Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4](=O)[CH2:3]1)[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[C:23](OC(=O)C)(=[O:25])[CH3:24].[OH2:30]>O1CCCC1.CN(C)C1C=CN=CC=1>[C:23]([O:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[CH2:4][CH2:3]1)[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][C:9]3=[O:30])(=[O:25])[CH3:24]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3[C@@H](O)CC(=O)[C@@]3(C)CC[C@@H]12
Reactant: O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)CC[C@H]3[C@@H](C(=O)CC4=CC(=O)CC[C@@]43C)[C@H]12
Yield: 88 %

Procedure:
According to this invention the 15α-hydroxy-androst-4-ene-3,17-dione of the formula (III) preferably is reacted with acetic anhydride in dry tetrahydrofuran in the presence of 4-dimethylaminopyridine below a temperature of 40° C., after the reaction has been completed the reaction mixture is added to water, when the precipitate is dense enough it is filtered, washed until free of mother liquor and dried. The 15α-acetoxy-androst-4-ene-3,7-dione is obtained with 88% yield. The reaction is easy-to-carry out, there are no safety and scale-up problems. The 15α-acetoxy compound obtained can be used in the next reaction step without purification.
Reaction SMILES: CN([CH2:4][CH2:5]N(C)C)C.C([Li])(CC)C.[C:14]([Si:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27]C=[C:25]([F:29])[C:24]=1[F:30])([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15].CI>C1COCC1>[C:14]([Si:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:4]([CH3:5])=[C:25]([F:29])[C:24]=1[F:30])([CH3:20])[CH3:19])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(F)c1F
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(CO[Si](C)(C)C(C)(C)C)c(F)c1F
Reaction time: 0.33 h
Yield: 105.3 %

Procedure:
To a solution of TMEDA (3.9 mL, 3.0 g, 26 mmol) in THF (33 mL) at −78° C. was added sec butyllithium (20 mL, 1.3 M in hexane, 26 mmol). After stirring for 20 minutes, a solution of tert-butyl-(2,3-difluoro-benzyloxy)-dimethyl-silane (6.0 g, 23 mmol) in 17 mL of THF was added dropwise. After stirring for 1 hour, the solution was added dropwise to a solution of methyl iodide (8 mL) in THF (40 mL) at −20° C. After stirring for 18 hours, the mixture was quenched with saturated aqueous NH4Cl, extracted 3× into ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo, giving 6.6 g of tert-butyl-(2,3-difluoro-4-methyl-benzyloxy)-dimethyl-silane as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ7.07 (app. t, 1H, J=7.2 Hz), 6.89 (app. t, 1H, J=7.3 Hz), 4.74 (s, 2H), 2.26 (d, 3H, J=1.9 Hz), 0.87 (s, 9H), 0.07 (s, 6H) ppm.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([CH3:13])=[CH:8][N:7]=1)=[O:5].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1>[NH2:12][C:11]1[C:6]([C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:5])=[N:7][CH:8]=[C:9]([CH3:13])[N:10]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1ncc(C)nc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)c2ccccc2)c(N)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-Amino-5-methyl-pyrazin-2-carboylic acid methoxy-methyl-amide (0.3 g, 1.53 mmol) is dissolved in anhydrous THF (30 ml) under N2. The clear yellow solution is cooled to −78° C., and a 1M solution of phenyl magnesium bromide in THF (7.6 ml, 7.6 mmol) is added. The resulting reaction mixture is stirred at −78° C. for 1 hour, and is then allowed to warm to room temperature and stirred for a further 2.5 hours. The reaction mixture is poured onto aq. NaHCO3 and EtOAc. The phases are separated and the aqueous layer is washed with EtOAc. The combined organic layers are washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 0-7% MeOH in DCM) yields (3-amino-5-methyl-pyrazin-2-yl)-phenyl-methanone as a yellow solid. [M+H]+ 214.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6]([OH:14])=[CH:5][C:3]1=[O:4].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6]([OH:14])=[C:5]([N+:15]([O-:17])=[O:16])[C:3]1=[O:4]
Reactant: Cc1ccc2c(c1)c(O)cc(=O)n2C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)c(O)c([N+](=O)[O-])c(=O)n2C
Temperature: 100 °C

