Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.C(N(CC)C1C=CC=CC=1)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C(OCC)(=O)C>[CH:29]([O:28][C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1)=[O:27])([CH3:31])[CH3:30]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1ccc(N)nc1OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCOc1ccc(NC(=O)OC(C)C)nc1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
2-Amino-5,6-diethoxypyridine (1.83 g) and N,N-diethylaniline (1.49 g) were dissolved in ethyl acetate (30 ml). To the resultant solution, there was dropwise added isopropyl chloroformate (1.23 g) in 5 minutes under ice-cooling. The resulting mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic alumina chromatography using a mixture of toluene and ethyl acetate as an eluent to give 2-isopropyloxycarbonylamino-5,6,-diethoxypyridine (2.24 g) in a yield of 83.5%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:32][C:33](=[O:45])[C:34]([NH:37]C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[C:11]([N:13]1[CH2:31][CH2:30][CH2:29][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:37][C:34]([CH3:36])([CH3:35])[C:33]([NH:32][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([N:13]1[CH2:31][CH2:30][CH2:29][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH2:14]1)=[O:12])=[O:45]
Reactant: Cc1ccc(C2CN(C)C(=O)C23CCCN(C(=O)[C@@H](COCc2ccccc2)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2CN(C)C(=O)C23CCCN(C(=O)[C@@H](COCc2ccccc2)NC(=O)C(C)(C)N)C3)cc1
Temperature: 7.5 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 1-((2R)-3-(benzyloxy)-1-(2-methyl-1-oxo-4-p-tolyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (302 mg, 0.486 mmol) in DCM (3 ml) was added TFA (562 I, 7.30 mmol) at 5° C. The reaction mixture was then left to stir at 5-10° C. overnight. The reaction mixture was added to 2M NaOH (2 ml) and extracted with DCM (3×5 ml). The extracts were washed with brine (5 ml), dried (MgSO4) and concentrated to give the mixture of diastereomers. The desired isomer was isolated via SFC chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]2)=[N:4][CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][O:19][S:18](=[O:21])[O:17][CH2:16]2)=[CH:11][CH:10]=1.C([O:38]CC)C>C(#N)C.O>[O:21]=[S:18]1(=[O:38])[O:19][CH2:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:7]3[N:6]=[CH:5][N:4]=[C:3]([O:22][CH:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)[C:2]=3[CH3:1])=[CH:10][CH:11]=2)[CH2:16][O:17]1
Reactant: CCOCC
Reactant: Cc1c(Oc2ccc(C3COS(=O)OC3)cc2)ncnc1OC1CCN(C(=O)OCC(C)C)CC1
Solvent: CC#N
Solvent: O
Product: Cc1c(Oc2ccc(C3COS(=O)(=O)OC3)cc2)ncnc1OC1CCN(C(=O)OCC(C)C)CC1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a solution of iso-butyl 4-((5-methyl-6-(4-(2-oxido-1,3,2-dioxathian-5-yl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate (100 mg, 0.000198 mole) in acetonitrile (1.2 mL) were added NaIO4 (59 mg, 0.000277 mole) and RuCl3.3H2O (0.5 mg, 0.0000198 mole) in 0.2 mL water. After stirring the suspension at 30° C. for 30 minutes, 0.8 mL water and 1.2 mL diethyl ether were added. The layers were separated, and the aqueous layer was extracted with diethyl ether. The combined ether layer was dried over sodium sulfate, the solvents were evaporated to yield 50 mg product as white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH2:5][CH2:6][CH:7]1[CH2:9][O:8]1.C(O)(=O)C.[Li+].[Br-:17]>C1COCC1>[Br:17][CH2:9][CH:7]([OH:8])[CH2:6][CH2:5][C:4]#[C:3][Si:2]([CH3:11])([CH3:10])[CH3:1]
Reactant: C[Si](C)(C)C#CCCC1CO1
Reactant: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[Si](C)(C)C#CCCC(O)CBr
Reaction time: 8 h
Yield: 37.2 %

Procedure:
