Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:24][O:23][CH:22](OCC)[S:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][P:31]([O:35]CC)[O:32][CH2:33][CH3:34])[CH3:29].P(Cl)(Cl)Cl>ClCCl.[Cl-].[Zn+2].[Cl-]>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][O:23][C@@H:22]([P:31]([O:32][CH2:33][CH3:34])([O:30][CH2:28][CH3:29])=[O:35])[S:21]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC1OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Reactant: CCOP(OCC)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CCOP(=O)(OCC)[C@@H]1OC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Temperature: 0 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
To a solution of 4-(t-butyldiphenylsilyloxymethyl)-2-ethoxy-1,3-oxathiolane (12.32 g, 30.6 mmol) and triethylphosphite (3.5 mL, 20.4 mmol, 0.66 eq) in dichloromethane (50 mL) were added phosphorus trichloride (890 μL, 10.2 mmol, 0.33 eq) and zinc chloride (catalytic) at 0° C. The solution was stirred at 0° C. for 1 hr and at room temperature for 3 days. The solvent was evaporated and the crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (60:40) to give the pure compound (8.02 g) in 53% yield with a ratio of 2:1 (trans:cis).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:18][CH3:19].O>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:9][C:8]1[C:3]([CH2:2][OH:1])=[N:4][C:5]([CH3:10])=[CH:6][CH:7]=1)[CH3:19]
Reactant: CCI
Reactant: Cc1ccc(O)c(CO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc(C)nc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(hydroxymethyl)-6-methyl-3-pyridinol (1.5 g, 10.78 mmol, available from Sigma-Aldrich #144428), K2CO3 (7.45 g, 53.9 mmol) and iodoethane (1.724 ml, 21.56 mmol) were dissolved in DMF (15 ml). The mixture was left stirring at room temperature overnight. Water and EtOAc were added and the two layers were separated. The aqueous one was back-extracted several times with EtOAc. The combined organic phases were washed with brine/ice, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the crude title compound D13 (1.67 g) as a pale yellow solid which was used in the next step without any further purification. MS: (ES/+) m/z: 168 (M+1). C9H13NO2 requires 167. 1H-NMR (400 MHz, CDCl3) δ (ppm): 6.96-7.07 (m, 2 H), 4.71 (s, 2 H), 4.04 (q, 2 H), 2.50 (s, 3 H), 1.43 (t, 3 H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH2:11]([N:14]=[C:15]=[O:16])[CH2:12][CH3:13]>>[CH2:11]([NH:14][C:15]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:16])[CH2:12][CH3:13]
Reactant: CCCN=C=O
Reactant: O=c1[nH]sc2ccccc12
Product: CCCNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6b (77% yield) was synthesized from benzo[d]isothiazol-3-one and n-propyl isocyanate as a white solid. mp 90-91° C.; IR(CHCl3) 3290, 1712, 1662, 1542 cm−1; 1H-NMR (CDCl3) δ1.00 (t, J=7.3 Hz, 3H), 1.52-1.72 (m, 2H), 3.39-3.44 (m, 2H), 7.42 (t, J=7.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 8.89 (br s, 1H); ESIMS m/e 237 (M++1).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])C>ClC1C=CC=CC=1>[Br:13][C:8]1[C:7]2[S:6][CH:5]=[CH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(CSc1ccccc1Br)OCC
Solvent: Clc1ccccc1
Product: Brc1cccc2ccsc12
Yield: 93.2 %

Procedure:
Chlorobenzene (100 mL) and polyphosphoric acid (30.4 g, PPA) were combined and heated to reflux. The 2-(2-bromophenylthio) acetaldehyde diethyl acetal (13.7 g, 44.88 mmol, Scheme I, step A above) dissolved in chlorobenzene (20 mL) was added dropwise to the refluxing mixture over 20 minutes. The reaction was refluxed for 4 hours and then cooled. The solvent was decanted from the residue and toluene (2×50 mL) was added to the residue, stirred and decanted. The toluene extracts were concentrated under vacuum and the residue taken up in ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to provide 7-bromobenzo(b)thiophene (8.91 g, 93%).
Reaction SMILES: [Cl:1][C:2]([F:8])(I)[C:3]([F:6])([F:5])[Cl:4].[CH2:9]([Si](C)(C)C)[CH:10]=[CH2:11].N(C(C)(C)C#N)=NC(C)(C)C#N>>[Cl:1][C:2]([F:8])([C:3]([Cl:4])([F:6])[F:5])[CH2:11][CH:10]=[CH2:9]
Reactant: C=CC[Si](C)(C)C
Reactant: FC(F)(Cl)C(F)(Cl)I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=CCC(F)(Cl)C(F)(F)Cl
Temperature: 80 °C

