Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.C1COCC1.C([Li])CCC.C1(C#CC2(O)C=CC([CH2:42][CH2:43][C:44]3([CH3:52])[O:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][O:45]3)(O)C=C2)C=CC=CC=1>CN1C(=O)N(C)CCC1>[OH:1][C:2]1([C:9]#[C:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]([CH2:42][CH2:43][C:44]2([CH3:52])[O:45][CH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][O:49]2)[CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1
Reactant: O=C1C=CC(O)(C#Cc2ccccc2)C=C1
Reactant: CC1(C)COC(C)(CCC2(O)C=CC(O)(C#Cc3ccccc3)C=C2)OC1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC1(C)COC(C)(CCC2CC(=O)C=CC2(O)C#Cc2ccccc2)OC1
Temperature: -78 °C

Procedure:
4-Hydroxy-4-(phenylethynyl)-2,5-cyclohexadiene-1-one (1.26 g, 0.006 mole), the compound of Example 1a and 25 mL of dry THF were placed in a dry 100 mL, three-necked round-bottomed flask under nitrogen. The reaction was cooled to -78° C. and treated dropwise with n-butyllithium (4 mL of 1.48M). The reaction was allowed to warm slowly to about 0° C. During this time, a white slurry formed. The reaction was cooled to -78° C. and treated with 4.6 mL of DMPU and one equivalent of the Grignard reagent prepared in Example 1b. The reaction was allowed to warm slowly to RT over a period of 1 hr, then quenched with ammonium chloride solution and extracted into ether. The ether extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated in vacuo. The residue was dried under vacuum overnight. The crude product was chromatographed using a flash silica gel column eluting with 1:4 EtOAc/hexane to yield a first compound-bearing fraction containing 1.5 g (68%) of the title 1,2-1,4 adduct and a third compound-bearing fraction containing 0.31 g (14%) of 1-(phenylethynyl)-4-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2,5-cyclohexadiene-1,4-diol, the 1,2-1,2 adduct.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[CH:8]2.[CH3:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH3:17][N:18]([CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[CH:8]2)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1ccc2cc(OCC3CO3)ccc2[nH]1
Reactant: CNCc1ccccc1
Solvent: CO
Product: CN(Cc1ccccc1)CC(O)COc1ccc2[nH]c(=O)ccc2c1
Yield: 32.5 %

Procedure:
A suspension of 6-(2,3-epoxypropoxy)carbostyril (15 g) and N-methylbenzylamine (11 g) in methanol (150 ml) is heated with refluxing for 2.5 hours. From the mixture, methanol is distilled off under reduced pressure, and to the resulting residue is added diethylether and the precipitated crystals are collected by filtration. The crystals thus obtained are purified by silica gel column chromatography (solvent; methanol:chloroform=1:100-1:25), and recrystallized from ethanol to give 6-[3-(N-methyl-N-benzylamino)-2-hydroxypropoxy]carbostyril (7.6 g), as white powder, m.p. 129°-132° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][CH:6]=1.[CH2:14]=[O:15]>CC(C)=O>[Br:1][C:2]1[C:3]([C:7]([F:13])([F:12])[C:8]([F:9])([F:10])[F:11])=[N:4][N:5]([CH2:14][OH:15])[CH:6]=1
Reactant: C=O
Reactant: FC(F)(F)C(F)(F)c1n[nH]cc1Br
Solvent: CC(C)=O
Product: OCn1cc(Br)c(C(F)(F)C(F)(F)F)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 50.3 %

Procedure:
The mixture of 13.72 g of 4-bromo-3-(pentafluoroethyl)-1H-pyrazole and 3.00 g of paraformaldehyde was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added. The mixture was filtered. The filtrate was concentrated under reduced pressure. Hexane was added to the filtrate, as a result, a crystal was formed. The crystal was collected to obtain 7.69 g of 4-bromo-3-(pentafluoroethyl)-1H-pyrazole-1-ylmethanol.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:7].C(Br)(Br)(Br)[Br:22]>ClCCl>[Br:22][CH2:2][CH2:3][O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:7]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COCCO)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COCCBr)C1
Reaction time: 3.5 h
Yield: 75.9 %

