Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>CN(C)C=O>[CH2:20]([O:9][C:8]([C:7]1[CH:6]=[CH:5][O:4][C:3]=1[Si:2]([CH3:12])([CH3:11])[CH3:1])=[O:10])[CH3:21]
Reactant: C[Si](C)(C)c1occc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccoc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.3 %

Procedure:
2-Trimethylsilyl-3-furancarboxylic acid (16.4 g) (synthesized in accordance with the method described in J. C. S. Perkin, 1, 1125 (1981)) was dissolved in N,N-dimethylformamide (50 ml), and potassium carbonate (12.3 g) and iodoethane (13.9 g) were added. The mixture was stirred at room temperature for 15 hours, poured into ice water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) as oil. 2-Trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) was dissolved in acetonitrile (75 ml), and sulfuryl chloride (10.9 g) in acetonitrile (25 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour, poured into ice water and extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-chloro-3-furancarboxylic acid ethyl ester (3.5 g) as oil. 2-Chloro-3-furancarboxylic acid ethyl ester (3.5 g) was dissolved in ethanol (25 ml), and 1N aqueous sodium hydroxide (25 ml) was added. The mixture was stirred at room temperature for 1.5 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with diisopropyl ether-hexane to give 2-chloro-3-furancarboxylic acid (2.2 g) as crystals. mp 138°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.Cl.[O:39]([NH2:41])[CH3:40].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:41][O:39][CH3:40])=[O:30])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21
Reactant: CON
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CONC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2ccnc3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and methoxylamine hydrochloride using diethyl cyanophosphonate as a coupling reagent Mass: 550.13 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:8]=1[C:9]([O:35][CH:36]([F:38])[F:37])=[C:10]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])=[CH:23][C:22]=1[Cl:34])[C:11]([CH2:18][CH3:19])=[N:12]2)[CH3:5].O1CCCC1.[OH-].[Li+]>O>[Cl:34][C:22]1[CH:23]=[C:24]([C:27]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)=[O:28])[CH:25]=[CH:26][C:21]=1[CH2:20][C:10]1[C:11]([CH2:18][CH3:19])=[N:12][C:13]2[C:8]([C:9]=1[O:35][CH:36]([F:38])[F:37])=[C:7]([O:6][C@@H:4]([CH3:5])[C:3]([OH:39])=[O:2])[CH:16]=[CH:15][C:14]=2[F:17]
Reactant: CCc1nc2c(F)ccc(O[C@@H](C)C(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)N2CCCC2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(O[C@@H](C)C(=O)O)c2c(OC(F)F)c1Cc1ccc(C(=O)N2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of (S)-2-{3-[2-chloro-4-(pyrrolidine-1-carbonyl)benzyl]-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy}propionic acid methyl ester (0.75 g), tetrahydrofuran (20 mL), water (20 mL) and lithium hydroxide (0.11 g) was stirred at room temperature for 20 minutes. The mixture was washed with ethyl acetate and the aqueous phase acidified by the addition of 1.0 M aqueous hydrochloric acid and then extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on C-18 column, eluting with a mixture of water and methanol (4:1 to 0:1 by volume) gave title compound as an off-white solid, 0.20 g.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>ClCCl>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:7][C:6]2[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CSc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc(NCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
To 5.0 mL (40.19 mmol) of 4-(methylthio)aniline and 8.4 mL (60.28 mmol) triethylamine dissloved in 30 mL dichloromethane was added 5.0 mL (40.19 mmol) 4-fluorobenzyl bromide. The mixture was stirred at room temperature for 12 h, partitioned between dichloromethane and sat. aqueous ammonium chloride, dried over MgSO4 and concentrated. Purification by column chromatography, eluting with ethyl acetate/hexane, provided 3.10 g of 4-[(4-fluorobenzyl)amino]thioanisole, along with recovered starting material.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(N(CC)CC)C.[CH3:16][Si:17]([CH3:20])([CH3:19])Cl>C1(C)C=CC=CC=1>[CH3:16][Si:17]([NH:7][C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([NH:8][Si:17]([CH3:20])([CH3:19])[CH3:16])[CH:2]=1)([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)Cl
Reactant: Nc1cccc(N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Nc1cccc(N[Si](C)(C)C)c1
Yield: 95.8 %