Procedure:
A mixture of 279 mg (1.0 mmol) of 1,2-dichloro-1-iodotrifluoroethane, 114 mg (1.0 mmol) of allyltrimethylsilane and 10 mg (0.06 mmol) of azobisisobutyronitrile (AIBN) was heated in a sealed glass tube at 80° C. for 3 hours. After cooling, 10 mg (0.06 mmol) of AIBN was added to the mixture, followed by heating in a sealed tube at 80° C. for 3 hours to obtain 4,5-dichloro-4,5,5-trifluoro-1-pentene (Compound 39) in a yield of 40%.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([C:18]#[N:19])=[C:5]([Cl:20])[N+:4]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[CH2:29]([N:31]([CH2:35][CH3:36])[C:32](=[S:34])[S-:33])[CH3:30].[Na+]>CN(C)C=O>[Cl-:20].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([C:18]#[N:19])=[C:5]([S:34][C:32](=[S:33])[N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])[N+:4]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCN(CC)C(=S)[S-]
Reactant: CCCCCCCCNc1cc(N)[n+](CCCCCCCC)c(Cl)c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCNc1cc(N)[n+](CCCCCCCC)c(SC(=S)N(CC)CC)c1C#N
Yield: 29.5 %

Procedure:
4.5 gms (.01 mole) of 2-amino-6-chloro-5-cyano-1-n-octyl-4-n-octylamino pyridinium chloride (compound 14 - Table 1) was dissolved in dimethylformamide and 2.2 gms (0.01 mole) of sodium diethyldithiocarbamate added and the solution refluxed for 60 minutes. This was then cooled, filtered and the solvent evaporated off. Methanol was added and 1.6 gms (30% yield) of 2-amino-5-cyano-6-diethylthiocarbamylthio-1-n-octyl-4-n-octylamino pyridinium chloride (compound 80 - Table 5) was filtered off and recrystallised from methanol (MPt 124° - 126°C.)
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[C:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH3:32])=[O:25]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][S:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)(=[O:14])=[O:13])=[C:18]([C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[CH3:32])=[O:25])[CH:19]=1
Reactant: Cc1ccncc1C(=O)c1cc(Cl)ccc1N
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: Cc1ccncc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared using 4-oxazol-5-yl-benzenesulfonyl chloride and (2-amino-5-chloro-phenyl)-(4-methyl-pyridin-3-yl)-methanone according to the general procedure for the preparation of the N-aryl-benzenesulfonamides.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>ClCCl>[CH3:25][C:24]([CH3:27])([CH3:26])[C:23]([N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[N:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1)=[O:28]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
To a stirred solution of 1-(6-nitro-pyridin-3-yl)-piperazine (3.00 g, 14.4 mmol) in dichloromethane (30 mL) was added triethylamine (2.91 g, 28.8 mmol) followed by the dropwise addition of pivaloyl chloride (1.90 g, 15.9 mmol) at r.t. and the resulting solution was stirred for 15 min. The reaction was quenched with sat. sodium bicarbonate solution and extracted with dichloromethane (×3). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was washed with petroleum ether to afford 2,2-dimethyl-1-[4-(6-nitro-pyridin-3-yl)-piperazin-1-yl]-propan-1-one (2.50 g, 59%) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:23][C:22](=[O:24])[N:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH:19]3[C:33]([O:35]C)=[O:34])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]3[CH2:23][C:22](=[O:24])[N:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH:19]3[C:33]([OH:35])=[O:34])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[O:7])=[CH:37][CH:38]=1
Reactant: CCCCCCCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCN1CC(C(=O)O)N(S(=O)(=O)c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)CC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
The compound of Example 59 (0.56 g, 0.99 mmol) was dissolved in 8 mL of THF, and 2 mL of 2N NaOH were added dropwise while maintaining the temperature at 0° C. After stirring at room temperature for 2 hours, 20 mL of distilled water were added and a 2N HCl solution was further added to control the pH to 1-2, and then the reactant was extracted with ethyl acetate. The supernatant was collected, and dried and concentrated under reduced pressure, and then recrystallized with ethyl acetate/hexane to obtain a light yellow solid compound (0.15 g, yield 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[N:9]2)=[CH:4][CH:3]=1.[C:29](Cl)([Cl:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:29]([Cl:31])=[O:30])[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1
Product: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride was prepared from 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole (example 1) and phosgene in an analogous manner as described in example 6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Na+].S(OC)(O[CH3:16])(=O)=O>O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:16])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(O)cc(Br)c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C)cc(Br)c1

