Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5](O)=[O:6])=[O:2].S(Cl)([Cl:18])=O>>[CH:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccc(C(F)(F)F)cc1C(=O)O
Product: O=Cc1ccc(C(F)(F)F)cc1C(=O)Cl
Temperature: 25 °C

Procedure:
A solution of Example 375A (0.6 g) and thionyl chloride (3.27 g, 27.5 mmol) was refluxed for 2 hr. The reaction solution was cooled to room temperature, concentrated, azeotroped with toluene, and used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:13])[CH3:12].FC1C=CC=C2C=1C=CN2.OS(O)(=O)=O.[N+:29]([O-])([OH:31])=[O:30]>C(O)(=O)C>[F:1][C:2]1[C:10]([N+:29]([O-:31])=[O:30])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:13])[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCc2c(F)cccc21
Agent: Fc1cccc2[nH]ccc12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2c1ccc([N+](=O)[O-])c2F

Procedure:
Treatment of 1-(4-fluoro-2,3-dihydro-indol-1-yl)-ethanone, prepared from 4-fluoroindole (See e.g., EP 0645385A1), with concentrated H2SO4 and fuming HNO3 in glacial acetic acid gave 1-(4-fluoro-5-nitro-2,3-dihydro-indol-1-yl)-ethanone. Deprotection of the acetyl group with Na2S in aqueous ethanol provided 4-fluoro-5-nitro-2,3-dihydro-1H-indole, which was treated with 2,3-dicyano-5,6-dichloro-parabenzoquinone (DDQ) to provide 4-fluoro-5-nitroindole. A subsequent hydrogenation over Pd/C gave 5-amino-4-fluoroindole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([F:48])=[C:36]([C@:38]2([CH3:47])[CH2:43][S:42](=[O:45])(=[O:44])[CH2:41][C:40]([NH2:46])=[N:39]2)[CH:37]=1.C([O-])(O)=O.[Na+]>CO>[NH2:46][C:40]1[CH2:41][S:42](=[O:44])(=[O:45])[CH2:43][C@:38]([C:36]2[CH:37]=[C:32]([NH:31][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)=[O:11])[CH:33]=[CH:34][C:35]=2[F:48])([CH3:47])[N:39]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)CC(N)=N1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)CS(=O)(=O)CC(N)=N1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
Method b): To a solution of 5-cyanopicolinic acid (69.1 mg, 466 μmol, Eq: 1.1) in Methanol (6 ml) at 0° C. was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride hydrate (187 mg, 636 μmol, Eq: 1.5) and the mixture was stirred at 0° C. for 15 minutes. Added (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (115 mg, 424 μmol, Eq: 1.00) in Methanol (6 ml) and stirred at 23° C. overnight. Poured into sat NaHCO3-sol., extracted with ethyl acetate, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a brown oil. The crude material was purified by silica gel flash chromatography (10 g): washed first with ethyl acetate, then added 5% of a 7 M solution of ammonia in methanol to give the 5-cyano-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-1,1-dioxo-1,2,3,6-tetrahydro-1λ6-[1,4]thiazin-3-yl)-4-fluoro-phenyl]-amide (63 mg, 157 μmol, 37.0% yield) as a light yellow solid. MS (ISP): m/z=402.4 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[O:14]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:12](=[O:15])[CH2:13][O:14][NH:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(C(N)=O)c1
Reactant: COC(=O)C=O
Solvent: Cc1ccccc1
Product: COC(=O)CONC(=O)c1cccc(OC)c1

Procedure:
3-Methoxybenzamide (13.25 g) and methyl glyoxylate (7.72 g) in toluene (150 ml) were heated under reflux in a Dean-Stark apparatus for 6 hours. On cooling the mixture the product separated and was crystallised from toluene. Yield, 12.0 g, m.p. 93°-94°.
Reaction SMILES: C(O)CCO.[C:6]([CH2:13][O:14]CC(CO)(CO)CO)([CH2:11][OH:12])([CH2:9][OH:10])[CH2:7][OH:8]>>[C:6]([CH2:13][OH:14])([CH2:11][OH:12])([CH2:9][OH:10])[CH2:7][OH:8]
Reactant: OCC(CO)(CO)COCC(CO)(CO)CO
Solvent: OCCCO
Product: OCC(CO)(CO)CO

