Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([O-])=O.[Na+]>S1(CCCC1)(=O)=O>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: F
Reactant: Nc1cc(Cl)cnc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: Fc1cc(Cl)cnc1Cl
Reaction time: 2 h
Yield: 82.7 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 60 g of hydrogen fluoride. A solution of 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine in 100 ml of sulfolane is added dropwise at a temperature in the range from 0° C. to +10° C. Then 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution at +50° C. The resultant nitrogen is removed from the reactor through the reflux condenser. Gas evolution ceases after 2 hours at +50° C. 150 ml of methylene chloride are added to the reaction mixture which is then poured into ice water. The two-phase mixture is neutralised with concentrated ammonia solution. The organic phase is separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phase are dried over sodium sulfate and concentrated by evaporation. The solution of the sulfolane product is separated by distillation, affording 34.3 g (82.6% of theory) of 2,5-dichloro-3-fluoropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([CH3:22])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([CH3:22])[N:19]=[CH:18][C:7]=3[CH2:8][N+:9]([O-:33])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2

Procedure:
A solution of 2.0 g (5.6 mmole) of 9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-d][2]benzazepine and 2.2 g (10.8 mmole) of 85% meta-chloroperbenzoic acid in 100 ml of methylene chloride was stirred at room temperature for 21 hr. The methylene chloride solution was washed with cold dilute aqueous sodium hydroxide, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to dryness. Purification by plug filtration (silica gel, 25 g; eluent 1000 ml 1:1 ether methylene chloride) gave a colorless solid, mp 215°-216° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.O[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2cc(C(=O)O)ccc21
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)SCCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 103.5 mg (0.466 mmol) of 4,4-dimethyl-7-carboxythiochroman and 77.8 mg (0.468 mmol) of ethyl 4-hydroxybenzoate in 10 ml of methylene chloride was treated sequentially with 14.2 mg (0.116 mmol) of 4-dimethylaminopyridine and 96.9 mg (0.47 mmol) of 1,3-dicyclohexylcarbodiimide. The reaction mixture was stirred at room temperature for 120 hours and then filtered and the residue washed with 10 ml of methylene chloride. The filtrate was concentrated in-vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a colorless oil. PMR (CDCl3): δ1.38 (6H, s), 1.42 (3H, t, J~7.1 Hz), 2.02 (2H, m), 3.08 (2H, m), 4.41 (2H, q, J~7.1 Hz), 7.29 (2H, d, J~8.7 Hz), 7.51 (1H, d, J~8.3 Hz), 7.81 (1H, dd, J~8.3 Hz, 1.9 Hz), 7.95 (1H, d, J~1.9 Hz), 8.14 (2H, d, J~8.7 Hz).
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]=[C:8]([NH:15][CH3:16])[N:7]=[C:6]2[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=1.C(N(CC)CC)C.C(O)C.[H][H]>[C].[Pd].O1CCCC1>[NH2:23][C:19]1[CH:18]=[C:17]([C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[C:8]([NH:15][CH3:16])[N:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CNc1nc(-c2cccc([N+](=O)[O-])c2)c2cc(OC)c(OC)cc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CNc1nc(-c2cccc(N)c2)c2cc(OC)c(OC)cc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.1 %

Procedure:
1.83 g of 6,7-dimethoxy-2-methylamino-4-(3-nitrophenyl) quinazoline obtained in Production Example 4,200 mg of 10% palladium-carbon powder (hydrate) and 1.44 g triethylamine were suspended in a mixed solvent of 10 ml ethanol and 10 ml tetrahydrofuran. After the atmosphere was replaced with hydrogen, the mixture was stirred for 15 hours at ordinary pressure at room temperature. The reaction solution was filtered, then the filtrate was evaporated, and the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=1:3). The product was recrystallized from hexane-ethyl acetate to give 1.22 g of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:25]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:32])=[CH:21][CH:22]=2)[CH2:15][CH2:16]1
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3cccnc3)cc2)CC1
Reaction time: 16 h
Yield: 79 %