Procedure:
A mixture of 5-bromo-3-hydroxytoluene (93 g, 0.5 m) and sodium hydroxide (21 g, 0.5 m) in water (200 ml) is stirred at 10°, treated with dimethyl sulfate (63 g, 0.5 m) over 1 hour, refluxed for 2 hours and cooled. The mixture is diluted with water and extracted with ether. The ether extract is washed, dried with sodium sulfate and concentrated in vacuo to give 5-bromo-3-methoxytoluene.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1.[N+:25]([O-])([OH:27])=[O:26].O>C(OC(=O)C)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:11][CH:12]=2)[N:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=2)[N:3]=1
Reactant: COc1ccc(-n2nc(Cl)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(-n2nc(Cl)cc2-c2ccc(S(C)(=O)=O)cc2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-chloro-1-(4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (278 mg) in a mixture of acetic anhydride (5 ml) and acetic acid (5 ml), nitric acid (sp. gr. 1.42) (0.5 ml) was added at 0° C. After 30 minutes, the resulting mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crystals. The resulting crystals were washed with ethyl acetate to give 3-chloro-1-(4-methoxy-3-nitro-phenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (297 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:42])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCCON1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 125.1 %

Procedure:
A solution of 2-[4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione (7.65 g, 17.3 mmol) in dichloromethane (100 mL) was treated with mCPBA (4.65 g, 20.7 mmol), and the resulting orange solution was stirred for four hours at room temperature. The solution was then diluted with dichloromethane (100 mL), washed with brine (3×100 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure to provide 9.92 g of 2-[4-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione as a red semi-solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(P(CCCC)CCCC)CCC.[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:35]2[CH:36]=[CH:37][C:32]([C:31]([O:30][CH3:29])=[O:39])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a stirred solution of N-Boc-4-piperidinemethanol (10 g, 46.45 mmol) in dry THF (500 mL) was added tributyl phosphine (18.77 g, 92.9 mmol) and 4-hydroxy benzoic acid methyl ester (10.6 g, 69.67 mmol). The reaction mixture was cooled to 0° C. and ADDP (23.41 g, 92.9 mmol) was added dropwise from an addition funnel over a period of 1 hr. The reaction was gradually brought to room temperature and stirring continued for 1 hr. The sol-vent was removed under vacuum and EtOAc (50 mL) was added and cooled to 0° C. The solid formed was filtered and the clear filtrate concentrated and purified by column chromatography (ISCO) using a step gradient starting with heptane going to EtOAc 100%. Desired fractions were collected and the solvent evaporated in vacuo affording 5.9 g (36%) of 4-(4-methoxycarbonyl-phenoxymethyl)-piperidine-1-carboxylic acid t-butyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=[S:25])[NH:23][NH2:24])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26](OC)(OC)(OC)[CH2:27][CH2:28][CH2:29][CH3:30]>COCCO>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[C:26]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:24][NH:23][C:22]2=[S:25])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCC(OC)(OC)OC
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=S)NN)cc1
Solvent: COCCO
Product: CCCCc1n[nH]c(=S)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
A solution of 1.11 g (3.1 mmole) of 4-[[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl]-3-thiosemicarbazide and 792 μl (745 mg, 4.6 mmole) of trimethyl orthovalerate in 10 ml of 2-methoxyethanol was stirred at reflux under N2 for 15 hours. The cooled solution was concentrated, and the residue was purified by column chromatography on silica gel (gradient elution with 0-1% methanol in CH2Cl2) to give a gum which could be crystallized by trituration with petroleum ether. The product (828 mg, 63%, mp 135°-137° C.) was homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 424 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:19]2[C:11](=[C:12]([OH:31])[C:13]3[C:14](=[O:30])[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16](=[O:21])[C:17]=3[C:18]=2[OH:20])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[O:20][C:18]1[C:17]2[C:16](=[O:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:14](=[O:30])[C:13]=2[C:12]([OH:31])=[C:11]2[C:19]=1[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[N:10]2)[CH3:43]
Reactant: O=C1c2c(c(O)c3c(ncn3Cc3ccccc3)c2O)C(=O)N1Cc1ccc(F)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)Oc1c2c(c(O)c3ncn(Cc4ccccc4)c13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 16 h
Yield: 13 %

