Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:19].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:21][O:20][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:19]
Reactant: COC(CN1C(=O)CCc2ncc(C(F)(F)F)cc21)OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(Cn1c(=O)ccc2ncc(C(F)(F)F)cc21)OC
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a solution of 0.11 g of 1-(2,2-dimethoxyethyl)-7-(trifluoromethyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one in 2 mL of dioxane, 0.16 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone was added, and the mixture was heated under reflux while stirring for 3 hours. Thereto were added water and ethyl acetate, the mixture was adjusted to pH 12 with a 2.0 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with an aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 90 mg of 1-(2,2-dimethoxyethyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one as a brown solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[O:8])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: ClCc1ccccc1
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 4-(methylthio)benzaldehyde and benzyl chloride by the same method as described in Step 1 of Example 4.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:18]=[CH:17][C:7]([C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[C:19](Cl)([Cl:21])=[S:20]>O.C(Cl)(Cl)Cl>[Cl:21][C:19]([O:3][C:4]1[CH:18]=[CH:17][C:7]([C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)=[S:20]
Reactant: S=C(Cl)Cl
Reactant: O=C(Sc1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Sc1ccccc1)c1ccc(OC(=S)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium hydroxide (1.55 g in 150 ml of water was added dropwise with vigorous stirring to a solution of 8.8 g of S-phenyl 4-(hydroxy)thiobenzoate and 3.70 ml of thiophosgene in 250 ml of chloroform, the temperature being kept below 10° C. The mixture was stirred at room temperature for 2 hours and the organic layer separated. The organic layer was washed successively with water and brine, dried over calcium chloride, and evaporated to dryness in vacuo to give 11.57 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=1)[C:28](O)=[O:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH:21][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([CH3:22])[CH:24]=[N:25][CH:26]=3)=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Cc1cncc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cncc(C(=O)NNC(=O)c2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
To a yellow solution of 0.200 g (0.623 mmol) of 2-(2,6-Dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (Intermediate 1), 0.0854 g (0.623 mmol) of 5-methyl nicotinic acid, and 5 mL of DMF was added 0.1453 g (0.747 mmol) of EDCI, and 0.1010 g (0.747 mmol) of HOBt. Allowed to stir at r.t. for 18 h. Added 5 mL of water, EtOAc and filtered off solid, to give 0.1680 g of the title compound. Used directly in next reaction. MS (m/z) 440.0 M (+1), tR=1.00, Meth 10
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O>C(#N)C>[Br:27][C:22]1[C:12]2[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]=2[C:19]([O:25][CH3:26])=[CH:20][C:21]=1[C:23]#[N:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C#N)cc(OC)c21
Solvent: CC#N
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C#N)cc(OC)c21
Yield: 44.5 %

Procedure:
A mixture of 110 mg (0.315 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonitrile and 56 mg (0.315 mmol) N-bromosuccinimide in 5 ml acetonitrile is stirred at reflux for 3 h. Then the solvents are evaporated and the residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) and recrystallized from EtOAc/diethyl ether/hexane to afford 60 mg of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([CH:18]([OH:20])[CH3:19])[CH:15]=[C:14]([CH3:21])[N:13]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([CH:18]([O:20][S:32]([CH3:31])(=[O:34])=[O:33])[CH3:19])[CH:15]=[C:14]([CH3:21])[N:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(c1nc(C)cc(C(C)O)n1)c1ccc(C(C)C)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(c1nc(C)cc(C(C)OS(C)(=O)=O)n1)c1ccc(C(C)C)cc1Br
Temperature: 0 °C
Yield: 81.2 %

Procedure:
A mixture of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-hydroxyethyl)-6-methylpyrimidinamine (1.1 g, 2.7 mmol), triethylamine (1.5 mL, 11 mmol) and dichloromethane (15 mL) was stirred at 0° C. under a nitrogen atmosphere. Methanesulfonylchloride (364 mg, 3.2 mmol) was added dropwise and the reaction mixture was then stirred for 1.5 h. The resulting turbid solution was washed successively with an ice-cold 1 N HCl solution, a saturated NaHCO3 solution and a saturated NaCl solution. Drying over MgSO4, filtration and removal of solvent in vacuo gave N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-methanesulfonyloxyethyl)-6-methylpyrimidinamine as a clear colorless oil (1.0 g): NMR (CDCl3, 300 MHz): 7.5 (d, 1H, J=1), 7.25-7.1 (m, 2H), 6.55 (s, 1H), 4.3-4.05 (m, 1H), 3.85-3.6 (m, 1H), 3.0-2.5 (m, 4H), 2.5-2.05 (br m, 3H), 1.3 (d, 6H, J=8), 1.2 (t, 3H, J=8); CI-MS, 456, 458 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][CH2:15][Mg+].[Br-]>C1COCC1.CN1C(=O)CCC1.CCOCC.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Fe]>[CH2:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)[CH3:15]
Reactant: COC(=O)c1ccc(Cl)cc1OC
Reactant: CC[Mg+]
Agent: [Fe]
Agent: CC(=O)/C=C(/C)O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCc1ccc(C(=O)OC)c(OC)c1
Yield: 50 %

