Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:18]1[O:31][C:30]2[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][N:25]=[C:26]=[O:27])=[CH:21][C:20]=2[O:19]1.C(N(CC)CC)C.O>C1COCC1>[O:31]1[C:30]2[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][NH:25][C:26]([N:14]3[CH2:15][CH2:16][CH2:17][CH:13]3[C:8]3[CH:9]=[C:10]([CH3:12])[N:11]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:7]=3)=[O:27])=[CH:21][C:20]=2[O:19][CH2:18]1
Reactant: Cc1cc(C2CCCN2)nc(-n2ccnc2)n1
Reactant: O=C=NCCc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C2CCCN2C(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Yield: 90.1 %

Procedure:
A solution of 2-imidazol-1-yl-4-methyl-6-pyrrolidin-2-yl-pyrimidine (21.8 mg, 0.095 mmol), 3,4-methylenedioxyphenethyl isocyanate (29 mg, 0.151 mmol) and triethylamine (0.4 mL) in anhydrous THF (1.5 mL) was reacted for 10 min. Water was added and the solution was extracted with ethyl acetate (2×3 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent and purification by TLC plate gave 36 mg (90%) of 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-1-carboxylic acid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide as a white solid. [M+H]+ 421.15; 1H-NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 7.99 (s, 1H), 7.14 (s, 1H), 7.11 (s, 1H), 6.65 (m, 3H), 5.88 (s, 2H), 4.98 (m, 1H), 3.62 (m, 1H), 3.55 (m, 1H), 3.34 (m, 2H), 2.69 (m, 2H), 2.56 (s, 3H), 2.41 (m, 1H), 2.03 (m, 3H); 13C-NMR (100 MHz, CD3OD) δ 173.9, 170.3, 166.5, 157.7, 147.6, 145.9, 133.2, 128.9, 121.3, 115.0, 108.6, 107.6, 106.9, 61.4, 46.4, 41.8, 35.7, 32.4, 23.3, 22.8.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]N)=[CH:27][CH:26]=1>CN(C)C=O>[OH2:24].[ClH:1].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(C)nc3ccc4nc[nH]c4c23)cc1
Product: O

Procedure:
A stirred mixture of the compound of Example I, C. (22 g. 0.1 mole) and p-methoxy-benzylamine (14 g. 0.1 mole) in 200 ml. of dimethylformamide was refluxed for 6 hours. The reaction solution was stripped in vacuo to give 35 g. (98%) of pale yellow solid. Recrystallization from CH3OH/ether gave m.p. 250°-255°C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([O:38][CH2:39][O:40][CH3:41])[CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH:17]=O)[CH:15]=3)[N:8]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:53][NH:54][CH3:55].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([O:38][CH2:39][O:40][CH3:41])[CH2:35][CH2:36][CH2:37]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:54]([CH3:55])[CH3:53])[CH:15]=3)[N:8]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: CNC
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CC=O)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CCN(C)C)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)acetaldehyde (14C) (300 mg, 0.490 mmol) in tetrahydrofuran (3.267 mL) was added sequentially acetic acid (0.056 mL, 0.980 mmol), sodium sulfate (139 mg, 0.980 mmol) and dimethylamine (0.368 mL, 0.735 mmol). The reaction was stirred for 0.5 hours at ambient temperature, and sodium triacetoxyborohydride (208 mg, 0.980 mmol) was added in a single portion. The reaction was stirred overnight and then quenched by the addition of saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated, and the aqueous layer was extracted with addition ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS ESI(+) m/z 641.2 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(=O)(O)[O-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.CC(C)=O>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:7]1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1