Procedure:
Di-pentaerythritol is a polyhydric alcohol which is chemically (2,2,-[oxy bis (methylene)]-bis[2(hydroxymethyl) 1)-1,3-propane diol]), or (HOCH2)3CCH2OCH2C(CH2OH)3. It is obtained as a by-product in the manufacture of pentaerythritol, chemically C(CH2OH)4, and it is separated by fractional crystallization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:13]\[C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:15]=[N:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(C(F)(F)F)nc1)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1ccc(C(F)(F)F)nc1)C2=O
Reaction time: 6 h

Procedure:
Compound 70 (55 mg, 0.136 mmol) was dissolved in methanol 20 mL, Pd/C 35 mg added, and the reaction stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 71. The crude 71 was purified by flash chromatography using 100-200 mesh silica gel. The compound was eluted at 28% ethyl acetate in hexane as half white coloured solid compound 6-methoxy-5-morpholino-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,3-dihydro-1H-inden-1-one 71. 1HNMR (400 MHz, CDCl3) δ ppm 8.61 (s, 1H), 7.74 (d, 1H), 7.59 (d, 1H), 7.17 (s, 1H), 6.80 (s, 1H), 3.89 (m, 3H), 3.86 (m, 4H), 3.39 (dd, 1H), 3.17 (m, 4H), 3.11 (m, 1H), 2.98 (m, 1H), 2.83 (m, 1H), 2.71 (m, 1H); MS (ESI) m/z 407.0 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16]2[S:19][C:20]([NH2:22])=[N:21][C:15]=2[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>N1C=CC=CC=1.ClCCl.O>[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16]2[S:19][C:20]([NH:22][C:1](=[O:3])[CH3:2])=[N:21][C:15]=2[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
95 mg acetyl chloride was added to 312 mg 2-amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylic acid tert-butyl ester in 5 mL pyridine at 15° C. The reaction was stirred 3 h at RT. The reaction was diluted with dichlormethane and 1 mL water was added. The solution was filtered over 40 mL Alox and 100 mL Extrelut and evaporated to give 127 mg of the desired product. (M+H)+: 312
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][OH:10])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12]>CC(C)=O.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]=[O:10])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:12])=[O:13]
Reactant: NS(=O)(=O)c1cc(CO)c(F)cc1Cl
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cc(C=O)c(F)cc1Cl
Reaction time: 50 h
Yield: 60.1 %