Procedure:
A solution of (S)-3-[2-(2-hydroxyethoxy)acetyl]amino-1-(tert-butoxycarbonyl)pyrrolidine (4 g) prepared in Step B and carbon tetrabromide (5.52 g, Wako Pure Chemical Industries) in dichloromethane (52 ml) was added with PS (polystyrene)-triphenylphosphine (7.86 g, Aldrich) at 0° C., and the mixture was stirred at the same temperature for 3.5 hours. The insoluble solids were removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (3.7 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.CO.[ClH:20]>>[ClH:20].[NH2:7][C:8]1([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(C(C)(C)O)CCCC1
Agent: Cl
Solvent: CO
Product: CC(C)(O)C1(N)CCCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
In a 25 mL round-bottomed flask [1-(1-hydroxy-1-methyl-ethyl)-cyclopentyl]-carbamic acid tert-butyl ester (0.31 g, 1.27 mmol) was dissolved in 1.0 M HCl solution in MeOH (8.2 mL, 8.2 mmol). The reaction mixture was stirred at 50° C. for 4 h then cooled to room temperature and concentrated under reduced pressure to afford 0.23 g (96%) of 2-(1-amino-cyclopentyl)-propan-2-ol hydrochloride as an off-white foam which was used without further purification.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][C:18](=[O:29])[C:19]2([S:26][CH2:27][CH3:28])[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:32])[C@:7]1([CH3:31])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:30])[CH:9]=[CH:8]1)(=O)C.[OH-].[Na+].O>CO.O1CCCC1>[CH2:27]([S:26][C:19]1([S:23][CH2:24][CH3:25])[C:18](=[O:29])[CH2:17][C@H:16]2[C@H:15]3[C@:6]([F:32])([C@@H:5]([OH:4])[CH2:22][C@:20]12[CH3:21])[C@:7]1([CH3:31])[C:12](=[CH:11][C:10](=[O:30])[CH:9]=[CH:8]1)[CH2:13][CH2:14]3)[CH3:28]
Reactant: CCSC1(SCC)C(=O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCSC1(SCC)C(=O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C

Procedure:
11β-(Acetyloxy)-17,17-bis(ethylthio)-9-fluoroandrosta-1,4-diene-3,16-dione was dissolved in a mixture of methanol (3.0 ml) and tetrahydrofuran (3.0 ml) and was exposed to 3 M sodium hydroxide (0.3 ml) for 1.0 hour under an atmosphere of nitrogen. The mixture was then added to water and was extracted with chloroform. The chloroform solution was washed with water, dried (MgSO4) and was evaporated to afford the title compound as a solid (80 mg). One crystallization of this form ethyl acetate-hexane followed by drying gave the analytical specimen of the title compound (58 mg), melting point 268°-270° C. (dec., discoloration starts from ca. 200° C.).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[NH:28]1[CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[N:28]1([CH2:2][CH2:3][O:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]3[NH:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=4[O:23][CH3:24])[N:13]=3)=[CH:7][C:6]=2[CH3:27])[CH2:31][CH2:30][CH2:29]1
Reactant: C1CNC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-[4-(2-bromoethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (216 mg, 0.50 mmol) in DMF (5 mL) was added azetidine (154 mg, 2.70 mmol). The reaction mixture was stirred at room temperature for 2 days. The solid was collected by filtration, washed with methanol, ethyl acetate, and water, and dried under vacuum to give the title compound as a white solid. Yield: 58 mg (28%). MP 204-205° C. 1H NMR (400 MHz, DMSO-d6): δ 7.85 (s, 2H), 6.71 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 1H), 3.70 (t, J=6.0 Hz, 2H), 3.18 (t, J=6.8 Hz, 4H), 2.70 (t, J=6.0 Hz, 2H), 2.26 (s, 6H), 1.97 (m, 2H). MS (ES) m/z: 410.20 (M+1) (100%).
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]#[N:17])[CH:12]=[N:11]2)[CH:5]=1.S(Cl)([Cl:22])(=O)=O>C(Cl)Cl>[Cl:22][C:5]1[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]#[N:17])[CH:12]=[N:11]2)=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1c(C#N)cnn1-c1cc(OC(F)F)n(C)n1
Solvent: ClCCl
Product: Cc1c(C#N)cnn1-c1nn(C)c(OC(F)F)c1Cl
Reaction time: 1 h

