Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=2[OH:18])[N:3]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=2[OH:18])[N:3]=1
Reactant: COC(=O)c1ccc(-n2nc(C)cc2C)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)n(-c2ccc(C(=O)O)cc2O)n1
Reaction time: 3.5 h
Yield: 43.3 %

Procedure:
100 mg of methyl 4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzene carboxylate was dissolved in 1 ml of methanol, and 1.6 ml of 1N-sodium hydroxide was added at room temperature and stirred for 3.5 hours. To the reaction mixture, 20 ml of water was added, neutralized with 1N-hydrochloric acid, and extracted with 20 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 40.8 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]3[CH2:14][CH2:13]3)[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][O:29]C(=O)C)[C@H:21]([O:22]C(=O)C)[C@@H:16]3[O:17]C(=O)C)[C:6]=2[CH:5]=[C:4]([Cl:33])[C:3]=1[Cl:34].C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]3[CH2:13][CH2:14]3)[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][OH:29])[C@H:21]([OH:22])[C@@H:16]3[OH:17])[C:6]=2[CH:5]=[C:4]([Cl:33])[C:3]=1[Cl:34]
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(NC3CC3)nc3c(Br)c(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: OC[C@@H]1O[C@H](n2c(NC3CC3)nc3c(Br)c(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Yield: 35.5 %

Procedure:
4-Bromo-2-(cyclopropylamino)-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (1.01 g, 1.74 mmol), sodium carbonate (0.265 g, 2.50 mmol), water (4 mL), methanol (5 mL), and ethanol (8 mL) were used according to general procedure III. The product was purified using silica gel chromatography using 10:1 dichloromethane/methanol to afford 0.28 g (36%) of a white solid: m.p. 205-208° C. Anal. calcd for C15H16Cl2BrN3O4-(0.25 C4H7O2): C, 40.45; H, 3.82; N, 8.84 Found: C, 40.38; H, 3.95; N, 8.90.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>[Rh]>[CH:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCO
Agent: [Rh]
Product: CCCCCCCCC=O
Yield: 66 %

Procedure:
Repetition of step 1 (12 ppm of Rh), rhodium catalyst/bottoms solution from (b) being used. A conversion of octenes of 99% and a yield of 66% nonanal and 15% nonanol were obtained at a 16% balance loss (based on octene-N: mechanical losses, formation of high-boilers and paraffin included).
Reaction SMILES: [O:1]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1.[ClH:30]>O1CCOCC1>[ClH:30].[O:29]=[C:27]1[O:26][N:25]=[C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[O:17][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][C:2]3=[O:1])[NH:28]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3noc(=O)[nH]3)ccc1O2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CC2(CCNCC2)Oc2ccc(-c3noc(=O)[nH]3)cc21

