosphine (12.5 g, 47.5 mmol) and N-hydroxyphthalimide in freshly distilled tetrahydrofuran (200 mL) at 0° C. was slowly added (over 20 minutes) diethylazodicarboxylate. The dark red solution was allowed to stir for 2 hours at 0° C. and then allowed to warm to room temperature while stirring for 17 hours. The yellow solution was concentrated in vacuo and dissolved in chloroform (100 mL). The solids were filtered and filtrate concentrated. This filtration was repeated twice. The remaining yellow oil was purified on silica gel eluting with hexanes-ethyl acetate (4:1) to afford 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (8.1 g, 58.7%). To a stirring solution of 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (0.86 g, 2.95 mmol) in dichloromethane (10 mL) at 0° C. was added methylhydrazine (0.16 mL, 2.95 mmol). The resultant solution was allowed to warm to room temperature and stirred for 3 days. The resulting suspension was diluted with diethyl ether (20 mL) and filtered. The filtrate concentrated in vacuo to afford O-(2,2-dimethyl-[1,3]dioxolan-4-ylethyl)-hydroxylamine (0.36 g, 75.3%): 1H NMR (400 MHz; CDCl3) δ 4.18 (quint, 1H, J=5.9), 4.07 (dd, 1H, J=5.9, 7.8), 3.86 (t, 2H, J=6.2), 3.56 (t, 1H, J=7.6), 1.89 (m, 2H), 1.36 (s, 3H), 1.20 (s, 3H); MS(APCI+)=162.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=O)[CH:14]=1)[CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:30]1([NH2:33])[CH2:32][CH2:31]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][NH:33][CH:30]2[CH2:32][CH2:31]2)[CH:14]=1)[CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C=O)c1)CC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CNC2CC2)c1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-cyclopropylmethyl-carbamic acid tert-butyl ester (1.00 g, 3.09 mmol), Et3N (0.646 mL, 4.64 mmol) and cyclopropylamine (0.325 mL, 4.64 mmol) in MeOH (10.5 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (292 mg, 7.71 mmol) was added. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 1:49) yielded the title compound (535 mg, 48%). LC-MS: tR=0.81 min; ES+: 406.20.