Procedure:
A solution of 2-chloro-4-fluoro-5-(hydroxymethyl)benzenesulfonamide (440 mg, 1.84 mmol) in acetone (18 mL) was added to a round bottom flask containing MnO2 (1.60 g, 18.4 mmol). The mixture was stirred for 50 hours until the starting material was gone, then filtered though a pad of celite. The filtrate was evaporated to afford the product (263 mg, 60%) as a white solid. MS (ES+) m/z 238 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[CH2:24]([O:26][C:27](=[O:34])/[CH:28]=[CH:29]\[CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:25]>C(Cl)Cl>[CH2:24]([O:26][C:27]([C@H:28]1[C@@H:29]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12]1)=[O:34])[CH3:25]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C\CC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CC(C)C
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (4.0 g, 16.8 mmol), followed by TFA (1.0 M solution in CH2Cl2, 1.0 mL, 1 mmol) were added to a solution of (Z)-5-methyl-hex-2-enoic acid ethyl ester 8 (3.0 g, 19.2 mmol) in methylene chloride (30 mL) maintained at −5° C. under nitrogen atmosphere. After 15 minutes, the bath was removed and stirring was continued overnight. The reaction mixture was washed with saturated NaHCO3 (10 mL), water (15 mL), brine (20 mL), and dried. The product was purified by chromatography on silica gel, and compound was eluted with 20% ethyl acetate in hexane to give (cis)-1-benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 9 as an oil (2.25 g, 41%).
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]=[N+:10]=[N-:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O.C(O)CCC.[CH2:18]([O:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[N:26][CH:27]=1)[C:19]#[CH:20].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:7][CH2:8][N:9]1[CH:20]=[C:19]([CH2:18][O:21][C:22]2[CH:27]=[N:26][C:25]([N:28]3[CH:32]=[N:31][N:30]=[N:29]3)=[CH:24][CH:23]=2)[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C#CCOc1ccc(-n2cnnn2)nc1
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCO
Solvent: O
Product: CC(C)(C)C(=O)OCn1cc(COc2ccc(-n3cnnn3)nc2)nn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of azidomethyl pivalate (4.26 g, 27.1 mmol) in 1:1 text -butanol water (90 mL total) was added 5-(prop-2-ynyloxy)-2-(1H-tetrazol-1-yl)pyridine (5.45 g, 27.1 mmol), sodium ascorbate (1.4 mL of a 1M solution in water) and copper sulfate (1.4 mL of a 1M solution in water). The solution was stirred at room temperature for 72 hours. Water was added and the suspension was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to afford the expected product which was used in the next step without further purification. 1H NMR (DMSO-d6): δ 10.07 (1H, s), 8.43-8.41 (2H, m), 8.00 (1H, d, J=8.8 Hz), 7.88 (1H, dd, J=3.2, 8.8 Hz), 6.32 (2H, s), 5.38 (2H, s), 1.08 (9H, s).
Reaction SMILES: [CH2:1]([CH:3]1[CH:6]([CH2:7][CH2:8][OH:9])[NH:5][C:4]1=[O:10])[CH3:2].P([O-])([O-])([O-])=[O:12].[Na+].[Na+].[Na+].OP([O-])(O)=O.[Na+].[OH-].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].S(=O)(=O)(O)O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O>[CH2:1]([C@@H:3]1[C:4](=[O:10])[NH:5][C@H:6]1[CH2:7][C:8]([OH:12])=[O:9])[CH3:2]
Reactant: CCC1C(=O)NC1CCO
Reactant: O=P([O-])([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC[C@@H]1C(=O)N[C@H]1CC(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of the crude 3-ethyl-4-[2(hydroxy)ethyl]-2-azetidinone (6.41 g) obtained according to step (g) above, sodium phosphate bibasic (5.5 g) and sodium phosphate monobasic (3.4 g) in water (65 ml) is stirred for 20 minutes at room temperature. The pH of the solution is brought to 6.6 by the gradual addition of 10% sodium hydroxide (4.6 ml). The temperature is lowered to 15° C. and potassium permanganate (9.92 g) is added. The reaction mixture is stirred at 15°-20° C. for 24 hours maintaining the pH in the range of 6.6-8.5 by the gradual addition of 10% sulfuric acid (4.6 ml). The mixture is cooled to 5° C. and the excess of potassium permanganate is reduced by adding dropwise a 3.3M sodium meta-bisulfite solution (about 1.5 ml). After removing manganese dioxide by vacuum filtration on Celite, the clear aqueous solution is saturated with ammonium sulfate, brought to pH 3.5 with 10% sulfuric acid, and extracted with ethyl acetate (90 ml followed by four 40-ml portions). The combined extracts are dried over magnesium sulfate and concentrated under reduced pressure at 35° C. to a small volume. Crystallization is allowed to proceed at room temperature and then for two days at 0° C. The precipitate is removed by filtration and dried under vacuum. The yield in crystalline trans-(±)-3-ethyl-4-oxo-2-azetidinacetic acid is 3.2 g (48%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[C:32]1[C:33]([C:42]2[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=2)=[N:34][C:35]2[N:36]([N:38]=[C:39]([CH3:41])[N:40]=2)[CH:37]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[C:32]1[C:33]([C:42]2[CH:43]=[CH:44][C:45]([CH2:46][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:48][CH:49]=2)=[N:34][C:35]2[N:36]([N:38]=[C:39]([CH3:41])[N:40]=2)[CH:37]=1
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccc(F)cc3F)cn2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C)nn6cc5-c5ccc(F)cc5F)cc4)C3)n[nH]2)n1
Reaction time: 1 h

