Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[H-].[Na+].O>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2ccc(F)cc2)CC1
Reaction time: 3.5 h
Yield: 96.2 %

Procedure:
To a solution of 0.75 g (6.02 mmol) of 4-fluorobenzylbromide and 0.58 g (2.7 mmol) of 1-t-butoxycarbonyl-4-hydroxymethylpiperidine in 5 mL of THF was added 0.136 g (5.4 mmol) of NaH in 3 portions over 30 min. After 3.5 h, 50 mL of H2O was added to the reaction mixture and it was extracted with ethyl acetate. The combined organic fractions were washed with sat'd Nacl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl aceate, 4:1) to give 0.84 g of the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:28])[C@@H:7]1[C@:23]2([CH3:24])[CH:10]([CH:11]3[C:20](=[CH:21][CH2:22]2)[C@:19]2([CH3:25])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][C@H:8]1[CH3:27])(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)Cl.CO>[OH:4][CH2:5][C:6]([C@@H:7]1[C@:23]2([CH3:24])[CH:10]([CH:11]3[C:20](=[CH:21][CH2:22]2)[C@:19]2([CH3:25])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@H:8]1[CH3:27])=[O:28]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)CC2C3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1CC2C3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CO
Temperature: 5 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
A solution of 2-oxo-2-((10S,13S,16R,17S)-10,13,16-trimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl acetate (1.0 g, 2.6 mM) in methylene chloride (5 mL) and methanol (15 mL) was put under an inert atmosphere and cooled in an ice bath. 1 mL of 1 M aqueous potassium carbonate was added by syringe. The reaction was stirred at 5° C. for 2 h. The reaction was then neutralized with 1N HCl and concentrated. After partitioning between water and methylene chloride, the product solution was dried over anhydrous magnesium sulfate, filtered and evaporated. Crystallization from ethyl acetate yielded a first crop of 0.33 g product. NMR (500 MHz, CDCl3, TMS): δ 0.67 (s, 3H), 1.01 (d, 3H, J=7 Hz), 1.13 (m, 1H), 1.33 (s, 3H), 1.47-1.80 (m, 3, H), 2.00 (m, 1H), 2.06-2.24 (m, 6H), 2.37 (d, 1H), 2.45-2.60 (m, 3H), 2.82 (m, 1H), 3.30 (m, 1H), 4.20 (m, 2H), 5.50 (d, 1H, J=5 Hz), 5.76 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=[O:13])[N:6]2[CH3:11].O[Li].O.OS([O-])(=O)=O.[K+]>C1COCC1.O>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[N:6]2[CH3:11]
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)cc2c(O)cccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of ethyl 4-hydroxy-1-methyl-1H-indole-2-carboxylate (0.20 g) in THF (20 mL) was added LiOH.H2O (0.1 g) in water (20 mL) and the resulting two phase solution was stirred at room temperature under nitrogen for 4 h. The reaction mixture was acidified with KHSO4 and the product was extracted into EtOAc, washed with brine, dried over MgSO4, and concentrated. The residue was chromatographed over silica gel with a mixture of EtOAc and hexane to give 0.12 g of the title compound. MS ES (M++H)=192.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3S[CH2:17][CH2:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=3[CH:23]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[S:35](=[O:39])(=[O:37])[CH2:17][CH2:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=3[CH:23]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OC)cc3)ccc2SCC1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(-c3ccc(OC)cc3)ccc2S(=O)(=O)CC1
Reaction time: 2 h

Procedure:
To a solution of methyl 7-(4-methoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.60 g) in THF (10 ml) was added at 0° C. 70% 3-chloroperbenzoic acid (1.0 g), and the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give solid, which was recrystallized from ethyl acetate/hexane to give colorless crystals of methyl 7-(4-methoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (584.5 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1.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>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1O
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: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CC(=O)Nc2cccc(-c3ccccc3)c2)ccc1O
Yield: 82.8 %