Procedure:
To a solution of methyl 4-chloro-2-methoxybenzoate (example 18d) (4.16 g, 20.8 mmol) in THF (120 mL) and NMP (12 mL) was added under inert atmosphere Iron (III) acetylacetonate (398 mg, 1.17 mmol) giving a red color. Then EtMgBr (29 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (1M, 50 mL). The crude product was extracted with ether and the combined organic layers were successively washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (Eluent: 30% EtOAc in hexanes) to give methyl 4-ethyl-2-methoxybenzoate (2.01 g, 50%) as an oil. 1H NMR (300 MHz, dMSO): δ 1.20-1.22(t, 3H), 2.65-2.7 (dd, 2H), 3.9 (s, 3H), 6.8 (s, 1H), 6.97 (m, 1H), 7.7 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][CH:11]=2)([CH3:7])[C:3]([O:5][CH3:6])=[O:4]>[Ni].CO>[NH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:2]([CH3:7])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[CH:16]2
Reactant: COC(=O)C(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C(C)(C)c1cc2cc(N)ccc2[nH]1
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A suspension of methyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (60 mg, 0.23 mmol) and Raney Nickel (10 mg) in MeOH (5 mL) was hydrogenated under hydrogen (1 atm) at room temperature overnight. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5/1) to give methyl 2-(5-amino-1H-indol-2-yl)-2-methylpropanoate (20 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 8.37 (br s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.63 (dd, J=2.0, 8.4 Hz, 1H), 6.20 (d, J=1.2 Hz, 1H), 3.72 (d, J=7.6 Hz, 3H), 3.43 (br s, 1H), 1.65 (s, 6H); MS (ESI) in/e (M+H+) 233.2.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18](OCC)(=[O:23])[CH2:19][C:20]([CH3:22])=O>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:23])[CH:19]=[C:20]([CH3:22])[NH:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(=O)n(-c2ccc(F)cc2)[nH]1
Reaction time: 4 h
Yield: 89 %

Procedure:
(4-Fluorophenyl)hydrazine hydrochloride (20.0 g, 0.123 mol) was added to a solution of triethylamine (20.5 mL) in methanol (350 mL). Then, a solution of ethyl acetoacetate (16.0 g, 0.123 mol) in methanol (50 mL) was added. The resulting reaction mixture was stirred for 4 hours under reflux and extracted with dichloromethane and sodium chloride aqueous solution. The aqueous layer was extracted again with dichloromethane. All the organic layers were collected, dried with Na2SO4 and then filtered. The filtrate was concentrated. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2). The target compound was yielded (21.0 g, 89% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[O:13]1[CH2:17][C:16](=O)[CH2:15][C:14]1=[O:19].[NH2:20][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][C:23]#[N:24].Cl>C(O)CCCC.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:22]([C:23]#[N:24])=[C:21]([C:25]([F:28])([F:27])[F:26])[NH:20][C:16]4[CH2:17][O:13][C:14](=[O:19])[C:15]3=4)[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Reactant: O=C1COC(=O)C1
Reactant: N#CC=C(N)C(F)(F)F
Agent: Cl
Solvent: CCCCCO
Solvent: O
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)(F)F)NC4=C3C(=O)OC4)cc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
100 mg (0.624 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A) and 62.5 mg (0.624 mmol) furan-2,4(3H,5H)-dione were heated up to reflux in 1-pentanol (3 ml) for 1 h. After addition of 425 mg (3.120 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [A. W. Lutz, U.S. Pat. No. 3,635,977], the reaction mixture was stirred at 100° C. for further 4 h. Then, conc. hydrochloric acid (115 μl) and water (350 μl) were added, and the mixture was stirred at 100° C. for another 1 h. After cooling, the mixture was directly purified by RP-HPLC (acetonitrile/water+0.1% TFA gradient) to give 33 mg (14% of th.) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCOC=[CH:18][C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl.[CH2:28](O)C>>[CH2:24]([O:23][C:21]([C:20]1[CH:28]=[N:13][N:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=2)[C:19]=1[CH3:18])=[O:22])[CH3:25]
Reactant: CCO
Reactant: CCOC=CC(=O)CC(=O)OCC
Reactant: NNc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Product: CCOC(=O)c1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C

