Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1.CN(C(ON1N=N[C:41]2[CH:42]=CC=N[C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)C=C.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([O:22][CH2:42][CH:41]=[CH2:40])=[O:21])=[CH:18][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cn1cc2ccc(-c3ncnc4c3c(C(=O)O)cn4COCC[Si](C)(C)C)cc2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C=CCO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3ccc4cn(C)nc4c3)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-(2-Methyl-2H-indazol-6-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (50 mg, 0.12 mmol), HATU (90 mg, 0.24 mmol), and allyl alcohol (0.016 mL, 0.24 mmol) were sequentially added to DMSO (1.0 mL) followed by the addition of Hunig's base (0.10 mL, 0.59 mmol). The reaction was stirred for 17 hours at room temperature at which point an additional amount of HATU (90 mg, 0.24 mmol), Hunig's base (0.10 mL, 0.59 mmol) and allyl alcohol (0.016 mL, 0.24 mmol) were added. The reaction was stirred at room temperature for 17 hours and then extracted with EtOAc (×3) from a saturated sodium bicarbonate solution. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give prop-2-en-1-yl 4-(2-methyl-2H-indazol-6-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calcd for C24H30N5O3Si [M+H]+: 464, found 464.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][C@@H:12]([CH3:29])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([Cl:27])[C:20]=3[F:28])=[N:15]2)=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[Cl:27][C:21]1[C:20]([F:28])=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:8]=3)=[O:10])[CH3:29])[N:15]=2)[CH:24]=[CH:23][C:22]=1[C:25]#[N:26]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3F)n2)[nH]n1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3F)n2)[nH]n1
Yield: 29.5 %

Procedure:
(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide of Example 227 (0.05 g, 0.122 mmol) was reacted with sodium borohydride (0.009 g, 0.244 mmol) using the method of Example 84. Yield of the title compound 0.015 g. 1H NMR (400 MHz; MeOD): δ 1.23 (d, 3H), 1.49 (d, 3H), 4.39 (m, 2H), 4.55 (m, 1H), 6.56 (s, 1H), 6.77 (dd, 1H), 7.67 (d, 1H), 7.75 (d, 1H), 8.17 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13](F)[CH:12]=2)[CH:7]=[N:6][CH:5]=1.NC1C=CC(O)=CC=1[F:28]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[F:28])[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Reactant: Nc1ccc(O)cc1F
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(Oc2ccc(N)cc2F)c1

Procedure:
The title compound was prepared in the same manner described 5-(4-Amino-3-fluorophenoxy)nicotinic acid methyl ester, substituting 4-amino-2-fluorophenol for 4-amino-3-fluorophenol. 1H NMR (DMSO-d6) δ 7.96 (d, J=1.5 hz, 1H), 7.64 (d, J=3.0 Hz, 1H), 6.88 to 6.87 (m, 1H), 6.16 (t, J=8.7 Hz, 1H), 5.79 to 5.69 (m, 2H), 4.07 (s, 2H), 3.09 (s, 3H); TLC (50% EtOAc/Hex), Rf=0.31.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](Br)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[CH2:33][C:34]([N:36]1[C:44]2[C:39](=[CH:40][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:43]=2)[CH2:38][CH2:37]1)=[O:35].C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:41]3[CH:40]=[C:39]4[C:44](=[CH:43][CH:42]=3)[N:36]([C:34](=[O:35])[CH2:33][C:27]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=3[F:25])[CH2:37][CH2:38]4)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(N)ncnc32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c3c(N)ncnc32)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To 1,1-dimethylethyl 4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (138 mg, 0.348 mmol), and 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (167 mg, 0.418 mmol) were dissolved in 1,4-Dioxane (5. mL) then added saturated NaHCO3 (2 mL). The mixture was then bubbled with N2 gas for 10 min then Pd(Ph3P)4 (40.2 mg, 0.035 mmol) was added, and then the mixture was bubbled for 5 additional minutes. The reaction was then capped and heated at 100° C. for 4 hr. The mixture was allowed to cool then diluted with water (10 mL) then extracted with EtOAc (3×20 ml). The organic were combined, washed with brine, dried over MgSO4, filtered and concentrated to isolated a amber color oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with Hexane eluting with a gradient of 0 to 10% MeOH in DCM for 30 min. to give 1,1-dimethylethyl 4-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (160 mg, 0.272 mmol, 78% yield) as a amber color oil. LC/MS (ES) m/z=589.6 [M+H]+.
Reaction SMILES: O[C:2]1[CH:10]=[C:9](O)[CH:8]=[CH:7][C:3]=1C(O)=O.[OH:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].S(OC)(OC)(=O)=O.C1(O)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>>[OH:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([O:17][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:16]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: COc1ccc(C(=O)O)c(O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Oc1ccccc1
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C(=O)Oc2ccccc2)c(O)c1
Yield: 66 %

