Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25](SC)=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:53][NH2:54]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25]([NH:54][CH3:53])=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccccc3)c(F)cc1C)C2
Reactant: CN
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccccc3)c(F)cc1C)C2
Yield: 66 %

Procedure:
Using a procedure analogous to Example A2, the sulfide was oxidized with mCPBA to the sulfone and then treated with methylamine to provide 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea (0.163 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.85 (brs, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.52 (m, 3H), 7.42 (m, 1H), 7.18 (d, J=12 Hz, 1H), 7.02 (m, 1H), 6.38 (s, 1H), 4.53 (d, J=14 Hz, 1H), 4.33 (d, J=14 Hz, 1H), 3.25 (brs, 3H), 2.78 (d, J=5 Hz, 3H), 2.04 (s, 3H), 1.25 (s, 9H); MS (ESI) m/z: 558.3 (M+H+).
Reaction SMILES: F[B-](F)(F)F.C(OCC=C)(=O)C.C([SiH](CC)CC)C.[CH2:20]([Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:21]=C>C1(C)C=CC=CC=1>[CH2:20]([Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:21]
Reactant: C=CC[Si](CC)(CC)CC
Agent: C=CCOC(C)=O
Agent: CC[SiH](CC)CC
Agent: F[B-](F)(F)F
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)CC
Reaction time: 1 h
Yield: 5 %

Procedure:
In a reactor were placed bis(1,5-cyclooctadiene)iridium tetrafluoroborate [Ir(cod)2]+BF4− (0.05 mmol), allyl acetate (20 mmol), and toluene (3 ml). The mixture was raised in temperature to 80° C. in a nitrogen atmosphere, triethylsilane (Et3SiH)(5 mmol) was added thereto over one hour, and a reaction was conducted at 80° C. for one hour. After the reaction, the reaction mixture was analyzed by gas chromatography to find that allyltriethylsilane was produced in a yield of 54% and tetraethylsilane was by-produced in a yield of 5%.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[CH3:22].B(Br)(Br)Br.COC1C=C2C(=CC=1)N(CC1C=CC=CC=1)C(C)=C2CC(O)=O.Cl>C(Cl)Cl.CCO>[OH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]([CH3:22])=[C:5]2[CH2:4][C:3]([OH:23])=[O:2]
Reactant: COC(=O)Cc1c(C)n(Cc2ccccc2)c2ccc(O)cc12
Agent: BrB(Br)Br
Agent: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: Cc1c(CC(=O)O)c2cc(O)ccc2n1Cc1ccccc1
Reaction time: 17 h
Yield: 100 %

Procedure:
5-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid methyl ester. Three mL (30 mmol) of BBr3 was added to 3.1 g (10 mmol) of 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid in 250 mL of CH2Cl2 and the mixture stirred for 17 hours. After stirring with 1N HCl, some EtOH was added, the organic layer separated, washed with a saturated NaCl solution, dried and concentrated at reduced pressure to give 2.95 g (100% yield) of crude 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid. A methanol solution of 1.7 g of he material was treated with sulfuric acid as described in Part A to give after silica gel chromatography (30% ether/hexane→60% ether/hexane) 1.5 g of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid methyl ester.
Reaction SMILES: [CH:1]([O:4][C:5]([CH:7]([NH2:17])[CH:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C>O.C(O)(C)C>[CH:1]([O:4][C:5]([CH:7]([NH2:17])[C@@H:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)CC(CC(=O)O)C(N)C(=O)OC(C)C
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](CC(=O)O)C(N)C(=O)OC(C)C
Temperature: 57.5 °C
Yield: 61.1 %

