Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1.[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[NH:25][CH2:24][C:23]=12>>[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]([C:13]([C:12]3[CH:16]=[CH:17][C:9]([C:6]4[CH:7]5[CH2:8][CH:3]([CH2:4][CH:5]=4)[C:2]5([CH3:18])[CH3:1])=[CH:10][CH:11]=3)=[O:14])[CH2:24][C:23]=12
Reactant: CC1(C)C2CC=C(c3ccc(C(=O)O)cc3)C1C2
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: CC1(C)C2CC=C(c3ccc(C(=O)N4Cc5cccn5Cc5ccccc54)cc3)C1C2
Yield: 74.2 %

Procedure:
4-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)-benzoic acid of Step B (0.160 g, 0.66 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.134 g, 0.726 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.200 g) as white crystals, m.p. 118–119° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:18]([CH3:19])=[CH:17][C:10]2[N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[S:13][C:9]=2[C:8]=1[Br:20])(=O)=O.[CH2:23](C([Sn])=C(CCCC)CCCC)[CH2:24]CC.[Li+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:20][C:8]1[C:9]2[S:13][C:12]([CH:14]3[CH2:16][CH2:15]3)=[N:11][C:10]=2[CH:17]=[C:18]([CH3:19])[C:7]=1[CH:23]=[CH2:24]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1cc2nc(C3CC3)sc2c(Br)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc2nc(C3CC3)sc2c1Br

Procedure:
To a solution of 7-bromo-2-cyclopropyl-5-methylbenzo[d]thiazol-6-yl trifluoromethanesulfonate (16) (410 mg, 0.988 mmol) in DMF (4 ml), was added tributylvinyltin (0.43 ml, 1.47 mmol), LiCl (125 mg, 2.94 mmol) and PdCl2(PPh3)2 (70 mg, 0.096 mmol). The reaction mixture was reacted at 80° C. overnight. The reaction was cooled down, washed by saturated NaHCO3 solution, extracted by EtOAc. The organic phase was combined, dry over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]=[CH:11][CH:10]2[OH:15])=[C:4]([CH3:16])[CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]2=[O:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)C=CC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: Cc1cc(Br)cc(C)c1C1C(=O)C=CC1=O
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 5-(4-bromo-2,6-dimethylphenyl)-4-hydroxycyclopent-2-enone (18.33 g. 65 mmol) in acetone (200 ml) at 0° C. is added, dropwise, a solution of Jones reagent (1.67 M, 39 ml, 65 mmol) and the resulting yellow solution is stirred at 0° C. for 90 minutes. The reaction is quenched by the addition of propan-2-ol (1 ml) and stirred for a further 2 hours. Brine (300 ml) is added and the reaction is extracted with ethyl acetate (3×250 ml). The organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 2-(4-bromo-2,6-dimethylphenyl)cyclopent-4-ene-1,3-dione (17.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH:7]1[CH2:11][C:10]([CH3:12])=[CH:9][C:8]1=[O:13])[OH:6])[CH3:2].C.[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([OH:6])[CH:7]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8]1=[O:13])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(O)C1CC(C)=CC1=O
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)C1CC(C)CC1=O