Procedure:
To a stirred suspension of 1,6-dimethyl-4-hydroxy carbostyril (1.70g; 0.009 mole) in glacial acetic acid (10 ml) was added concentrated nitric acid (2.5 ml; d, 1.42) with swirling. The solid dissolved on warming to 100° C to give a red solution which precipitated the 3-nitro compound as yellow crystals on cooling. m.p. 185° C. (Found; C, 56.05; H, 4.33; N, 11.86%, C11H10N2O4 requires; C, 56.41; H, 4.30; N, 11.96%).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2ccccc2)CC1
Yield: 21.6 %

Procedure:
General procedure D (See Example 4) was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), benzene boronic acid (13 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative hplc (H2O, MeCN, gradient 90:10 to 10:90 over 30 min) to furnish the title compound as a white solid (6 mg, 22%), LC-MS (ESI) Rt 1.63 min, m/z 316 (100%, [M+H]+); m/z (ESI) C17H18ClN3NaO requires 338.1031 found [M+Na]+ 338.1030.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]1[CH2:12][C@@H:11]([CH3:13])[N:10]([CH2:14][C@H:15](O)[CH:16]=[CH:17][C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:9]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[C:29]([OH:33])(=[O:32])[CH2:30]C.[CH2:34](C(CC)(CC)C([O-])([O-])[O-])[CH3:35]>C(OCC)(=O)C>[CH2:34]([O:33][C:29](=[O:32])[CH2:30][C@@H:17]([C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:16]=[CH:15][CH2:14][N:10]1[C@H:11]([CH3:13])[CH2:12][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[C:9]1=[O:27])[CH3:35]
Reactant: COc1ccc(C=C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]2C)cn1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CCC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](C=CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)c1ccc(OC)nc1
Temperature: 25 °C

Procedure:
A stirred solution of 4-5 (400 mg) and propionic acid (5 mg) in triethylorthoacetate (5 mL) was heated at 130° C. for 2 hours, then cooled to ambient temperature, The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, and filtered. Following evaporative removal of the solvent, the residue was purified by flash column chromatography (silica gel, 7:3 ethyl acetate/hexanes) to give 4-6 as a colorless oil.
Reaction SMILES: Cl.[C:2]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])(=[O:4])[NH2:3].[CH2:24]([O:26][C:27]1[CH:32]=[C:31]([CH:33]=O)[CH:30]=[C:29]([O:35][CH2:36][CH3:37])[C:28]=1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[CH3:25].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[C:2]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:10]([NH:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:33][C:31]2[CH:30]=[C:29]([O:35][CH2:36][CH3:37])[C:28]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=2)[CH2:17][CH2:18]1)=[O:11])(=[O:4])[NH2:3]
Reactant: COc1cc(OCC(N)=O)cc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC(N)=O)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 50k), 3-carbamoylmethoxy-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride (example 250b) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 580.2 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:46]=[CH:47][CH:48]=1)[C:24]([NH:26][C:27]1[C:28]([N:37]2[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44]O)[CH2:39][CH2:38]2)=[N:29][CH:30]=[C:31]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:32]=1)=[O:25].C(Br)(Br)(Br)[Br:50]>C(Cl)Cl>[Br:50][CH2:44][CH2:43][CH:40]1[CH2:41][CH2:42][N:37]([C:28]2[C:27]([NH:26][C:24](=[O:25])[C:23]3[CH:46]=[CH:47][CH:48]=[C:21]([Cl:20])[CH:22]=3)=[CH:32][C:31]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:30][N:29]=2)[CH2:38][CH2:39]1
Reactant: BrC(Br)(Br)Br
Reactant: CS(=O)(=O)c1cnc(N2CCC(CCO)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cnc(N2CCC(CCBr)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a mixture of 0.300 g (1.14 mmol) of triphenylphosphine, and 0.500 g (1.14 mmol) of 3-chloro-N-[4-(2-hydroxy-ethyl)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]benzamide in methylene chloride (20 mL), cooled to 0° C., is added 0.380 g (1.14 mmol) of carbon tetrabromide in multiple portions. The mixture is warmed to room temperature and stirred overnight then concentrated under reduced pressure and the residue purified by flash silica gel chromatography to provide 0.285 g (50% yield) of N-[4-(2-bromo-ethyl)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-3-chloro-benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[CH:10]1([CH2:13][OH:14])[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([O:14][CH2:13][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: OCC1CC1
Reactant: Fc1cc(Br)cnc1F
Product: Fc1cc(Br)cnc1OCC1CC1