Procedure:
m-Phenylenediamine (10.8 g; 0.1 mole) and triethylamine (20.2 g; 0.2 mole) in dry toluene (100 ml) were stirred and treated with trimethylchlorosilane (21.7 g; 0.2 mole) which was added dropwise over 1 hour. Stirring was continued for a further hour, and the mixture was then heated under reflux for 1 hour. After cooling and filtering the product, the solvent was evaporated to leave 24.2 g of m-bis(trimethylsilylamino)benzene, which is hereinafter referred to as Silamine II. This product has a theoretical amino-hydrogen equivalent weight of 63, i.e., its theoretical amino-hydrogen content is 15.87 equivalents/kg.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]2[O:8][C:22](=[O:23])[NH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 24 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
4-(Trifluoromethyl)benzoic acid hydrazide (commercially available from Maybridge Chemicals) (5 g, 24.5 mmol) was taken up in THF (250 ml)/triethylamine (2.7 ml, 26 mmol) under N2 and 1,1'-carbonyl-diimidazole (4.2 g, 26 mmol) added. The solution was stirred for 18 h at 24° C., concentrated, and the residue was taken up in ethyl acetate, washed with 1N HCl solution, sat'd NaHCO3 solution, and brine prior to drying (MgSO4). Concentration gave 5 g (89%) of the title compound from which a sample was recrystallized from diethyl ether/hexanes: mp 214-216° C. MS m/z: 231 (MH+).
Reaction SMILES: F[C:2]1[CH:10]=[C:9](F)[CH:8]=[C:7]2[C:3]=1[C:4]([S:12][CH2:13][C:14]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1)=[O:15])=[CH:5][NH:6]2.[OH:23]O>C(O)(C(F)(F)F)C(F)(F)F>[NH:6]1[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[C:4]([S:12]([CH2:13][C:14]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[O:15])=[O:23])=[CH:5]1
Reactant: Cc1cc(NC(=O)CSc2c[nH]c3cc(F)cc(F)c23)no1
Reactant: OO
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: Cc1cc(NC(=O)CS(=O)c2c[nH]c3ccccc23)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
2-((4,6-difluoro-1H-indol-3-yl)thio)-N-(5-methylisoxazol-3-yl)acetamide (100 mg, 0.348 mmol) from Step C was dissolved in hexafluoro-2-propanol (500 μL) and hydrogen peroxide (30% by weight, 88.0 μL, 0.696 mmol). The mixture was stirred at ambient temperature for 2 hours. The reaction was quenched with saturated aqueous sodium sulfite (500 μL) and extracted with ethyl acetate (3×1 mL). The organics were combined, dried over magnesium sulfate, and concentrated in vacuo to give a residue which was purified on a silica gel column (0-100% ethyl acetate:hexanes over 19 min) to yield the desired product (79.0 mg, 0.174 mmol, 75% yield). LCMS>99% at 220 nm, RT=1.00 min, m/z=304 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:4](OCC)=[O:5].O.[NH2:20][NH2:21]>C(O)C>[CH3:1][O:2][CH:3]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:4]([NH:20][NH2:21])=[O:5]
Reactant: CCOC(=O)C(OC)c1cccc2ncccc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(C(=O)NN)c1cccc2ncccc12
Temperature: 85 °C
Yield: 76.7 %

Procedure:
To a solution of ethyl 2-methoxy-2-(quinolin-5-yl)acetate (0.9 g, 3.67 mmol) in absolute ethanol (25 mL) was added hydrazine hydrate (1.0 mL, 20.5 mmol) and the mixture was heated at 85° C. for 18.5 hours. After cooling to room temperature, the mixture was poured into ice-water (˜150 mL) then concentrated in vacuo. The residue was taken up in EtOAc, washed with diluted brine once, water twice then brine. The organics were dried over Na2SO4 and concentrated in vacuo to give 2-methoxy-2-(quinolin-5-yl)acetohydrazide as an off-white foam (0.651 g, 77% yield) that was used without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23](=[O:26])[CH:24]=[CH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C.C(N(CC)CC)C>[O:26]=[C:23]([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH:24]=[CH:25]/[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(C(=O)O)c2ccccc12)OCc1ccccc1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-1-naphthalenecarboxylic acid (100 g), benzylacrylate (96.8 g), triphenylphosphine (10.2 g) palladium(II) acetate (2 g), triethylamine (258 ml) and DMF (600 ml) are heated at 90-100° C. for 4-12 h (typically 10-12 h). Two further portions of palladium(II) acetate (20 g) are added at four hour intervals during the stir period. The mixture is treated with charcoal (3×15 g) at 50-80° C. (typically 70-80° C.) filtering after each charge at 40-45° C. The DMF is then distilled off at 80-90° C. under vacuum and the residue is cooled to 25-35° C. Dichloromethane (100 ml) and water (100 ml) are added to the residue and the mixture is acidified with concentrated hydrochloric acid and is stirred at 20-35° C. for about 30 min. The mixture is filtered, and the solid product dried. The residue is dissolved in a mixture of DMF (600 ml) then water (400 ml) at 90-100° C. and stirred for 1-1.5 h. The solution is filtered at 80-85° C., cooled to 20-35° C., and stirred for about 2 h. The product is filtered off and dried (dry weight 43 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8][C:7]=2[C:6]([CH:15]=O)=[CH:5][CH:4]=1.[C:17]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:15]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]([O:25][CH2:26][CH3:27])=[O:24])=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(C=O)c2ccc(=O)n(C)c12
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Temperature: 95 °C
Reaction time: 6 h
Yield: 53 %

