Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:22]1[CH2:31][C@H:30]([OH:32])[CH2:29][C@H:23]1[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:12]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=1[O:20][CH3:21].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[C:37]([O:45][C:46]([F:49])([F:48])[F:47])[CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:41]([C:38]1[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][C:37]=1[O:45][C:46]([F:47])([F:48])[F:49])(=[O:43])=[O:42])[C:6](=[O:11])[C:5]2([N:22]1[CH2:31][C@H:30]([OH:32])[CH2:29][C@H:23]1[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:12]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: COc1ccc(C=O)cc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 10.9 g of the compound obtained in Step 198-2 and 6.63 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 6.76 g of a mixture of two species of diastereoisomers of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23].[BH4-].[Na+]>C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH:22]([OH:23])[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(C(=O)c3cccnc3)sc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(C(O)c3cccnc3)sc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[(3-hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-[(pyridin-3-yl)carbonyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.35 g, Example 37) in dry ethanol (40 ml) at 0° C. was added sodium borohydride (0.03 g). The reaction was allowed to warm to room temperature and stirred for 2 hours. The solution was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-5% ethanol in dichloromethane to give the title compound as a white foam. (0.27 g).
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][CH:5]([C:7](=[CH2:13])[C:8](OCC)=[O:9])[CH3:6]>C(O)C>[OH:4][CH:5]([CH:7]1[CH2:13][NH:3][NH:2][C:8]1=[O:9])[CH3:6]
Reactant: C=C(C(=O)OCC)C(C)O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(O)C1CNNC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To hydrazine hydrate (38.6 g) was added dropwise a solution of ethyl 2-(1-hydroxyethyl)acrylate (106 g) in ethanol (20 ml) at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 4 hours at the same temperature. The resulting reaction mixture was chromatographed on silica gel (2.2 l) eluting in turn with chloroform and a mixture of chloroform and methanol (8:1→2:1→1:1, V/V) to give 4-(1-hydroxyethyl)-3-pyrazolidinone (68 g).
Reaction SMILES: CCC(CCCCC(NC(C(NC(C(NC(C(NC1C(=O)NC(CCN)C(=O)NC(C[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)C(=O)NC(CC(C)C)C(=O)NC(CCN)C(=O)NC(CCN)C(=O)NC(C(O)C)C(=O)NCC1)=O)CCN)=O)C(O)C)=O)CCN)=O)C.OS(O)(=O)=O.[Cl:91][S:92]([OH:95])(=[O:94])=[O:93]>O>[S:92]([Cl:91])([OH:95])(=[O:94])=[O:93].[Cl:91][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(Cc2ccccc2)NC(=O)C(CCN)NC1=O)C(C)O
Agent: O=S(=O)(O)Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Clc1ccccc1

Procedure:
adding said reaction mixture to water or diluted sufuric acid to decompose said excess chlorosulfonic acid and to form a chlorobenzene sulfochloride layer and a sulfuric acid layer having a sulfuric acid concentration of from 60 to 90% after completion of said decomposition, said decomposition being carried out at a temperature of from 50° to 85° C., and driving off remaining hydrogen chloride from the system; and
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)O.C(OS(C1C=CC=CC=1)(=O)=O)CCCCCCCCCCC.[Na].C1(C)C=CC=CC=1.[ClH:43]>O>[Cl:43][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: Cl
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CCl)o1
Reaction time: 7 h