Procedure:
Following Typical Procedure 6, reaction of 5-bromo-2,3-difluoro-pyridine with cyclopropyl-methanol provided the subtitle compound. MS ESI+: m/z=246 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])C.O.[NH2:14][NH2:15]>C(O)C>[O:11]=[C:7]1[N:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[CH2:10][CH2:9][O:8]1
Reactant: NN
Reactant: CCOC(=O)CN1CCOC1=O
Solvent: O
Solvent: CCO
Product: NNC(=O)CN1CCOC1=O
Yield: 77 %

Procedure:
As described for example 112a, (2-oxo-oxazolidin-3-yl)-acetic acid ethyl ester (Potts, Kevin T.; Bhattacharjee, Debkumar; Kanemasa, Shuji. Journal of Organic Chemistry (1980), 45(24), 4985-8.) in ethanol was reacted with hydrazine hydrate (1 equivalent) at rt for 72 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 77%). MS: m/e=160.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[S:25]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cc(Cl)ccc3Cl)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 g of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine in 100 ml DCM and 4 ml pyridine, 11.6 g of 2,5-dichloro-benzenesulfonyl chloride were added, and the reaction mixture was stirred for 16 h at RT. Then, the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/EtOAc. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 17.9 g.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.Cl[CH2:7][N:8]([CH3:13])[S:9]([Cl:12])(=[O:11])=[O:10]>C1C=CC=CC=1>[CH3:1][O:2][CH2:7][N:8]([CH3:13])[S:9]([Cl:12])(=[O:11])=[O:10]
Reactant: C[O-]
Reactant: CN(CCl)S(=O)(=O)Cl
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COCN(C)S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 13.5 parts of sodium methylate in 110 parts of methanol is added, in the course of 15 minutes at from 0 to 5° C., to a mixture of 44.5 parts of N-chloromethyl-N-methylsulfamic acid chloride in 260 parts of benzene. The reaction mixture is then stirred for 2 hours at 25° C., after which the sodium chloride which has precipitated is filtered off. After removing the solvent under reduced pressure, distillation gives 29.1 parts (67% of theory) of N-methoxymethyl-N-methylsulfamic acid chloride of boiling point 84-87° C./12 mbar and nD25 = 1.4536.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)CCC.Cl[C:21]1[S:22][CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]>>[N+:26]([C:25]1[CH:24]=[CH:23][S:22][C:21]=1[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)([O-:28])=[O:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: O=[N+]([O-])c1ccsc1-c1cnccn1

Procedure:
The title compound was prepared from 2-(tributylstannyl)pyrazine and 2-chloro-3-nitrothiophene using protocol E and was purified by flash chromatograpy (hexane:ethyl acetate). Method [7] Retention time 2.38 min by HPLC (MH+ 208).
Reaction SMILES: C(NC([C:8]1[CH:25]=[CH:24][C:11]2[NH:12][C:13]([C:15]3[C:23]4[C:18](=CC=CC=4)[NH:17][N:16]=3)=[N:14][C:10]=2[CH:9]=1)=O)C(C)C.C1(N)C=CC=CC=1N.S(=O)(O)[O-].[Na+]>CN(C)C=O>[NH:17]1[CH:18]=[CH:23][C:15]([C:13]2[NH:12][C:11]3[CH:24]=[CH:25][CH:8]=[CH:9][C:10]=3[N:14]=2)=[N:16]1
Reactant: CC(C)CNC(=O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Agent: Nc1ccccc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(-c3cc[nH]n3)nc2c1
Temperature: 25 °C
Yield: 121.5 %

