Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[CH3:25][C:26]1([CH3:33])[O:31][CH2:30][C:29](=O)[CH2:28][O:27]1.[BH3-]C#N.[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:29]3[CH2:30][O:31][C:26]([CH3:33])([CH3:25])[O:27][CH2:28]3)[CH:17]=2)=[CH:3]1
Reactant: CC1(C)OCC(=O)CO1
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cn1cc(C2=C(c3cccc(NC4COC(C)(C)OC4)c3)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
A mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (200 mg, 0.63 mmol) and 2,2-dimethyl-1,3-dioxane-5-one (98 mg, 0.76 mmol) in MeOH (10 mL) was stirred at room temperature for 15 min., and then NaCNBH3 (79 mg, 1.26 mmol) was added. After stirring the reaction mixture overnight the volatiles were removed under vacuo and the residue was purified by preparatory TLC (1% MeOH/CH2Cl2) to give 3-(1-methylindol-3-yl)-4-[3-(2,2-dimethyl-1,3-dioxan-5-ylamino)phenyl]-1H-pyrrole-2,5-dione (185 mg, 68%). MS(EI): M+ 431, MP: 201-203° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6](/[CH:7]=[CH:8]/[C:9]2[C:10]([C:18]([OH:20])=[O:19])=[CH:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=2)=[CH:5][CH:4]=1>CN(C)C=O.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=2[C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1
Reactant: COc1ccc(/C=C/c2cc(C(=O)O)ccc2C(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(CCc2cc(C(=O)O)ccc2C(=O)O)cc1

Procedure:
45 G. of a mixture of 3-(p-methoxybenzylidene)phthalide-5- and -6- carboxylic acids, obtained by the condensation of p-methoxyphenylacetic acid and benzene-1,2,4-tricarboxylic anhydride as described in Example 1, was hydrogenated for 20 hours in 250 ml of dimethylformamide containing 10.5 g. of 10% palladium on carbon catalyst. The solution was filtered and the filtrate evaporated. The residue was recrystallized from aqueous acetic acid to afford 3-(p-methoxybenzyl)phthalide-5- and -6- carboxylic acids. 24.1 G of this mixture was dissolved in 90 ml of dimethylsulfoxide and 30 g. of potassium tertbutoxide was added. After 15 minutes the solution was poured into water, acidified with acetic acid, and the product filtered off. Fractional crystallization from dioxan afforded 4'-methoxy-trans-stilbene 2,4-dicarboxylic acid as the less soluble isomer, and 4'-methoxy-trans-stilbene-2,5-dicarboxylic acid as the more soluble isomer. 2.4 G. of 4'-methoxy-trans-stilbene-2,5-dicarboxylic acid was hydrogenated for 41/2 hours in 20 ml dimethylformamide and 20 ml of acetic acid containing 0.3 g. of 10% palladium on carbon catalyst. The solution was filtered and evaporated and the residue recrystallized from aqueous ethanol to afford 2-(4-methoxyphenethyl)benzene-1,4-dicarboxylic acid. This compound was then cyclized by the procedure of part A of this example to give 2-carboxy-7-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 201°-203° C.
Reaction SMILES: IC.[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3([C:33]#[N:34])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[CH:22]=2)=[N:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1.[CH2:35](N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3([C:33]#[N:34])[CH2:32][CH2:31][CH2:30][N:29]([CH3:35])[CH2:28]3)[CH:22]=2)=[N:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1
Reactant: CCN(CC)CC
Reactant: N#CC1(c2cc(-c3cnc(N)c(-c4cc(-c5ccccc5)no4)n3)ccn2)CCCNC1
Solvent: CI
Solvent: ClC(Cl)Cl
Product: CN1CCCC(C#N)(c2cc(-c3cnc(N)c(-c4cc(-c5ccccc5)no4)n3)ccn2)C1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Iodomethane (17.09 mg, 7.496 μL, 0.1204 mmol) w as added to a stirred solution of 3-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]piperidine-3-carbonitrile (51 mg, 0.1204 mmol) and triethyl amine (30.46 mg, 41.96 μL, 0.3010 mmol) in chloroform (1 mL) and the reaction stirred at ambient temperature for 23 hours. A further portion of iodomethane (213.6 mg, 93.68 μL, 1.505 mmol) was added and the reaction stirred at ambient temperature for a further 5.5 hours. The solvent was removed in vacuo and the residue re-dissolved in dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 0%-100% B (solvent A: 10 mM ammonium formate in water; solvent B: 10 mM ammonium formate in 1:1 MeOH:CH3CN) over 14 minutes at 25 mL/min]. The relevant fractions were concentrated in vacuo and partitioned between dichloromethane/saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer extracted with dichloromethane (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was freeze-dried to give 3-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]-1-methyl-piperidine-3-carbonitrile Compound I-37 as a yellow solid (14.1 mg, 27% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.96-1.71 (m, 4H), 2.20 (s, 3H), 2.21-2.19 (m, 1H), 2.68 (br d, 1H), 2.75 (br d, 1H), 3.22-3.20 (m, 1H), 7.21 (br s, 2H), 7.51-7.44 (m, 3H), 7.68 (s, 1H), 7.94-7.91 (m, 2H), 8.00 (dd, 1H), 8.12 (s, 1H), 8.59 (d, 1H) and 8.93 (s, 1H) ppm LC/MS m/z 438.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][C:8]([C:14]([O-:16])=[O:15])=[C:7]([C:17]1[S:18][CH:19]=[C:20]([CH3:22])[N:21]=1)[C:6]2=[O:23])[CH3:2].[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.C(OCC)(=O)C>[C:24]1([O:15][C:14]([C:8]2[O:9][C:10]3[C:5]([C:6](=[O:23])[C:7]=2[C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[CH:4][C:3]([CH2:1][CH3:2])=[C:12]([OH:13])[CH:11]=3)=[O:16])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1ccccc1
Reactant: CCc1cc2c(=O)c(-c3nc(C)cs3)c(C(=O)[O-])oc2cc1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cc2c(=O)c(-c3nc(C)cs3)c(C(=O)Oc3ccccc3)oc2cc1O
Reaction time: 20 h
Yield: 40.9 %