Procedure:
A 500 ml three-necked round-bottom flask, under nitrogen atmosphere, is added with raceme 3-(isopropoxycarbonyl-amino-methyl)-5-methyl-hexanoic acid (44.2 g, 0.180 moles), triethylamine (8.20 g, 0.081 moles) and (S)-(−)-phenyl-ethylamine (12.00 g; 0.099 moles) in a 95:5 water/isopropanol mixture (200 ml) heated at 55-60° C. The mixture is spontaneously left to cool to room temperature, then it is cooled to 0-5° C. for at least 1 h. The solid is filtered off and washed with cool water (2×20 ml) and then with cool toluene (4×20 ml), it is dried in oven at 55-60° C. for 16-18 h. 27.0 g of white solid are obtained with an enantiomer ratio of 99:1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.O.FC(F)(F)[C:29](O)=[O:30]>>[C:1]([O:4][C:5]1[C:6]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:8]([OH:11])=[C:9]([CH:10]=1)[CH:29]=[O:30])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(O)cc1C(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(=O)Oc1cc(C=O)c(O)cc1C(C)(C)C
Yield: 52 %

Procedure:
To 6.25 g of 4-acetoxy-3-t-butylphenol dissolved in 15 ml of trifluoroacetic acid was added 4.63 g of hexamethylenetetramine and the mixture was heated under reflux for 1 hour. The reaction mixture was allowed to attain room temperature, then poured into water and extracted with ethyl acetate. The organic layers were successively washed with a 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 20% ethyl acetate) to give 3.68 g of 5-acetoxy-4-t-butyl-2-hydroxybenzaldehyde as a pale yellow oil (52%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[NH:9][CH:8]=1)=[N+:2]=[N-:3].CC([O-])(C)C.[K+].[Cl:23][C:24]1[N:25]=[C:26]2[N:30]([C:31]=1[S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:28][S:27]2>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([S:32]([C:31]2[N:30]3[C:26]([S:27][CH:28]=[CH:29]3)=[N:25][C:24]=2[Cl:23])(=[O:33])=[O:34])[CH:8]=1)=[N+:2]=[N-:3]
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: [N-]=[N+]=NCCCc1c[nH]c2ccc(F)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccc(F)cc12
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A stirred solution of 3-(3-azidopropyl)-5-fluoro-1H-indole (150 mg, 0.53 mmol) in THF is treated with KOt-Bu (0.55 ml, 0.55 mmol, 1M in THF solution) under nitrogen at room temperature, stirred for 30 min, treated with 6-chloroimidazo[2,1-b]thiazole-5-sulfonylchloride (141 mg, 0.55 mmol), stirred for 18 h at room temperature, quenched with 1N HCl and water and diluted with EtOAc. The two phases are separated and the aqueous phase is extracted with EtOAc. The extracts are combined with the organic phase and are dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane: 3/7) to give the title product as a yellow solid, 203 mg (88% yield), mp 84–86° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]=[N:7][N:6]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].[ClH:22]>C1C=CC=CC=1>[ClH:22].[C:17]([NH:21][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]=[N:7][N:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: c1ccc(-n2nnnc2OCC2CO2)cc1
Agent: Cl
Solvent: c1ccccc1
Product: CC(C)(C)NCC(O)COc1nnnn1-c1ccccc1

Procedure:
2,3-Epoxy-1-[(1-phenyl-5-tetrazolyl)oxy]propane (43.7 g., 0.20 mole) was heated at the reflux temperature in 150 ml. of tert.-butylamine and 300 ml. of benzene for 9 hours. The solvents were evaporated in vacuo and the residual oil was dissolved in 100 ml. of EtOH and acidified with ethanolic HCl. Dilution with diethyl ether gave 44.8 g. of the hydrochloride of the product, m.p. 73°-82°. Recrystallization from i-PrOH-IPE gave 30.8 g., m.p. 152.5°-154.5° (corr.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][N:11]([CH2:13]N(C)C)[CH3:12]>O1CCOCC1>[CH3:10][N:11]([CH2:13][C:3]1[C:2]([OH:1])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:12]
Reactant: CN(C)CN(C)C
Reactant: N#Cc1cccc(O)c1
Solvent: C1COCCO1
Product: CN(C)Cc1c(O)cccc1C#N