Procedure:
Five grams of a commercially available D-glucose and 97.6 mg of sodium laurylbenzenesulfonate were added to the same three-necked flask. Then, 5 ml of water and 30 ml of toluene were added thereto and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride was passed through the mixture at room temperature for about 25 minutes. Stirring was continued at 50° C. for a further 7 hours. The reaction solution was diluted with a little water and filtered through Celite while being washed with toluene. The upper toluene layer was neutralized, dried and concentrated to obtain about 1.4 g of 5-chloromethylfurfural.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@H:12]1[CH2:16][O:15][C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:13]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH2:1]([O:8][C@@H:9]([C@H:12]1[CH2:16][O:15][C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:13]1)[CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=C[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A solution of 4.30 g (0.015 mmol) of α(S)-benzyloxy-1,4-dioxaspiro[4,5]decane-2(R)-acetaldehyde in 50 ml of anhydrous diethyl ether was cooled to -8° C. and 15 ml of a 2M solution of phenylmagnesium chloride in tetrahydrofuran were added dropwise over a period of 1 hour. The mixture was stirred at -5° C. for 2 hours, then allowed to warm to room temperature and poured into 50 ml of 10% ammonium chloride solution. The mixture was extracted twice with 100 ml of ethyl acetate each time. The ethyl acetate extracts were dried over anhydrous magnesium sulphate and evaporated. The residue was subjected to flash chromatography on silica gel using 5% methanol in dichloromethane for the elution. There were obtained 2.47 g of β(R)-benzyloxy-α(RS)-phenyl-1,4-dioxaspiro[4,5]decane-2(R)-ethanol in the form of a colourless gum; MS (C.I.): m/e 369 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:16]=[N:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C:13]=1[NH2:25].B(Br)(Br)Br.CO.[OH-].[Na+]>ClCCl.O>[NH2:25][C:13]1[N:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:15]=[N:16][C:12]=1[C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[F:1]
Reactant: COc1ccc(-n2nnc(-c3ccc(C(F)(F)F)cc3F)c2N)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Nc1c(-c2ccc(C(F)(F)F)cc2F)nnn1-c1ccc(O)cc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of 5-(2-fluoro-4-trifluoromethyl-phenyl)-3-(4-methoxy-phenyl)-3H-[1,2,3]triazol-4-ylamine (16) (0.450 g, 1.2774 mmol) in anhydrous dichloromethane (15 ml), cooled to −78° C. and under a nitrogen flow, a solution of boron tribromide (2.240 g, ˜0.84 ml, 8.9418 mmol) in 5 ml of anhydrous dichloromethane is added drop-wise. The mixture is allowed to reach room temperature spontaneously overnight and it is then cooled again in an ice-salt bath and the excess of the reagent is decomposed upon drop-wise addition of 10 ml of methanol and 10 ml of water. After 10 min stirring, 10% sodium hydroxide solution (15 ml) is added and the aqueous layer, once separated, is acidified with 10% hydrochloric acid solution and extracted with chloroform (3×50 ml). The combined organic layers are dried over MgSO4, filtered and evaporated to afford a solid residue (0.380 g, 88% yield, 99.71% pure at HPLC). M.p. 176.2-177.5° C. LC-ESI-HRMS of [M+H]+ shows 339.0854 Da. Calc. 339.086898 Da, dev. −4.4 ppm.
Reaction SMILES: I.[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:9][C:10](=[NH:13])SC)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.Cl[O-].[Na+].[OH-].[Na+]>C(O)(C)(C)C>[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:9][C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[NH:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CSC(=N)NC(c1ccccc1)c1ccccc1
Agent: I
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(C)(C)O
Product: N=C(NC(c1ccccc1)c1ccccc1)N1CCOCC1

Procedure:
1-(Diphenylmethyl)-2-methyl-2-thiopseudourea hydriodide (19.2g., 0.05 mole) in 75 ml. tert-butanol is heated at reflux for 24 hours with morpholine (8.7 g., 0.1 mole) under a slow stream of nitrogen. The effluent gas is passed through sodium hypochlorite and sodium hydroxide traps to remove the methyl mercaptan formed in the reaction. The mixture was taken to dryness in vacuo and the residue was treated with 3N sodium hydroxide. Extraction with methylene chloride, washing the combined extracts with water, drying over potassium carbonate, filtration and solvent removal under reduced pressure furnishes an oil which solidifies on standing. Recrystallization several times from acetone-ether gives N-(diphenylmethyl)-4-morpholinecarboximidamide as a white solid; mp 122°-124° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C@@:11]([CH2:16][CH:17]([CH2:19][OH:20])[OH:18])([C@H:12]([CH2:14][OH:15])[OH:13])[O:10][C:8](=[O:9])[C:7]=1[OH:21])[CH2:2][CH2:3][CH3:4].C(=O)([O-])O.[Na+].[CH2:27](Br)[C:28]1C=CC=[CH:30][CH:29]=1>CS(C)=O>[CH2:1]([O:5][C:6]1[C@@:11]([CH2:16][CH:17]([CH2:19][OH:20])[OH:18])([C@H:12]([CH2:14][OH:15])[OH:13])[O:10][C:8](=[O:9])[C:7]=1[O:21][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1=C(O)C(=O)O[C@]1(CC(O)CO)[C@@H](O)CO
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCOC1=C(OCCCC)[C@@](CC(O)CO)([C@@H](O)CO)OC1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 26.2 %