Procedure:
Intermediate 1 (500 mg), phenylboronic acid (300 mg), tetrakis(triphenylphosphine)palladium (0) (150 mg) are dissolved in tetrahydrofuran (20 ml), and thereto are added cesium carbonate (850 mg) and water (10 ml). The mixture is heated under reflux for 18 hours under argon atmosphere. The reaction solution is extracted with ethyl acetate, and the organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (360 mg).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1.Cl>CC(N(C)C)=O.O>[CH2:1]([O:8][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
Benzyl alcohol (12.6 ml, 122 mmol) was added dropwise over 15 minutes to a slurry of sodium hydride (60% dispersion in mineral oil, 7.6 g, 190 mmol) in dimethylacetamide (100 ml) cooled in an ice-bath. The mixture was stirred at 0° C. for 15 minutes and then 7-fluoroquinazolin-4(3H)-one (prepared as described in WO03/055491) (10.0 g, 61 mmol) was added portionwise over 15 minutes. The mixture was warmed to room temperature and then heated at 60° C. for 15 hours and then at 80° C. for 3 hours. The mixture was poured into water (600 ml) and made acidic (pH˜6) by the addition of concentrated hydrochloric acid. The resultant precipitate was filtered and washed with water to yield 7-(benzyloxy)quinazolin-4(3H)-one as a colourless solid (11.5 g, 75% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:25])[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[C@@H:15]([NH:19][CH:20]=O)[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:24])[CH3:23])=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([OH:25])[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[C@@H:15]([N+:19]#[C-:20])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:23])[CH3:24])=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC=O)C(=O)C1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: [C-]#[N+][C@H](C(=O)C1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a mixture of N-((2S)-1-((4R)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylcyclohexyl)-3-methyl-1-oxobutan-2-yl)formamide (109 mg, 0.298 mmol) and TEA (0.208 mL, 1.490 mmol) in CH2Cl2 (5 mL) was added POCl3 (0.027 mL, 0.298 mmol) at 0° under N2. The mixture was stirred at 0-5° C. for 3 h. The mixture was quenched with NaHCO3 (aq), extracted into CH2Cl2, and dried over Na2SO4. After concentrating, the crude residue was purified via column chromatography (CH2Cl2) to give (2S)-1-((4R)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylcyclohexyl)-2-isocyano-3-methylbutan-1-one (85 mg, 0.244 mmol, 82% yield) as a light yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[Na])(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C(C)=CC=CC=1>[C:15]1([C:10]2[C:11]3[NH:12][C:13]4[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=4)[C:6]=3[CH:7]=[CH:8][CH:9]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1C
Product: c1ccc(-c2cccc3c2[nH]c2ccccc23)cc1
Yield: 84.1 %

Procedure:
In a stream of argon, 670 g of carbazole, 850 kg of iodobenzene, 20 L of xylene, 460 g of t-BuONa, and palladium acetate (Pd(OAc)2) were loaded, and then the mixture was refluxed for 8 hours. Impurities were filtrated, and then the filtrate was concentrated under reduced pressure and washed with hexane. After that, the washed product was dried. As a result, 820 g of phenylcarbazole were obtained as a white powder. A reaction was performed in the same manner as in the synthesis of Intermediate 1-1 except that phenylcarbazole was used instead of 4-bromobiphenyl. As a result, 650 g of a white powder were obtained. The powder was identified as Intermediate 1-11 by FD-MS analysis.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Cl)[N:9]=1)[CH2:2][C:3]#[CH:4].[I-].[K+].[C:19](/[C:21](=[N:28]\[O-:29])/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[N:20].[Na+]>C(#N)C.CN(C=O)C>[CH2:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:29]/[N:28]=[C:21](\[C:19]#[N:20])/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]=1)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCOC(=O)Nc1cccc(CCl)n1
Reactant: N#C/C(=N\[O-])c1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: C#CCCOC(=O)Nc1cccc(CO/N=C(\C#N)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Phenylacetonitrile (9.72 g, 82.97 mmol) was metered into a suspension of 3.31 g (82.97 mmol) of NaOH in 60 ml of ethanol. Following the complete addition, 11.66 g (99.56 mmol) of isopentyl nitrite were metered in dropwise at temperatures of 15° C. The mixture was then stirred for a further 2 hours at this temperature. The reaction mixture was diluted with 300 ml of diethyl ether, and the precipitated solid was filtered off and washed twice with in each case 50 ml of diethyl ether. The white salt sodium {[(Z)-cyano(phenyl)methylene]amino}oxidanide (7.89 g, 56% yield) can be dried in vacuo or be further used directly. 1.49 g (6.24 mmol) of but-3-yn-1-yl[6-(chloromethyl)pyridin-2-yl]carbamate and 103 mg (0.624 mmol) of potassium iodide were added to a solution of 1.05 g (6.24 mmol) of sodium {[(Z)-cyano(phenyl)methylene]amino}oxidanide in 25 ml of acetonitrile and 10 ml of DMF. The reaction mixture was stirred for 7 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in 100 ml of ethyl acetate. The organic phase was washed with water and dried over MgSO4. After removing the solvent, 2.21 g (99% yield, only 1 oxime isomer) of but-3-yn-1-yl{6-[({[(Z)-cyano(phenyl)methylene]-amino}oxy)methyl]pyridin-2-yl}carbamate were isolated as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([NH2:15])=[C:6]2[C:10]=1[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7]2.[O:17]=[C:18](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7][C:6]=2[C:5]([N:15]=[C:18]=[O:17])=[C:4]([F:16])[CH:3]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCN1c2c(Cl)cc(F)c(N)c2CS1(=O)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCN1c2c(Cl)cc(F)c(N=C=O)c2CS1(=O)=O