Procedure:
A suspension of 437 mg of tert-butyl 4-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-spiro[chroman-2,4′-piperidine]-1′-carboxylate in 10 mL of 4N HCl in dioxane was stirred at rt for 1d, the resultant white solid was filtered, and washed with ether. The collected white solid was dried in vacuo at 50° C. to give the intended compound as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:32]([NH:33][C:34](=[O:36])[CH3:35])=[C:13]3[C:14](=[O:31])[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>O1CCCC1>[CH3:44][S:45]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:32]([NH:33][C:34](=[O:36])[CH3:35])=[C:13]3[C:14](=[O:31])[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[N:11]2)=[CH:8][CH:9]=1)(=[O:47])=[O:46]
Reactant: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCO)cc4)nc3c3ccccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCOS(C)(=O)=O)cc4)nc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of N-{2-[4-(2-hydroxyethyl)phenyl]-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-3-yl}acetamide (3.2 g) and triethylamine (1.85 ml) in tetrahydrofuran (400 ml) was added dropwise methanesulfonyl chloride (0.77 ml) at 0° C. The mixture was stirred at room temperature for 5 hours, triethylamine (0.46 ml) and methanesulfonyl chloride (0.19 ml) were added thereto, and stirred again for 3 hours. The mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, water, saturated brine, dried and concentrated under reduced pressure to obtain the target compound (3.5 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:52])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27]=4[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:41][C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][C:50]=2[F:51])[NH:47][CH:46]=[CH:45]3)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:53]([O-:55])=[O:54].[NH2:56][CH2:57][C@H:58]1[CH2:63][CH2:62][C@H:61]([OH:64])[CH2:60][CH2:59]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C:27]2[CH2:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH2:31][C:26]=2[CH2:25][N:22]2[CH2:21][CH2:20][N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:11][S:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:56][CH2:57][C@H:58]5[CH2:63][CH2:62][C@H:61]([OH:64])[CH2:60][CH2:59]5)=[C:3]([N+:53]([O-:55])=[O:54])[CH:4]=4)(=[O:10])=[O:9])=[O:52])=[C:14]([O:41][C:42]4[CH:43]=[C:44]5[C:48](=[CH:49][C:50]=4[F:51])[NH:47][CH:46]=[CH:45]5)[CH:15]=3)[CH2:24][CH2:23]2)=[CH:39][CH:38]=1
Reactant: NC[C@H]1CC[C@H](O)CC1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(Cl)c([N+](=O)[O-])c4)c(Oc4cc5cc[nH]c5cc4F)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC[C@H]5CC[C@H](O)CC5)c([N+](=O)[O-])c4)c(Oc4cc5cc[nH]c5cc4F)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A mixture of EXAMPLE 240A (153 mg), trans-4-(aminomethyl)cyclohexanol (73.5 mg) and N-ethyl-N-isopropylpropan-2-amine (0.16 mL) in dioxane (2 mL) was heated at 100° C. for 20 hours and concentrated. The residue was dissolved in dimethylsulfoxide-methanol (1:1) and purified by HPLC, eluting with 40%-65% acetonitrile in 0.1% TFA water over 40 minutes to provide the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.22 (s, 2H), 8.56-8.62 (m, 2H), 7.85 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H), 7.29-7.36 (m, 4H), 7.12 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.41 (s, 1H), 6.09 (d, 1H), 4.51 (d, 1H), 3.24 (t, 2H), 3.03 (s, 4H), 2.74 (s, 2H), 2.16 (d, 6H), 1.95 (s, 2H), 1.83 (d, 2H), 1.74 (d, 2H), 1.56 (dd, 1H), 1.38 (t, 2H), 0.95-1.16 (m, 4H), 0.92 (s, 6H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:31]2[CH2:36][C@H:35]([CH3:37])[O:34][C@H:33]([CH3:38])[CH2:32]2)=[C:22]([F:30])[C:23]([F:29])=[C:24](/[CH:26]=[N:27]/O)[CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:31]2[CH2:32][C@H:33]([CH3:38])[O:34][C@H:35]([CH3:37])[CH2:36]2)=[C:22]([F:30])[C:23]([F:29])=[C:24]([CH:25]=1)[C:26]#[N:27])([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(/C=N/O)c(F)c2F)C[C@H](C)O1
Solvent: CC(=O)OC(C)=O
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C#N)c(F)c2F)C[C@H](C)O1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
A mixture of (E)-1-{5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorophenyl}-N-hydroxymethanimine (Intermediate 5, 8.0 g, 14.8 mmol) and acetic anhydride (10 mL) was stirred at 130° C. for 12 hours. the reaction mixture cooled to room temperature and concentrated, and the residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give the title compound as yellow solid. Yield: 6.5 g, (85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(F)cc1
Reactant: ClCCCBr
Product: Fc1ccc(OCCCCl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-fluorophenol and 1-bromo-3-chloropropane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[H][H].C(OCC)(=O)C>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:18])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(N)c(F)c1
Yield: 127.5 %

Procedure:
10% Palladium on carbon (200 mg) was added to a solution of 2-(3-fluoro-4-nitro-phenoxy)-2-methyl-propionic acid ethyl ester (1.15 g, 4 mmol) in ethanol (20 ml). The suspension was hydrogenated at a hydrogen gas pressure of 1.7 bar for 8 h at ambient temperature. Ethyl acetate was added (100 ml), the solid was filtered off and the filtrate was brought to dryness under reduced pressure to give the title compound (1.23 g, quant.) which was used in the next step without further purification.
Reaction SMILES: C(SC1C(=CC=CC=1)C(Cl)=O)C1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][S:25][C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]([OH:30])=O)=[CH:22][CH:21]=1.O=S(Cl)Cl.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C1C=CC=CC=1.O>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][S:25][C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]([N:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)=[O:30])=[CH:35][CH:36]=1
Reactant: COc1ccc(CSc2ccccc2C(=O)O)cc1
Reactant: CN1CCNCC1
Agent: O=C(Cl)c1ccccc1SCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(CSc2ccccc2C(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound N1-(S-(4-methoxybenzyl) thiosalicyloyl)-N4-methylpiperazine (compound 2) was prepared in a manner similar to that described above for S-(4-methoxybenzyl)-N-(2-(N′,N′-dimethylamino)ethyl) thiosalicylamide. After preparing the S-benzylthiosalicyloyl chloride from 0.02M(5.487 g) of S-(4-methoxybenzyl)thiosalicylic acid and 20 mL of SOCl2, the mixture was suspended in warm benzene (30 mL) and was slowly added to a 20 mL cold solution of 4.007 g(0.04M) 1-methylpiperazine in benzene. The mixture was stirred overnight at room temperature. The next day 40 mL of water were added, the aqueous layer was separated, and extracted twice with 15 mL CH2Cl2. The extracts were combined with the benzene layer, washed with 10% NaOH solution and dried over anhydrous MgSO4. Removal of the solvents under reduced pressure left an oily product which was dissolved in petroleum ether (10 ml). A precipitate separated out upon cooling in an ice bath. The separated solid was collected by suction filtration and washed with petroleum ether to give 3.372 g(47%) of the product in the form of white crystals and having a melting point of 77-78° C. and the following specifications:
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.[OH-:14].[K+].C>O>[Br:13][C:9]1[N:10]=[C:11]([OH:14])[C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:7][CH:8]=1
Reactant: [OH-]
Reactant: Brc1cnc(NC2CCC2)c(Br)n1
Agent: [K+]
Solvent: O
Product: Oc1nc(Br)cnc1NC1CCC1
Yield: 80 %

