Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1>CO>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:1][C:2](=[O:3])[C:4]=2[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C1CCCC1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCCC2)Oc2ccc(Br)cc21

Procedure:
A solution of 5-bromo-2-hydroxyacetophenone (31.6 g, 0.1477 mol), cyclopentanone (26 mL, 0.2939 mol) and pyrrolidine (24 mL, 0.288 mol) in methanol (600 mL) was stirred at 25° C. overnight. The mixture was then concentrated to a red oil. Water was added and the solution was adjusted to pH 1 with concentrated hydrochloric acid. The product was extracted with diethylether. The organic layer was evaporated under reduced pressure. The residue was then dissolved in a small volume of methanol. The solution was treated with charcoal, filtered and water was added to the filtrate. The residue was extracted with diethylether. The organic layer was dried over magnesium sulfate and diethylether was evaporated under reduced pressure. The product was used directly in the next step (77%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23]C)=[O:22])[CH:17]=[CH:18][CH:19]=2)([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:25]#[C:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([C:36]2[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[CH:37]=2)=[O:35])[CH:28]=1.[OH-].[Na+].Cl>CO.O.[Cl-].[Na+].O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:25]#[C:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([C:36]2[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[CH:37]=2)=[O:35])[CH:28]=1
Reactant: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cnc(N)c(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cc(C(=O)N=S(C)(=O)c4cccc(CC(=O)O)c4)cnc3N)c2)n(C)n1
Yield: 91.8 %

Procedure:
A solution of methyl {3-[N-({6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}acetate (13 mg, 0.021 mmol) and 1.0M NaOH (0.171 ml, 0.171 mmol) in 2.0 ml MeOH and 0.1 ml H2O was stirred at room temperature for 1 hour 10 minutes. The pH of the mixture was adjusted to pH 4 using 10% HCl, brine added, and the aqueous extracted with EtOAc. The combined EtOAc layers were washed with brine, dried with anhydrous Na2SO4 and rotary evaporated. The white solid was triturated with hot EtOAc to give white solid (11 mg, 92%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH2:18])[C:16]#[CH:17].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.C(Cl)CCl>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:18][CH2:15][C:16]#[CH:17])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCN
Reactant: O=C(O)CCCOCc1ccccc1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C#CCNC(=O)CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of 4-Benzyloxy-butyric acid (1.00 g, 5.15 mmol) and Propargylamine (284 mg, 5.15 mmol) in DMF (10.3 ml) was treated with Diisopropylethylamine (0.90 ml, 5.15 mmol), Hydroxybenzotriazole (788 mg, 5.15 mmol) and EDC (665 mg, 5.15 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature under nitrogen. The reaction was concentrated under reduced pressure and the crude product is taken up in Ethyl acetate, washed with water, dried using Na2SO4, filtered, and concentrated to yield 4-Benzyloxy-N-prop-2-ynyl-butyramide (1.02 g, 86%) as a viscous oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:42][CH2:41][C:39]1[N:40]=[C:36]([C:32]2[CH:31]=[C:30]([C:29]3[CH2:28][C:27](=[O:50])[NH:20][C:9]4[CH:10]=[C:11]([CH3:19])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[O:37][CH:38]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-methyl-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.21 g) (Example J24) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K11) (0.31 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.16 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16](=[O:17])[N:15]([CH2:18][C:19](O)=[O:20])[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[S:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C([N:28](CC)CC)C.O.N>C(Cl)Cl.C(OC(Cl)=O)C(C)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16](=[O:17])[N:15]([CH2:18][C:19]([NH2:28])=[O:20])[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[S:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)Oc1ccc(C2Sc3ccccc3N(CC(=O)O)C2=O)cc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C2Sc3ccccc3N(CC(N)=O)C2=O)cc1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a stirred solution of [2-(4-acetoxyphenyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-4-yl]acetic acid (compound No. 26, 4.6 g) and triethylamine (1.8 ml) in CH2Cl2 (45 ml), isobutylchloroformate (1.7 ml) is added dropwise at -12° C. After the addition, the reaction mixture is stirred for 10 minutes at the same temperature. Conc. ammonia water (7.2 ml) is added to the mixture. The mixture is stirred for 30 minutes at room temperature, and washed with saturated sodium hydrogen carbonate solution and N HCl. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 3.5 g (76%) of the titled compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CCOCC>[CH3:30][S:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CSC(CCCCO)CCCc1cccnc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSC(CCCCOS(C)(=O)=O)CCCc1cccnc1
Reaction time: 1 h