Procedure:
A mixture of 3-hydroxybenzonitrile (20.0 g) and N,N,N',N'-tetramethyldiaminomethane (22.9 ml) in 1,4-dioxane (200 ml) was heated on a steam bath for 48 hours. The mixture was evaporated to dryness and the residue dissolved in 2M hydrochloric acid. The solution was washed with ethyl acetate and then the acidic layer was basified with concentrated sodium hydroxide solution and extracted with dichloromethane to give an oil which was purified by column chromatography on silica to give 2-dimethylaminomethyl-3-hydroxybenzonitrile. The structure was confirmed by 1H NMR spectroscopy.
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][CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)/[C:9]1=[O:34])=C)(C)(C)C.[F:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:51])=[C:40]([CH:42]=[N:43][C:44]([O:46][Si](C)(C)C)=[CH2:45])[CH:41]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:34])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[CH2:45][C:44](=[O:46])[NH:43][CH:42]3[C:40]3[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=3[CH3:51])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(OC(C)(C)C)N1C(=O)/C(=C\c2cc(Cl)ccc2OCC2CCOCC2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC2CCOCC2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 33.2 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-1-(1-tert-butoxy-vinyl)-6-chloro-3-[5-chloro-2-(tetrahydro-pyran-4-ylmethoxy)-benzylidene]-1,3-dihydro-indol-2-one (2 g, 3.97 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (20 mmol) in toluene to give the title compound as a white solid (770 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>S(=O)(=O)(O)O.O1CCOCC1>[Cl:2][C:3]1[C:4]2[NH:10][C:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][C:15]=3[C:5]=2[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2,4-Dichlorophenyl hydrazine hydrochloride (1 equiv.) is taken in 7% sulfuric acid in 1,4-dioxan. N-Methylpiperidine-4-one (0.76-1.4 equiv.) is added and the contents are stirred at RT for 15 min., followed by heating at 80° C. for 14 h. After completion of the reaction, as monitored by LCMS, the solvent is removed in vacuo, basified with saturated aq. NaHCO3 and extracted with EtOAc. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated. The resulting crude product is purified by column chromatography to afford 6,8-dichloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:15][N:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-]>N1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[N:15][N:16]4[CH:21]=[CH:20][C:19]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccn2nc(-c3ccc(F)cc3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccn2nc(-c3ccc(F)cc3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine (60 mg, 0.15 mmol) in anhydrous pyridine (5 mL) was added methylsulfonyl chloride (36 mg, 0.3 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, then saturated aquous bicarbonate was added. The phases were separated, the organic phase was washed with water, brine and dried (magnesium sulfate). Filtration and concentration, followed by flash chromatography (1:1 ethyl acetate-hexane) gave N-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]methanesulfonamide (35 mg, 50%) as a solid. 1H-NMR (CDCl3): δ 8.42 (d, 1H), 8.15 (d, 1H), 8.05 (d, 1H), 7.60 (q, 2H), 7.13 (t, 2H), 6.90 (dd, 1H), 6.30 (d, 1H), 5.34 (d, 1H), 4.30 (m, 1H), 3.12 (s, 3H), 1.5–2.2 (m, 8H); 19F-NMR (CDCl3): δ −112.64; MS m/z 467 (M+1).
Reaction SMILES: [C:1]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1O>>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:17][CH2:16][CH:15]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:8][CH:9]=1)=[O:33]
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(I)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccccc2Cl)NS(=O)(=O)c2ccc(I)cc2)cc1
Yield: 63.1 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(carbethoxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (430 mg) was reacted with 2-chlorophenol (163 mg) to obtain (RS)-3-(2-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)propanamide (285.8 mg).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([NH2:29])=[S:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]2[S:28][CH:2]=[C:3]([CH2:4][O:5][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]4)[N:29]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: NC(=S)Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(CBr)COc1ccc2c(c1)CCC(=O)N2
Solvent: CCO
Product: O=C1CCc2cc(OCc3csc(Nc4ccc(Cl)c(Cl)c4)n3)ccc2N1
Yield: 23.6 %