Procedure:
A suspension of 2-(N-cyclobutylamino)-3,5-dibromopyrazine (EX-15B) (25.03 g, 81.53 mmol) in 500.0 mL water (0.16 M) was added potassium hydroxide (22.90 g, 408.1 mmol) in 480.0 mL water. The resulting suspension was heated to reflux for approximately 18 hours. The reaction mixture was then added charcoal and refluxed for an additional 15 minutes. The mixture was then allowed to cool for 5 minutes and was filtered through Celite 545. The filtrate was cooled in an ice bath and was acidified to a pH of approximately 5 (litmus paper) upon which a white precipitate forms. The precipitate was collected by filtration, washed twice with water, and dried under vacuum to afford pure 5-bromo-2-(N-cyclobutylamino)-3-hydroxypyrazine (EX-115C) in 80% yield: 1H NMR (400 MHz, DMSO) δ 12.43 (s, 1H), 7.18 (br d, J=5.1 Hz, 1H), 6.87 (s, 1H), 4.29-4.19 (m, 1H), 2.16-2.09 (m, 2H), 2.03-1.93 (m, 2H), 1.63-1.51 (m, 2H); 13C NMR (100 MHz, DMSO) δ 147.0, 144.2, 119.9, 41.3, 26.0, 10.8; HRMS (EI) calcd for C8H11BrN3O 244.0085, found 244.0086.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[N:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Clc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncccn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-chloropyrimidine (171 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (397 mg, 78%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(Cl)c1
Yield: 75.5 %

Procedure:
By the method of Example 7, Step C, 141.4 g (0.978 mole) of 2-chloro-4-fluorotoluene, 175.8 g (0.978 mole) of N-bromosuccinimide, and 5.0 g of benzoyl peroxide in 15 liters of carbon tetrachloride were reacted, yielding 165 g of 2-chloro-4-fluorobenzyl bromide as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]([O:9][C@H:10]1[CH2:29][C@@:28]2([CH3:30])[C@@H:21]([CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[C@H:20]2[C@H:11]1[C@:12]1([CH3:32])[C@@H:17]([CH2:18][CH2:19]2)[CH2:16][C@@H:15]2[O:31][C@@H:14]2[CH2:13]1)=[O:8])[CH2:4][CH3:5])[CH3:2].C(=O)(O)[O-].[Na+].[ClH:38]>>[Cl:38][C@H:14]1[CH2:13][C@@:12]2([CH3:32])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:11]2[C@@H:10]([O:9][C:7](=[O:8])[CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:29][C@@:28]2([CH3:30])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[CH2:16][C@@H:15]1[OH:31]
Reactant: CCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@@H]4O[C@@H]4C[C@]3(C)[C@H]21
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)[C@@H](Cl)C[C@]3(C)[C@H]21