Procedure:
Under an argon atmosphere, 3-O-butylglyceryl ascorbic acid (3.06 g) obtained in Example 6 was stirred in DMSO (10 mL), and further, sodium hydrogen carbonate (0.84 g) was added. To the mixture, benzyl bromide (2.06 g) was added and the mixture was heated up to 100° C. and stirred for 3 hours, followed by extraction with ethyl acetate. Then, the extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 3.52 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:50/3/0.3), and concentration was performed under reduced pressure to obtain 3-O-butylglyceryl-2-O-butyl ascorbic acid (0.95 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:18]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[C:30]([Cl:37])[C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:32][C:20]=3[N:19]=2)[CH:17]=1)=[O:12])[CH3:9]>N1C=CC=CC=1>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:18]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[C:30]([Cl:37])[C:31]([S:33](=[O:35])(=[O:34])[NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:32][C:20]=3[N:19]=2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)Cl)c(Cl)cc3n2COCCOC)c1
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)Nc4ccccc4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 42.9 %

Procedure:
Aniline (15.8 μL, 0.173 mmol) was added to a solution of 1-[6-chloro-5-chlorosulfonyl-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (75.0 mg, 0.157 mmol) in pyridine (0.79 mL) and the reaction mixture was allowed to stir at 23° C. for 1.5 h. At this point it was partitioned between EtOAc (20 mL) and water (20 mL). The aqueous layer was further extracted with EtOAc (20 mL) and the combined organic layers were washed with brine (10 mL), dried, filtered, and concentrated. The residue was purified via FCC (5-80% EtOAc/hexanes) to yield the titled compound (36.0 mg, 43% yield). MS (ESI/CI): mass calcd. for C23H24ClN5O6S, 533.1; m/z found, 534.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][OH:12])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][CH:11]=[O:12])=[CH:7][CH:8]=1
Reactant: OCC#Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=CC#Cc1ccc(C(F)(F)F)cc1
Yield: 84 %

Procedure:
In 20 ml of methylene chloride were dissolved 2.21 g (11.0 mmol) of 3-[4-(trifluoromethyl)phenyl]-2-propyn-1-ol, and 7.43 g (17.5 mmol) of Dess-Martin reagent were added to the solution under ice-cooling for 1.7 hours. Benzene was added to the resulting mixture and the insolubles were removed by filtration, followed by concentration of the filtrate to obtain 1.83 g (yield: 84%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11])[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=2[O:26]C)=[C:4]([CH3:28])[N:3]=1.C[S-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11])[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=2[OH:26])=[C:4]([CH3:28])[N:3]=1
Reactant: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1O
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To the product from example 30 step (v) (250 mg) in DMF (20 ml), sodium thiomethoxide (180 mg) was added and stirred at 100° C. for 16 h. The solvents were evaporated, and crude product purified by RPHPLC to give the subtitle compound as a colourless gum, 120 mg. LC/MS m/z 375 APCI+
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:23]=[C:22]([C:24]([O:26]C)=O)[C:21]([N:28]4C5C=CC=CC=5[C:34]5[C:29]4=[CH:30][CH:31]=[CH:32][CH:33]=5)=[CH:20][C:15]=3[C:16]([O:18]C)=O)[C:11]3[C:6](=CC=CC=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:41]1([Li])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH:45]1[C:46]2[N:28]([C:21]3[CH:20]=[C:15]([C:16]([OH:18])([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:14]([N:12]4[C:11]5[CH:34]=[CH:29][CH:30]=[CH:31][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)=[CH:23][C:22]=3[C:24]([C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=3)([C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:15]=3)[OH:26])[C:29]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:41]=2[CH:42]=[CH:43][CH:44]=1
Reactant: [Li]c1ccccc1
Reactant: COC(=O)c1cc(-n2c3ccccc3c3ccccc32)c(C(=O)OC)cc1-n1c2ccccc2c2ccccc21
Product: OC(c1ccccc1)(c1ccccc1)c1cc(-n2c3ccccc3c3ccccc32)c(C(O)(c2ccccc2)c2ccccc2)cc1-n1c2ccccc2c2ccccc21

