Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8])#[N:2].N.[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(OCC)P(=O)(CCC#N)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CCCN)OCC

Procedure:
A solution of 9.6 g of ethyl 2-cyanoethyl(diethoxymethyl)phosphinate in 450 ml of ethanol is added to 82 g of an 8% solution of ammonia in ethanol. To this is added 5 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered, the filtrate is concentrated under reduced pressure and the crude product is distilled to give ethyl 3-aminopropyl(diethoxymethyl)phosphinate, b.p. 150° C./0.01 mbar, 31P=+46.4 ppm (CDCl3).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:15][OH:16])[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].Cl>CN(C=O)C>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:15][O:16][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a suspension of NaH (60% in mineral oil, 2.88 g, 72 mmol) in DMF (25 mL) at 0° C. was added (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (7 g, 34 mmol) in DMF (25 mL). After 2 h 1-fluoro-2-nitrobenzene (5.29 g, 37.5 mmol) in DMF (25 mL) was added and the resulting mixture stirred for 3 h at 0° C. The mixture was poured into ice/H2O (200 mL), acidified to pH 5.0 with 1 N HCl and extracted with EtOAc. The combined extracts were dried over Na2SO4, concentrated and purified by flash chromatography to give (S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenoxy)-propionic acid (10.9 g, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:8]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=2)[N:9]2[C:14]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:10]2)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:8]([C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=2)[N:9]2[C:14]=1[C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[N:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
HCO2NH4 (29 mg, 0.459 mmol) was added to a suspension of 9 (50 mg, 0.092 mmol) and 10% Pd/C (10 mg) in EtOH (10 mL). The reaction mixture was stirred at ambient temperature for 24 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The resulting residue was triturated in (1:1) Et2O/hexane and the resulting precipitate was collected by vacuum filtration to provide the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 0.84 (t, J=7.1 Hz, 3H), 1.09 (t, J=7.0 Hz, 3H), 3.39 (m, 4H), 3.51 (q, J=7.1 Hz, 2H), 3.67 (m, 4H), 4.07 (q, J=7.2 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 6.80 (s, 1H), 7.27 (d, J=8.3 Hz, 2H), 7.44 (m, 5H). Mass Spectrum (ESI+) m/e=515.3 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[Br:15][CH2:16][C:17](Br)=[O:18].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:15][CH2:16][C:17]([C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([F:5])[CH:7]=2)[NH:12][CH:13]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Fc1cnc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)c1c[nH]c2ncc(F)cc12
Temperature: 50 °C

Procedure:
Aluminum chloride (0.48 g, 3.6 mmol) was added slowly to a stirred solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (0.164 g, 1.2 mmol) in CH2Cl2 (5 mL)). Bromoacetyl bromide (0.1 mL, 1.5 mmol) was added and the resulting solution was heated at 50° C. for 1 h and cooled to room temperature. Water (25 mL) was added, the solution was basified with saturated NaHCO3 and the mixture was extracted with EtOAc (3×25 mL). The organic extracts were dried and concentrated under reduced pressure to give 2-bromo-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone as a pale brown solid. A mixture of 2-bromo-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (0.28 g) and thiourea (0.13 g) in ethanol (10 mL) were heated at 70° C. for 1 h. Water (50 mL) was added and the solution was basified with concentrated NH4OH. The aqueous layer was extracted with EtOAc (3×25 mL). The organic extracts were dried and concentrated under reduced pressure to give 4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-amine (0.21 g, 75%, 2 steps) as pale brown solid. Mass Spec.; MS 235 (M+1); 1H NMR(DMSO-d6, 500 MHz) δ 11.86(s, 1H), 8.27(d, 1H), 8.22(s,1H), 7.83(d,1H), 6.95(brs,2H), 6.81(s,1H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:11]1[N:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:14][CH:15]=1)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:21](OC)=[O:22].C(=O)(O)[O-].[Na+]>CN(C=O)C>[OH:22][CH:21]=[C:16]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)Cn1cccc1C=Cc1ccccc1
Reactant: COC=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)n1cccc1/C=C/c1ccccc1
Yield: 112.5 %