Procedure:
8-Methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-5-carboxaldehyde (18.9 g), diethyl malonate (26.5 ml) and piperidine (2.7 ml) were added to pyridine (90 ml), and the resulting mixture was stirred at 90 to 100° C. for 6 hours. After cooling to room temperature, the reaction mixture was added to cold concentrated hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and dried to thereby obtain 16.62 g (yield: 53%) of diethyl 2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethylene)malonate as a yellow powder.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13]>O1CCCC1>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:23])=[O:22])([O-:14])=[O:13]
Reactant: CCCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of propan-1-amine (2.36 g, 0.04 mol) in tetrahydrofuran (100 mL) at 0° C. was added triethylamine (4.05 g, 0.04 mol) and 2-nitrobenzene-1-sulfonyl chloride (8.88 g, 0.04 mol) in several portions over 10-15 minutes. The reaction mixture was stirred at room temperature for 4 hours, filtered and concentrated to afford the product 2-nitro-N-propylbenzenesulfonamide (9.18 g, yield 93.9%). 1H NMR (400 MHz, CDCl3) δ ppm 8.11-8.16 (m, 1H), 7.84-7.89 (m, 1H), 7.74-7.79 (m, 2H), 5.26 (s, 1H), 3.05-3.10 (t, 2H, J=6.4 Hz), 1.51-1.60 (m, 2H), 0.89-0.92 (t, 3H, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([NH:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1Cl
Reactant: COC(=O)c1sccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1cc(F)c(F)cc1Cl
Yield: 33.5 %

Procedure:
Synthesized as described for 3 using 2-chloro-4,5,-difluorobenzenesulfonyl chloride (500 mg; 2.02 mmol), methyl 3-aminothiophene-2-carboxylate (382 mg; 2.43 mmol), 4-dimethylaminopyridine (62 mg; 0.51 mmol), pyridine (10 mL), and anhydrous dichloromethane (10 mL). The crude product was purified by automated silica gel chromatography (Biotage®) using ethyl acetate/hexanes as eluant system (0 to 20% v/v over 7 column volume gradient elution) to yield the title product as a white solid (249 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([C:31]2[S:35][C:34]([C:36]3([OH:40])[CH2:39][CH2:38][CH2:37]3)=[N:33][CH:32]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=3)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.Cl>CO.[OH-].[Na+]>[F:1][C:2]1[C:3]([C:31]2[S:35][C:34]([C:36]3([OH:40])[CH2:39][CH2:38][CH2:37]3)=[N:33][CH:32]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cccc(S(C)(=O)=O)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3[nH]2)c1
Temperature: 25 °C

Procedure:
A solution of 1-(5-(5-fluoro-2-(3-(methylsulfonyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 91A) (94.2 mg, 0.158 mmol) in methanol (2.500 mL) and 2N sodium hydroxide solution (833 μL) was heated by microwave irradiation (Biotage, Initiator) to 120° C. for 30 minutes. The reaction was cooled to room temperature, and the pH adjusted to ˜3 with 10% aqueous HCl solution. The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v ammonium acetate and B is acetonitrile) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.73 (b s, 1H), 8.60 (b s, 1H), 8.57 (s, 1H), 8.39 (d, J=8.85 Hz, 1H), 8.38 (d, J=3.51 Hz, 1H), 7.91 (d, J=7.78 Hz, 1H), 7.78 (t, 1H), 7.56 (s, 1H), 3.33 (s, 3H), 2.64-2.59 (m, 2H), 2.45-2.37 (m, 2H), 2.03-1.93 (m, 2H); MS ESI(+) m/z 443.9 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)(=[O:22])=[O:21])[C@@H:5]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]=[CH2:3].B.CSC.B1([O-])O[O:36]1.O.O.O.O.[Na+].O>C1COCC1>[OH:36][CH2:3][CH2:2][CH2:1][N:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)(=[O:22])=[O:21])[C@@H:5]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CCN([C@@H](C(=O)OCc1ccccc1)C(C)(C)C)S(=O)(=O)c1cccc(OC)c1
Reactant: [O-]B1OO1
Agent: B
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(S(=O)(=O)N(CCCO)[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To a solution of benzyl N-allyl-N-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinate (12.7 g, 29.3 mmol) in THF (90 mL) cooled to 0° C., borane-DMS complex (5M in diethyl ether, 12 mL, 60.0 mmol) is added dropwise. The reaction mixture is slowly warmed up to rt and is allowed to stir at rt for 24 h. To the reaction mixture, sodium perborate tetrahydrate (27.1 g, 176 mmol) and de-ionized water (90 mL) are added in portions. The reaction mixture is stirred for additional 3 h. The reaction mixture is filtered to remove the white precipitates, then the aqueous layer is extracted with EtOAc. The organic extracts are combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to obtain a highly viscous yellow oil. The crude product is purified by column chromatography eluting with a gradient of 25-65% EtOAc/heptane to obtain the desired alcohol as a colorless oil (9.08 g). Mass spectrum (450.46; M+1).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([O:14]CC2C=CC=CC=2)=[C:10]([O:22]CC2C=CC=CC=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([C:8]1[CH:9]=[C:10]([OH:22])[C:11](=[O:14])[NH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cc(Cc3ccccc3)nnc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]nc(Cc2ccccc2)cc1O
Yield: 77 %