Procedure:
In a 5 mL Schlenk tube 18 mg (0.054 mmol) 6-ethyl-7-hydroxy-3-[(4-methyl)-1,3-thiazol-2-yl]-4-oxo-4H-chromene-2-carboxylate 10 (Aldrich, no. R66,464-2) were suspended in 0.5 mL methylene chloride. Then 51 mg (0.54 mmol) phenol and 18 μl (0.108 mmol) triflate anhydride were added at ambient temperature. The resulting mixture was stirred for 20 hours, diluted in 10 mL of ethyl acetate and washed with water and saturated solutions of sodium bicarbonate and sodium chloride. The organic layer was separated, dried over magnesium sulfate and filtered. Evaporation of the solvent on a rotavapor yielded 9 mg of a yellow solid. This crude product was used without further purification.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)=[O:6].Cl.NO>O1CCOCC1.O>[O:6]1[C:5]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=CC(=O)c1cccc(O)c1
Agent: Cl
Agent: NO
Solvent: O
Solvent: C1COCCO1
Product: Oc1cccc(-c2ccno2)c1
Temperature: 0 °C
Yield: 75.5 %

Procedure:
A solution of 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (2.2 g, 11.5 mmol) and hydroxylamine hydrochloride (1.17 g, 16.8 mmol) in 45 ml dioxane/water 1:1 is heated for 2 hours at 60° C. The reaction is poured into ice-water and the precipitate is collected by filtration, washed with water, and dried in vacuo to give 1.4 g of 3-(5-isoxazolyl)phenol (75.5%). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 1.33 g of the title epoxide (70%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:4]=[C:3]1[CH3:34].O.NN>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][N:4]=[C:3]1[CH3:34]
Reactant: Cc1ncc(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2ccccc2)n1C
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(C(=NOCc2cccc(N)n2)c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 28 h
Yield: 50.9 %

Procedure:
To a solution of 2-{6-[({[(1,2-dimethyl-1H-imidazol-5-yl)(phenyl)methylene]amino}-oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (1.02 g, 2.26 mmol) in tetrahydrofuran (30 mL) was added dropwise hydrazine hydrate (0.55 mL, 11.3 mmol). After stirring at room temperature for 28 h, the reaction mixture was filtered, the insolubles washed with ethyl acetate, and the filtrate concentrated in vacuo. Purification on silica gel afforded 6-[({[(1,2-dimethyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine [370 mg, yield 43%; HPLC/MS: m/z=322 (M+H); log P(HCOOH)=0.39].
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].OP([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:7][C:5]1[S:6][C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]2)=[N:3][N:4]=1
Reactant: Nc1nnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nnc(N)s2)CC1
Temperature: 100 °C
Yield: 56.6 %

Procedure:
A mixture of 5-bromo-1,3,4-thiadiazol-2-ylamine (9.27 g), Boc-piperazine (11.51 g), and K2HPO4 (13.4 g) in 30 ml of DMF is heated at 100° C. under argon for four hours, then cooled and added to 100 g of ice. The mixture is extracted with ethyl acetate, and the organic phase washed twice with water and dried (MgSO4). Following removal of the solvent under reduced pressure, the residue is flash chromatographed on silica using 4% methanol in dichloromethane to afford 8.32 g of the title compound as a solid. Recrystallization from 240 ml of 1:1 acetonitrile-toluene provides 6.65 g of solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].Cl.[Al+3].[Cl-].[Cl-].[Cl-]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(Br)cc1O
Reaction time: 2 h

