Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=O)C.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[Cl-].[Na+].Cl>CN(C)C=O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][O:10][CH:7]1[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1
Reactant: CC(=O)N1CCC(O)CC1
Reactant: COCCCBr
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COCCCOC1CCNCC1

Procedure:
A solution of N-acetyl-4-hydroxypiperidine (30.5 g.) in dimethylformamide (200 ml.) is added dropwise to a stirred suspension of sodium hydride (11.26 g., 50% dispersion in mineral oil) in dimethylformamide (300 ml.) under an atmosphere of nitrogen. The reaction temperature is kept below 30° C. by external cooling and, after the addition is complete, stirring is continued for a further 11/4 hours. A solution of 1-bromo-3-methoxypropane (35.2 g.) in dimethylformamide (100 ml.) is then added dropwise with external cooling, and the resulting clear solution is stirred at room temperature overnight. The reaction mixture is then evaporated in vacuo, the residue partitioned between water and chloroform, the organic extracts dried (Na2SO4) and evaporated to leave a crude residue. The above aqueous phase is saturated with sodium chloride, further extracted with chloroform, and the organic phase is dried (Na2SO4), and evaporated to leave a further residue. This residue is combined with the original residue and heated on a steam bath overnight with hydrochloric acid (243 ml., 2 N). The reaction mixture is extracted with chloroform to remove the residual mineral oil, the aqueous phase concentrated, basified with sodium hydroxide (pH 12), then reextracted with chloroform. The organic extracts are washed with brine, dried (Na2SO4) and evaporated to afford the desired product.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]([Cl:40])([Cl:39])[CH2:14][O:15][C:16]([CH:18]1[N:22]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:21]2[S:20][C:19]1([CH2:37][Cl:38])[CH3:36])=[O:17]>C(Cl)(Cl)Cl>[Cl:38][CH2:37][C:19]1([CH3:36])[CH:18]([C:16]([O:15][CH2:14][C:13]([Cl:39])([Cl:12])[Cl:40])=[O:17])[N:22]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:21]2[S:20]1=[O:9]
Reactant: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1(CCl)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Yield: 79.5 %

Procedure:
A solution of m-chloroperbenzoic acid (2.03 g) in chloroform (30 ml) was added dropwise to a solution of 2,2,2-trichloroethyl-2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (5.0 g) in chloroform (40 ml) at -10° - -5° C under stirring, and then the mixture was stirred at -10° - -5° C for 1 hour. After the solid was filtered off, the filtrate was washed with a saturated sodium bicarbonate aqueous solution and water, in turn, and then dried over magnesium sulfate. After removal of solvent, the residue was crystallized by adding ethanol. The crystal was filtered and recrystallized from ethanol to give 2,2,2-trichloroethyl 2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-oxide (4.10 g), mp 130° - 131° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[CH:10][CH:9]=1)([O:5][CH2:6][CH3:7])=[O:4].[Si:23]([O:30][CH:31]1[C:36]2([CH3:53])[C:37]3[CH:42]=[C:41]([CH:43]=O)[C:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:39][C:38]=3[C:32]1([CH3:54])[CH2:33][CH2:34][CH2:35]2)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:30][CH:31]1[C:36]2([CH3:53])[C:37]3[CH:42]=[C:41](/[CH:43]=[CH:12]/[C:11]4[CH:10]=[CH:9][C:8]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:21]=4)[C:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:39][C:38]=3[C:32]1([CH3:54])[CH2:33][CH2:34][CH2:35]2)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CCCCCCCOc1cc2c(cc1C=O)C1(C)CCCC2(C)C1O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1cc2c(cc1/C=C/c1ccc(C(=O)OCC)cc1)C1(C)CCCC2(C)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
248 mg of NaH (about 50% in oil) were placed in 12 ml of abs. DMF under argon. 2.45 g of diethyl (4-carbethoxybenzyl)phosphonate were added thereto at 0° and the mixture was subsequently stirred at room temperature for about 2 hours until the H2 evolution had finished. The mixture was cooled to −10° C. and 2.20 g of (5RS,9SR,10RS)-10-t-butyldimethylsilyloxy-2-formyl-3-heptyloxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocycloheptene dissolved in 10 ml of abs. DMF were slowly added dropwise thereto. Then, the cooling bath was removed and the mixture was left to react at room temperature for 2 hours. It was then poured into ice/NH4Cl solution, extracted with diethyl ether, washed with NaCl solution, dried over Na2SO4 and concentrated. Flash chromatography on SiO2 (hexane/ethyl acetate 98/2) gave 2.32 g of ethyl (E)-4-[2-[(5RS,9SR,10RS)-10-t-butyldimethylsilyloxy-3-heptyloxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocyclohepten-2-yl]vinyl]benzoate as a yellowish oil.
Reaction SMILES: [F:1][C:2]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:19])[N:7]([CH2:12][CH2:13][C:14](OCC)=[O:15])[C:8]([CH3:11])=[CH:9][N:10]=1.CO.[BH4-].[Na+]>O1CCCC1.O.ClCCl>[F:26][C:2]([F:1])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:19])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[C:8]([CH3:11])=[CH:9][N:10]=1
Reactant: CCOC(=O)CCn1c(C)cnc(NCC(F)(F)c2ccccc2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(NCC(F)(F)c2ccccc2)c(=O)n1CCCO
Reaction time: 5 h
Yield: 93.4 %