Procedure:
164.5 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are dissolved in 4.8 mL NMP. After addition of 0.2 mL triethylamine the reaction mixture is stirred for one hour. 200 mg (0.57 mmol) 4-[6-(2,4-Difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-benzaldehyde and 0.06 mL acetic acid are added. The reaction mixture is stirred overnight at room temperature. 207.4 mg (0.98 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for another night. The reaction mixture is poured on saturated NaHCO3/ice water. The precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 92.2 mg (27.9%) of the desired product are obtained.
Reaction SMILES: C([O-])(=O)C.[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH2:10])=[NH2+:9])#[N:6].C(N(CC)CC)C.BrBr.[C:23]([S-:25])#[N:24].[K+]>CO>[NH2:24][C:23]1[S:25][N:10]=[C:8]([C:7](=[N:11][O:12][CH3:13])[C:5]#[N:6])[N:9]=1
Reactant: N#C[S-]
Reactant: CON=C(C#N)C(N)=[NH2+]
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C(C#N)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a suspension of 2-cyano-2-methoxyiminoacetamidinium acetate (125 g, 0.672 mole) in CH3OH (1.25 L) were added dropwise triethylamine (234 ml, 1.68 mole) at -10° C., and subsequently Br2 (41.6 ml, 0.806 mole) over 20 minutes at -15° to -10° C., and the mixture was stirred for 20 minutes. To the mixture was added dropwise a solution of KSCN (78.3 g, 0.806 mole) in CH3OH (550 ml) over 1 hour at -15° to -10° C. After stirring at 0°-5° C. for 1 hour, the mixture was poured into ice-water (12 L) to form a crystalline precipitate, which was collected by filtration, washed with water and air-dried to give 120 g (98%) of the title compound. M.p. 263°-5° C. (dec.). The m.p. of the compound prepared by us is higher by about 60° C. than that given in the literature* [m.p. 210°-15° C. (dec.)], but our spectral and microanalytical data are consistent for the structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:37]=[CH:36][N+:35]([O-])=[CH:34][CH:33]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.O.[PH2]([O-])=O.[Na+].[PH2]([O-])=O.[Na+]>[Pd].C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3cc[n+]([O-])cc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(-c2nn(-c3ccncc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 24 h
Yield: 10.3 %

Procedure:
A suspension of 4-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.200 g, 0.00039 mol) and 10% palladium on carbon (0.042 g, 0.00004 mol) in acetic acid (3 mL) was reacted with sodium hypophosphite monohydrate (0.063 g, 0.00059 mol) at 60° C. for 2 hours. Additional 10% palladium on carbon (0.042 g, 0.00004 mol) and sodium hypophosphite (0.045 g, 0.00042 mol) was added and the mixture was stirred for 24 hours. The solvent was removed in vacuo and the residue was slurried in methanol for 4 hours. The mixture was filtered through Celite® 521, washing with methanol. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 25 cm; 50% isocratic for five minutes, then 50%-100% acetonitrile—0.1M ammonium acetate over 25 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give N2-{4-[4-amino-1-(4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.020 g, 0.00004 mol) as a white solid:
Reaction SMILES: [F:1][C:2]1[C:7](C)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[C:12](=[O:15])([O-])[O-:13].[K+].[K+].[Mn]([O-])(=O)(=O)=O.[K+].[Mn]([O-])(=O)(=O)=O>O>[F:1][C:2]1[C:7]([C:12]([OH:13])=[O:15])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1c(F)cccc1[N+](=O)[O-]