To a stirred solution of trimethyl(4-(oxiran-2-yl)but-1-ynyl)silane (4.5 g, 27 mmol) in THF (90 mL) containing acetic acid (4.81 g, 80.21 mmol), was added at 0° C. ahydrous LiBr (3.71 g, 42.78 mmol). The reaction mixture was left stiffing overnight at room temperature. The reaction was quenched with saturated NaCl and extracted with Et2O. The organic phase was washed once with a solution of 1M K2CO3 saturated with NaCl, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, from Cyclohxane 100% to DCM 100% as eluent) to afford 2.5 g of 1-bromo-6-(trimethylsilyl)hex-5-yn-2-ol (Yield: 38%) as a yellow oil.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][N:25]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[C:32]2[C:27](=[CH:28][C:29]([NH2:38])=[CH:30][CH:31]=2)[C:26]1=[O:39].O>CN(C=O)C>[CH3:24][N:25]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[C:32]2[C:27](=[CH:28][C:29]([NH:38]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:30][CH:31]=2)[C:26]1=[O:39]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN1C(=O)c2cc(N)ccc2C(C)(C)C1=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)c2cc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)ccc2C(C)(C)C1=O
Temperature: 120 °C

Procedure:
Prepared from 3-(1-ethoxy-1-phenylmethylidene)-5-nitro-2-indolinone and 1.5 equivalents of 2-methyl-7-amino-4,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydro-isoquinoline, melting point 169-171° C., in DMF by heating to 120° C. for 1 hour, pouring into water, filtering and washing the precipitate with MeOH and ether.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17])[C:11]([OH:13])=[O:12].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:18])[C:16]=1[O:17][C:19](=[O:21])[CH3:20])[C:11]([OH:13])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
To 60 ml of benzene was suspended 10 g/60 mmol of 3,5-dimethyl-4-hydroxybenzoic acid, and 7.5 g/74 mmol of acetic anhydride and 150 μl of pyridine were added to the suspension. The reaction mixture was refluxed under heat for 12 hours, and allowed to stand at room temperature for 12 hours. The precipitated crystals were separated by filtration and washed with a small amount of benzene and air dried to obtain 7.1 g of the desired 3,5-dimethyl-4-acetoxybenzoic acid. 1H-NMR (CDCl3): δ2.22 (6H, s), 2.37 (3H, s), 7.85 (2H, s), 11.53 (1H, s).
Reaction SMILES: [N:1]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:9]2[CH:8]=[CH:7][N+:6]([O-])=[CH:5][C:4]=2[CH:3]=[CH:2]1.[CH3:21][C:22]([NH2:29])([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH3:21][C:22]([NH:29][C:5]1[C:4]2[CH:3]=[CH:2][N:1]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:9]=2[CH:8]=[CH:7][N:6]=1)([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23]
Reactant: O=C(OCc1ccccc1)n1ccc2c[n+]([O-])ccc21
Reactant: CC(C)(C)CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A solution of benzyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate 5-oxide (500 mg, 1.9 mmol, Step b) in chloroform was treated dropwise with 2,4,4-trimethylpentan-2-amine (1.57 mL, 8.5 mmol) and stirred for about 15 minutes. The mixture was cooled to 0° C. followed by the portion wise addition of p-toluenesulphonyl chloride (745 mg, 4.2 mmol). The reaction mixture was then stirred at room temperature for 1 hour, diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum to yield viscous oil. The crude product was purified by silica gel (100-200 mesh) column chromatography using ethyl acetate in hexane (1.5%) as eluent to yield benzyl 4-[(2,4,4-trimethylpentan-2-yl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (390 mg, 43%) as a pale yellow solid.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][C:5]=2[N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[N:37]1[C:46]2[C:41](=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[O:15]1[CH2:16][CH2:17][CH:12]([O:11][C:7]2[C:6]3[C:2]([C:42]4[CH:43]=[CH:44][CH:45]=[C:46]5[C:41]=4[CH:40]=[CH:39][CH:38]=[N:37]5)=[N:3][NH:4][C:5]=3[CH:10]=[CH:9][N:8]=2)[CH2:13][CH2:14]1
Reactant: Ic1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccnc(OC3CCOCC3)c12
Reactant: OB(O)c1cccc2ncccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: c1cc(-c2n[nH]c3ccnc(OC4CCOCC4)c23)c2cccnc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a microwave tube was added 3-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (120 mg, 0.20 mmol), quinolin-5-ylboronic acid (43 mg, 0.25 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (14 mg, 0.02 mmol), a 2 M aqueous solution of sodium carbonate (0.20 mL) and acetonitrile (1.5 mL, 0.029 mmol). The tube was then sealed and the reaction was irradiated in a microwave reactor at 140° C. for 30 minutes. The reaction mixture was filtered through Celite® and concentrated. The crude residue was then dissolved in DCM (3 mL) and cooled to 0° C. To the cooled reaction mixture