Procedure:
Then, [3-chloro-5-(trifluoromethyl)pyridin-2-yl]hydrazine (10 g) and ethyl (2-ethoxymethylene)acetoacetate (8.8 g) synthesized according to the method described in J. Chem. Soc. Perkin trans. I, p. 1875 (1988) were added to a mixed solvent of 1 N hydrochloric acid aqueous solution (150 ml) and ethanol (150 ml), and stirred under reflux. After completion of the reaction, the mixture was allowed to cool, and the organic solvent was evaporated in vacuo. Then, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (13.6 g) as a light brown oil. MS (ESI) m/z: 334 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33](=[O:39])[NH:34][C:35](=[S:38])[NH:36][CH:37]=2)=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][S:38][C:35]3[NH:36][CH:37]=[C:32]([CH2:31][C:28]4[CH:29]=[N:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=4)[C:33](=[O:39])[N:34]=3)=[CH:10][C:7]=2[C:8]#[N:9])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Yield: 33.2 %

Procedure:
The same procedure as E63 from 5-(chloromethyl)-2-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}benzonitrile (198 mg, 0.599 mmol), 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (150 mg, 0.599 mmol) and K2CO3 (166 mg, 1.199 mmol) in DMF (3 mL), except that the reaction time was prolonged to 1.5 h, to afford the title compound (108 mg, 33.2% yield). LCMS: rt=3.32 min, [M+H+]=544
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]=12.[CH2:16]=[O:17]>C(O)C>[CH2:16]([N:10]1[C:11](=[O:12])[C:6]2=[C:5]([Br:13])[C:4]([Br:14])=[C:3]([Br:15])[C:2]([Br:1])=[C:7]2[C:8]1=[O:9])[OH:17]
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: C=O
Solvent: CCO
Product: O=C1c2c(Br)c(Br)c(Br)c(Br)c2C(=O)N1CO
Temperature: 85 °C
Yield: 87.6 %

Procedure:
Tetrabromophthalimide (30 gm) was suspended in 100 ml of ethanol and 50 gm of 38 percent formaldehyde was added. Then the solution was stirred and heated for three hours at 85° C. Upon cooling, the product was filtered yielding 28 gm of a white solid having a melting point greater than 350° C. The infrared spectrum of the product showed the disappearance of the imide NH and the appearance of an OH absorption at 3450 cm-1. Analysis: Calculated for C9H3Br4NO3 ; Br, 64.8; hydroxyl number: 89.0; Found: Br, 63.28; hydroxyl number: 90.45.
Reaction SMILES: O.[CH2:2]([O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][S:8]([N:11]=C=O)(=[O:10])=[O:9])[CH3:3].C(=O)=O>ClC(Cl)(Cl)Cl>[S:8](=[O:9])(=[O:10])([O:7][C:6]1[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=1[O:4][CH2:2][CH3:3])[NH2:11]
Reactant: CCOc1ccccc1OS(=O)(=O)N=C=O
Agent: O=C=O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccccc1OS(N)(=O)=O
Temperature: 0 °C
Yield: 93.3 %

Procedure:
2.2 g of water are added dropwise at 30° C. to 40° C. to a solution of 19.2 g of 2-ethoxyphenoxysulfonyl isocyanate in 150 ml of tetrachloromethane. The mixture is stirred at room temperature until the evolution of carbon dioxide has ceased and cooled to 0° C., the product is filtered off with suction, and the filter residue is washed with ice-cold tetrachloromethane. Drying in vacuo gives 16 g of 2-ethoxyphenyl sulfamate of melting point 62°-65° C.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([OH:11])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.C1COCC1>[CH:12]1([C:5]([OH:11])([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:18])=[O:3])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C(O)(c1cccs1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(O)(c1cccs1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of cyclohexyl-hydroxy-thiophen-2-yl-acetic acid ethyl ester (361.8 g, 1.35 mol) in MeOH (1.5 litres) and THF (1.5 litres) is treated portionwise with 2M NaOH (1.1 litres) over 30 minutes. The reaction mixture is stirred at room temperature overnight and then concentrated in vacuo to remove the organic solvents. The remaining aqueous portion is partitioned between EtOAc (2 litres) and 20% citric acid in water (1 litre). The organic layer is separated, washed with brine and concentrated in vacuo to afford the titled compound which is used crude in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=1[C:29]([F:32])([F:31])[F:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:1][C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=4[C:4]=3[CH:3]=2)=[CH:23][C:22]=1[C:29]([F:30])([F:31])[F:32]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: FC(F)(F)c1cc(CCl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.7 %