Procedure:
A mixture of [4-(4-amino-phenyl)-piperazin-1-yl]-phenyl-acetic acid methyl ester (50 mg, 0.15 mmol), nicotinic acid (23 mg, 0.18 mmol), and HATU (70 mg, 0.18 mmol) in DMF (2 mL) was treated with iPr2NEt (32 μL, 0.18 mmol). After 16 h, the mixture was diluted with H2O and extracted with DCM. The organic layer was washed with satd. aq. NaHCO3 and brine, dried (MgSO4), and concentrated to give an oil, which was purified by PTLC to give a tan solid (51 mg, 77%). MS (ESI): mass calcd. for C25H26N4O3, 430.50; m/z found, 431.4 [M+H]+. 1H NMR (CDCl3): 9.07-9.06 (m, 1H), 8.77-8.76 (m, 1H), 8.20-8.18 (m, 1H), 8.01 (s, 1H), 7.68 (br s, 1H), 7.51-7.42 (m, 4H), 7.38-7.32 (m, 3H), 6.92-6.90 (m, 2H), 4.06 (s, 1H), 3.71 (s, 3H), 3.22-3.20 (m, 4H), 2.64-2.62 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][C:12](=O)[NH:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([Cl:26])[CH:3]=1.B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([Cl:26])[CH:3]=1
Reactant: Cn1nc(-c2ccccn2)c2c1NC(=O)CSC2c1ccc(Br)cc1Cl
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(Br)cc1Cl
Temperature: 4 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a solution of 4-(4-bromo-2-chloro-phenyl)-1-methyl-3-(2-pyridyl)-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one (5.83 g, 13.0 mmol) in THF (50 mL) was added a solution of borane THF complex (40 mL, 1M in THF, 40 mmol, Acros) at rt. Subsequently, the mixture was heated under reflux for about 2 h. After cooling to about 4° C., HCl (5 M aq, 40 mL) was added dropwise and the mixture was stirred for about 18 h at rt, then NaOH (2 M aq, 110 mL) and ethyl acetate (200 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water (2×50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate) to give 4-(4-bromo-2-chloro-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (4.86 g, 11.1 mmol, 86%). LC-MS (Table 1, Method a) Rt=4.54 min, m/z 435, 437 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Reactant: O=C=Nc1ccc(Br)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(O)=C(C(=O)Nc2ccc(Br)cc2)c2cscc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4 g (18.4 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature under nitrogen for 24 hours with 3.6 g (18.4 mmol) of p-bromophenylisocyanate and 1.86 g (18.4 mmol) of triethylamine in 40 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 150 ml of 2-N hydrochloric acid and 100 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is taken up in 500 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 1 g of active carbon and filtered. The filtrate is extracted with four 250 ml portions of semi-saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with three 300 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The residual oil is covered with 5 ml of ethanol, the product separating out after standing for several days. The crystals are filtered off under suction, digested with a small amount of ethanol and dried. There is obtained 3-hydroxy-2-methyl-4-(4-bromophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 138°-140° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([O-])=[O:5].C[NH2:13].C1COCC1>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: CN
Reactant: O=C([O-])c1c(O)cccc1O
Solvent: C1CCOC1
Product: NC(=O)c1c(O)cccc1O
Temperature: 100 °C

Procedure:
The mixture of 2,6-dihydroxybenzoate (168 mg, 1.0 mmol) and 2M methylamine in THF (3 mL, 6.0 mmol) in a sealed tube was heated at 100° C. overnight. The reaction mixture was then concentrated under reduced pressure and purified by flash chromatography on silica gel with hexane/ethyl acetate (1:1) to provide the titled compound (67 mg) as white solid. MS (ESI(+)) m/e 168 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 12.57(bs, 2H), 8.82 (bs, 1H), 7.14 (t, J=8.1 Hz 1H), 6.35 (d, J=8.5 Hz, 2H), 2.85(d, J=4.7 Hz, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1.[CH3:16]O>>[Cl:5][C:6]1[CH:14]=[C:10]([C:11]([O:13][CH3:16])=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1O

Procedure:
To a cold solution of 100 ml methanol is slowly added 100 ml thionyl chloride followed by 30 g of 5-chlorosalicylic acid. This is then refluxed overnight, the solvent removed and the residue dissolved in ether. The ether is washed with a sodium bicarbonate solution, water, dried over magnesium sulfate and evaporated to dryness to obtain methyl 5-chlorosalicylate which is used directly in the next step.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:38]1[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=1)CCC>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>[CH3:32][O:31][C:5]1[CH:4]=[N:3][C:2]([C:38]2[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:30])[C:12](=[O:13])[N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)[C:6]=12
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)N4CCc5c(cccc5-c5ccccn5)C4)c[nH]c23)n[nH]1
Temperature: 110 °C
Yield: 30.4 %