Procedure:
To a solution of 3-(2,2-difluoro-2-phenylethylamino)-1-[(2-ethoxycarbonyl)ethyl]-6-methylpyrazinone (2-11) (0.37 g, 1.01 mmol) in tetrahydrofuran (10 mL) containing 5% methanol, was added sodium borohydride (0.229 g, 6.07 mmol) at room temperature. The reaction mixture was stirred for 5 hours. Then 2 mL of water was added and the mixture was fractionated between dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified using a silica gel column chromatography with ethyl acetate/n-hexane (1:1) as eluent to afford the title compound (0.305 g, 93%) as a pale yellow solid. Rf 0.28 (MeOH/CH2Cl2 5/95); 1H-NMR (CDCl3): δ 1.85 (quintet, J=6.4 Hz, 2H), 2.19 (d, J=1.2 Hz, 3H), 3.47 (q, J=6.4 Hz, 2H), 3.65 (t, J=6.8 Hz, 1H), 4.05 (dt, J=6.4, 14.0 Hz, 2H), 4.12 (t, J=6.4 Hz, 2H), 6.14 (t, J=6.4 Hz, 1H), 6.68(d, J=0.8 Hz, 1H), 7.23-7.41 (m, 3H), 7.49-7.52 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=1)[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[C:2]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=1)(=[O:1])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Oc2cc([C@H](C)O)[nH]n2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 17.6 h
Yield: 84.7 %

Procedure:
To toluene-4-sulfonic acid 5-[(S)-1-hydroxyethyl]-1H-pyrazol-3-yl ester (6.09 g, 21.6 mmol) in anhydrous dichloromethane (180 ml) was added pyridinium dichromate (9.74 g, 25.9 mmol) and the resulting slurry was stirred at room temperature for 17.6 h. The mixture was poured directly onto a column of silica gel, which was eluted with ethyl acetate to yield 5.13 g (85%) of the title compound as a whitish solid: 1H NMR (360 MHz, DMSO-d6) δ 2.43 (3H, s), 2.45 (3H, s), 6.78 (1H, s), 7.49 (2H, d, J=8.2 Hz), 7.80 (2H, d, J=8.3 Hz), 13.72 (1H, s); MS (ES+) m/e 281 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19]CC)=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23].C(O)(=O)C.Cl>O>[NH2:13][C:10]1[C:9]2[C:14](=[O:22])[C:15]([C:17]([OH:19])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]([CH2:4][CH2:5][N:6]3[CH3:23])=[C:2]([F:1])[C:11]=1[F:12]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)CCN2C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Yield: 71.2 %

Procedure:
20 mg of the compound (201) obtained in Example 72 was added to 0.4 ml of acetic acid and 0.1 ml of 12N hydrochloric acid, and the solution was heated at 100° C. for 2 hours. After air-cooling, the water was added to the reaction solution, and the deposited solids were filtered off and washed consecutively with water, ethanol and ether to obtain 13 mg of the subject compound (202) in a 72% yield.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=3[CH3:22])[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C1CCCCC=1>>[F:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:22])[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1nc2c(F)cccc2c1-c1ccc(OC)cc1C
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCn1nc2c(F)cccc2c1-c1ccc(O)cc1C
Yield: 91.4 %

Procedure:
Prepared according to Method D step C from 7-fluoro-3-(4-methoxy-2-methylphenyl)-2-propyl-2H-indazole (0.059 g, 0.20 mmol), boron tribromide (0.05 mL, 0.5 mmol) and 1.0 mL of cyclohexene to give the product (0.052 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(CCO)cc1
Yield: 84.3 %

Procedure:
A solution of 100 g (0.60 mol) of p-methoxyphenylacetic acid in ether is introduced into a 4 l reactor, under nitrogen, which contains 28 g (0.74 mol) of lithium aluminum hydride and 600 ml of anhydrous ether. The mixture is heated under reflux for 3 hours and then cooled in a bath of ice and salt and the excess hydride is removed by cautiously adding 25 ml of water, followed by 25 ml of 15% strength NaOH and, finally, 20 ml of water. The white precipitate is removed by filtration, and after evaporation of the ether, 80 g of an oil are obtained. This oil, when distilled under 0.07 mm Hg at a temperature of 115° C., gives 77 g of 2-(p-methoxyphenyl)-ethan-1-ol. Yield: 85%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(I)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(I)cc1C
Yield: 103.2 %