Procedure:
3-Bromo-phenol (10.0 g, 57.8 mmol) was dissolved in 10 ml of pyridine and 10 ml of acetic anhydride and stirred overnight at RT. The mixture was then poured into water, and 1 M HCl was added until reaching a neutral pH value. Extraction with AcOEt furnished a crude product, which was treated with AlCl3 (13.25 g, 100 mmol) at 140° C. After 2 h, the mixture was poured into water and extracted with diethyl ether. The crude residue was purified by column chromatography (eluent:hexane/AcOEt 70:30) to give 1-(4-bromo-2-hydroxy-phenyl)-ethanone (10.1 g) as a red solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[O:10][CH:11]=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1F>>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:7]1[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[CH:12]=[CH:11][O:10][C:6]1=2
Reactant: CCN1Cc2ccoc2C(O)C1
Reactant: Fc1ccccc1Br
Product: CCN1Cc2ccoc2C(Oc2ccccc2Br)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 34) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1.[OH-].[Na+]>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:8]1
Reactant: Clc1cnccn1
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Product: c1cnc(N2CCNCC2)cn1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To piperazine (48.0 g) dissolved at 110° C. was added 2-chloropyrazine (5.0 ml) and the mixture was stirred at 150° C. for 2 hr. The reaction mixture was poured into an aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (6.4 g) as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccccc1N
Reactant: O=C(O)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1Nc1ccccc1C(=O)O
Temperature: 120 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A mixture of 40 g (0.25 mole) of 2-chlorobenzoic acid, 21 ml (0.26 mole) of 2-methoxyaniline, 3.84 g cupric acetate, 35.4 g of potassium carbonate and 155 ml of dimethylformamide was heated at 120° C. for 12 hours. The reaction mixture was poured into ice-water, acidified with concentrated hydrochloric acid to pH 2, and stirred for one hour. The solid product was collected by filtration, air dried and recrystallized from toluene to give 28.61 g of 2-(2-methoxyphenylamino)benzoic acid.
Reaction SMILES: [OH-:1].[Na+].BrC(Br)[C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=[O:6]>O>[C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)([OH:6])=[O:1]
Reactant: [OH-]
Reactant: O=C1CCc2cc(C(=O)C(Br)Br)ccc2N1
Agent: [Na+]
Solvent: O
Product: O=C1CCc2cc(C(=O)O)ccc2N1
Yield: 54.5 %

Procedure:
Into 250 ml of water, 26 g sodium hydroxide was dissolved, then at a temperature of 90°-100° C. and under stirring condition, 35 g of 6-dibromoacetyl-3,4-dihydrocarbostyril was added thereinto and reacted for 3 hours. After the reaction was completed, the reaction mixture was cooled and insoluble matters formed in the mixture were removed by filtration. The mother liquor was acidified with concentrated hydrochloric acid and the crystals precipitated were collected by filtration and washed with water. The crystals thus obtained were recrystallized from ethanol twice to obtain 10.5 g of 6-carboxy-3,4-dihydrocarbostyril in the form of light yellow amorphous crystals. Melting point: 324.5°-327° C. (decomposed)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[Li+].[OH-]>CO.O>[OH:17][CH2:16][C:15]([N:9]1[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1cnn(C(C)(C)CO)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CO)n1ncc(C(=O)O)c1C(F)(F)F
Yield: 94.9 %