Procedure:
0.57 g (2.25 mmol) 1-(5-Difluoromethoxy-1-methyl3-pyrazolyl)-5-methyl-4-pyrazolecarbonitrile was dissolved in 30 ml methylene chloride and at room temperature was treated with 0.30 g (2.25 mmol) sulfuryl chloride. The mixture was stirred for one hour and then concentrated.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])/[C:9]1=[O:35])=O)(C)(C)C.[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([O:52][CH3:53])=[C:41]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])[CH:42]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])[CH2:47][C:45](=[O:46])[NH:44][CH:43]3[C:41]3[CH:42]=[C:37]([Cl:36])[CH:38]=[CH:39][C:40]=3[O:52][CH3:53])[C:11]2=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(Cl)ccc1OC)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2OC)C12C(=O)Nc1cc(Cl)ccc12
Yield: 10 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (7 g, 13.5 mmol) was reacted with 1-(5-chloro-2-methoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (45 mmol) in toluene to give title compound as a white solid (850 mg).
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[CH:6]=[CH:5][S:4][C:3]=2[O:2]1.S1C=CC=C1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>C(O)CCCC.O>[CH2:9]1[O:8][C:7]2[C:6](=[CH:5][S:4][CH:3]=2)[O:2][CH2:1]1
Reactant: c1cc2c(s1)OCCO2
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCCCCO
Solvent: O
Solvent: c1ccsc1
Product: c1scc2c1OCCO2
Temperature: 80 °C

Procedure:
Block copolymers of EDOT with poly(propylene glycol), Poly(EDOT-block-PG), were synthesized from EDOT and a low molecular weight poly(propylene glycol) (PPG) oligomer following a two-step method in Example 1. PPG (MW=1500) was reacted with 2-thiophene carbonyl chloride in the presence of pyridine to form a di-thiophene derivative macromonomer PPGdTh. This macromonomer was then copolymerized with ethylenedioxythiophene (EDOT) in the presence of an oxidizing agent and a suitable counterion. This second step was preferably conducted in diffusion-controlled conditions to avoid the homopolymerization of thiophene; for example, a solution of the PPGdTh (2×10−1 M) in 1-pentanol was mixed with a solution of sodium persulfate (2×10−1 M) and poly(para-styrenesulfonate) in water. To this mixture a diluted solution of EDOT in 1-pentanol (10−2 M) was added dropwise under strong stirring at 80° C. The product was filtered to eliminate the homopolymer and then extracted with water to eliminate unreacted monomer and byproducts.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][C:10]#[N:11].O1CCCCC1OC1(CC#N)CCCCC1>>[NH2:11][CH2:10][CH2:9][C:8]1([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCCCCC(CC#N)OC1CCCCO1
Agent: N#CCC1(OC2CCCCO2)CCCCC1
Product: NCCC1(OC2CCCCO2)CCCCC1

Procedure:
This compound is prepared essentially by the same method as described in Example 1, Step A-3, except that the 3-(tetrahydro-2H-pyran-2-yloxy)caprylonitrile is replaced by a 2-[1-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]acetonitrile. This process yields the title compound as a pale yellow oil.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.Cl.[Cl:22][C:23]1[CH:24]=[C:25]([C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][CH:57]=2)[CH:26]=[CH:27][C:28]=1[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH2:39][NH:40][CH:41]1[CH2:50][CH2:49][CH2:48][C:47]2[N:46]=[C:45]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:44]=[CH:43][C:42]1=2>C(#N)C>[Cl:22][C:23]1[CH:24]=[C:25]([C:56]2[CH:57]=[CH:58][C:59]([C:62]([F:64])([F:65])[F:63])=[CH:60][CH:61]=2)[CH:26]=[CH:27][C:28]=1[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH2:39][N:40]([CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH:41]1[CH2:50][CH2:49][CH2:48][C:47]2[N:46]=[C:45]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:44]=[CH:43][C:42]1=2
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: COC(=O)c1ccc(CCI)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Cl
Temperature: 25 °C