Procedure:
A mixture of 1H-pyrazole-3-carbaldehyde (0.961 g, Reference Example 10), o-phenylenediamine (0.973 g), sodium bisulfite (1.898 g) and dry dimethylformamide (10 mL) was stirred at reflux for 2 hours, then cooled to room temperature and then poured onto cracked ice (35 g). The mixture was filtered and the solid was washed with aqueous sodium bicarbonate and then with water. The solid was vacuum dried at 70° C. and then recrystallised from ethanol to give 2-(1H-pyrazol-3yl)-1H-benzoimidazole (0.645 g) as a pale yellowish solid, mp 335-338° C. [Elemental analysis:—C, 62.56%; H, 4.04%; N, 29.14%. Calculated for C10H8N4:—C, 65.19%; H, 4.39%; N, 30.42%].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:36]=[CH:37][C:38]=1[OH:39])[O:7][CH2:8][CH2:9][N:10](CC1C=CC=CC=1)[CH2:11][CH:12]([OH:28])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:17][CH:16]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH:36]=[CH:37][C:38]=1[OH:39])[O:7][CH2:8][CH2:9][NH:10][CH2:11][CH:12]([OH:28])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:17][CH:16]=1)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(CCOCC3CC3)cc2)ccc1O
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNCC(O)COc2ccc(CCOCC3CC3)cc2)ccc1O

Procedure:
A solution of 30 g of crude 1-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-benzylamino]-3-[4-[2-(cyclopropylmethoxy)-ethyl]-phenoxy]-2-propanol in 600 ml of methanol is hydrogenated, with the addition of 4 g of a Pd/C catalyst (5%), under normal conditions until 1 mol-equivalent of hydrogen has been absorbed. By the addition of dioxane and by heating, the product which has already crystallised out is taken into solution; the catalyst is filtered off and the filtrate is concentrated by evaporation. Recrystallisation from isopropanol and then from methanol yields pure 1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-3-[4-[2-(cyclopropylmethoxy)-ethyl]-phenoxy]-2-propanol, m.p. 149°-150°.
Reaction SMILES: [CH3:1][CH:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:38][C:39](=[O:41])[CH3:40])[CH2:25][C@@H:26]2[O:34][C:35](=[O:37])[CH3:36])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[Br-:42].[Li+]>CC(C)=O>[Br:42][CH2:3][CH:2]([CH3:1])[C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:38][C:39](=[O:41])[CH3:40])[CH2:25][C@@H:26]2[O:34][C:35](=[O:37])[CH3:36])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1
Reactant: [Br-]
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1