Procedure:
2,4-Dihydroxybenzoic acid was converted to 2-hydroxy-4-methoxybenzoic acid by treatment with dimethyl sulfate according to the procedure of M. Gomberg and L. C. Johnson (J. Amer. Chem. Soc., 1917, 39, 1687). Treatment of 2-hydroxy-4-methoxybenzoic acid with phenol and phosphorus oxychloride according to the general method of N. G. Gaylord and P. M. Kamath (Organic Syntheses, Coll. Vol. IV, p. 178, 1963) gave phenyl 2-hydroxy-4-methoxybenzoate in 66% yield. Reaction of this phenyl ester with two molar equivalents of benzamidine in boiling ethanol for 20 hours gave a precipitate of 2,4-diphenyl-6-(2'-hydroxy-4'-methoxyphenyl)-s-triazine, which recrystallised from formdimethylamide as pale yellow needles, m.p. 211°-212° C., in 44% yield. Elemental analysis: C, 74.0%; H, 4.4%; N, 11.6%. C22H17N3O2 requires C, 74.4%; H, 4.8%; N, 11.8%. This compound was then sulfonated by treatment with 1.1 molar equivalents of chlorosulfonic acid in boiling chlorobenzene for one hour. The resultant precipitate was collected, rinsed with light petroleum, and treated with sodium hydroxide solution to give the sodium salt of 2,4-diphenyl-6-(2'-hydroxy-4'-methoxy-5'-sulfophenyl)-s-triazine. It was obtained in 87% yield after recrystallisation from 30% aqueous ethanol. Elemental analysis: C, 55.6%; H, 3.6%; N, 9.0%; S, 6.4%. C22H16N3O5SNa.1H2O requires C, 55.6%; H, 3.6%; N, 8.8%; S, 6.7%.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(#N)C>[N:30]1([C:2]2[N:10]=[C:9]([Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: C1COCCN1
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Yield: 91.3 %

Procedure:
6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-2-(tributylstannyl)-9H-purine (3.3 g, 6.25 mmol) was dissolved in acetonitrile (30 ml) followed by the addition of morpholine (2.2 ml, 25 mmol) and the resulting mixture was heated to reflux for 1 hour. The reaction mixture was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1 to 8:2) to give the title compound (3.3 g, 91%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1)[NH2:24]>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([N:28]2[CH2:29][CH2:30][CH:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:32][CH2:33]2)=[C:21]([CH3:20])[CH:22]=1)=[O:18]
Reactant: Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2C)ccc1N1CCC(N2CCOCC2)CC1
Yield: 60.4 %

Procedure:
By the reaction and treatment the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl) pyrazole-4-carboxylic chloride (1.0 g) and 3-methyl-4-(4-morpholinopiperidin-1-yl)aniline (0.95 g), the title compound (1.1 g) was obtained, melting point: 252–255° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[C:5](=[O:12])[N:4]1[C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[C:23]([O:28][C@@H:29]([C:31]1[N:36]=[C:35](Cl)[CH:34]=[CH:33][N:32]=1)[CH3:30])(=[O:27])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(O)(C)C>[C:23]([O:28][C@@H:29]([C:31]1[N:32]=[C:33]([N:8]2[CH2:9][CH2:10][C:11]3[N:3]([CH3:2])[N:4]([C:13]4[CH:22]=[N:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[C:5](=[O:12])[C:6]=3[CH2:7]2)[CH:34]=[CH:35][N:36]=1)[CH3:30])(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: Cn1c2c(c(=O)n1-c1cnc3ccccc3n1)CNCC2
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 1-methyl-2-quinoxalin-2-yl-1,2,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one hydrochloride (prepared according to the method of Example 75, Step C, 175 mg, 0.55 mmol) and (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 126 mg, 0.55 mmol) in isopropanol (6 mL) was added triethylamine (230 μL, 1.66 mmol). This mixture was heated to reflux overnight, cooled to room temperature, and evaporated. The residue was diluted, with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5% methanol/chloroform) to give 248 mg (95%) of the title compound of Example 75, Step D as a yellow oil. 1H NMR (CDCl3, 250 MHz) δ 9.70 (s, 1H), 8.29 (d, 1H), 8.15 (dd, 1H), 8.03 (m, 1H), 7.82-7.70 (c, 2H), 6.48 (d, 1H) 5.72 (q, 1H), 4.36 (s, 2H), 4.35-4.15 (c, 2H), 3.42 (s, 3H), 2.77-2.82 (c, 2H), 2.43 (t, 2H), 1.79-1.60 (c, 2H), 1.61 (d, 3H), 0.99 (t, 3H); MS (APCI) 474 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Na+].[CH3:23]I.O>C1COCC1>[CH3:23][O:1][CH2:2][C@@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a solution of di-tert-butyl [(2S)-3-hydroxypropane-1,2-diyl]biscarbamate (2.45 g, 8.10 mmol) in THF (80 mL) at 0° C., was added NaH (60%, 357 mg, 8.91 mmol). The reaction was allowed to stir at 0° C. for 30 min, and then methyl iodide (0.556 mL, 8.91 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h and then allowed to warm to rt and stirred for 3 h. Water was added and the reaction was extracted into EtOAc. The combined organic solutions were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography (SiO2, EtOAc/hexane) to yield the title compound as a white solid (895 mg, 36%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH2:29][NH2:30])[C:25]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)C1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].C(N(CC)CC)C.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:23][C:12]1[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:24]2[O:28][N:27]=[C:26]([CH2:29][NH:30][C:38](=[O:40])[CH3:39])[C:25]=2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(F)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1noc(-c2cc(Cl)c(O)cc2O)c1-c1ccc(F)cc1
Yield: 14 %