Procedure:
To a sealable rb flask containing 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (0.5 g, 1.018 mmol) and ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (0.480 g, 1.119 mmol) in 1,4-dioxane (2 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.235 g, 0.204 mmol). The flask was flushed with N2, sealed, and heated to 110° C. After heating the mixture for 17 h, the mixture was cooled to rt. The crude LC/MS showed no starting material remained and the mass for the expected product was present. The crude mixture was diluted with MeOH and was passed through a plug of CELITE® to remove solids. The CELITE® was washed with MeOH, and the organic solution was concentrated under reduced pressure. The residue was diluted with MeOH and ether was added slowly to the mixture. The product that formed was collected by filtration and washed with MeOH. The mother liquor was concentrated under reduced pressure. A second recrystallization was performed using hot MeOH and Et2O. The expected product, ethyl 3-(4-methoxy-3-(2-oxo-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate (0.17 g, 0.309 mmol, 30.3% yield), was isolated as a light-brown solid and was used in the next step although impurities were still apparent by 1H NMR. LC/MS: m/z 551.18 (M+H)+, 1.778 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 14.04-14.50 (m, 1H) 11.90-12.88 (m, 1H) 8.58-8.76 (m, 1H) 7.81-8.28 (m, 3H) 7.14-7.67 (m, 6H) 4.29-4.96 (m, 4H) 3.53-3.89 (m, 5H) 2.79-3.06 (m, 2H) 1.36 (t, J=7.02 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[N:6][CH:7]=[CH:8][CH:9]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O>[OH:12][CH2:11][CH:10]([C:5]1[C:4]([CH3:3])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:13][O:14][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1cccnc1C(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccnc1C(CO)COc1ccc([N+](=O)[O-])cc1

Procedure:
60% Oil-borne sodium hydride (2.8 g) was added little by little to a solution of 2-(3-methyl-2-pyridyl)-1,3-propylene glycol (10.0 g) and p-fluoronitrobenzene (8.45 g) in dimethylformamide (100 ml) under ice-cooling with stirring. After stirring under ice-cooling for 1 hour, the reaction solution was poured in ice-cold water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and freed of the solvent by distillation, and the residue was chromatographed on a silica-gel (200 g) column. Elution was effected with cyclohexane-ethyl acetate (3:1, V/V) to give 4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]nitrobenzene in the form of crystals. Yield of 9.6 g. Recrystallization from ethyl acetatehexane produced colorless prisms. m.p. 135°-136° C.
Reaction SMILES: [Si:1]([O:8][C@H:9](C1C=CC(O)=C2C=1C=CC(=O)N2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[CH:27]=[C:28]([S:32]([C:35]3[CH:36]=[C:37]4[C:42](=[C:43]([CH3:45])[CH:44]=3)[N:41]=[CH:40][C:39]([C:46]([NH2:48])=[O:47])=[C:38]4[NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=3)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:19][CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].NC[C@@H]([C:81]1[C:86]2[O:87][CH2:88][C:89](=[O:91])[NH:90][C:85]=2[CH:84]=[C:83]([OH:92])[CH:82]=1)O[Si](C(C)(C)C)(C)C>>[Si:1]([O:8][C@H:9]([C:81]1[C:86]2[O:87][CH2:88][C:89](=[O:91])[NH:90][C:85]=2[CH:84]=[C:83]([OH:92])[CH:82]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]2[CH:27]=[C:28]([S:32]([C:35]3[CH:36]=[C:37]4[C:42](=[C:43]([CH3:45])[CH:44]=3)[N:41]=[CH:40][C:39]([C:46]([NH2:48])=[O:47])=[C:38]4[NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=3)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:21][CH:22]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1cc(O)cc2c1OCC(=O)N2
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6cc(O)cc7c6OCC(=O)N7)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 153, using (R)-8-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-6-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one in place of Intermediate 2. ES/MS calcd. for C52H57N6O9SSi+ 969.4. Found m/z=969.5 (M+H)+.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.C[Si](Cl)(C)C.C(=[N:25][C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31]([NH2:33])=[O:32])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CS(C)=O>[NH2:25][C:26]1[N:27]=[CH:28][N:29]([CH2:1][C:2]2[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=2)[C:30]=1[C:31]([NH2:33])=[O:32]
Reactant: COc1ccc(CO)cc1OC
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(Cn2cnc(N)c2C(N)=O)cc1OC
Yield: 62.6 %