Procedure:
Sodium hydride (0.63 g, 0.013 mol) was washed with petrol 60°-80° and suspended in DMF (30 ml) under nitrogen. To this methyl (2-styrylpyrrol-1-yl)acetate (1.6 g, 0.0066 mol) and methyl formate (8.2 ml, 0.13 mol) in DMF (10 ml) was added dropwise at room temperature. After 4 hours it was poured into 200 ml of saturated sodium bicarbonate, extracted with diethyl ether (2×100 ml), then the aqueous layer was neutralised with concentrated hydrochloric acid and extracted again with diethyl ether (2'100 ml). This was washed with brine, dried and evaporated to give methyl 3-hydroxy-2-[(E)-2-styrylpyrrol-1-yl]acrylate (2.0 g) as an orange-yellow oil. This was used in the following reaction without further purification.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5].C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[F:18][C:16]([F:17])([F:19])[C:12]1[CH:11]=[C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)CC(O)CCSc1cccc(C(F)(F)F)c1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1cccc(C(F)(F)F)c1
Yield: 94.5 %

Procedure:
5.84 Grams of 4-hydroxy-6-(3-trifluoromethylphenylthio)-2-hexanone were dissolved in 58 ml of toluene, and 0.62 g of oxalic acid was added thereto. The resulting mixture was refluxed for 4 hours with stirring, allowed to cool and then treated in the same manner as in Production example 34. Thus, 5.26 g of 6-(3-trifluoromethylphenylthio)-3-hexen-2-one (trans : cis =2.9 : 1) were obtained (purity: 98.5%). Further, the product was column chromatographed to obtain a purified product having a refractive index (nD25.5) of 1.5222. The yield was 94.5%.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:19]=[CH:18][C:10]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)(=[O:5])=[O:4].C(=O)(O)[O-].[Na+].[Br:25]Br>CO.C(Cl)Cl>[Br:25][C:9]1[CH:8]=[C:7]([CH2:6][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[CH:19]=[CH:18][C:10]=1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: BrBr
Reactant: CNS(=O)(=O)Cc1ccc(NC(=O)C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CNS(=O)(=O)Cc1ccc(NC(=O)C(F)(F)F)c(Br)c1
Yield: 29.7 %

Procedure:
To a chilled suspension of 4-methylaminosulfonylmethyl-N-trifluoroacetylaniline(10.9 g) in methanol (100 mL) was added sodium bicarbonate (28 g), followed by bromine (18.3 g) in methylene chloride (30 mL). The reaction mixture was then diluted with methylene chloride (70 mL) and quenched by the addition of sodium sulfite (20 g), filtered through CELITE and concentrated in vacuo to a yellow residual solid. This solid was twice reslurried in methylene chloride (300 mL) then refiltered and the filtrates evaporated in vacuo. The residual materials were combined in 10% acetone/methylene chloride solution and concentrated then purified by column chromatography (eluting with 4% acetone in methylene chloride) to give the title compound (4.10g) mp 170° C.; TLC (methylene chloride/acetone 15:1) Rf=0.36, and the corresponding dibromide (5.56 g) TLC (methylene chloride/acetone 15:1) Rf=0.31.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[C:7]1([C:13]2[CH:14]=[C:15]3[C:21]([NH2:22])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>N1C=CC=CC=1>[C:7]1([C:13]2[CH:14]=[C:15]3[C:21]([NH:22][C:4](=[O:5])[CH2:3][CH2:2][CH3:1])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2ncc(-c3ccccc3)cc12
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2ncc(-c3ccccc3)cc12

Procedure:
n-Butyryl chloride (40 μl, 0.36 mmol) was added to a solution of 5-phenyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine (Description 2; 100 mg, 0.47 mmol) in pyridine (0.5 ml). The reaction mixture was stirred at reflux for 16 hours, then allowed to cool. The solution was acidified to pH 1 with 5N HCl, and the resulting solids were filtered and dried. Crystallization from DMF/MeOH afforded the title compound as a solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32](O)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:33])=[CH:24][CH:25]=1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1ccccc1-c1ccc(F)cc1
Product: O=C(c1ccccc1-c1ccc(F)cc1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 4′-fluoro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C27H23FN4O, 438.51; m/z found, 439.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.I[C:26]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:29]=[C:28]([NH2:37])[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])O.[Na+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:26]2[N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:29]=[C:28]([NH2:37])[CH:27]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])[CH:7]=1
Reactant: C[C@@H](OCc1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1)C(F)(F)F
Reactant: Nc1cc(I)n(-c2ccccc2)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccccc2)c1)C(F)(F)F
Temperature: 25 °C
Yield: 77.2 %