Procedure:
A solution of 0.094 g (0.29 mmol) ethyl 8-hydroxy-4-[3-(3-pyridyl)propyl]-3-thiaoctanoate in 1.5 ml methylene chloride is cooled to 0° and then 0.1 ml of triethylamine is added followed by 0.027 ml methylsulfonyl chloride. The reaction mixture is stirred at 0° for 1 h and diluted with ether. The ether layer is washed with saturated sodium bicarbonate, water, brine, then dried, filtered and evaporated to yield ethyl 8-methylsulfonyloxy-4-[3-(3-pyridyl)propyl]-3-thia-octanoate; NMR (CDCl3): delta 3.2 (s,2H), 3.1 (s,3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:65][C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:70][C:69]3[CH:71]=[CH:72][C:66]([F:65])=[CH:67][CH:68]=3)=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: Nc1ccc(F)cc1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 91.6 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (1.2 g, 2.71 mmol) in CH2Cl2 (80 mL) were added diisopropyl ethyl amine (0.96 mL, 5.5 mmol), HATU (1.044 g, 2.75 mmol) and 4-floroaniline (0.276 mL, 2.92 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (50 mL) and water (50 mL) and shaked. The layers were separated and the organic layer was washed with brine (75 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (load column with DCM, mobile phase EtOAc/Hexane) then provided the title compound as a white solid 1.33 g (92%). LC-MS m/z 536 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[N:14]([CH3:26])[C:13]([CH:15]([CH3:17])[CH3:16])=[C:12]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[N:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cccc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)c1c(Sc2cccc(Cl)c2)nc(COCc2ccccc2)n1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 2.7 %

Procedure:
In 218 g of dry dimethylformamide was dissolved 21.8 g (58.5 mmol)of 2-benzyloxymethyl-5-(3-chlorophenylthio)-4-isopropyl-iH-imidazole (16e), followed by addition of 12.2 g (88.3 mmol)of anhydrous potassium carbonate and 11.6 g (81.7 mmol)of methyl iodide, the mixture was stirred at room temperature for 7 hours. To the reaction mixture was added ice-water, and the mixture was extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate:methylene chloride=1:8). From the first eluted fraction, 620 mg (yield 3%)of 2-benzyloxymethyl-4-(3-chlorophenylthio)-5-isopropyl-1-methyl-1H-imidazole (17ab') was obtained as oil. From the latter eluted fraction, 17.6 g (yield 78%)of 2-benzyloxymethyl-5-(3-chlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (17ab)was obtained as oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
A mixture of methyl 2-{[(tert-butoxycarbonyl)amino]sulfonyl}benzoate 1a (400 mg, 1.3 mmol, 1 equiv) and lithium hydroxide (1.6 g, 39 mmol, 30 equiv) in tetrahydrofuran (10 mL) and water (2.5 mL) was stirred at RT for 18 h. The reaction was partially concentrated, acidified with 1N HCl and the product extracted into ethyl acetate. The organic layer was dried and concentrated to afford 2-{[(tert-butoxy carbonyl)amino]sulfonyl}benzoic acid (1b) as a white solid (200 mg, 51% yield). 1H NMR (300 MHz, DMSO) δ 7.94 (m, 1H), 7.71 (m, 3H), 1.26 (s, 9H). ES-LCMS m/z 300.08 (M−H).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9]Br>B(F)(F)F.O>[Br:9][C:4]1[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=1
Reactant: CSc1ccccc1
Reactant: BrBr
Agent: FB(F)F
Solvent: O
Product: CSc1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
A one-liter four-necked flask equipped with a stirrer, thermometer, dropping funnel and Liebig condenser was charged with 124.2 g (1.0 mole) of thioanisole and 0.068 g (0.001 mole) of boron trifluoride, and 160 g (1.0 mole) of bromine was added dropwise with stirring at 50° C. over 4 hours. Thereafter, the reaction was further allowed to proceed for 1 hour. After completion of the reaction, 50 g of water was added, and the organic layer was separated, whereby 203.9 g of crude 4-bromothioanisole was obtained. The purity of the thus-obtained crude 4-bromothioanisole was 90.5% as determined by gas chromatography.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22]3[C:17](=[CH:18][C:19]([O:24][CH3:25])=[CH:20][CH:21]=3)[C:16](=[O:26])[CH2:15]2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[ClH:27]>C(O)C.O>[ClH:27].[CH3:25][O:24][C:19]1[CH:18]=[C:17]2[C:22]([CH2:23][C:12]3([CH2:15][C:16]2=[O:26])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3ccccc3)CC1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)C(=O)CC1(CCNCC1)C2
Temperature: 90 °C