Procedure:
685 mg (2.36 mmol) of methyl 4-(2-iodoethyl)benzoate and 188 mg (1.77 mmol) of anhydrous sodium carbonate were added to a solution of 740 mg (1.18 mmol) of ethyl 5-{[2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}-5-fluorophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate dihydrochloride (Enantiomer 2, Example 116A) in 20 ml of dry acetonitrile, and the mixture was heated under reflux overnight. A further 342 mg of methyl 4-(2-iodoethyl)benzoate were then added, and the mixture was stirred under reflux overnight. This procedure was repeated two more times on the subsequent days. Then, another 342 mg of methyl 4-(2-iodoethyl)benzoate and 188 mg of anhydrous sodium carbonate were added and the mixture was again stirred under reflux overnight. Another 342 mg of methyl 4-(2-iodoethyl)benzoate were then added to the reaction solution, and the mixture was heated under reflux overnight and then cooled to room temperature. The reaction was filtered, the filter cake was washed with acetonitrile and the filtrate was concentrated to dryness. The residue was taken up in ethyl acetate, and water was added. The organic phase was separated, dried over magnesium sulphate, filtered and evaporated to dryness. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). This gave 588 mg (0.40 mmol, 63% of theory) of the title compound.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:33]([CH2:34][CH2:35][C@:17]12[CH3:18])[C@:30]1([CH2:31][OH:32])[C:25]([CH2:26][C:27](=[O:36])[CH2:28][CH2:29]1)=[CH:24][CH2:23]3.[OH-].[Na+].OO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:18][C@:17]12[CH2:35][CH2:34][C@H:33]3[C@@H:22]([CH2:23][CH:24]=[C:25]4[C@:30]3([CH2:31][OH:32])[CH2:29][CH2:28][C@@H:27]([OH:36])[CH2:26]4)[C@@H:19]1[CH2:20][CH2:21][C@@H:16]2[OH:15]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@H](O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1 M solution of lithium tri-sec-butylborohydride in tetrahydrofuran under nitrogen is cooled in a dry ice-acetone bath to about -78° C. and 17β,19-dihydroxy-5-androsten-3-one in tetrahydrofuran is slowly added. The reaction mixture is stirred for a period of two hours at this temperature, warmed to 0° C. and stirring continued for an additional two hours. The reaction mixture is decomposed by the addition of a 3 N sodium hydroxide solution followed by the addition of a 30% hydrogen peroxide solution. Solid potassium carbonate is added and the tetrahydrofuran solution decanted therefrom. The solid residue is washed with fresh tetrahydrofuran and the combined tetrahydrofuran solutions are dried over anhydrous sodium sulfate, filtered, and evaporated. The residue is crystallized from acetone to yield 5-androstene-3α,17β,19-triol.
Reaction SMILES: N1C=CN=C1.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.[Cl-].[Na+].O>[C:17]([Si:21]([O:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([CH3:6])(=[O:8])=[O:9])=[CH:11][CH:12]=1)([CH3:24])[CH3:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(S(C)(=O)=O)cc1
Yield: 96 %