Procedure:
To 2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (49 mg) were sequentially added a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (36 mg) prepared according to the same procedures as Preparation 2 in 1,2-dimethoxyethane (1.0 ml), a 2M aqueous solution of sodium carbonate (0.5 ml), tricyclohexylphosphine (7.3 mg) and palladium (II) acetate (3.0 mg) at room temperature, and the mixture was stirred at 100° C. for 2 hours. This reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added thereto, the mixture was filtered through Celite, and extracted with ethyl acetate. The filtrate was extracted with ethyl acetate, the separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1) to give the titled compound (37 mg).
Reaction SMILES: [OH:1][C:2]1[C:9](C)=CC(C)=C[C:3]=1[CH:4]=O.[OH:12][C:13]1[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:14]=1[CH:15]=O>>[Cl:22][C:18]1[CH:17]=[C:14]2[C:13](=[C:20]([CH3:21])[CH:19]=1)[O:12][CH2:4][C:3]([C:2](=[O:1])[CH3:9])=[CH:15]2
Reactant: Cc1cc(Cl)cc(C=O)c1O
Reactant: Cc1cc(C)c(O)c(C=O)c1
Product: CC(=O)C1=Cc2cc(Cl)cc(C)c2OC1

Procedure:
Using the procedure described in Example 1, stage A, but with 2-hydroxy-3,5-dimethylbenzaldehyde replaced by 2-hydroxy-3-methyl-5-chlorobenzaldehyde, the expected product is obtained, and this is purified by an additional recrystallization in an isopropyl ether/petroleum ether mixture.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:18]([CH3:19])[CH2:17][O:16][C:15]2[CH:20]=[C:21]([S:24]([N:27](CC3C=CC(OC)=CC=3)[C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:26])=[O:25])[CH:22]=[CH:23][C:14]1=2)#[N:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:18]([CH3:19])[CH2:17][O:16][C:15]2[CH:20]=[C:21]([S:24]([NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:25])=[O:26])[CH:22]=[CH:23][C:14]1=2)#[N:2]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCC(C)N3c2ccc(C(F)(F)F)cc2C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1COc2cc(S(=O)(=O)Nc3nccs3)ccc2N1c1ccc(C(F)(F)F)cc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
To a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-3-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (790 mg, 1.31 mmol) in dichloromethane (20 mL) was added TFA (2.0 mL, Spectrochem) at 0° C. and the mixture was allowed to stir at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to get the crude material which was basified (pH˜9) with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude material which was purified by column chromatography (silica gel 100-200 mesh, elution 0-5% methanol in dichloromethane) to obtain 4-(2-cyano-4-(trifluoromethyl)phenyl)-3-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (530 mg, 84%) as off white solid. 1H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 8.44 (s, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.27-7.22 (m, 2H), 7.19 (d, J=8.5 Hz, 1H), 6.82 (d, J=4.5 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 4.28-4.03 (m, 3H), 1.20 (d, J=6.5 Hz, 3H); MS (ESI, positive ion) m/z 481.1 (M+H).
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[OH-].[Na+]>CC(N(C)C)=O>[CH3:30][N:7]1[CH2:6][C@@H:3]2[C@@H:2]([N:1]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]5)=[CH:17][CH:16]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:8]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1cccnn1-c1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a stirred solution of the product of Example 41F (13.80 g, 31.41 mmol) in dimethylacetamide (500 mL) was added a solution of 37% aqueous formaldehyde (7.2 mL, 94.23 mmol, 3.0 equivalents) followed by sodium triacetoxyborohydride (20.0 g, 94.23 mmol, 3.0 equivalents). The mixture was stirred at 25+/−5° C. for 30 minutes during which the starting material was consumed, giving a clear solution. The mixture was diluted with 1N HCl (94 mL, 94 mmol, 3 equivalents) and stirred for one hour. The mixture was adjusted to pH 9.0+/−0.5 with 1N NaOH (335 mL). The mixture was stirred for 1 hour then filtered. The wet cake was washed with water and dried in a vacuum oven at about 50° C. to provide the title compound (10.40 g, 88.9%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C-:25]#[N:26].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([C:25]#[N:26])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: [C-]#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1ccc(C(=O)C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
p-Toluoyl cyanide was prepared according to the general procedure reported by Olah et al. [supra]. Under dry conditions, 1.35 mL of p-toluoyl chloride (98%, Aldrich) (10.2 mmol), 26 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.53 mL of trimethylsily cyanide (11.5 mmol) were added to a 100-mL round bottom flask. To this solution 0.25 mL of tin (IV) chloride (2.1 mmol) was added. This mixture was stirred for 2 hr at room temperature. During the 2 hr, the color of the solution changed from pale yellow to dark brown. After 2 hr the reaction mixture was quenched with 75 mL of ice-cold water and then extracted with two 75-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 75-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation to yield a dark brown oil which solidified on standing. This crude product was dissolved in hexanes and filtered. The solvent was removed by rotary evaporation to yield 1.266 g (86%) of p-toluoyl cyanide as a yellow solid: IR (CCl4) (partial) 2220, 1685, 1607 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[C:8]2[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc2c1CCCC2=O
Reactant: C1CCNC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCC=C2N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Titanium tetrachloride (31.1 ml) in dry toluene (210 ml) is added slowly to a stirred solution of 5-methoxy-1-tetralone (100 g) and pyrrolidine (263 g) in anhydrous toluene (2 l) cooled in a methanol ice bath under N2 while maintaining a temperature of less than 7° C. When the addition is complete, the reaction mixture is allowed to stir at RT for 31/2 hrs. The reaction mixture is filtered, the solid washed with anhydrous toluene, and the filtrate evaporated in vacuo, resulting in a gold viscous liquid, which is dissolved in 1.8 l of dry tetrahydrofuran and filtered. The filtrate is used as is in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[OH:18])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O>>[F:1][C:2]1[C:3]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][OH:18])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1cc(/C=N/O)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: O=C(O)C(Cl)Cl
Product: O=C(NOCCO)c1cc(CNO)c(F)c(F)c1Nc1ccc(I)cc1F
Yield: 81 %