Procedure:
To a solution of 1-(2-hydroxy-1,1-dimethyl-ethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (328 mg, 1.17 mmol) in methanol (5 mL) and water (5 mL) was added LiOH (34 mg, 1.4 mmol). The reaction mixture was stirred at reflux overnight, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH=2 with concentrated HCl. The resulting mixture was then extracted with ethyl acetate three times. The combined organic extracts were concentrated in vacuo to give 1-(2-hydroxy-1,1-dimethyl-ethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (280 mg, 95%), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:20][O:21][C:22](Cl)=[O:23]>ClCCl>[CH3:4][C:2]([N:5]([CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[C:22](=[O:23])[O:21][CH3:20])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NCC(O)C(Cl)(Cl)Cl
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N(CC(O)C(Cl)(Cl)Cl)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a stirred solution of 5 grams of 3-(1,1-dimethylethylamino)-1,1,1-trichloro-2-propanol and 2.15 grams of triethylamine in 50 grams of dichloromethane, cooled to -60° C., 2.01 grams of methylchloroformate was added dropwise during 5 minutes. After allowing the reaction mixture to warm to ambient temperature during 1 hour, the mixture was stirred for 3 hours. The reaction mixture was evaporated under a reduced pressure of 100 mm. Hg to 5.6 grams of an oil which was crystallized from 50 grams of hexane to yield 5.2 grams of white methyl (1,1-dimethylethyl)-(3,3,3-trichloro-2-hydroxypropyl)carbamate melting 100°-101° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([N:11]([CH3:13])[CH3:12])[CH2:8][CH2:7][C@@H:6]1[N:14]1[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OCC2C=CC=CC=2)[C:15]1=[O:30])(=[O:3])[CH3:2]>[Pd].CCOC(C)=O>[NH2:19][C@H:16]1[CH2:17][CH2:18][N:14]([C@H:6]2[CH2:7][CH2:8][C@@H:9]([N:11]([CH3:13])[CH3:12])[CH2:10][C@H:5]2[NH:4][C:1](=[O:3])[CH3:2])[C:15]1=[O:30]
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H]1C[C@H](N(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a mixture of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(dimethylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (70 mg) and 10% Pd/C (30 mg of 50% wet catalyst) was added EtOAc (50 mL) and then the flask was evacuated and back-filled with hydrogen. The mixture was stirred under 1 atm H2 for 16 h and the catalyst was removed by filtration through Celite. The filtrate was concentrated in vacuo to give N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(dimethylamino)cyclohexyl)acetamide as a white solid (40 mg, 85% yield), which was taken on to the next step without further purification. LC/MS found [M+H]+=283.
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N-:10]=[N+:11]=[N-:12].[Na+]>C(#N)C>[P:4]([N:10]=[N+:11]=[N-:12])([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOP(=O)(Cl)OCC
Agent: [Na+]
Solvent: CC#N
Product: CCOP(=O)(N=[N+]=[N-])OCC

Procedure:
Following the procedure of Shioiri, Nimomiya, and Yamada, J. Amer. Chem. Soc., 94, 6203 (1972), 5.13 g (0.03 mole) of diethylphosphorochloridate and 1.95 g (0.03 mole) of sodium azide were added to 50 ml dry acetonitrile purified by distillation from calcium hydride under a nitrogen atmosphere. The slurry was stirred at reflux for 1 hour, cooled and filtered by gravity to remove the solid precipitate. The acetonitrile solvent was distilled under vacuum. The sample was isolated by vacuum distillation.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][OH:27])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.CCN(CC)CC.[C:50](Cl)(=[O:54])[CH:51]([CH3:53])[CH3:52]>C(Cl)Cl>[C:50]([O:27][CH2:26][CH2:25][O:24][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([C:10]3[N:8]4[CH:9]=[C:4]([C@@H:3]([N:28]5[CH2:32][CH2:31][C@H:30]([NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:40])[CH2:29]5)[C:2]([F:1])([F:41])[F:42])[CH:5]=[CH:6][C:7]4=[N:12][N:11]=3)=[N:14]2)=[CH:19][C:18]=1[F:23])(=[O:54])[CH:51]([CH3:53])[CH3:52]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)OCCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a stirred solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (80 mg, 0.14 mmol) in DCM (1 mL) and Et3N (0.057 mL, 0.41 mmol) was added dropwise isobutyryl chloride (0.036 mL, 0.34 mmol) at 0° C. under nitrogen. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give 2-(2-(6-((R)-1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-7-yloxy)ethyl isobutyrate (75 mg, 84%).
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([CH3:20])[CH:14]=1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[C:15]([CH3:20])[CH:14]=1
Reactant: Cc1cc(F)ccc1N
Reactant: COC(=O)c1cccoc1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(-c2ccc(F)cc2C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.9 %

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (3 g, 19.5 mmol) in N,N-dimethylformamide, (18 mL) was added 4-fluoro-2-methylaniline (2.44 g, 19.5 mmol), and the mixture was stirred at room temperature for 3 hr. 4-Dimethylaminopyridine (119 mg, 0.974 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.48 g, 23.4 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for 16 hr. 2N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1), and the obtained solid was washed with hexane/ethyl acetate (=1/1) and collected by filtration to give the title compound (0.40 g, 8%) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10](=[CH:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:9]1=[O:33])=O)(C)(C)C.[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:50])=[C:39]([CH:41]=[N:42][C:43]([O:45][Si](C)(C)C)=[CH2:44])[CH:40]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:33])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)[CH2:44][C:43](=[O:45])[NH:42][CH:41]3[C:39]3[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=3[CH3:50])[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(=Cc2cc(Cl)ccc2Oc2ncccn2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2Oc2ncccn2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 3.5 %

Procedure:
In a manner similar to the method described in example 1e, 6-chloro-3-[5-chloro-2-(pyrimidin-2-yloxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 g, 2 mmol) was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mL, 20 mmol) in toluene to give title compound as a white solid (Yield: 40 mg).