Procedure:
Step 2, Hydrogenation Process (Ethyl Ester): 99.1 g of crude alpha-hydroxy-(4-methyl-2-oxo-3-cyclopenten-1-yl)-acetic acid ethyl ester (as prepared in Example 1) in 882 ml of toluene was hydrogenated over 9.91 g of 10% by weight of palladium and 90% by weight of charcoal at room temperature and 25-50 psi. After hydrogen uptake had ceased, the catalyst and solvent were removed by filtration and evaporation to give 101 g of a viscous, amber-colored oil. This oil is distilled to provide the product alpha-hydroxy-4-methyl-2-oxo-cyclopentane acetic acid ethyl ester, bp 96°-111°/0.05 mmHg, for use in Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[N:16][C:17](Cl)=[C:18]([Cl:20])[CH:19]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.N.O.[CH3:29][N:30](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:20][C:18]1[CH:19]=[C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:22]([F:23])([F:24])[F:25])[O:13][N:12]=2)[CH:15]=[N:16][C:17]=1[C:29]#[N:30]
Reactant: CC(=O)N(C)C
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2cnc(Cl)c(Cl)c2)=NO1
Agent: [Pd]
Agent: N
Agent: [C-]#N
Solvent: O
Product: N#Cc1ncc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
In a solution of 1.40 g of 5-(3,5-dichlorophenyl)-3-(5,6-dichloro-3-pyridyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 30 mL of N,N-dimethylacetamide, 0.075 g of zinc cyanide and 0.37 g of tetrakis(triphenylphosphine) palladium(0) were added, and stirred at 80° C. to 120° C. for 4.5 hours under nitrogen atmosphere. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, 5 mL of ammonia water and 50 mL of water were added, and extracted with ethyl acetate (50 mL×1). The organic phase were dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was purified with medium pressure preparative liquid chromatography (medium pressure collection apparatus: YFLC-Wprep manufactured by Yamazen Corporation) that was eluted with ethyl acetate-hexane (gradient of 1:8 to 1:3) to obtain 1.20 g of the aimed products as yellow resinous substance.
Reaction SMILES: [NH2:1][C:2]1[C:14](Br)=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH3:17])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[CH3:19])=[CH:4][CH:3]=1.[C:20]([Cu])#[N:21].CN1CCCC1=O.CCOC(C)=O>O>[NH2:1][C:2]1[C:14]([C:20]#[N:21])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH3:17])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[CH3:19])=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CCC12CCC(=O)C(C)=C1c1ccc(N)c(Br)c1C2
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC12CCC(=O)C(C)=C1c1ccc(N)c(C#N)c1C2
Temperature: 25 °C
Yield: 59.7 %

Procedure:
A mixture of crude 7-amino-8-bromo-9a-ethyl-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.97 g, 3.02 mmol), CuCN (0.318 g, 3.55 mmol), and 1-methyl-2-pyrrolidinone (NMP, 6 mL) was placed under a N2 atmosphere, stirred, and heated in an oil bath at 160–170° C. for 5.5 hours. After cooling to room temperature, the mixture was added to EtOAc (200 mL) and water (200 mL) and filtered through a pad of solka-floc. The organic portion of the filtrate was washed with water (5×200 mL) and brine (100 mL), dried over MgSO4, filtered, and evaporated under vacuum to a red oil (0.8 g). The crude product was purified by chromatography on EM silica gel 60 (2.75×25 cm column), eluting with 5% EtOAc in CH2Cl2, to afford 7-amino-8-cyano-9a-ethyl-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.48 g) as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)(=[O:3])[CH3:2].FC(F)(F)S(O[C:19]1[CH2:24][CH2:23][NH:22][CH:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]=1)(=O)=O.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.[Li+].CC([N-]C(C)C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>O.COCCOC.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:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:19]1[CH2:24][CH2:23][NH:22][CH:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)C1C=C(OS(=O)(=O)C(F)(F)F)CCN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1ccccc1C1=CC(C(=O)OC(C)(C)C)NCC1

Procedure:
The title compound was prepared according to the procedure described in Preparation A using 2-acetylphenylboronic acid (Aldrich) (1.63 g, 10 mmol), tert-butyl 4-[(trifluoromethyl)sulfonyloxy]-1,2,5,6-tetrahydropyridinecarboxylate [prepared by the method of Wustrow, D. J. and Wise, I. D. Synthesis, 1991, 993-995, from tert-butyl-4-oxopiperidine-1-carboxylate (Aldrich), LDA (Aldrich) and N-phenyltrifluoromethane-sulfonimide (Aldrich)) (3.64 g, 11 mmol), tetrakis(triphenylphosphine)palladium (0) (Strem Chemicals) (0.578 g, 0.5 mmol), LiCl (Aldrich) (1.27g, 30 mmol), and Na2CO3 (Aldrich) (2.46 g, 30 mmol) in water (15 mL) and DME (20 mL). Purification by silica gel chromatography (5:1 hexane:EtOAc) provided the title compound as a white foam (1.77 g). MS (ESI, pos. ion) m/z: 302 (M+1); MS (ESI, neg. ion) m/z: 300 (M−1). Calc'd for C18H23NO3: 301.38.
Reaction SMILES: [BH4-].[Na+].[CH:3]1[C:13]2[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[CH2:9][S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)C.[OH-].[Na+]>[CH:3]1[C:13]2[CH:12]([OH:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[CH2:9][S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2CSc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC1c2ccccc2CSc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a similar manner, 0.5 gram (13 millimoles) of sodium borohydride was added to a solution of 2.26 grams (13 millimoles) of 6,11-dihydrodibenzo[b,e]thiepin-11-one in 50 milliliters of ethanol to which a few drops of 40 percent sodium hydroxide had been added and the mixture stirred at room temperature overnight to obtain 6,11-dihydrodibenzo[b,e]thiepin-11-ol intermediate in the reaction mixture. Thereafter, in the manner previously described, the thiepinol intermediate was recovered by adding water to the mixture, subjecting the mixture to reduced pressure, adding ether and extracting therewith, washing and drying the ether solution, filtering the drying agent and vaporizing the ether to obtain an oily residue of 6,11-dihydrodibenzo[b,d]thiepin-11-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2Cl)=[O:5])[CH3:2].[CH2:19](B(O)O)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(Cl)c2c1
Reactant: CCCCCCB(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCc1c(C#N)cnc2ccc(C(=O)OCC)cc12