Procedure:
To a stirred solution of 6-(3-bromo-2-oxopropoxy)-3,4-dihydroquinolin-2(1H)-one (0.15 g, 0.503 mmol) in ethanol (3 mL) was added 1-(3,4-dichlorophenyl)thiourea (0.133 g, 0.604 mmol). The reaction mixture was refluxed for 12 h, then concentrated and purified by preparative HPLC to afford a white solid (0.05 g, 24%). 1H NMR 400 MHz, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.85 (t, J=8.00 Hz, 2H), 4.99 (s, 2H), 6.80 (d, J=8.80 Hz, 1H), 6.87 (q, J=2.80 Hz, 1H), 6.92 (d, J=2.40 Hz, 1H), 6.98 (s, 1H), 7.48-7.49 (m, 2H), 8.06 (d, J=2.00 Hz, 1H), 9.92 (s, 1H), 10.56 (s, 1H). LCMS: RT 1.99 min; LCMS (ES-API), m/z 420. LCMS: RT 1.99 min; LCMS (ES-API), m/z 420.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][CH2:11][CH2:12]O)[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4].C[CH2:23][N:24](CC)CC.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:23]([CH2:12][CH2:11][O:10][C@H:8]1[CH2:7][N:6]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:5]([C:3]([N:2]([CH3:1])[CH3:21])=[O:4])[CH2:9]1)#[N:24]
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](OCCO)CN1C(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@@H]1C[C@@H](OCCC#N)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of 3.00 g of the compound obtained in Step 143-2 and 2.01 g of Et3N in CHCl3 (30 ml) was added 1.36 g of methane sulfonyl chloride under ice cooling and the reaction mixture was stirred at room temperature for one hour. To the solution was added a saturated aqueous solution of NaHCO3 and the resulting mixture was extracted with EtOAc; the organic layer was washed with saturated brine and dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in MeCN (40 ml) was added 2.58 g potassium cyanide and 260 mg of 18-crown-6-ether, and the reaction mixture was refluxed for two hours. To the solution was added water and the resulting mixture was extracted with EtOAc; the organic layer was washed with saturated brine and dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: EtOAc) obtained 1.22 g of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1.[CH2:16](O)[CH3:17]>>[CH2:16]([O:14][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1)=[O:15])[CH3:17]
Reactant: CCO
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Thionyl chloride (0.80 ml, 11 mmol) was added dropwise to a suspension of the HCl salt of 1-methyl-piperidine-4-carboxylic acid (1.80 g, 10 mmol) in ethanol (25 ml). The reaction mixture was stirred at ambient temperature overnight, then reduced in vacuo and dried by azeotrope with toluene (×3) to give 1-methyl-piperidine-4-carboxylic acid ethyl ester as a colourless solid (1.7 g, 100%). (LC/MS: Rt 0.41, [M+H]+ 172.08).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([O:14]C)=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.BrC1C=CC(CN)=CC=1.N.Cl>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[CH3:24])=[CH:19][CH:18]=1
Reactant: CC(N)c1ccc(Br)cc1
Reactant: COC(=O)Cc1cccc2cnccc12
Agent: Cl
Agent: N
Agent: NCc1ccc(Br)cc1
Product: CC(NC(=O)Cc1cccc2cnccc12)c1ccc(Br)cc1

Procedure:
The title compound was prepared using the procedure described in Example 132C using the product from Example 133B and 1-(4-bromophenyl)ethanamine instead of the product from Example 132B and 4-bromobenzylamine. 1H NMR (300 MHz, d6-DMSO) 9.81 (s, 1H), 9.00 (d, 1H), 8.70 (d, 1H), 8.48 (d, 1H), 8.40 (d, 1H), 8.04 (d, 1H), 7.92 (m, 1H), 7.51 (d, 2H), 7.23 (d, 2H), 4.84 (m, 1H), 4.10 (s, 2H), 1.35 (d, 3H). MS (DCI/NH3) m/e 369 (M+H)+; Anal. Calcd. For C19H17N2OBr.1.0 HCl.1.0H2O: C, 53.86; H, 4.76; N, 6.61. Found: C, 53.47; H, 4.53; N, 6.76.
Reaction SMILES: [O:1]=[C:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[OH:1][CH:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1
Reactant: O=C1CCC2=C(C1)c1ccccc1Oc1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OC1CCC2=C(C1)c1ccccc1Oc1ccccc12