Procedure:
The compound is synthesised by the same procedure as for the corresponding step of Example 5 by reaction of 73 g (140 mmol) of dimethyl 2,5-biscarbazol-9-ylterephthalate with 400 ml (600 mmol) of 1.6 M phenyllithium solution. The yield is 89 g (115 mmol), corresponding to 82% of theory.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C@@H:26]([OH:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C@H:3]1[CH2:4][CH2:5][C:6]1[C:7]3[C@:19]([CH3:29])([CH2:20][CH2:21][C:22]=12)[C@@H:10]([C@H:11]([CH3:18])[O:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:9][CH:8]=3.[C:31]1(=[O:37])[O:36][C:34](=[O:35])[CH2:33][CH2:32]1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:34]([OH:36])(=[O:35])[CH2:33][CH2:32][C:31]([O:27][C@H:26]1[CH2:25][CH2:24][C@@:23]2([CH3:28])[C@@H:3]([CH2:4][CH2:5][C:6]3[C:7]4[C@:19]([CH3:29])([CH2:20][CH2:21][C:22]=32)[C@@H:10]([C@H:11]([CH3:18])[O:12][CH2:13][CH:14]=[C:15]([CH3:16])[CH3:17])[CH2:9][CH:8]=4)[C:2]1([CH3:1])[CH3:30])=[O:37]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)=CCO[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)=CCO[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)CCC(=O)O)C(C)(C)[C@@H]1CC3
Temperature: 60 °C
Yield: 56.3 %

Procedure:
A mixture of (3β,5α,20S)-4,4-dimethyl-22-oxacholesta-8,14,24-trien-3-ol (Example 1; 0.50 g), dry pyridine (8 ml), succinic anhydride (3.0 g), and 4-dimethylaminopyridine (20 mg) was heated at 60° C. overnight. After cooling the reaction mixture was poured into a 0.1 M aqueous solution of hydrochloric acid and the product extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded (3β,5α,20S)-4,4-dimethyl-22-oxacholesta-8,14,24-trien-3-ol hydrogen butanedioate (0.35 g). M.p. 60-67° C.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:26][OH:27])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(CC1c2ccccc2CCc2ccccc21)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: ON=C(CC1c2ccccc2CCc2ccccc21)c1ccncc1