Procedure:
(R)-2-methylpiperazine (13.85 g, 138 mmol), and sodium bicarbonate (52.3 g, 622 mmol) were dissolved/suspended in water (182 mL) and acetone (112 mL). The flask was cooled in an ice bath and a solution of benzoyl chloride (17.7 mL, 152 mmol) in acetone (56 mL) was added drop-wise over 1 hour. After 16 hours the acetone was removed on the rotovap. Water (400 mL) was added and the resulting mixture acidified using 6 M HCl to pH <2. The aqueous layer was washed with 200 mL CH2Cl2 three times. Aqueous sodium hydroxide (5M) was added to pH >12, and this solution was extracted three times with 200 mL of CH2Cl2. The combined organics were dried (MgSO4) and evaporated to give a thick yellow oil. MS (M+H)+=205.1
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li].[C:9]1([CH:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])C)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:23](Br)CC.C(O)(=O)C>O1CCCC1>[CH2:15]([N:17]1[CH2:21][CH2:20][CH:19]([CH2:2][CH2:1][CH3:3])[C:18]1=[O:22])[CH2:9][C:14]1[CH:23]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)NC(C)C
Reactant: CC(c1ccccc1)N1CCCC1=O
Reactant: CCCBr
Agent: [Li]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC1CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a 2 M lithium diisopropylamine solution in tetrahydrofuran of −78° C. is added 1-phenylethyl-2-pyrrolidone and the mixture is stirred for 1.5 h at −78° C. Then 1-propyl bromide is added and the reaction is stirred for another 1.5 h at −78° C. The reaction mixture is allowed to warm up to 0° C. before ice-cold water with acetic acid is added and subsequently extracted 3 times with dichloromethane. The dichloromethane is concentrated in vacuo and the residue is dissolved in dichloromethane, washed with saturated NaHCO3 and brine. Crude 1-phenethyl-3-propylpyrrolidin-2-one is obtained after removal of the solvents in vacuo. The product is purified by column chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:34]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1cc(OC)ccc1CO
Temperature: 100 °C
Reaction time: 7 h
Yield: 64.4 %

Procedure:
2-Hydroxy-4-methoxybenzaldehyde (5 g, 32.9 mmol), 1-bromodocosane (16.6 g, 42.7 mmol) and potassium carbonate (14.8 g, 107 mmol) were mixed with DMF (150 ml), and the mixture was stirred at 100° C. for 7 hr. Chloroform (400 ml) and 1N hydrochloric acid (300 ml) were added to the reaction mixture, and the mixture was washed. The organic layer was washed successively with 1N hydrochloric acid and saturated brine. The organic layer was concentrated and slurry-washed with methanol. The precipitate was collected by filtration and dried under reduced pressure. The obtained dried crystals were dissolved in THF (150 ml), sodium borohydride (3.7 g) was added, and the mixture was stirred at 40° C. for 3 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was concentrated. The mixture was extracted with chloroform, and washed successively with aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated. The obtained residue was washed with acetonitrile, and the precipitate was collected by filtration and dried under reduced pressure to give 2-docosyloxy-4-methoxybenzyl alcohol (9.8 g).
Reaction SMILES: [CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>O1CCCC1>[CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH2:9][CH2:10][O:11][S:30]([CH3:29])(=[O:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cc(Br)ccc1N(CCO)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)OCCN(Cc1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A solution of 2-[benzyl-(4-bromo-2-nitro-phenyl)-amino]-ethanol (19.52 g, Reference Example 9) and triethylamine (7.8 ml) in anhydrous tetrahydrofuran (95 ml), at 25° C., was treated dropwise with methanesulphonyl chloride (4.75 ml). After stirring for 4 hours at 25° C. a further portion of methanesulphonyl chloride (4.75 ml) was added and stirring was continued for a further 16 hours at 25° C. The reaction mixture was treated with water (100 ml), the organic phase was separated and the aqueous phase was extracted three times with ethyl acetate (150 ml). The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution (50 ml), then three times with distilled water (50 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. to give the title compound (25.41 g) as a brown oil. 1H NMR, 300 MHz, (CD3)2SO: δ3.1 (s, 3H); 3.4 (t, 2H); 4.2 (t, 2H); 4.4 (s, 2H); 7.2(m, 5H); 7.4 (d, J=8 Hz, 1H); 7.7 (dd, J=8 Hz and J=1.5 Hz, 1H); 8 (d, J=1.5 Hz, 1H). MS (EI): M+ 430 and 428 (5%), 321 and 319 (20%), 91 (100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:30][OH:31])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([N:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:36]=[C:37]=[O:38])(=O)=O.O>C(Cl)Cl>[C:37]([O:31][CH2:30][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([N:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)(=[O:38])[NH2:36]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2onc(OCC(CO)NC(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1

Procedure:
To a solution of 0.11 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-(N-methyl-N-tert-butoxycarbonylamino)-1,2-benzoisoxazole in 5 ml of methylene chloride is added 0.10 g of chlorosulfonyl isocyanate at -45° to -40° C., and the temperature is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. To the reaction mixture is added 10 ml of water and they are subjected to reaction at 20°-25° C. for one hour, after which the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate and the solvent is then removed by distillation under reduced pressure, to obtain 0.10 g of yellow, oily 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-(N-methyl-N-tert-butoxycarbonylamino)-1,2-benzoisoxazole.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([N:10]=[C:11]=[O:12])=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C(OCC)(=O)C>[OH:17][CH2:16][CH2:15][N:14]([CH3:13])[C:11]([NH:10][C:7]1[S:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9][N:8]=1)=[O:12]
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Reactant: CNCCO
Solvent: CCOC(C)=O
Product: CN(CCO)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 2 h