Procedure:
A solution of 11β-diethylaminoacetoxy-2α,3α-epoxy-5α-pregnan-20-one (800 mg) in concentrated hydrochloric acid (6 ml) was kept at room temperature for 15 minutes and then diluted with a large excess of sodium bicarbonate solution. The precipitated solid (767 mg) was collected by filtration and purified by preparative TLC (ethylacetate) and crystallization from petroleum ether to afford title compound, (305 mg). m.p. 182°-187°, [α]D +101.4°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH:17]1([N:23]=[C:24]=S)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].BrN1C(=O)CCC1=O>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([CH3:10])([CH3:11])[O:12][C:24]([NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:16][S:13]2(=[O:14])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: S=C=NC1CCCCC1
Reactant: CC(C)(O)C(c1cccc(Br)c1)S(N)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(Br)c1
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
A solution of 1.00 g of 1-(3-bromophenyl)-2-hydroxy-2-methylpropane-1-sulfonamide and 0.483 g of cyclohexyl isothiocyanate in 7 ml of NMP was admixed with 1.62 ml of a 2 N solution of sodium bis(trimethylsilyl)amide. After stirring for 20 minutes, 578 mg of N-bromosuccinimide were added and the mixture was stirred at room temperature for a further 60 minutes. The reaction solution was admixed with 150 ml of water and extracted twice with 150 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC, and the product-containing fractions were lyophilized. This gave the product (411 mg) with a molecular weight of 415.3 g/mol (C17H23BrN2O3S); MS (ESI): m/e=416 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][N:13]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(OC(=O)C)(=O)C.CS(Cl)(=O)=O.[CH3:45][O:46][C:47](=[O:80])[NH:48][CH:49]([C:53]([N:55]1[CH2:59][CH2:58][CH2:57][CH:56]1[C:60]1[NH:61][CH:62]=[C:63]([C:65]2[CH:70]=[CH:69][C:68](B3OC(C)(C)C(C)(C)O3)=[CH:67][CH:66]=2)[N:64]=1)=[O:54])[CH:50]([CH3:52])[CH3:51].C(=O)([O-])[O-].[K+].[K+]>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.O.COCCOC>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:68]4[CH:69]=[CH:70][C:65]([C:63]5[NH:64][C:60]([CH:56]6[CH2:57][CH2:58][CH2:59][N:55]6[C:53](=[O:54])[CH:49]([NH:48][C:47]([O:46][CH3:45])=[O:80])[CH:50]([CH3:52])[CH3:51])=[N:61][CH:62]=5)=[CH:66][CH:67]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CN(S(C)(=O)=O)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(S(C)(=O)=O)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 22.3 %

Procedure:
{1-[4-(4-Bromo-phenyl)-1′-methanesulfonyl-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (62.9 mg, 0.119 mmol) [prepared as described for the synthesis of {1-[1′-Acetyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl (Example BY)]-2-methyl-propyl}-carbamic acid methyl ester substituting the acetic anhydride with methyl sulfonyl chloride] was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (54.6 mg, 0.110 mmol) under an argon atmosphere. Potassium carbonate (33.1 mg, 0.240 mmol) and Pd(PPh3)4 (12.7 mg, 0.011 mmol) were added, followed by DME (2.0 mL) and water (0.4 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product (20.1 mg): LCMS-ESI+: calc'd for C40H51N9O8S: 817.9 (M+); Found: 818.6 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.90-7.81 (m, 10H), 5.69 (d, J=7.5 Hz, 1H), 5.48 (dd, J=6.9, 6.9 Hz, 1H), 5.27 (dd, J=8.1, 8.1 Hz, 1H), 5.17 (d, J=8.4 Hz, 1H), 4.41 (dd, J=12.0, 7.8 Hz, 1H), 4.24 (d, J=7.2 Hz, 1H), 4.11 (m, 2H), 4.00 (d, J=8.1 Hz, 1H), 3.87 (m, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.17 (s, 3H), 2.57 (m, 1H), 2.29-1.99 (m, 5H), 1.03-0.89 (m, 12H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]=[N+]=[N-])=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NCCCc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: NCCCc1ccc(F)cc1
Yield: 57.1 %

Procedure:
The product from step e (0.79 g, 6.4 mmol) was dissolved in 100 mL of MeOH and added carefully to 0.20 g of 10% Pd/C under N2. The mixture was hydrogenated in a Parr shaker at 50 PSI overnight. Filtration through fiberglass filter paper under N2 and under vacuum yielded 0.56 g of a clear colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3>BrCCCO>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:7][CH2:8][CH2:9][OH:16])[CH:10]=3
Reactant: O=c1c(Cc2cncnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Agent: OCCCBr
Product: O=c1c(Cc2cncnc2)cn2c3c(cc(OCCCO)cc13)Sc1ccc(Br)cc1-2
Yield: 75.3 %

Procedure:
According to Example 34, the compound (150 mg) produced in Example 76 was reacted with 3-bromopropanol (50 μl) to obtain the title compound (64 mg; 38%).
Reaction SMILES: Cl[C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH:8]=[O:9].[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([O-:19])=[O:18]>>[Cl:7][C:5]1[S:4][C:3]([CH:8]=[O:9])=[C:2]([S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)(=[O:19])=[O:18])[CH:6]=1
Reactant: O=Cc1sc(Cl)cc1Cl
Reactant: O=S([O-])c1ccccn1
Agent: [Na+]
Product: O=Cc1sc(Cl)cc1S(=O)(=O)c1ccccn1

Procedure:
The title compound was prepared by the method of Preparation 42a using 3,5-dichlorothiophene-2-carbaldehyde and pyridine-2-sulfinate sodium salt.