Procedure:
A dimethyl sulfoxide solution of 4.29 ml (30 mmol) veratryl alcohol (3,4-dimethoxybenzyl alcohol) was treated in 22.86 ml (180 mmol) trimethylsilyl chloride at room temperature for 1 hour. The resulting product was dissolved in ethyl acetate, washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under vacuum, the resulting residue was reacted with 2.14 g (10 mmol) of 4-benzylideneamino-5-imidazole carboxamide and 5.52 (40 mmol) of potassium carbonate in the same manner as in Reference Example 2 to obtain 1.73 g of 4-amino-1-(3,4-dimethoxybenzyl)-5-imidazolecarboxamide (yield 63%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:8])[CH2:3][CH2:2]1.O.O[Li].O>C1COCC1>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(=O)C2CCOCC2)cc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC(=O)C2CCOCC2)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-(4-tetrahydropyranoyloxy)-2-methoxy-benzoate (369 mg, 1.38 mmol) in THF:H2O (2.5 mL: 0.5 mL) was added LiOH.H2O (116.4 mg, 2.77 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid was passed through a small plug of silca gel packed in 80:20 hexanes:EtOAc and eluted with 50:50 hexanes:EtOAc. The solvent was removed under reduced pressure to afford 4-(4-tetrahydropyranoyloxy)-2-methoxy-benzoic acid as a foam.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH2:21][OH:22])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC1=CC(=O)CC2.[BH4-].[K+]>C(O)C>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH2:13][C:14]4[C@:20]3([CH2:21][OH:22])[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=4)[C@@H:7]1[CH2:8][CH2:9][CH:10]2[OH:11]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2O

Procedure:
Also known as 19-Hydroxytestosterone, this compound is commercially available from Steraloids, Inc. Alternatively, 19-hydroxyandrost-4-en-3,17-dione (11) is treated with potassium borohydride (KBH4, a) in ethanol at -10° to 0° C. Aqueous work up is followed by extraction and purification to yield 19-hydroxytestosterone (12).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([CH3:34])=[C:22]([C:24]4[N:29]=[C:28]5[CH:30]=[N:31][N:32]([CH3:33])[C:27]5=[CH:26][CH:25]=4)[CH:23]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([CH3:34])=[C:22]([C:24]4[N:29]=[C:28]5[CH:30]=[N:31][N:32]([CH3:33])[C:27]5=[CH:26][CH:25]=4)[CH:23]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc(C)c(-c4ccc5c(cnn5C)n4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3cnc(C)c(-c4ccc5c(cnn5C)n4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 60 °C

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(6-methyl-5-(1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)acetate (26 mg, 0.042 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was added 2N NaOH (410 μL). The reaction mixture was heated at 60° C. for 3 h. The reaction mixture was concentrated down, the residue was dissolved in DMF and MeOH, filtered and purified by reverse phase HPLC, (10-100% ACN/H2O+0.1% TFA) to give the product. 1H NMR (400 MHz, CD3OD) δ 9.11 (d, J=0.8 Hz, 1H), 8.59 (d, J=1.0 Hz, 1H), 8.22-8.18 (m, 2H), 7.81 (s, 1H), 7.69-7.62 (m, 2H), 7.53-7.51 (m, 3H), 5.23 (s, 1H), 4.15 (s, 3H), 2.67 (s, 3H), 2.57 (s, 1H), 0.95 (s, 9H). LCMS-ESI+: calc'd for C33H30ClN5O3S: 612.2 (M+H+); Found: 612.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.5 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole) in anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 21/2 hours. The nitrogen flow was stopped and a solution of monomethylamine (1M in tetrahydrofuran) (33 ml) was added. The solution was stoppered and stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake (5.5 g, 96%) was recrystallized from tetrahydrofuran-ethanol to give 3.0 g of a white flocculent solid, mp 258°-259° C. after forming a polymorph from 250°-255° C.