Procedure:
4-Iodo-2-methylphenol (3.0 g, 12.9 mmol) was dissolved in acetone (250 ml) at room temperature, and then potassium carbonate (2.67 g, 19.4 mmol, 1.5 eq.) was added thereto and vigorously stirred. Ethyl bromoacetate (1.56 ml, 14.1 mmol, 1.5 eq.) was quickly added to the mixture, and then reacted further at room temperature for 4 hours. After completion of the reaction, the reaction mixture was extracted with aqueous ammonium chloride solution and ethyl acetate, and dried over magnesium sulfate. The crude product was purified on silica flash column. The solvent was evaporated under reduced pressure to thereby yield 4.26 g of the title compound (yield: 98.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[S:29][CH:30]=[C:31]([C:33]([O:35]C)=[O:34])[N:32]=2)[CH2:24][CH:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[S:29][CH:30]=[C:31]([C:33]([OH:35])=[O:34])[N:32]=2)[CH2:24][CH:23]1[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1csc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2nc(C(=O)O)cs2)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 112 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-1,3-thiazole-4-carboxylate were added 2.0 mL of THF, 1.0 mL of methanol and 1.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at 60° C. overnight. To the mixture was added 1.1 mL of 1 M hydrochloric acid, followed by concentration under reduced pressure, and to the residue were added chloroform and anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dried to obtain 116 mg of a colorless foamy substance of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-1,3-thiazole-4-carboxylic acid as a crude product.
Reaction SMILES: [CH:1]([CH:3]([C:14]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[CH:16][CH:15]=1)[C:4](=O)[C:5]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[CH:7][CH:6]=1)=O.[NH2:22][C:23]([NH2:25])=[S:24].Cl>C(O)C>[SH:24][C:23]1[N:25]=[C:4]([C:5]2[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[CH:7][CH:6]=2)[C:3]([C:14]2[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[CH:16][CH:15]=2)=[CH:1][N:22]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(C=O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cnc(S)nc2-c2ccc(OC)cc2)cc1
Yield: 47.7 %

Procedure:
A solution of α-formyl desoxyanisoin (21.3 g, 75 mmole) and thiourea (9.75 g, 1.7 equiv) in 375 ml ethanol was treated with 3 N HCl (7.5 ml) and heated at reflux for 3.5 hours. The reaction mixture was concentrated on the rotary evaporator and the residue recrystallized from ethanol to give the title compound (11.6 g), m.p. 188°-191°. Infrared and H-NMR spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:16]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCCCCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: O=C(NCCCCCNC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
Under N2, 1,5-diaminopentane (2.86 ml., 2.5 g., 0.0245 mol) was dissolved in 50 ml. CH2Cl2 and cooled to 0°. With stirring, benzyloxycarbonyl chloride (3.67 ml., 4.17 g., 0.0245 mol) was added dropwise, maintaining the temperature near 0°. The mixture was warmed to room temperature, washed 2×50 ml. 5% HCl, 1×50 ml. saturated NaHCO3, and 1×50 ml. brine, dried (MgSO4) and stripped to yield title product as a white solid., 4 g.; 1H-nmr (CDClhd 3) includes delta 5.2 ppm (s, 4H, two benzyl CH2 groups). The yield is greatly enhanced by use of two molar equivalents of the acid chloride.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[O:11]=[C:7]1[NH:6][C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[N:4][C:3]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:8]1[C:9]#[N:10]
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: C1CCNC1
Product: N#Cc1c(N2CCCC2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 270 mg (3.80 mmol) of pyrrolidine to give 64 mg (59% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:9][NH:10][C:11](N)=[O:12].C(OCCO)C.S(=O)(=O)(O)O>O>[N:9]1[NH:10][C:11](=[O:12])[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Clc1ccccn1
Reactant: NNC(N)=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOCCO
Solvent: O
Product: O=c1[nH]nc2ccccn12
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
A mixture of 50 g. (0.44 mole) of 2-chloropyridine and 98.22 g. (0.88 mole) of semicarbazide hydrochloride in 150 ml. of 2-ethoxyethanol was heated to reflux and then treated with a solution of 1 ml. of concentrated sulfuric acid (36 N) in 5 ml. of 2-ethoxyethanol. The resulting solution was refluxed for 18 hr., cooled to about 60°, and treated with 150 ml. of water. The mixture was stirred, cooled to 0°, and kept 0.5 hr. and the solid was collected on a filter. The solid was washed well with water and dried under reduced pressure, to give 35.0 g (59%) of product, m.p. 230°-231°, which was sufficiently pure to be used for the next step.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>C1COCC1.O>[CH2:1]([N:8]([CH2:21][C:22](=[O:24])[CH3:23])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: CCOC(=O)CNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN(CC(C)=O)Cc1ccccc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 2-(benzylamino)acetate (40 g, 207 mmol) and NaHCO3 (20.9 g, 248 mmol) in THF (400 mL) and water (30 mL) was heated to 50° C. 1-chloropropan-2-one (23.9 g, 259 mmol) was added and the reaction was stirred at 50° C. for 2 d. Water was added the solution extracted with hexanes. The organic layer was separated, dried, filtered, and concentrated to afford crude ethyl 2-(benzyl(2-oxopropyl)amino)acetate (118) which without further purification
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.O.CC1[NH:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1CO>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:26]1([C:24]2[NH:23][CH:22]=[C:1]([C:2]([CH3:4])=[O:3])[N:25]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)=O
Reactant: Cc1[nH]c(-c2ccccc2)nc1CO
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1c[nH]c(-c2ccccc2)n1
Reaction time: 0.5 h

