Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:18]=[C:17]([F:19])[C:14]([CH:15]=[O:16])=[C:13]([F:20])[CH:12]=3)[C:5]2=[CH:4][N:3]=1.[OH-:22].[Na+].OO.O>>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([F:20])[C:14]([C:15]([OH:22])=[O:16])=[C:17]([F:19])[CH:18]=3)[C:5]2=[CH:4][N:3]=1
Reactant: Cn1nc(-c2cc(F)c(C=O)c(F)c2)c2cnc(N)nc21
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cn1nc(-c2cc(F)c(C(=O)O)c(F)c2)c2cnc(N)nc21
Temperature: 25 °C
Reaction time: 56 h

Procedure:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-benzaldehyde (Example 79) (0.103 g, 0.345 mmol) is suspended in 2M NaOH (0.431 ml, 0.862 mmol), 35% H2O2 in water (17.3 ml, 17.025 mmol) is added and the reaction mixture is stirred at room temperature for 56 hours. The reaction mixture is filtered through filter paper, ice is added to the filtrate and the mixture is quenched with 5M HCl resulting in a white precipitate after 1.5 hours. This solid is collected by filtration, washed with water and dried under vacuum for 24 hours at 45° C. to afford the title compound.
Reaction SMILES: Br[CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:3]([C:5]1[S:19][C:8]2[C:9]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=3[O:11][CH2:12][CH2:13][C:7]=2[CH:6]=1)=O.CC(C)=O.[NH2:31][C:32]([NH2:34])=[S:33]>>[Br:18][C:15]1[CH:16]=[CH:17][C:9]2[C:8]3[S:19][C:5]([C:3]4[N:31]=[C:32]([NH2:34])[S:33][C:2]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:6][C:7]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:14]=1
Reactant: NC(N)=S
Reactant: O=C(c1cc2c(s1)-c1ccc(Br)cc1OCC2)C(Br)c1ccccc1Cl
Solvent: CC(C)=O
Product: Nc1nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(-c2ccccc2Cl)s1
Temperature: 80 °C
Yield: 84.6 %

Procedure:
2-Bromo-1-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-(2-chlorophenyl)ethanone (ca. 2.3 mmol) was suspended in acetone (15 mL, 0.20 mol) and treated with thiourea (0.26 g, 0.0034 mol). The mixture was sealed and heated at 80° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated, suspended in water and the solid was collected by filtration. The solid was rinsed with water to give 953 mg of 271 as a light yellow solid. 1H NMR (dmso-d6, 500 MHz) δ 7.64 (m, 1H), 7.53 (m, 2H), 7.45 (m, 1H), 7.35 (m, 1H), 7.23 (m, 1H), 7.17 (m, 1H), 6.47 (s, 1H), 4.19 (t, 2H), 2.95 (t, 2H). MS (ESI) 491.0
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13]OS(C)(=O)=O)[C:9]2=[O:19])=[CH:4][CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:25][CH2:26]3)[C:9]2=[O:19])=[CH:4][CH:3]=1
Reactant: COCCN1CCNCC1
Reactant: CS(=O)(=O)OCC1CCN(c2ccc(Br)cc2)C1=O
Product: COCCN1CCN(CC2CCN(c3ccc(Br)cc3)C2=O)CC1