Procedure:
Similar procedure as described in example 46d was used, starting from 4-chloro-3-cyano-quinoline-6-carboxylic acid ethyl ester (example 46c), n-hexylboronic acid, sodium carbonate and POPd to give 3-cyano-4-hexyl-quinoline-6-carboxylic acid ethyl ester as a clear oil. LC-MS m/e 311 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:29])[C:13](=[O:28])[N:14]([C:15]4[C:16]([CH3:27])=[N:17][N:18]([CH2:20][C:21]([N:23]([CH2:25][CH3:26])[CH3:24])=[O:22])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:30]1([C:35]2[N:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:25]([N:23]([CH3:24])[C:21](=[O:22])[CH2:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:38]5[CH:39]=[N:40][C:35]([N:30]6[CH2:31][CH2:32][CH2:33][CH2:34]6)=[N:36][CH:37]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:29])[C:13]2=[O:28])[C:16]([CH3:27])=[N:17]1)[CH3:26]
Reactant: CC1(C)OB(c2cnc(N3CCCC3)nc2)OC1(C)C
Reactant: CCN(C)C(=O)Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Product: CCN(C)C(=O)Cn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(N6CCCC6)nc5)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 2-[4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-N-ethyl-N-methyl-acetamide (Intermediate P) and 2-(pyrrolidin-1-yl)pyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA, 37 mg, 0.132 mmol) to give the title compound as an off-white solid. (HPLC: tR 2.53 min (Method A); M+H=526 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) cis&trans amide 8.92 (s, 1H), 8.59-8.55 (m, 2H), 8.08-8.01 (m, 2H), 7.88-7.84 (m, 1H), 7.68-7.63 (m, 1H), 5.23-5.15 (m, 1H), 5.11-5.04 (m, 1H), 3.57 (s, 3H), 3.53-3.21 (m, 6H), 3.01, 2.83 (2×s, 3H), 1.97-1.89 (m, 4H), 1.94, 1.93 (2×s, 3H), 1.17, 0.99 (2×t, 3H))
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH3:2].[NH2:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=1>ClCCl>[CH3:27][O:26][C:20]1[CH:21]=[C:22]([O:24][CH3:25])[N:23]=[C:18]([NH:17][C:11](=[O:12])[NH:10][S:7]([O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[O:3][CH2:1][CH3:2])(=[O:9])=[O:8])[N:19]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: CCOc1ccccc1OS(=O)(=O)N=C=O
Solvent: ClCCl
Product: CCOc1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A solution of 97.2 g (0.4 mol) of the product of Example 1 in 100 ml of dichloromethane is added dropwise at 25° C. to 62.0 g (0.4 mol) of 2-amino-4,6-dimethoxypyrimidine in 600 ml of dichloromethane. Stirring at room temperature is continued for 16 hours, the mixture is diluted with 600 ml of dichloromethane, and the organic phase is washed twice with 500 ml portions of 2N hydrochloric acid and once with 500 ml of water. After the mixture has been dried using sodium sulfate and after the solvent has been removed on a rotary evaporator, an oily product remains which crystallizes on trituration with diethyl ether. 145.0 g (91% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-1-(2-ethoxyphenoxysulfonyl)urea of melting point 145°-147° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH:7]=NCCCC)([O-:3])=[O:2].[N+:16]([CH2:19][C:20](=[O:22])[CH3:21])([O-:18])=[O:17]>C(OC(=O)C)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:19]([N+:16]([O-:18])=[O:17])[C:20](=[O:22])[CH3:21])[CH:13]=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: CCCCN=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)C[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)[N+](=O)[O-]
Reaction time: 5 h
Yield: 27.1 %