Procedure:
1-Benzyl-6-(4-fluoro-benzyl)-4,8-dihydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione 255 (1 g, 2.39 mmol, 1 equiv.) was dissolved in a flask containing DMF (24 mL, 0.1 M) and pyridine (290 μL, 2.88 mmol, 1.5 equiv.). Ethyl chloroformate was added (231 μL, 2.88 mmol, 1.2 equiv.) under a nitrogen atmosphere. The reaction was stirred for 16 hours before being quenched with saturated NH4Cl (30 mL) and extracted with ethyl acetate (2×30 mL) and the organic layer washed several times with water (4×30 mL), saturated NaHCO3 (50 mL), brine solution (50 mL). It was dried over Na2SO4, filtered and concentrated in vacuo. Trituration was carried out with Hexanes/Ethyl acetate (1/4, 100 mL) to remove the corresponding biscarbonate to give carbonic acid 3-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-4-yl ester ethyl ester 256 (13%, 145 mg, 0.296 mmol). 1H NMR (300 MHz) DMSO d6 δ 8.63 (s, 1 H), 7.45-7.35 (m, 6 H), 7.15-7.33 (m, 4 H), 5.59 (s, 2 H), 4.63 (s, 2 H), 3.98 (q, J=6.9 Hz, 2 H), 1.17 (t, J=6.9 Hz, 3 H). MS: 490.2 (M+1). TLC Rf: 0.6 Ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:17]3[N:12]([N:13]=[CH:14][CH:15]=[CH:16]3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2]>C(Cl)Cl.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[C:17]3[N:12]([N:13]=[CH:14][CH:15]=[CH:16]3)[N:11]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(C2=NN3N=CC=CC3C2c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Pd]
Solvent: ClCCl
Product: CCOc1ccc(-c2nn3ncccc3c2-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
The residue from Example 6(i), 2-(4-ethoxyphenyl)-3-(4-methanesulfonyl-phenyl)-3,3a-dihydro-pyrazolo[1,5-b]pyridazine, was redissolved in DCM (5 mL) and palladium on carbon (10% wt, 0.25 g) was added. The mixture was heated under reflux for 18 hours, whereupon analysis of the mixture by mass spectrometry showed the presence of a main component, MH+ 394, corresponding to the title compound. The reaction mixture was purified directly by silica gel chromatography (ethyl acetatelcyclohexane 2:1) to give the title compound as a white solid (0.181 g, 59%). MH+ 394
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[N:13]([C:33](Cl)=[O:34])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:4]([O:36][CH2:37][CH3:38])[CH:3]=1.Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:44])=[O:43]>>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:6][C:5]([C:12]2[N:13]([C:33]([N:51]3[CH2:50][CH2:49][N:48]([CH2:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:53][CH2:52]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:4]([O:36][CH2:37][CH3:38])[CH:3]=1
Reactant: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, 2-(4-chloro-2-ethoxy-5-methanesulfonylphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C35H42N4O6S2Cl3 [(M+H)+] 783.1606, observed 783.1596
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:29](=[O:31])[NH2:30])[CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:32][CH3:33])=[O:10])(C)(C)C.[Cl:43]CCCl>Cl.O1CCOCC1>[ClH:43].[NH2:7][CH:8]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:29]([NH2:30])=[O:31])[CH2:13][CH:12]1[CH2:32][CH3:33])=[O:10]
Reactant: ClCCCl
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(N)=O)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(N)=O)CCN1C(=O)C(N)Cc1ccc(F)cc1
Reaction time: 1 h

Procedure:
[2-[4-(1-carbamoyl-2-naphthalen-2-yl-ethyl)-2-ethyl-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 37, (0.26 g, 0.5 mmol) is dissolved in 4M HCl in dioxane (7 mL). The reaction mixture is stirred for 60 minutes, then 1,2-dichloroethane (7 mL) is added. The solution is concentrated in vacuo to afford 0.24 g (quantitative yield) of the desired product.