Procedure:
9.9 g (145.18 mmol) of imidazole was added to and dissolved in an N,N-dimethylformamide solution (150 mL) of 10 g (58.07 mmol) of 4-methylsulfonylphenol, and then 10.5 g (69.7 mmol) of tert-butyldimethylchlorosilane was added thereto and stirred. After the reaction, brine was added thereto and extracted with ethyl acetate. The organic layer was washed three times with brine, and dried over anhydrous magnesium sulfate. Purifying by silica gel column chromatography (hexane/ethyl acetate=5/1→3/1) gave 15.97 g (55.75 mmol) of tert-butyl-(4-methanesulfonylphenoxy)dimethylsilane (XII-6) (yield 96%). Its physical properties are shown below.
Reaction SMILES: [H-].[Na+].CN1C(=O)N(C)CCC1.C1(C)C=CC(S(O[CH2:22][CH2:23][CH2:24][CH:25]([CH3:34])[CH2:26][CH:27]([OH:33])[CH:28]=[CH:29][C:30]([CH3:32])=[CH2:31])(=O)=O)=CC=1>C(COC)OC>[CH3:34][CH:25]1[CH2:24][CH2:23][CH2:22][O:33][CH:27](/[CH:28]=[CH:29]/[C:30]([CH3:32])=[CH2:31])[CH2:26]1
Reactant: C=C(C)C=CC(O)CC(C)CCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: COCCOC
Product: C=C(C)/C=C/C1CC(C)CCCO1

Procedure:
The procedure described in Example 1 h) was carried on with 2.68 g of NaH (111 mmole) in 130 ml of monoglyme, 3.80 ml of DMPU (31.6 mmole) and 8.52 g (24 mmole) of the above-mentioned p-toluenesulfonate in monoglyme (130 ml). After purification of 5.1 g of crude product, 3.0 g of a more than 98% pure mixture, containing two diastereoisomeric forms (ca. 1:1) of (E)-4-methyl-2-(3-methyl-1,3-butadienyl)oxepane were obtained. P.b. 111°-112°/14.67×102Pa; yield: 69%.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1.C([O-])(=O)C.[Na+].[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>O.C(#N)C>[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Oc1cc(O)nc(S)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Oc1cc(O)nc(SCc2cccc(F)c2F)n1
Temperature: 40 °C

Procedure:
To a slurry of 2-mercaptopyrimidine-4,6-diol (55.6 g) in water (735 ml) was added sodium acetate (47.4 g) with stirring forming a complete solution over 20 minutes. A solution of 2,3-difluorobenzyl bromide (80 g) in acetonitrile (73.5 ml) was then added dropwise over 15 minutes and the resulting mixture heated at 40° C. with stirring for 18 h. After cooling to ambient temperature the resulting precipitate was then filtered and washed with H2O (1 L) before drying in vacuo at 100° C. to afford the subtitle compound as a cream solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([S:32](Cl)(=[O:34])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:32]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])=[N:7][CH:6]=2)[CH2:13][CH2:12]1)=[O:15]
Reactant: CCCCCCS(=O)(=O)Cl
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCS(=O)(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Temperature: 60 °C
Yield: 7.6 %

Procedure:
To a solution of [4-(6-aminopyridin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.035 g, 0.10 mmol) in pyridine (3 mL) was added hexanesulfonyl chloride (0.022 mL, 0.12 mmol). After heating at 60° C. for 20 h, the mixture was diluted with ethyl acetate (100 mL), washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. Purification by preparative thin layer chromatography afforded the title compound as a white solid (3.8 mg, 8% yield). 1H NMR (300 MHz, CDCl3) δ 7.66, 7.29, 4.08, 3.91, 3.38, 3.27, 3.08, 1.84, 1.35, 1.27, 0.87. MS (ES+) m/z 499.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:28][CH:27]=[CH2:26])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.8 g, 2.5 mmol) in dimethylformamide (10 mL). Add sodium hydride (0.13 g, 60% in oil, 3.25 mmol). After about 30 minutes, when the gas evolution ceases, add allyl bromide (0.35 mL 4.0 mmol). Heat to 75° C. After 4 hours, dilute with ethyl acetate and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-t-butoxycarbonyl-4-(1-(allyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.83 (silica gel, 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia). Combine 1-t-butoxycarbonyl-4-(1-(allyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.9 g, 2.5 mmol) and ethanol (10 mL). Add aqueous hydriodic acid (10 mL, 57%). Heat to reflux. After 1 hour, cool to ambient temperature and dilute with diethyl ether (250 mL) and stir to give a solid. Collect the solid by filtration, rinse with diethyl ether, and dry to give the title compound.