Procedure:
To a solution of 28.6 g (0.39 mole) of the butanamine in 75 mL of acetic anhydride was added 15 g of 1-nitro-2-propanone. A white precipitate formed almost at once. The mixture was warmed gently until the solid dissolved, cooled, stirred for five hours, carefully poured onto water and extracted with ether. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. After storage at 0° C. overnight, the residue had crystallized. Recrystallization of the resulting solid from dibutyl ether gave 9.3 g of 4-(3-nitrophenyl)-3-nitro-3-buten-2-one, 1H NMR 8.4 (m, 2H), 7.7 (m, 2H), 7.5 (s, 1H), 2.5 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[N:11]([CH2:17][C:18]([N:20]([CH:29]([CH3:31])[CH3:30])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:19])[C:10]3[CH:32]=[CH:33][CH:34]=[CH:35][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.Br[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:39]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:14](=[O:15])[CH:13]([CH2:37][C:38]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:39]=3)[C:12](=[O:16])[N:11]([CH2:17][C:18]([N:20]([CH:29]([CH3:31])[CH3:30])[C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[O:19])[C:10]3[CH:32]=[CH:33][CH:34]=[CH:35][C:9]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccc(F)c3)c3ccccc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3cccc(F)c3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
To a stirring solution of 260 mg (0.55 mmol) 2-[5-(3-Fluorophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, in 4 mL DMF at 0° C. is added 1.3 mL (0.66 mmol, 1.2 equiv) KN(TMS)2 via syringe under N2. The reaction is allowed to warm to RT, and is stirred at RT for 20 min. The reaction is cooled to 0° C., and 200 mg (0.66 mmol, 1.2 equiv) 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole is added in one portion. The reaction is allowed to warm to RT, and after 20 min is concentrated. The reaction is then transferred to a separatory funnel containing water and ethyl acetate. The layers were separated, and the aqueous layer is extracted with ethyl acetate. The combined organics were dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography (gradient 3:1-2:1 hexanes:ethyl acetate) to afford 248 mg of the title compound as a pale yellow foam: 1H NMR (CDCl3, 400 MHz) δ8.03 (d, br, 1H, J=8.4), 7.84 (d, 1H, J=8.0), 7.46 (t, 1H, J=7.7), 7.38-7.11 (m, 6H), 6.99-6.93 (m, 3H), 4.97 (m, 1H), 4.19 (d, 1H, J=16.6), 3.83 (s, 3H), 3.83 (m, 1H) 3.52 (dd, 1H, J=4.8, 16.6), 1.64 (s, 9H), 1.04 (d, 6H, J=6.7); low resolution MS (FAB)m/e 706 (MH+).
Reaction SMILES: [Se].[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[O:14]1CCOCC1>>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH:13]=[O:14])[CH:7]=[CH:6]2
Reactant: C1COCCO1
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: [Se]
Product: O=Cc1ccc2cc(Br)ccc2n1
Temperature: 25 °C

Procedure:
Selenium dioxyde (1.3 g, 12 mmol, 1.3 eq) in suspension in dioxane (50 mL) was heated at 60° C. 6-bromoquinaldine (2 g, 9 mmol) was then introduced and the mixture was left to react at 80° C. for 3 hours. After cooling to room temperature, the mixture was filtered on celite, eluted with dioxane and concentrated under reduced pressure. The product obtained is a pure white solid (3.3 g, >98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:9][CH:8]2[CH:6]([O:7]2)[CH2:5][N:4]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])[CH2:3]1.[N-:20]=[N+:21]=[N-:22].[Na+].[NH4+].[Cl-]>CO.O>[N:20]([CH:8]1[CH2:9][C:2]([CH3:19])([CH3:1])[CH2:3][N:4]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])[CH2:5][CH:6]1[OH:7])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CC2OC2CN(S(=O)(=O)c2ccccn2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CC(N=[N+]=[N-])C(O)CN(S(=O)(=O)c2ccccn2)C1
Yield: 28.6 %