Procedure:
To a solution of C-[5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-fluoro-phenyl)-isoxazol-3-yl]-methylamine (100 mg, 0.19 mmol) in DCM was added acetic anhydride (130 μl, 7.0 equiv.) and triethylamine (81 μl, 3.0 equiv.). The solution was stirred at room temperature until the amine was consumed. The solvent was removed in vacuo to leave the yellow tinged oily crude benzyl protected product. This was deprotected using the standard procedure with boron trichloride described above and purified by preparative TLC and soxhlet extraction of the silica by ether gave the pure compound as a colourless solid (10 mg, 14% yield).
Reaction SMILES: [O:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4].[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 50.3 %

Procedure:
To a magnetically stirred solution of α-oxo-2-nitrobenzenepropanoic acid (40.00 g) in absolute ethanol (500 ml) cooled in ice water was added sodium borohydride (20.0 g) in portions at such a rate as to maintain the temperature between 25 and 30°. The temperature of the solution was maintained between 25°-30° for a further 4 hours after the addition. The solution was evaporated to near dryness, and the residue was dissolved in water. The solution was acidified with concentrated hydrochloric acid and extracted four times with ethyl acetate. The organic extract was washed twice with water and dried over magnesium sulfate. Evaporation gave a syrup which was crystallized (seeding) from dichloromethane-cyclohexane; yield 28.26 g (70%), m.p. 87-90°. Recrystallization with decolorization from water gave 20.31 g (50%) of the titled compound; m.p. 104°-105°; MH+ 212 (CI mode), λmaxKBr 1715 (COOH), 3445 (OH) cm-1 ; pmr (CDCl3, DMSO-d6) δ 3.04-3.72 (8 lines, AB part of an ABX system, --CH2 --), 4.34-4.54 (q centered at 4.45, width 12 Hz, symmetrically spaced, X part of ABX system, --CH(OH)), 7.28-7.68 (m, 3 aromatic protons and exchangeable OH), 7.80-8.00 ("d" centered at 7.95, "J" 8 Hz, 1 aromatic proton).
Reaction SMILES: [CH3:1][N+:2]#[C-:3].C([Li])CCC.[CH2:9]([O:11][CH:12]([O:18][CH2:19][CH3:20])[C:13](OCC)=[O:14])[CH3:10].CCOC(C)=O.CCCCCC>C1COCC1>[CH2:9]([O:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]1[O:14][CH:1]=[N:2][CH:3]=1)[CH3:10]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: [C-]#[N+]C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(OCC)c1cnco1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
Prepared according to the procedure of Schollkopf (J. Am. Chem. Soc. 112 (10) 4070 (1990)). To a solution of methyl isocyanide (2.88 g, 0.0702 mol) in THF (50 mL) under argon at -78° C. was added dropwise n-butyllithium solution (1.6M in hexanes, 44 mL) over 15 mins. After stirring for an additional 20 mins at -78° C., a solution of ethyl diethoxyacetate (12.62 g, 0.0702 mol) in THF (15 mL) was added dropwise over 20 mins. The bath was allowed to warm to -30° C. over the next 2 hrs and the reaction was then stirred at 0° C. for 30 mins. The reaction was quenched at 0° C. with glacial HoAc (4.22 g, 0.0702 mol) and the solvent was removed by rotary evaporation in vacuo. The golden solid was partitioned with H2O (45 mL) and EtOAc (200 mL), and the aqueous extracted with EtOAc (2×200 mL). The combined organic was washed with satd aq NaCl, dried over Na2SO4, and concentrated in vacuo to a brown oil. Chromatography on a 300 g SiO2 flash column with a gradient of EtOAc/hexane (10%, 15%, 20%) afforded the desired compound as a colorless liquid (7.46 g, 0.0436 mol, 62%): 1H NMR (CDCl3) δ1.25 (t, J=6.9 Hz, 6H), 3.56-3.70 (m, 4H), 5.62 (s, 1H), 7.26 (s, 1H), 7.86 (s, 1H). Mass spectrum: (M+H)+ =172.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([NH:45][C:14]([NH:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[C:10]([C:23]([F:24])([F:25])[F:26])[CH:11]=2)=[O:22])[CH:46]=[CH:47][CH:48]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(F)cc4)c3)c2cc1OC
Yield: 89 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 171B (0.146 g, 0.4 mmol), dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.203 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.79 (s, 1H), 8.55 (d, 1H), 7.68 (m, 2H), 7.55 (m, 2H), 7.41 (m, 4H), 7.20 (d, 1H), 6.96 (d, 1H), 6.85 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 569 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:10]2[CH2:11][C:6]3([NH:13]C(=O)OC(C)(C)C)[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[NH:3]1)[CH2:9]2.[ClH:21]>O1CCOCC1>[ClH:21].[NH2:13][C:6]12[CH2:11][CH:10]3[CH2:9][CH:8]([CH2:12][CH:4]([NH:3][C:2]3=[O:1])[CH2:5]1)[CH2:7]2.[ClH:21]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)NC(=O)C(C3)C2
Agent: Cl
Solvent: C1COCCO1
Product: NC12CC3CC(C1)NC(=O)C(C3)C2
Temperature: 25 °C