Procedure:
To a degassed solution of 6-benzyl-3,4-bis(benzyloxy)pyridazine (Intermediate 23: 0.16 g, 0.418 mmol) in methanol (4.18 ml) was added 10% palladium on carbon (0.045 g, 0.042 mmol). The mixture was degassed, evacuated and filled with hydrogen from a balloon. After 1 hour the reaction mixture was degassed and filtered through a pad of “Celite” diatomaceous earth, washing with methanol and concentrated to give a yellow oil. The crude oil was purified by reverse phase chromatography (25 g C18) cartridge eluting with 5-100% acetonitrile/water with acidic modifier and the appropriate fractions combined to give a cream solid (yield=77%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:24]([NH2:25])=[CH:23][NH:22][N:21]=2)=[O:19])=[CH:13][CH:12]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O.O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:20]2[C:24]([NH:25][C:7]([C:6]3[CH:5]=[CH:4][S:3][C:2]=3[CH3:1])=[O:9])=[CH:23][NH:22][N:21]=2)=[O:19])=[CH:15][CH:16]=1
Reactant: Cc1sccc1C(=O)O
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: O
Product: Cc1sccc1C(=O)Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methyl-3-thiophenecarboxylic acid (36 mg, 0.25 mmol) was added to a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (Example 2B) (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol), and HOBt (37 mg, 0.27 mmol) in DMSO (1 ml). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was added dropwise to water (30 ml) and the resultant solid was collected by filtration, washed with water and sucked dry. The title compound was obtained as a beige solid (15 mg, 19%). (LC/MS: Rt 4.08, [M+H]+344.67).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:34]=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:33][CH:34]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4].[N:27]1([CH2:26][C:25]2[CH:33]=[CH:34][C:22]([NH2:16])=[CH:23][CH:24]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Reactant: Brc1ccc(CN2CCOCC2)cc1
Product: CS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(CN5CCOCC5)cc4)nn23)c1
Product: Nc1ccc(CN2CCOCC2)cc1
Yield: 285.5 %

Procedure:
[5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-ylmethyl-phenyl)-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (125 mg, 0.43 mmol) and 4-(4-bromobenzyl)morpholine (122 mg, 0.48 mmol) in a manner analogous to Example 77 to yield 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-ylmethyl-phenyl)-amine (118 mg, 59%) as an off-white powder following purification on a 4 g Isco silica gel column using methanol in dichloromethane (0-20%) as eluent. MP=210-211° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.64 (s, 1H), 8.78 (s, 1H), 8.36 (d, J=7.50 Hz, 1H), 8.11 (d, J=7.50, 1H), 7.89 (t, J=15.0 Hz, 7.50 Hz, 1H), 7.70 (m, 1H), 7.63 (m, 3H), 7.35 (d, J=7.50 Hz, 1H), 7.18 (d, J=9.6 Hz, 2H) 3.55 (m, 4H), 3.40-3.28 (m, 5H), 2.32 (m, 4H). MS=464 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]([NH2:12])=[S:11].[CH2:13](Br)[CH2:14][CH3:15]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10](=[NH:12])[S:11][CH2:13][CH2:14][CH3:15]
Reactant: NC(=S)NCc1ccccc1Cl
Reactant: CCCBr
Solvent: CC#N
Product: CCCSC(=N)NCc1ccccc1Cl
Yield: 78 %

Procedure:
A mixture of 1-(2-chlorophenyl)methyl thiourea (3 g, 14.9 mmol) and propylbromide (13.5 g, 110 mmol) in acetonitrile (20 mL) was refluxed for 5 hours. The solvent was evaporated, the residue was dissolved in 200 mL of 50% water/ether and acidified with 48% hydrobromic acid solution. The two phases were separated, the aqueous layer was washed with ether and then the aqueous layer was basified with 10% sodium carbonate solution. The liberated product was extracted with diethyl ether, washed with water and brine, dried and concentrated to give 1-(2-chlorophenyl)methyl-2-propyl-2-thiopseudourea (2.82 g, 78%); mp 112°-114° C.