Procedure:
In analogy to example 1, step 2, from 2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-pyridin-4-yl-ethanone and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound containing less than 5% of the Z-isomer as a white solid, MS (ESI+): m/z=([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])[CH3:14]
Reactant: CC(C)=O
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
A round bottom flask equipped with magnetic stirrer and nitrogen inlet was charged with 2,6-dichlorobenzaldehyde (5.0 g, 28.57 mmol), acetone (42 ml, 0.571 mol) and water (20 ml). The mixture was cooled to 0° C. and a solution of sodium hydroxide (1.14 g, 28.57 mmol) in water (20 ml) was added drop wise during 1 hour to the vigorous stirred suspension. The reaction mixture was stirred for an additional 0.5 hour. The reaction mixture was concentrated in vacuo, poured onto 10% HCl (100 ml) and extracted with ethyl acetate (3×50 ml). Combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (350 g) (eluent: n-hexane/ethyl acetate 10:1) to afford 6.0 g (97% of theory) of (E)-4-(2,6-dichloro-phenyl)-but-3-en-2-one in form of a pale yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=[O:4].[BH4-].[Na+].[OH-].[Na+]>CO>[Cl:12][C:7]1[CH:6]=[C:5]([CH:3]2[CH2:2][O:4]2)[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(C2CO2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a solution of 2-bromo-1-(3,4-dichlorophenyl)ethanone (5.1 g, 18.96 mmol) in methanol (50 mL) at 0° C. was added sodium borohydride (2.1 g, 56.98 mmol). The reaction mixture was stirred at 0° C. for 1 hour. The pH was adjusted to 12 using 2 M sodium hydroxide solution, the solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane. The resultant solution was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 2-(3,4-dichlorophenyl)oxirane (1.79 g, 50% crude). The crude product was used in the next step without further purification: 1H NMR (CDCl3, 500 MHz) 7.41 (d, J=8.5 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.12 (dd, J=8.5, 2.0 Hz, 1H), 3.81 (dd, J=4.0, 2.5 Hz, 1H), 3.14 (dd, J=5.5, 4.0 Hz, 1H), 2.73 (dd, J=5.5, 2.5 Hz, 1H); ESI MS m/z 189 [M]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][C:8]=2[F:18])=[N:4][C:3]=1[C:19]([NH2:21])=[O:20].Br[C:23]1[N:28]=[C:27]([CH:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:30][OH:31])[CH:26]=[CH:25][CH:24]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:13][C:12]1[CH:11]=[C:10]([C:14]([OH:17])([CH3:16])[CH3:15])[CH:9]=[C:8]([F:18])[C:7]=1[C:5]1[S:6][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:30][OH:31])[N:28]=2)=[C:3]([C:19]([NH2:21])=[O:20])[N:4]=1
Reactant: OCC(c1cccc(Br)n1)N1CCOCC1
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(N)=O)c(N)s2)c(F)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)c1cc(F)c(-c2nc(C(N)=O)c(Nc3cccc(C(CO)N4CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure in Example 15, Step 7 using 5-amino-2-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 15, Step 5) (99 mg, 0.32 mmol), 1-[(6-bromopyridin-2-yl)methoxy]-2-methylpropan-2-ol (Example 3, Step 1) (91 mg, 0.32 mmol), Pd2(dba)3 (17 mg, 0.019 mmol), X-PHOS (45 mg, 0.095 mmol), potassium carbonate (48 mg, 0.35 mmol), and tert-amyl alcohol (0.64 ml) as starting materials. 1H NMR (500 MHz, d6-DMSO) δ 11.34 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 7.33 (d, 2H), 7.13 (d, 1H), 6.95 (d, 1H), 5.37 (s, 1H), 4.47 (t, 1H), 3.94 (m, 2H), 3.62 (t, 1H), 3.52 (m, 4H), 2.48 (m, 4H), 1.44 (s, 6H). LRMS (APCI) calc'd for C24H28F2N5O4S [M+H]+ 520.2, found 520.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CO>[NH:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC1CCNCC1)OCc1ccccc1
Yield: 99.1 %

Procedure:
A mixture of tert-butyl 4-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate obtained in Example 1a (13.1 g, 39.2 mmol), a 5 N aqueous hydrochloric acid solution (40 ml, 200 mmol) and methanol (40 ml) was stirred at mom temperature for 23 hours. A 5 N aqueous sodium hydroxide solution (40 ml) was added to the reaction mixture under ice-cooling. Water and the solvent were distilled off from the reaction mixture while the mixture was azeotropically distilled with ethanol. Ethanol was added to the residue, the insoluble matter was removed by filtration, and the filtrate was concentrated to give the title compound (9.10 g, yield 99.1%).