was added triethylsilane (0.13 mL, 0.80 mmol) and trifluoroacetic acid (3.0 mL, 0.039 mmol). The mixture was stirred at room temperature for 30 minutes before concentrated under vacuum. The resulting residue was re-suspended in methanol and filtered to remove insoluble solids. The filtrate was concentrated and purified by reverse-phase HPLC to give the title compound (30 mg, 43%). LC-MS (Method G): m/z=347.1 [M+H]+; 2.98 min. 1H-NMR (400 MHz, DMSO): δ 13.69 (s, 1H), 8.94 (s, 1H), 8.23 (d, J=8.4, 1H), 8.14 (d, J=8.3, 1H), 7.89 (m, 2H), 7.78 (d, J=6.8, 1H), 7.49 (m, 1H), 7.22 (m, 1H), 5.28 (m, 1H), 3.24 (m, 2H), 3.06 (m, 2H), 1.69 (m, 2H), 1.17 (m, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[O:2].[BrH+][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[OH-].[K+].CN(C)C=O>O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2)=[O:2]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: N#Cc1ccc(C[BrH+])cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccc3cc(C=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Mix 5-formylindole (0.50 g, 3.4 mmol), 4-bromniomethyl-benzonitrile (0.74 g, 3.8 mmol), powdered potassium hydroxide (0.23 g, 4.1 mmol) and dimethylformamide (7 mL) in a flask. Stir at rt overnight. Pour into water (20 mL) and extract with EtOAc/Hexanes (2:1, 3×50 mL). Evaporate solvents to give a yellow oil. Purification on silica using a 10% EtOAc/Hexanes to 30% EtOAc/Hexanes gradient eluent yields the product (0.75 g, 83%). Mass spectrum (ion spray): m/z=259.2 (M−1); 1H NMR (CDCl3) 10.04 (s, 1H), 8.20 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.5 Hz, 1H), 7.22 (d, J=3.1 Hz, 1H), 7.15 (d, J=8.2 Hz, 2H), 6.77 (d, J=3.1 Hz, 1H), 5.44 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]([CH3:33])[CH:16]2[CH2:20][CH2:19][C:18]3([CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:15]([CH3:33])[CH:16]2[CH2:20][CH2:19][C:18]3([CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCCN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCCNC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of tert-butyl 2-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(methyl)amino)-7-azaspiro[4.5]decane-7-carboxylate (270 mg, 0.567 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH3 in MeOH (7 M)/MeOH/DCM (v/v/v)=1/20/60) to give the title compound as a beige solid (0.20 g, 93.8%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([NH2:26])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:24]2[CH:23]=[CH:22][C:21]3[O:16][CH2:17][CH2:18][O:19][C:20]=3[CH:25]=2)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Clc1nc(Cl)nc(Nc2ccccc2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1nc(Nc2ccccc2)nc(Nc2ccc3c(c2)OCCO3)n1
Reaction time: 24 h
Yield: 69 %

Procedure:
To a solution of 4,6-dichloro-N-phenyl-[1,3,5]triazine-2-amine (95 mg, 0.39 mmoles) in tetrahydrofuran (2 ml) was added a solution of 1,4-benzodioxan-6-amine (64 mg, 0.42 mmoles) and triethylamine (0.07 ml, 0.50 mmoles) in tetrahydrofuran (0.5 ml). After stirring for 24 hours, the mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (10 ml). The solution was washed with a solution composed of saturated aqueous sodium chloride solution and 1 M hydrochloric acid (1:1, 2×10 ml), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate-hexanes to provide CT-32028 (97 mg, 69% yield). 1H NMR (d6-DMSO) δ 9.88–10.28 (m, 2 H), 7.60–7.85 (m, 2 H), 7.20–7.40 (m, 3 H), 6.96–7.10 (m, 2 H), 6.77–6.81 (m, 1 H), 4.21 (s, 4 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(-c3cccc(O)c3)cc(=O)oc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(-c3cccc(OCc4ccccc4)c3)cc(=O)oc2c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
4-[3'-(hydroxy)phenyl]-7-methoxycoumarin (prepared as in Example 1 (ii) (268 g) and 95% sodium methoxide (102 g) were dissolved in methanol (3.00 L) and stirred while heating to 45° C. Benzyl bromide (314 g) was added and the reaction was heated to 60° C. A thick precipitate formed in the pink reaction mixture. After 3 hours, the slurry was cooled in an ice-water bath and filtered to collect the product, which was washed with methanol (500 mL) and water (1.0 L), then dried under vacuum (20 inches of Hg) at 70° C. to give 4-[3-(benzyloxy)phenyl]-7-methoxycoumarin (320 g, 89%).