Procedure:
To a mixture of 7-chloro-1-ethyl-5-fluoro-1,3-dihydro-2,1-benzisothiazol-4-amine-2,2-dioxide (1.30 g, 4.91 mmol), diphosgene (1.17 g, 1.2 eq) in p-dioxane (20 mL), triethylamine (0.6 g, 1.2 eq) was added and the resulting reaction mixture was heated at reflux for overnight. The precipitated triethylamine hydrochloride was filtered off and the solvents were removed in vacuo and dried to give the title compound of Step A as a brown semisolid. 1H NMR (CDCl3, 400 MHz): δ7.21 (d,1H, J=9.5 Hz), 4.28 (s,2H), 3.94 (q,2H), 1.22 (t,3H, J=7.5 Hz).
Reaction SMILES: CO.N1CC[CH2:6][CH2:5][CH2:4]1.Cl.Cl.[CH3:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][NH:17][C:18]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[NH:22])=[NH:19])=[CH:14][CH:13]=1>CC(C)=O>[CH2:24]([NH:23][C:21]1[NH:20][C:18]([NH:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([CH3:11])=[CH:33][CH:32]=2)=[N:19][C:5]([CH3:6])([CH3:4])[N:22]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C1CCNCC1
Reactant: CCCCCCCCNC(=N)NC(=N)NCc1ccc(C)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(C)cc2)N1
Yield: 47.2 %

Procedure:
40 ml of methanol, 80 ml of acetone and 16 ml (16.2 mmol) of piperidine were added to 3.0 g (7.7 mmol) of N1-(4-methylbenzyl)-N5-octyl-biguanide dihydrochloride, and the mixture was refluxed for 23 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform, methanol and acetic acid (9:0.5:0.5)). 50 ml of ethanol and 50 ml of water were added to the resulting colorless resinous solid, and the pH of the mixture was adjusted to 11 to 12 with 5N sodium hydroxide. The mixture was refluxed for 1 hour, and the solvent was distilled off under reduced pressure. The residue was washed with water, and dried well under reduced pressure to obtain 1.3 g of a colorless solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:27])[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].[Na+].ClC1C=C(C2C=CC(C([O-])=O)=CC=2)C=CC=1CC1CCN(C2CCCCC2)C1=O>CN(C=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:16]2[CH:15]=[C:14]([Cl:27])[C:13]([CH2:12][CH:9]3[CH2:10][CH2:11][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:8]3=[O:28])=[C:18]([Cl:19])[CH:17]=2)=[CH:21][CH:22]=1)[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: O=C1C(Cc2c(Cl)cc(-c3ccc(O)cc3)cc2Cl)CCN1C1CCCCC1
Agent: O=C([O-])c1ccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Yield: 87.6 %