Procedure:
5,5-Dimethyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5.1.0]octane from Example 92e (1.2 g, 4.3 mmol) was dissolved in the mixture of 7 ml MeOH and 1 ml H2O. NaN3 (0.83 g, 13 mmol) and NH4Cl (0.7 g, 13 mmol) were added to the solution. The resulting mixture was refluxed overnight. After the removal of MeOH, the residue was diluted in EtOAc and washed with 10% NaHCO3 and brine. Purified on column chromatography gave 0.4 g 4-azido-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-3-ol (yield 29%); MS (M+H+): 326.2; 1H-NMR (400 MHz, CDCl3): •8.68-8.67(m, 1H), 8.05-7.90(m, 2H), 7.53-7.50(m, 1H), 3.75-3.60(m, 3H), 3.49-3.30(m, 3H), 1.73-1.66(m, 1H), 1.56-1.52(d, 1H), 1.07(s, 3H), 0.99(s, 3H)
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH3:24][CH:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C(Cl)Cl>[C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: N[C@@H]1CCC[C@H]1c1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
(+,−) Trans-2-phenyl-cyclopentylamine (5.95 g, 37.0 mmol, preparation 3) was dissolved in dry methylene chloride and cooled to 0° C. under a nitrogen atmosphere. 6.1 mL (40.7 mmol) of DBU was added followed by dropwise addition of 2-propanesulfonyl chloride (4.6 mL, 40.7 mmol). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was judged incomplete by TLC and an additional 20% of DBU and 2-propanesulfonyl chloride were added. Stirring at room temperature was continued for 3 days. The reaction was diluted with methylene chloride and washed (1×100 mL) with 1N HCl. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to 9.3 g. The product was purified on silica by Chromatotron® eluting with 99:1 methylene chloride:ethyl acetate to yield 5.7 g (31%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH2:16][C:17]([CH3:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1/[C:16](=[CH:22]/[N:23]([CH3:25])[CH3:24])/[C:17](=[O:18])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Cc1cc(Cl)ccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)/C(=C\N(C)C)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of the product from step (ii) (5.72 g) and dimethylformamide dimethyl acetal (3.5 ml) in toluene (50 ml) were heated at 100° C. for 12 h. The solvent was evaporated under reduced pressure to give an oil, 6.37 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13]N(C)C)[C:7](=O)[C:6]=2[CH:18]=1.Cl.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([NH2:24])=[NH:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:23][C:22]([C:21]([CH3:26])([CH3:25])[CH3:20])=[N:24][C:7]=3[C:6]=2[CH:18]=1
Reactant: CC(C)(C)C(=N)N
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Cl)cc2C1=O
Agent: Cl
Product: CC(C)(C)c1ncc2c(n1)-c1cc(Cl)ccc1NC(=O)C2
Yield: 88 %

Procedure:
Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2,2-dimethylpropionamidine hydrochloride. Yield: 88%. Off-white solid, m/z (ISP) 302 (MH)
Reaction SMILES: [CH3:1][C@@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[C@H]1[C@H](O)C[C@H]2C(C)(C)[C@@H]1C2.CC1C(O)CC2C(C)(C)C1C2.C[C@@H]([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@@H]4CC[C@H]3[C@@H]2CC1)CCCC(C)C.C[C@@H]([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@@H]4CC[C@H]3[C@@H]2CC1)CCCC(C)C>>[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@@H](C)O
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC1C(O)CC2CC1C2(C)C
Product: CCCCCC[C@H](C)O

Procedure:
(R)-2-octanol (6a), Example 13: (1S, 2S, 3S, 5R)-(−)-isopinocampheol (7a), Example 14: (1R, 2R, 3R, 5S)-(−)-isopiriocampheol (8a), Example 15: β-cholestanol (9a) and Example 16: α-cholestanol (10a).