Procedure:
A solution of N-Benzoyl-3,4-dihydro-7-methoxyspiro-[naphthalene-3,4'-piperidine]-1-one (3.4 g, 7.8 mmole) in ethanol (100 mL) is treated with 6 N HCl (100 mL) and heated to reflux for 5 hours. The reaction is cooled to 90 ° C. and heated at this temperature for 16 hours. The reaction is cooled to room temperature, diluted with 300 mL water and extracted with two 75 mL portions of ethyl acetate. The aqueous phase is then diluted with ethanol (1 L) and concentrated at reduced pressure to dryness. The residue is crystallized from ethanol (100 mL) to give the product as the hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](OCC)=[O:12])=[CH:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2cc(F)ccc2[nH]1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 89.4 %

Procedure:
To ethyl 5-fluoro-1H-indole-2-carboxylate 45 (3.1 g, 14.96 mmol) in THF at 0° C. was added lithium aluminum hydride solution (1M, in THF 0.625 g, 16.44 mmol) dropwise and the reaction mixture was stirred for 3.5 hours at 0° C. The reaction mixture was quenched with H2O, 15% NaOH, and H2O before it was filtered and rinsed with THF. Reaction mixture was dried (anhydrous Na2SO4) and evaporation of the solvent gave 2.21 g (90% yield) of the crude (5-fluoro-1H-indol-2-yl)methanol 46 which was used directly in the next step.
Reaction SMILES: [CH3:1][Si:2]([CH3:37])([CH3:36])[O:3][C@H:4]1[CH2:27][C@@:26]2([CH3:28])[C@@H:15]([CH2:16][CH2:17][C@:18]2(OC(=O)C)[C:19](=[O:25])[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@H:14]2[C@@:5]1([F:35])[C@:6]1([CH3:34])[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C:9](=[O:33])[CH2:8][CH2:7]1.C([O-])(=O)C.[K+].CN(C)C=O>O>[CH3:37][Si:2]([CH3:1])([CH3:36])[O:3][C@H:4]1[CH2:27][C@@:26]2([CH3:28])[C@@H:15]([CH2:16][CH:17]=[C:18]2[C:19](=[O:25])[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@H:14]2[C@@:5]1([F:35])[C@:6]1([CH3:34])[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C:9](=[O:33])[CH2:8][CH2:7]1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@]12C
Reaction time: 0.5 h

Procedure:
A mixture of 8.0 g of 11β-trimethylsiloxy-17α,21-diacetoxy9αfluoro-5α-pregnane3,20-dione obtained according to Example 19, 4 g anhydrous potassium acetate and 20 ml of dimethyl formamide was heated for a period of 4 hours at 110° -120° in an atmosphere of nitrogen. The reaction mixture was cooled and poured into 120 ml of water and ice. The mixture was left stirring for 30 minutes, then lft standing for a period of 2 hours, filtered, washed on the filter with abundant water, collected and dried. Trituration of this crude product with acetone/ether gave 11β-trimethylsiloxy-21-acetoxy-9α-fluoro-5α-pregn-16-ene-3,20-dione (compound 44). Yield: 7.0 g.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[N:3]=1.[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH2:25][N:19]4[CH:18]=[CH:17][CH:16]=[C:20]4[CH2:21]3)=[O:12])=[CH:9][CH:8]=2)[N:3]=1
Reactant: Cc1ccn(-c2ccc(C(=O)Cl)cc2)n1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The 4-(3-methylpyrazol-1-yl)benzoyl chloride was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.55 g) and diisopropylethylamine (0.44 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and a saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the title compound (0.90 g) was obtained as an amorphous solid, MS, m/z: 369 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:14][S:15]SC>>[CH3:14][S:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CSSC
Reactant: O=C(O)c1ccccc1C(F)(F)F
Product: CSc1cccc(C(F)(F)F)c1C(=O)O

Procedure:
The title compound, white solid, MS: m/e=191.1 [(M−CO2H)−], was prepared in accordance with the general method of intermediate E from 2-(trifluoromethyl)benzoic acid and dimethyl disulfide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.CC(O)=O>O.O=[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccncc1
Agent: O=[Pt]=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CC1CCNCC1
Reaction time: 72 h