Procedure:
2-t-Butyl-1,3,4-thiadiazol-5-yl isocyanate dimer (10 grams), N-methyl-N-β-hydroxyethylamine (4.4 grams) and ethyl acetate (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, reflux condenser and thermometer. The reaction mixture was heated at reflux with stirring for a period of about 2 hours. After this time the reaction mixture was stripped of solvent under reduced pressure to yield the desired product N-(β-hydroxyethyl)-N-methyl-N'-(2-t-butyl-1,3,4-thiadiazol-5-yl)urea as an oily residue.
Reaction SMILES: [O:1]1[CH2:10][CH:2]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:11]=[N+:12]=[N-:13].[Na+].C(OC)=O.CO>O>[C:4]1([CH2:3][CH:2]([OH:1])[CH2:10][N:11]=[N+:12]=[N-:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(CC2CO2)cc1
Agent: [Na+]
Solvent: COC=O
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCC(O)Cc1ccccc1
Yield: 91.3 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 5 g of (±)-(2,3-epoxypropyl)benzene, 12.1 g of sodium azide, 60 ml of methyl formate and 270 ml of an 8:1 by volume mixture of methanol and water were used, to give 6.03 g of the title compound as a colorless oil having an Rf value of 0.3 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[S:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[S:25][C:24]([C:26]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]2[CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)=[O:27])=[CH:23][CH:22]=1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Cc1ccc(C(=O)O)s1
Product: Cc1ccc(C(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)s1

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 5-methyl-2-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound, melting at 71°-73° C., was obtained in a yield.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)[O:12]2)=[C:4]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:3]=1.[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CS(C)=O>[CH:18]([OH:22])=[O:37].[CH2:23]([C:20]1[N:19]=[C:18]([C@@H:13]2[C@@H:14]([OH:17])[C@@H:15]([OH:16])[C@H:11]([N:8]3[CH:7]=[N:6][C:5]4[C:9]3=[N:10][C:2]([NH:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:3][C:4]=4[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[O:12]2)[O:22][N:21]=1)[CH3:24]
Reactant: NCCN1CCOCC1
Reactant: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Solvent: CS(C)=O
Product: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(NCCN5CCOCC5)nc43)[C@H](O)[C@@H]2O)n1
Product: O=CO
Temperature: 80 °C