Procedure:
The title compound was obtained by a procedure similar to that in Step C of Example 9. Namely, (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(hydroxyimino-methyl)-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic acid to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-hydroxyaminomethyl-N-(2-hydroxy-ethoxy)-benzamide (28.14 mg, 81%).
Reaction SMILES: [C:1]([OH:12])(=O)[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[OH:4][CH2:3][CH:2]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:1]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: C1CCNC1
Reactant: O=C(O)C(CO)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C(CO)c1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of tropic acid (0.12 mmol) and pyrrolidine (0.12 mmol) in DMF (20 mL) are added HOAt (0.18 mmol) and EDCI-HCl (0.18 mmol). The reaction mixture is stirred at room temperature for 14 h. The reaction mixture is diluted with water, then extracted with AcOEt. The organic extracts are successively washed with water, sat. aq, NaHCO3, H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 3-hydroxy-2-phenyl-1-pyrrolidin-1-yl propan-1-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](SC)[N:3]=1.OO.O1CCOCC1.[NH:28]1[CH2:33][CH2:32][S:31][CH2:30][CH2:29]1>FC(F)(F)C(O)=O.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][S:31][CH2:30][CH2:29]2)[N:3]=1
Reactant: CSc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: C1CSCCN1
Agent: OO
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCSCC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To 6-[2-amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine (0.43 g, 1.58 mmol) in trifluoroacetic acid (TFA) (15 mL) at 0° C. was added aqueous H2O2 (0.97 mL, 9.47 mmol, 30% (w/w)) dropwise. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 30 minutes. LCMS showed a mixture of sulfoxide and sulfone. The reaction mixture was cooled to 0° C. and quenched with dimethyl sulfide (1.0 mL, 13.5 mmol, dropwise addition) to ensure no hydrogen peroxide is left. The reaction mixture was warmed to room temperature and diluted with diethyl ether (Et2O). When the oxidation converts all the starting material to the sulfone, this material precipitate out when Et2O is added. However, this time the sulfoxide species was the dominant (˜80%) as shown in the LCMS. Therefore, hexane was added to ensure complete precipitation of the sulfoxide and sulfone mixture. The material was filtered, and the solid was treated with 1,4-dioxane (10 mL) and thiomorpholine (1.21 mL, 12.6 mmol). The reaction mixture was stirred overnight at 100° C. The mixture was cooled to room temperature and poured onto water and EtOAc. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The crude mixture was purified via flash chromatography on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH). The fractions containing the desired product were combined and concentrated. Trituration with Et2O afforded the title compound (205 mg, 40%) as a yellow solid. LC-MS (ES) m/z=328 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.61 (m, 4H), 3.99 (m, 4H), 5.37 (s, 2H), 6.12 (s, 2H), 6.61 (s, 1H), 7.58 (dd, J=8.6, 1.3 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 11.50 (s, 1H).