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH:1]1([N:7]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:14][N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: ClCCN1CCOCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCN3CCOCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)morpholine
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.S(=O)(=O)(O)O.C(OCC)(=O)C>CCCCCC>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 0 °C

Procedure:
9α-Hydroxyandrostenedione (9.07 g.) is added to aqueous sulfuric acid (22.5 ml. of 70%; 3 parts water and 7 parts sulfuric acid). The resulting slurry is stirred at 23°-25° until the reaction is complete as measured by TLC(ethyl acetate:hexane, 60:40). When complete the reaction mixture is cooled (10°) and added dropwise to ice-water (800 ml.) with rapid stirring. The resulting slurry is stirred overnight, filtered and the solids washed with water (500 ml.), sodium bicarbonate solution (10%, 500 ml.) and water (500 ml.). The solids are air-dried to give androsta-4,9(11)-diene-3,17-dione, 8.31 g. (97.4% chemical yield); m.p. 196°201°; [α]D +219° (chloroform); UV (methanol)λmax =240 nm (ε=16,500). GC (Example 1) shows an androsta-4,9(11)-diene-3,17-dione/androsta-4,8-diene-3,17-dione ratio of greater than 99 to 1.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[C:19]([CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[S:20][C:21]=1[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]([C:17]2[N:18]=[C:19]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[NH:8][S:9]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: Cc1nccc(-c2sc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccc(-c2sc(C3CCNCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-piperidinecarboxylate (115 mg, 0.192 mmol) in dichloromethane (2 mL) was added TFA (0.015 mL, 0.192 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to give 62 mg of the title compound. MS (ESI): 500.3 [M+1]+.
Reaction SMILES: CO.[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[F:12][C:13]([F:24])([F:23])[C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15].[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C(O)(=O)C>[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:9][CH:19]2[CH2:20][CH2:21][N:16]([C:14](=[O:15])[C:13]([F:12])([F:23])[F:24])[CH2:17][CH2:18]2)=[CH:6][CH:5]=1
Reactant: O=C1CCN(C(=O)C(F)(F)F)CC1
Reactant: Cc1ccc(CN)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(CNC2CCN(C(=O)C(F)(F)F)CC2)cc1

Procedure:
Methanol (150 ml) was added to an Erlenmeyer flask and acetic acid was added under stirring until pH 5. 4-Methylbenzylamine (3.14 g, 25.9 mmol) and N-trifluoroacetyl-4-piperidone (from reaction step 1) (5.065 g, 25.9 mmol) were added to a 250 ml round-bottomed flask and dissolved in the methanol/acetic acid (150 ml) solution previously made. The reaction mixture was stirred for 5 min and NaCNBH3 (2.46 g, 38.9 mmol) was added slowly under stirring. After 20 hours the reaction was concentrated and transferred to a reparatory funnel containing dichloromethane and distilled water. The aqueous phase was made basic by addition of Na2CO3. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were collected and dried with Na2SO4. Concentration afforded, 4-(4-methylbenzylamine)-1-(trifluoroacetyl) piperidine. UV/MS 60/53 (M+ 301), tr (A, MS) 3.267.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C)([O-])=O>[C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)OCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: O=C(O)Cc1ccccc1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A mixture of benzyl phenylacetate (218 mg), methylene chloride (2 ml), aluminum chloride (357 mg), and nitromethane (1 ml) is stirred for 1 hour under ice cooling. The mixture is acidified with cold dilute hydrochloric acid and extracted with methylene chloride. The organic layer is extracted again with 5% aqueous sodium hydrogen carbonate solution. The aqueous extract is acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to give phenylacetic acid (114 mg) melting at 77° C. Yield: 87%.
Reaction SMILES: BrCCC[N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[S:6]1(=[O:22])=[O:21].[Cl:23][CH2:24][CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([N:7]2[S:6](=[O:21])(=[O:22])[N:5]([CH:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH2:24][Cl:23])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=3)=[CH:19][CH:18]=1
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccc(Cl)cc1
Reactant: O[C@@H](CCCl)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S1(=O)N(c2ccc(Cl)cc2)c2ccccc2N1C(CCCl)c1ccccc1
Reaction time: 16 h
Yield: 39.2 %

Procedure:
To a mixture of 1-(3-bromopropyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.28 g, 1.0 mmol), (S)-(−)-3-chloro-1-phenyl-1-propanol (0.17 g, 1.0 mmol), and triphenylphosphine (314 mg, 1.2 mmol) in anhydrous THF (15 mL) was added DIAD (0.23 mL, 1.2 mmol) under nitrogen at 25° C. The mixture was stirred for 16 hours followed by concentration of the mixture in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-40% ethyl acetate in hexane) to afford 0.17 g of 1-(4-Chloro-phenyl)-3-(3-chloro-1-phenyl-propyl)-1,3-dihydro-benzo[1,2,5]-thiadiazole 2,2-dioxide that was immediately carried on to the next step. MS (ESI) m/z [M−H]− 431;