Procedure:
6.2 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added to a suspension of 3.7 g of lithiumaluminiumhydride in 300 ml of dry ether. After refluxing for 2 hours 14.8 ml of water are added carefully. The suspension obtained is filtered off and after that the filtrate is dried and evaporated to dryness.
Reaction SMILES: C(N(N=O)[C:9](=[O:34])[CH:10]([N:16]1[C:20]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=2[N:18]=[C:17]1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.[OH2:37].[OH-].[Li+].OO.Cl>O1CCCC1.O.C(OCC)(=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:17]2[N:16]([CH:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[C:9]([OH:37])=[O:34])[C:20]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=3[N:18]=2)=[CH:32][CH:31]=1
Reactant: O=NN(Cc1ccccc1)C(=O)C(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: O
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a ice-cold suspension of 8.10 g (15.91 mmol) N-benzyl-N-nitroso-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopentyl-acetamide in 45 ml tetrahydrofuran and ml water were added dropwise over 30 min. a solution of 6.68 g (159 mmol) lithium hydroxide monohydrate in 32.50 ml (318 mmol) 30% hydrogen peroxide solution and 15 ml water. After stirring for 4.5 h at room temperature, 150 ml water and 100 ml ethyl acetate were added and the pH adjusted to 1 using 25% aqueous hydrochloric acid. The phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, then dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate:methanole (100:0:0 to 0:100:0 to 0:85:15). Off-white solid (55%). MS (Turbo Spray): m/z=391.1 [M+H].
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH2:9][CH2:10][CH2:11][O:12]/[N:13]=[C:14]1/[C:15]([CH3:37])([CH3:36])[C@@:16]2([OH:35])[C@:29]([CH3:32])([CH2:30][CH2:31]/1)[C@@H:28]1[C@H:19]([C@H:20]3[C@@:24]([CH2:26][CH2:27]1)([CH3:25])[C@@H:23]([OH:33])[CH2:22][CH2:21]3)[CH2:18][C@@H:17]2[OH:34].C1C(=O)N(Br)C(=O)C1.C1COCC1>O1CCOCC1.O.[Cl-].[Na+].O>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH2:9][CH2:10][CH2:11][O:12]/[N:13]=[C:14]1/[C:15]([CH3:37])([CH3:36])[C@@:16]2([OH:35])[C@:29]([CH3:32])([CH2:30][CH2:31]/1)[C@@H:28]1[C@H:19]([C@H:20]3[C@@:24]([CH2:26][CH2:27]1)([CH3:25])[C:23](=[O:33])[CH2:22][CH2:21]3)[CH2:18][C@@H:17]2[OH:34]
Reactant: CC1(C)/C(=N/OCCN)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@H](O)[C@@]12O
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C1CCC(=O)N1Br
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC1(C)/C(=N/OCCN)CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)CC[C@H]4[C@@H]3C[C@H](O)[C@@]12O
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
To a stirred solution of (E)-3-(2-aminoethoxyimino)-4,4-dimethylandrostane-5α,6α,17β-triol (Example 16, 109 mg) in dioxane (3.5 ml) and water (0.4 ml), NBS (112 mg) was added. After 5 h THF (15 ml) and brine (20 ml) were added and the mixture stirred for 10 min. The phases were separated and the aqueous phase was extracted with THF. The combined organic extracts were washed with aqueous NaHSO3, brine, dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (SiO2, DCM/MeOH/26% NH4OH 90/10/1). To the concentrated fractions a stoichiometric amount of fumaric acid in MeOH was added and evaporated to dryness. The residue was triturated with Et2O for 0.5 h and the precipitate was filtered to give the title compound as a white solid (58 mg, 55%).