Procedure:
Jones reagent [5 ml; a solution of chromium trioxide (10.3 g) is a mixture of ⟦sulfunic⟧ sulfuric acid (8.7 ml) and water (30 ml)] is added at 0°-5° C. over 1 hour to a solution of methyl-2-phenyl-4-imidazolemethanol (3.0 g, 0.016 mole) in acetone (25 ml). The temperature is allowed to rise to 20° C. for 30 minutes then water (150 ml) is added. The mixture is stirred for 1 hour and the precipitated solid collected by filtration. The solid is treated with 2N hydrochloric acid (15 ml), stirred 5 minutes, and is then neutralized with 10% sodium hydroxide. The aqueous mixture is extracted with methylene chloride (3×75 ml.) Removal of the methylene chloride yields the ketone as a white crystalline solid (1.73 g), m.p. 158°-158.5° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:36][CH:35]([C:37]#[N:38])[CH2:34]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:34][CH:35]([C:37]#[N:38])[CH2:36]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(C#N)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCN4CC(C#N)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.7 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(1-(3-(3-cyanoazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 68.9 μmol) in dichloromethane (4.00 mL) was added TFA (740 mg, 0.5 mL, 6.49 mmol, Eq: 94.1), the reaction mixture turned orange and was stirred at 25° C. for 18 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow solid, which was dissolved in dichloromethane (added few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, light yellow flakes separated by decantation and dried under high vacuum to give N-tert-butyl-2-(1-(3-(3-cyanoazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 63.2 μmol, 91.6%). MS (M+H)+=523; 1H NMR (DMSO-d6) δ: 12.80 (br. s., 1H), 9.06 (s, 1H), 8.37 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.81-7.96 (m, 2H), 7.39 (dd, J=9.1, 2.3 Hz, 1H), 7.19 (t, J=74.4 Hz, 1H), 4.53 (t, J=6.6 Hz, 2H), 3.35-3.57 (m, 3H), 3.16-3.25 (m, 2H), 2.38 (t, J=6.8 Hz, 2H), 1.78-2.02 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([N:22]1[CH2:31][C@H:30]([F:32])[CH2:29][C@H:23]1[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[C:5](=[O:12])[NH:6]2.[H-].[Na+].[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=1[S:45](Cl)(=[O:47])=[O:46].C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)C.O1CCCC1>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([N:22]1[CH2:31][C@H:30]([F:32])[CH2:29][C@H:23]1[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[C:5](=[O:12])[N:6]2[S:45]([C:38]1[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:37]=1[O:36][CH3:35])(=[O:47])=[O:46]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: COc1ccc(C)cc1C1(N2C[C@H](F)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](F)C[C@H]3C(=O)N(C)C)c3c2ccc(Cl)c3Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
301 mg of the compound obtained in step 16-2 (diastereoisomer mixture) was added under ice cooling and a nitrogen atmosphere to a 3 mL tetrahydrofuran solution of 26 mg of sodium hydride, and the reaction mixture was stirred for 20 minutes. After this, a 2 mL tetrahydrofuran solution of 170 mg of 2,4-dimethoxybenzenesulfonyl chloride was added dropwise, and the reaction mixture was stirred for 2 hours at room temperature. Then 5 mL of ethylacetate and 10 mL of a 5% potassium carbonate aqueous solution were added and the reaction mixture was stirred for 30 minutes at room temperature. After liquid separation, the aqueous layer was extracted with ethyl acetate (10 mL×3), and the combined organic layer was dried with sodium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was separated and purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/acetone=99/1; v/v) to obtain two kinds of diastereoisomer of the titled compound in amounts of 115 mg (isomer A: colorless, amorphous) and 127 mg (isomer B: colorless, amorphous).