Procedure:
A mixture of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (222 mg, 0.856 mmol), 1-chloro-4-(chloromethyl)-2-(trifluoromethyl)benzene (240 mg, 1.048 mmol), and cesium carbonate (165 mg, 0.856 mmol) in DMF (5 mL) was stirred at room temperature. After 3 days, more cesium carbonate (165 mg, 0.856 mmol) was added. After stirring for an additional 2 d, the mixture was extracted with water and CH2Cl2. The organics were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a white solid (258 mg). LCMS m/z=452.1 [M+H]+; NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.2 Hz, 3H), 2.06-2.14 (m, 1H), 2.47-2.54 (m, 1H), 2.71-2.86 (m, 4H), 3.51-3.57 (m, 1H), 4.17-4.25 (m, 2H), 5.10 (s, 2H), 6.82 (dd, J=8.8, 2.5, 1H), 6.96 (d, J=2.5 Hz, 1H), 7.21 (dd, J=8.8, 0.32 Hz, 1H), 7.49-7.52 (m, 1H), 7.58 (dd, J=8.2, 2.6 Hz, 1H), 7.80 (d, J=1.92 Hz, 1H), 8.48 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]2.[BH4-].[Na+].C(O)(=O)C>CO.O>[CH3:1][O:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C@@H:7]([OH:23])[CH2:6][CH2:5]2
Reactant: COC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COC[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
19-Methoxyandrost-4-ene-3,17-dione is dissolved in methanol and the solution cooled to 0° C. Sodium borohydride is added over a period of fifteen minutes and stirring continued for an additional two hours. The solution is poured into water containing a few drops of acetic acid. The white precipitate which forms is collected by filtration, dried and crystallized from acetone to yield the desired 19-methoxy-androst-4-ene-3β,17β-diol.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][CH2:14][C@H:15]([OH:26])[C:16]([NH:18][C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)=[O:17])[CH3:12].Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=3)[N:35]=[CH:36][C:29]=12>C1COCC1.CCOC(C)=O>[Cl:43][C:42]1[C:37]([N:34]2[C:30]3[N:31]=[CH:32][N:33]=[C:28]([O:26][C@@H:15]([CH2:14][O:13][CH2:11][CH3:12])[C:16]([NH:18][C:19]4[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=4)=[O:17])[C:29]=3[CH:36]=[N:35]2)=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC[C@H](O)C(=O)Nc1cnc(C)cn1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1.40 mL, 1.40 mmol) was added dropwise to a stirred solution of (S)-3-ethoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate H1) (315 mg, 1.40 mmol) in THF (15 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (372 mg, 1.40 mmol) in anhydrous THF (3 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 3 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography eluting with EtOAc to afford (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxy-N-(5-methylpyrazin-2-yl)propanamide (330 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 1.24 (3H, t), 2.54 (3H, s), 3.60-3.68 (2H, m), 4.07-4.16 (2H, m), 6.09 (1H, t), 7.47 (1H, dd), 8.01 (1H, dd), 8.12 (1H, d), 8.47 (1H, s), 8.62 (1H, dd), 8.64 (1H, s), 8.66 (1H, s), 9.44 (1H, d); m/z (ESI+) (M+H)+=455; HPLC tR=1.77 min.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:10]Cl)([CH3:9])[CH3:8])=[CH:3][CH:2]=1.[Na].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(OCC)(=O)C>CN(C)C=O.O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:9])([CH3:8])[CH2:10][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(Cn1ccnc1)c1ccc(-c2ccccc2)cc1
Yield: 28.7 %

Procedure:
A mixture of 2.6 g (0.010 mol) of (1,1'-biphenyl-4-yl)chloromethyldimethylsilane and 1.1 g (0.012 mol) of imidazole sodium salt in 5 ml of dimethylformamide was warmed to 80°-90° for 2 hours, cooled, diluted with water, and extracted with ether. The ether solution was washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2.0 g of a viscous, pale yellow oil. Trituration of a small sample with hexanes gave a solid. The bulk of the crude product was then taken up in a hot mixture of 20 ml of hexanes and 3 ml of ethyl acetate, the solution was cooled slowly, and seed crystals were added when cloudiness was observed. The resulting crystals were collected and dried to give 0.84 g (29%) of the title compound as colorless flakes: m.p. 51°-53°; ir (NujolR) 1235, 1215, 1105, 1065, 900, 830, 785, 750, 730, 685 cm-1 ; nmr (CDCl3) 0.4 (6 H, s), 3.7 (2H, s), 6.7 (1H, broad s), 7.0 (1H, broad s), 7.1-7.8 (10H, m); analysis for C18H20N2Si (mw 292.45):