Procedure:
To a solution of lactam 14B (0.18 mmol) in 1,4-dioxane (2 mL) was added a solution of 4 N HCl in dioxane (1.0 mL) and the mixture was maintained at rt for 16 h. The reaction mixture was concentrated and the residue was dissolved in water (2 mL). The aqueous layer was washed with EtOAc (3×5 mL) and concentrated to provide amine 14 in 88% yield as a hydrochloric acid salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1
Reactant: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Solvent: CN(C)C=O
Product: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reaction time: 0.17 h

Procedure:
To a 50 mL beaker was added about 1 g of (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole to 30 mL of dimethylformamide (DMF). Additional (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole was added to the resulting solution until a suspension of the material was formed. The solution was stirred for approximately 10 minutes, and then filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) or Nylon filter. The resulting saturated solution was placed in a shallow petri dish, covered and stored under refrigerated conditions (approximately 5° C.) with a humidity range of about 0 to 50 percent until crystals formed (between 4-6 days). The identity of the title compound is confirmed by single crystal x-ray diffraction and Raman spectroscopy, and shown to contain between about 96 and 98 percent (w/w) of the 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole and between about 2 and 4 percent (w/w) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][N:12]=[C:13]=[S:14]>C(O)C>[SH:14][C:13]1[N:12]([CH3:11])[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: CN=C=S
Reactant: Nc1ccccc1C(=O)O
Solvent: CCO
Product: Cn1c(S)nc2ccccc2c1=O
Yield: 41.2 %

Procedure:
A mixture of anthranilic acid (22.5 g), methyl isothiocyanate (12.5 g) and ethanol (200 ml) was refluxed for three hours, cooled and the precipitate filtered off and washed with water. Recrystallisation from ethanol gave 2-mercapto-3-methyl-3,4-dihydroquinazolin-4-one (13.0 g, m.p. 265°-266°). A mixture of this material (5.76 g) hydrazine hydrate (20 ml) and ethanol (30 ml) was refluxed for 30 minutes, then cooled. The precipitate was filtered off, washed with water and dried to give the 2-hydrazinoquinazolinone (3.16 g, m.p. 220°-223°). Recrystallisation from ethanol gave material m.p. 223°. A stirred solution of the crude product (1.9 g) in a mixture of hydrochloric acid (20 ml, 2N) and acetic acid (10 ml) was treated dropwise at 0°-5° with a solution of sodium nitrite (0.69 g) in water (5 ml). The mixture was allowed to attain room temperature and, after one hour, was filtered and the precipitate washed with water and dried to give the title compound (1.04 g., m.p. 164°-167°). Recrystallisation from ethanol gave material m.p. 167°.