Procedure:
Combine 1-cyclohexyl-3-(3,5-dichloro-4′-hydroxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one (Preparation 52) (0.15 g, 0.36 mmol), ethyl bromoacetate (0.12 g, 0.718 mmol) and Cs2CO 3 (0.29 g, 0.89 mmol) in DMF (6 mL) and heat to 60° C. for 16 hours. Cool the reaction, extract with diethyl ether and water, dry the organic layer (Na2SO4) and then purify by normal phase chromatography (30 to 80% gradient of ethyl acetate in hexanes) to afford 159 mg (88%) of the title compound: LC-MS (ES+) m/z=exact mass calcd for C27H31Cl2NO4 503, found 504 and 506 (M+1 and M+3, 100%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:29][C:30]1[S:31][C:32]([CH:36]=O)=[C:33]([Cl:35])[N:34]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:36][C:32]2[S:31][C:30]([Cl:29])=[N:34][C:33]=2[Cl:35])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1sc(Cl)nc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2sc(Cl)nc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Add sodium triacetoxyborohydride (1.70 g, 8.02 mmol) to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.0124 g, 5.06 mmol), 2,4-dichloro-thiazole-5-carbaldehyde (1.0113 g, 5.56 mmol), glacial acetic acid (0.31 mL, 5.42 mmol), and 1,2-dichloroethane (40 mL). Stir for 18 hours under nitrogen at room temperature. Pour the reaction into 2N NaOH (100 mL) and extract with ethyl acetate (3×100 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 35% ethyl acetate/hexanes then with 100% ethyl acetate to yield 1.1547 g (62%) of 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=366.1 (M+1); 1H NMR (CDCl3): δ=4.04 (br s, 2H), 3.96 (s, 2H), 2.87-2.81 (m, 2H), 2.72-2.65 (m, 1H), 1.90-1.86 (m, 2H), 1.48-1.39 (m, 10H), 1.33-1.23 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH2:6][C:7](=O)[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([F:22])[CH:11]=1)[CH3:9]>O.[OH-].[Na+]>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:12]([F:22])[CH:11]=2)[CH3:9])[N:4]=1
Reactant: CC(C(=O)CCl)c1ccc(-c2ccccc2)c(F)c1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
To thiourea (1.77 g, 23.3 mmol) in water (50 ml) was added 1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (5.25 g, 19.0 mmol). After addition, the mixture was heated for 3 hr, and the solution was cooled to room temperature, then added IN sodium hydroxide to pH 8. The mixture was extracted with chloroform and the chloroform extracts were washed with water, dried over, and evaporated under reduced pressure to a residue, which was chromatographed to afford 2-amino-4-[1-(2-fluoro-4-biphenylyl)ethyl] thiazole (4.12 g, 73% yield) as crystalline material: mp 167°-168° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:23](/[CH:24]=[CH:25]/[C:26]2[CH:34]=[CH:33][C:29]([C:30]([O-:32])=[O:31])=[CH:28][CH:27]=2)=[CH:22][C:12]2[C:13]3([CH3:21])[CH:18]([OH:19])[C:17]([CH3:20])([C:11]=2[CH:10]=1)[CH2:16][CH2:15][CH2:14]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:8][C:9]1[C:23](/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:33][CH:34]=2)=[CH:22][C:12]2[C:13]3([CH3:21])[CH:18]([OH:19])[C:17]([CH3:20])([C:11]=2[CH:10]=1)[CH2:16][CH2:15][CH2:14]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1cc2c(cc1/C=C/c1ccc(C(=O)[O-])cc1)C1(C)CCCC2(C)C1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCOc1cc2c(cc1/C=C/c1ccc(C(=O)O)cc1)C1(C)CCCC2(C)C1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
1.255 g of (E)-4-[2-[(5RS,9SR, 10RS)-3-heptyloxy-10-hydroxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocyclohepten-2-yl]vinyl]benzoate were dissolved in 30 ml of ethanol/THF=1/1 and treated with 2.56 ml of 3N NaOH. The mixture was stirred at room temperature for 5 hours, then poured into ice/conc. HCl, extracted with ethyl acetate, washed with water, dried over Na2SO4 and evaporated. Recrystallization from hexane/ethyl acetate yielded 873 mg of (E)-4-[2-[(5RS,9SR,10RS)-3-heptyloxy-10-hydroxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocyclohepten-2-yl]vinyl]benzoic acid as yellow crystals of melting point 89-90° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([OH:35])=[S:34])[CH2:28][CH2:27]1.O>CC(C)=O>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][CH2:14][S:34][C:33](=[O:35])[CH2:32][N:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)[CH2:3]1
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: OC(=S)CN1CCOCC1
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCSC(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Yield: 66.8 %

Procedure:
3α-Hydroxy-21-methylene-5α-pregnane-11,20-dione (500 mg) was dissolved in acetone (20 ml) and the solution treated with morpholinothioacetic acid (300mg), at reflux for 3 hours. The mixture was poured into water and the emulsion extracted with either. The extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to a foam (540 mg) which was purified by preparative t.l.c. in ethyl acetate/petrol (1:1). The main band gave title compound (490mg.) as a white foam. [α]D + 48° (c = 1.03).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:22]([CH3:32])[CH:21]=1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:28][CH2:27]2)=[C:22]([CH3:32])[CH:21]=1
Reactant: Cc1cc(F)ccc1N1CCNCC1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1cc(F)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCN32)CC1
Temperature: 105 °C
Yield: 56.8 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 1-(4-fluoro-2-methylphenyl)piperazine dihydrochloride (122 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-((4-(4-fluoro-2-methylphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (102.3 mg, 0.259 mmol, 56.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80-2.02 (m, 3 H) 2.09-2.20 (m, 1 H) 2.23 (s, 3 H) 2.37-2.49 (m, 4 H) 2.77 (br. s., 4 H) 3.34-3.44 (m, 3 H) 3.52-3.65 (m, 1 H) 3.93-4.03 (m, 1 H) 6.88-7.07 (m, 4 H) 7.62 (s, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C22H26FN5O, 396; found, 396.