Procedure:
A mixture of 34.5 g (0.22 mol) of 6-fluoro-2-nitrotoluene, 30.7 g (0.22 mol) of potassium carbonate, 105.4 g (0.66 mol) of potassium permanganate and 3.3 liters of water is heated at 100° C. until the permanganate is decolorised (ca 2.5 hours). After cooling and removal of the unreacted 6-fluoro-2-nitrotoluene by extraction with ethyl acetate, the aqueous phase is adjusted to pH 1 with hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts are dried over magnesium sulphate and concentrated, there being obtained 6-fluoro-2-nitrobenzoic acid. After recrystallisation from ethyl acetate/n-hexane, the product melts at 146°-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:28]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:30]=[CH:31][CH:32]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])[CH:30]=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cccc(NC(=O)Oc2ccccc2)c1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cccc(C(C)(C)C)c4)c3)c2cc1OC
Yield: 58 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol) and phenyl 3-tert-butylphenylcarbamate from the previous step (114 mg, 0.42 mmol) using Example 115C. The final product was purified by silica gel column chromatography (25-100% EtOAc/hexanes) to give 1-(3-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (83 mg, 0.18 mmol, 58%). 1H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.50-7.36 (m, 3H), 7.31-7.14 (m, 3H), 7.05-6.86 (m, 2H), 4.00 (s, 6H), 1.28 (s, 9H); LC-MS (ESI) m/z 473 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Cl)[CH2:18][CH3:19]>CCOCC>[C:13]([C:11]1[CH:10]=[C:7]([CH:8]([OH:9])[CH2:17][CH2:18][CH3:19])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCC[Mg]Cl
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Solvent: CCOCC
Product: CCCC(O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To 2.0 g (9.17 mmol) of aldehyde 18 in 10 mL of dry ether at 0 ° C. was added 5.5 mL (11.0 mmol) of propylmagnesium chloride (2.0M in ether). The reaction mixture was warmed to RT and quenched with water (50 mL), extracted (ether, 2×50 mL), washed (water then brine), dried (MgSO4), filtered and concentrated to give 2.37 g (9.05 mmol) of alcohol 19 (pure by 1H-NMR) which was directly used in the next step (98% yield): TLC (20% EtOAc-80% hexanes) Rf 0.5; 1H-NMR (CDCl3) δ0.96 (t, 3H, CH2 CH3), 1.34 (s, 18H, 6(CH3)), 1.66 (m, 2H, CH2), 1.84 (m, 1H, CH), 4.66 (m, 1H, CHOH), 7.18 (d, J=1 Hz, 2H, Ar-H), 7.34 (t, J=1 Hz, 1H, Ar-H).
Reaction SMILES: CO[CH2:3][N:4]([CH2:20][Si](C)(C)C)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].[CH:25]([C:27]1[S:28][CH:29]=[C:30]([CH3:32])[N:31]=1)=[CH2:26].[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>ClCCl.C(O)(C(F)(F)F)=O.CC(C)=O>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[CH3:32][C:30]1[N:31]=[C:27]([CH:25]2[CH2:26][CH2:20][N:4]([CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[CH2:3]2)[S:28][CH:29]=1
Reactant: COCN(CCc1ccccc1N1CCCCC1=O)C[Si](C)(C)C
Reactant: C=Cc1nc(C)cs1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(C2CCN(CCc3ccccc3N3CCCCC3=O)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
At 0° C., 1-[2-(2-{(methoxymethyl)[(trimethylsilyl)methyl]amino}ethyl)phenyl]piperidin-2-one a5-2 (696 mg, 2 mmol, 2 eq) is slowly added to 2-ethenyl-4-methyl-1,3-thiazole a5-3 (125 mg, 1 mmol, 1 eq) diluted in dichloromethane/TFA (90 μl/10 μl). The mixture is stirred at room temperature overnight. Solvent is removed under reduced pressure and the residue is purified by basic reverse phase chromatography on silicagel (gradient: acetonitrile/H2O/NH4OH from 30/70/0.1 to 60/40/0.1 in 10 minutes). The product is dissolved in a minimum of acetone and oxalic acid (1 eq) is added to form the salt that is filtered, washed with diethyl ether and dried under vacuum to afford 215 mg of 1-(2-{2-[3-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one oxalate 87.
Reaction SMILES: C([O:5][C:6](=[O:37])[C@@H:7]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH2:8][NH:9][C:10](=[O:26])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[CH:13][CH:12]=1)(C)(C)C.Cl>CCOC(C)=O>[N:21]1([CH2:20][CH2:19][CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:6]([OH:37])=[O:5])=[O:26])=[CH:16][CH:15]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCCn2ccnc2)cc1)NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc(OCCCn2ccnc2)cc1
Temperature: 0 °C

Procedure:
A solution of 27-4 (1.2 g, 2.27 mmol) in EtOAc (15 mL) was cooled to -78° C. and saturated with HCl gas. This solution was warmed to 0° C. for 1.5 hours, degassed with argon and concentrated to give a colorless oil, which was chromatographed (10:0.5:0.5 EtOH/H2O/NH4OH) to give 27-5 as a white solid.