Procedure:
To a solution of 51 mg of 20-methyl-1α,3β-diacetoxy-21-p-toluenesulfonyloxypregna-5,7-diene in 5 ml of acetone was added 100 mg of lithium bromide and the mixture was heated under reflux for 10 hours. The same isolation and purification procedure in Example 47 gave mg of 21-bromo-20-methyl-1α,3β-diacetoxypregna-5,7-diene, whose 1H NMR spectrum was identical with that obtained in Example 12.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[NH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]([N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])=[CH:18][C:13]=2[N:12]=[C:11]1[NH:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1.[O:43]1C[CH:44]1[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])O>C(#N)C.ClCCl>[OH:43][CH:44]([NH:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]([N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:20])=[CH:18][C:13]=2[N:12]=[C:11]1[NH:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCN)cc(OC)c1OC
Reactant: c1ccc(CC2CO2)cc1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCNC(O)Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
Lithium perchlorate (16 mg, 3 eq) then after 5 minutes 1-(2-aminoethyl)-N,N-diisobutyl-2-[(3,4,5-trimethoxy phenyl)amino]-1H-benzimidazole-5-carboxamide (25 mg, 1 eq) are added, at a temperature of approximately 20° C. to a solution of 2,3-epoxypropylbenzene (7 mg, 1 eq) in acetonitrile (0.5 ml). The mixture is heated under reflux for 24 hours then cooled down to ambient temperature and hydrogen carbonate and dichloromethane saturated water is added. After decanting and extracting, the organic phases are combined and washed with salt water, followed by drying over sodium sulphate and evaporating under reduced pressure at 40° C. Purification of the oil obtained by flash chromatography on silica gel (100% dichloromethane to dichloromethane/methanol 80:20) produces the expected compound in the form of an oil (31 mg, 55% yield)
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=1
Reactant: C1=COCCC1
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc(OCCCCCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3,4-Dihydro-2H-pyran (24.7 g) was added drop wise at room temperature to a solution of 4[(6-hydroxyhexyl)oxy]benzoic acid (35 g), toluene-4-sulfonic acid monohydrate (1.8) in diethylether (440 ml) and stirred at room temperature for 18 h. The resulting mixture was filtered over Hyflo Super Cel (FLUKA), organic solvents were removed in vacuum. The residue (60 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (1:1) as eluent, to give after crystallisation from ethyl acetate/hexane (5:40) 4{[6(tetrahydro-2H-pyran-2-yloxy)hexyl]oxy}benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19](=O)[C:20]([F:23])([F:22])[F:21])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:25][NH2:26].O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)=[N:25][NH:26][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(=O)C(C(=O)C(F)(F)F)c2ccc(F)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 89 %

Procedure:
Crude 2-(4-fluorophenyl)-1-[4-(methylthio)phenyl]-4,4,4-trifluoro-1,3-butanedione (Example 3, Step 2) (1.0 g) was reacted with anhydrous hydrazine (0.13 g) in glacial acetic acid. The mixture was held at 80°-110° C. for 18 hours and poured into water. The resulting solid precipitate was filtered, purified by HPLC and recrystallized from methylene chloride-hexane to give 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-5-(trifluoromethyl)-1H-pyrazole as a solid (0.88 g, 89%): mp 189°-190° C.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]([O:9][C:10](=[O:22])[NH:11][C@:12]([C:16](=[O:21])N(OC)C)(C)[CH2:13][CH3:14])([CH3:8])([CH3:7])[CH3:6].O1CCC[CH2:24]1>>[C:5]([O:9][C:10](=[O:22])[NH:11][C@H:12]([CH:13]([CH3:14])[CH3:24])[C:16](=[O:21])[CH:1]=[CH2:2])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reactant: C=C[Mg]Br
Reactant: C1CCOC1
Product: C=CC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Yield: 64 %

Procedure:
Tetrahydrofuran (THF, 100 mL) and a 1.0M solution of vinyl magnesium bromide in THF (360 mL. 360 mmol. 3.1 equiv) was cooled to −78° C. while stirring under a nitrogen atmosphere. The mixture was treated dropwise with a solution of [(R)-(methoxy-methyl-carbamoyl)-methyl-propyl]-carbamic acid tert-butyl ester (30.3 g, 116 mmol. 1 equiv) in THF (50 mL) over 30 min. After the resultant dark yellow mixture was stirred for 30 min at −78° C., the cooling bath was removed and the reaction mixture was warmed slowly to room temperature overnight (15 h). The reaction mixture was poured slowly into an ice-chilled solution of 1N aqueous hydrochloric acid (700 mL) and then warmed to room temperature. The organics were extracted with (3×600 mL) ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography (5-10% ethyl acetate/hexanes) provided the product as a white solid (16.8 g, 64%). ESMS [M+H]+: 228.4.