Procedure:
Intermediate 9 (0.070 g, 0.161 mmol) and 4-(2-aminoethyl)morpholine (0.106 ml, 0.807 mmol) were dissolved in DMSO (0.03 ml) and heated at 80° C. in a sealed vial (eg Reacti vial™), for 26 h, a further portion of 4-(2-aminoethyl)morpholine (0.053 ml, 0.403 mmol) was added after the first 6 h. The product was purified by Autoprep. HPLC to give the title compound after freeze drying as a beige solid (0.049 g). LC/MS system B Rt=2.27 min, m/z=532 MH+.
Reaction SMILES: N1C=CN=C1.[F:6][C:7]1[CH:8]=[C:9]([C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][C:12]=1[OH:13].[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18].O>ClCCl>[Si:21]([O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14](=[O:16])[CH3:15])=[CH:8][C:7]=1[F:6])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(O)c(F)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of imidazole (7.29 g, 107.0 mmol) and 1-(3-fluoro-4-hydroxyphenyl)-1-ethanone (15.0 g, 97.3 mmol) in anhydrous dichloromethane (500 mL) was added drop-wise a solution of t-butyldiphenylchlorosilane (28.09 g, 102.0 mmol) in anhydrous dichloromethane (100 mL). The solution was stirred overnight at room temperature. The mixture was poured into water (500 mL) and the organic layer separated and washed with saturated sodium hydrogen carbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to give the title compound which was used without further purification (37.9 g, 96.55 mmol). MS (APCI+, m/z): 393 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:17])([C:13]([F:16])([F:15])[F:14])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:51]([C:53]([C:55]1[C:60]([NH:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[CH:59][C:58]([C:69]([F:72])([F:71])[F:70])=[C:57]([O:73][CH3:74])[N:56]=1)=[O:54])[NH2:52]>CN(C=O)C.O>[CH2:1]([O:8][C:9]([CH3:17])([C:13]([F:16])([F:15])[F:14])[C:10]([NH:52][NH:51][C:53]([C:55]1[C:60]([NH:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[CH:59][C:58]([C:69]([F:70])([F:71])[F:72])=[C:57]([O:73][CH3:74])[N:56]=1)=[O:54])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(OCc1ccccc1)(C(=O)O)C(F)(F)F
Reactant: COc1nc(C(=O)NN)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1nc(C(=O)NNC(=O)C(C)(OCc2ccccc2)C(F)(F)F)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(benzyloxy)-3,3,3-trifluoro-2-methylpropanoic acid (Int. D) (0.709 g, 2.85 mmol) in DMF (15 ml) was added HATU (1.303 g, 3.43 mmol) followed by DIPEA (0.598 ml, 3.43 mmol). After 30 mins, tert-butyl 2-(hydrazinecarbonyl)-6-methoxy-5-(trifluoromethyl)pyridin-3-ylcarbamate (Int. C) (1 g, 2.85 mmol) was added and the reaction mixture was stirred at RT for 3 h. The mixture was poured into water and the product extracted with EtOAc. The organic portion was washed with 1 MHCl, brine, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with 0% to 50% EtOAc in iso-hexane afforded the title compound:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[C:10]3[CH:16]=[CH:15][N:14](S(C4C=CC=CC=4)(=O)=O)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.CO.[Li+].[OH-]>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([N:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
tert-Butyl 4-(5-(3-fluorophenyl)-1-(phenyl sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.220 g, 0.410 mmol) was placed in 1:1 THF:MeOH (6 mL). 3M LiOH (0.683 mL, 2.05 mmol) was then added, and the reaction was stirred at 50° C. for 1 hour. The reaction was then cooled, added to water and extracted with DCM. The organic fractions were dried, filtered and concentrated to give the crude product tert-butyl 4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.150 g, 92.29% yield), which was used without further purification.
Reaction SMILES: Cl.[Si]([O:9][C@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:11]1)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>CO.O>[OH:9][C@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:12]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](Cn2ccnc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1Cn1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
Conc. hydrochloric acid (0.5 ml) was added to a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(imidazol-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (1.55 g) in methanol (15 ml). After stirring at ambient temperature for one hour, saturated aqueous sodium hydrogen carbonate (3 ml) was added to the mixture. The reaction mixture was concentrated under reduced pressure to give a residue. To the residue was added a mixture of chloroform (30 ml) and water (30 ml). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98, V/V) to give (2S,4R)-4-hydroxy-2-(imidazol-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine (0.80 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][SH:8])=[CH:3][CH:2]=1.Cl[CH2:10][CH2:11][OH:12].BrCCO.C1OC1>>[OH:12][CH2:11][CH2:10][S:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OCCCl
Reactant: SCc1ccncc1
Agent: OCCBr
Solvent: C1CO1
Product: OCCSCc1ccncc1

Procedure:
By following the method of Examples 10-14, 4-picolyl mercaptan is reacted with 2-chloroethanol, 2-bromoethanol or ethylene oxide to yield 4-(2-hydroxyethylthiomethyl)pyridine, with 2-bromo-1-propanol to yield 4-(2-hydroxy-1-propylthiomethyl)-pyridine, with 1-chloro-2-propanol to yield 4-(1-hydroxy-2-propylthiomethyl) pyridine, with bromoacetaldehyde diethyl acetal (followed by acid catalyzed hydrolysis) to yield 4-picolylthioacetaldehyde, with 3-bromo-2-butanol to yield 4-(3-hydroxy-2-butylthiomethyl) pyridine, with ethyl 2-bromoacetate to yield ethyl 4-picolylthioacetate, with ethyl 2-chloropropionate to yield ethyl 2-(4-picolylthio)propionate and with methyl 2-phenyl-2-bromoacetate to yield methyl phenyl(4-picolylthio)acetate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1>CCN(C(C)C)C(C)C>[OH:15][CH:12]1[CH2:13][CH2:14][N:9]([C:2]2[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=2)[CH2:10][CH2:11]1
Reactant: OC1CCNCC1
Reactant: O=c1ccc(Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc(N2CCC(O)CC2)n[nH]1
Temperature: 120 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 6-chloropyridazin-3(2H)-one (2.6 g, 20 mmol) in DIPEA (30 mL) was added piperidin-4-ol (2.4 g, 20 mmol) and the mixture was stirred at 120° C. for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was further purified by silica gel chromatography (DCM/MeOH=20/1) to afford the title compound (3.9 g, 100%) as a yellow solid. [LCMS: Rt=0.77 min, m/z 196.2 (M+H)+].