Procedure:
4-pyridine acetic acid (50 g, 0.314 mole) was dissolved in H2O (50 mL), and HOAc (100 mL), PtO2 (1 g) was added and the mixture was hydrogenated at 55 psi for 72 h. An additional 1 g of PtO2 was added after 48 h. The solution was filtered through celite, the cake was washed with H2O and the filtrate was evaporated, using heptane to azeotrope off excess HOAc. The 4-piperidine acetic acid was obtained as a white solid. Rf (9:1 EtOH/H2O) 0.11.1H NMR (400 MHz, CD3OD) δ3.36 (bd, 2H), 330 (bt, 2H), 2.3 (d, J=7 Hz, 2H), 2.08 (m, 1H), 1.99 (bd, 2H), 1.47 (m, 2H). This solid was dissolved in H2O (200 mL), and dioxane (200 mL), treated with triethylamine (76 mL, 0.546 mole), and di-t-butyldicarbonate (59.5 g, 0.273 mole) and stirred for 96 h. After 72 h, an additional equivalent of triethylamine and 10 g of di-t-butyldicarbonate was added. The organic solvent was evaporated and the remaining aqueous solution was brought to pH 10 with saturated NaHCO3, washed with 3×50 mL EtOAc, acidified with 10% KHSO4 to pH 2-3, extracted with 3×100 mL EtOAc, dried with MgSO4, filtered and evaporated to give 4-(N-t-butyloxycarbonyl)piperidine acetic acid. Rf (9:1 EtOH/H2O) 0.68. 1H NMR (CDCl3) δ4.1 (bs, 2H), 2.7 (bt, 2H), 2.27 (d, J=7 Hz, 1.95 (m, 1H), 2.7 (bd, 2H), 1.45 (s, 9H), 1.18 (m, 2H). This acid was reduced with borane to yield 2-(4-N-t-butyloxycarbonylpiperidine)ethanol, 1-5, as an oil. 1H NMR (400 MHz, CDCl3) δ4.08 (bd, J=12 Hz, 2H), 3.7 (t, J=6.5 Hz, 2H), 2.4 (bt, 12 Hz, 2H), 1.67 (bd, 2H), 1.6-1.45 (m, 3H), 1.45 (s, 9H), 1.12 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:4]([CH3:21])[CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.CC([O-])=O.[Na+]>CC(O)=O.C(Cl)Cl>[Br:29][C:10]1[S:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:21])[N:9]=1
Reactant: Cc1cc(Cl)ccc1-c1ncsc1-c1ccc(Cl)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1-c1nc(Br)sc1-c1ccc(Cl)cc1C
Yield: 93 %

Procedure:
A solution of 4,5-Bis(4-chloro-2-methylphenyl)thiazole (170 mg, 0.51 mmol), NBS (100 mg, 0.56 mmol) and NaOAc (82 mg, 1.0 mmol) in AcOH (5 mL) and DCM (3 mL) was stirred overnight at rt, and then quenched with water (25 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography to afford 196 mg of product.
Reaction SMILES: [S-2:1].[K+].[K+].CN(C=O)C.Cl[C:10]1[CH:29]=[CH:28][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.Cl>CC1C=CC=CC=1>[C:22]1([C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[C:13]3[CH:28]=[CH:29][C:10]([SH:1])=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [S-2]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(S)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
15 g anhydrous potassium sulfide and 100 ml DMF are added into a 250 ml three-neck flask. The solution is heated to 50° C. under stirring, and then 8 g 4-chloro-4′-phenyl benzophenone is added into the solution; the solution is heated to reflux (about 110° C.), and is cooled after 7 h; adding 100 ml methylbenzene, regulating the pH value to 5-6 with diluted hydrochloric acid, and separating the solution; the organic phase is extracted twice with 50 ml NaOH solution having a content of 5%, and the aqueous phases are mixed; the obtained aqueous phase is put into a 250 ml three-neck flask, and nitrogen is supplied to blow for 30 min, then 15% hydrochloric acid is dropped into the aqueous solution while agitating to regulate the pH value to 5-6, and light yellow solid precipitate; filtering to obtain a light yellow solid, and the weight after drying at a reduced pressure is 5.0 g, the purity is 99.11%, the yield is 63%, the melting point is 173˜176.7° C., and 1H-NMR data (solvent CDCl3): δ3.654 ppm, s, 1H; δ7.432, 7.370 ppm, d, 2H; δ7.413, 7.436 ppm, d, 1H; δ7.466, 7.491, 7.515 ppm, t, 2H; δ7.641, 7.665 ppm, d, 2H; δ7.695, 7.719 ppm, 7.743, t, 4H; δ7.850, 7.874 ppm, d, 2H.