Procedure:
The title compound was prepared from 1-(4-bromophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 1-(2-methoxyethyl)piperazine, in the same manner as in Preparation Example 1(8).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-:16].[Na+].[Na+].C([SiH](CC)CC)C.[C]=O>CN(C=O)C>[CH:15]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1)=[O:16]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](NS(C)(=O)=O)c1ccc(Br)cc1
Agent: CC[SiH](CC)CC
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NS(C)(=O)=O)c1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Combine N-[(1R)-1-(4-bromophenyl)ethyl]-methanesulfonamide (10 g, 35 mmol), (1,1′-bis(diphenylphosphino)-ferrocene)palladium(II)chloride (733 mg, 0.9 mmol), sodium carbonate (3.81 g, 35 mmol) and DMF (50 mL) in a 300 mL PARR reactor. Add triethylsilane (11.6 mL, 0.72 mmol) and purge the reactor with carbon monoxide three times. Charge the reactor with carbon monoxide (50 psi); seal; and stir the mixture at 90° C. for 15 hours. Cool the reactor to ambient temperature; filter the resulting mixture over Celite® pad; and wash the pad with DCM (150 mL). Collect the filtrate and sequentially wash the filtrate with water then brine (2×80 mL). Concentrate the organic filtrate under reduced pressure to obtain the residue as an orange oil. Purify by silica gel flash chromatography eluting with hexane/EtOAc (0 to 30% EtOAc) to provide the title compound (5.6 g, 70%, ee>98%). MS (m/z): 228 (M+1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(=O)[CH2:22][N:23]([S:31](=[O:43])(=[O:42])[NH:32][C:33](OCC[Si](C)(C)C)=[O:34])[C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1>O1CCCC1>[I:30][C:27]1[CH:28]=[CH:29][C:24]([N:23]2[S:31](=[O:43])(=[O:42])[NH:32][C:33](=[O:34])[CH2:22]2)=[CH:25][CH:26]=1
Reactant: COC(=O)CN(c1ccc(I)cc1)S(=O)(=O)NC(=O)OCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(I)cc2)S(=O)(=O)N1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Tetrabutylammonium fluoride (6.39 g, 24.48 mmol) is added to a solution of the title A compound, N-(2-trimethylsilylethoxycarbonyl-sulfamoyl)-N-(4-iodo-phenyl)glycine methyl ester (3.15 g, 6.12 mmol) in freshly distilled tetrahydrofuran (60 mL). The reaction is stirred under argon and heated at 90° C. The reaction is monitored by reverse phase HPLC (YMC CombiScreen Pro C18, 50×4.6 mm I.D., particle size S-5 micron, 12 nM) eluting at 3 mL/min with a gradient of 90:10 (0.1% TFA in water: MeCN) to 10:90 at 7.0 min. Starting material has a retention time of 4.88 min and the product has a retention time of 2.83 min. After 24 h, the reaction is poured into 500 mL of 1N aqueous HCl and extracted with EtOAc. The organic solution is treated with Na2SO4 and charcoal, filtered through celite and concentrated to give an oil. Crystallization from EtOAc/hexane (and some additional charcoal) yields 5-(4-iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a light yellow powder: mp=191-193° C., [M−H]−=336.8.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]([CH:23]1[O:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25][CH2:24]1)=[O:22].C(N(CC)CC)C.O>CN(C)C=O>[C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:20][C:21]([CH:23]2[O:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][CH2:24]2)=[O:22])[CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCNCC1
Reactant: O=C(CBr)C1COc2ccccc2O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(=O)c1ccccc1)NC1CCN(CC(=O)C2COc3ccccc3O2)CC1
Reaction time: 1 h
Yield: 76 %

Procedure:
1-Benzoyl-3-(piperid-4-yl)urea (2.46 g, 0.01 mol) and 2-bromoacetyl-1,4-benzodioxan (2.57 g, 0.01 mol) in dry dimethylformamide (40 mls) were stirred at room temperature. Triethylamine (1,1 g, 1.5 cm3) was added and the suspension stirred for 1 hour. Water was added and the solid filtered off (4.20 g, 100%). The solid was suspended in methanol (40 mls) and ethanolic hydrogen chloride added until the solution was acidic. The title compound was filtered off as the hydrochloride salt and dried (yield 3.51 gm 76% yield). Melting pt. 160°-161° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=1[CH2:25]O)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:29])=O.C(=O)([O-])O.[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=1[CH2:25][Cl:29])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCOc1c(CO)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Yield: 89.9 %

Procedure:
To a solution of 4-butoxy-6-ethoxy-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (0.43 g, 1.2 mmol) in tetrahydrofuran (10 ml) and toluene (10 ml) was added thionyl chloride (0.18 ml, 2.4 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-butoxy-6-ethoxy-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (0.41 g, 91.1%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:15])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Br:16]Br.C(OCC)(=O)C.C(OCC)C>ClCCl>[Br:16][CH:8]([C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: BrBr
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)s1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(Br)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-(5-chlorothiophen-2-yl)-4-oxobutyrate (900 mg) in dichloromethane (9 ml) was added bromine (200 μl) under ice-cooling, and after stirring at the same temperature for 30 minutes, the reaction mixture was warmed to room temperature and the mixture was stirred for one hour. The reaction mixture was poured into ice-water, and ethyl acetate and diethyl ether were added thereto. The organic layer was collected, washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain ethyl 3-bromo-4-(5-chlorothiophen-2-yl)-4-oxo-butyrate (1.22 g) as pale brownish liquid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]([F:17])([F:16])[CH2:8][N:7]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:23]=1.[NH2:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([NH:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:30])=[CH:27][C:26]=1[O:41][CH3:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:18]1([N:7]2[CH2:8][C:9]([F:17])([F:16])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:24][C:25]4[CH:40]=[CH:39][C:28]([C:29]([NH:31][CH:32]5[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]5)=[O:30])=[CH:27][C:26]=4[O:41][CH3:42])=[N:23][C:6]2=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc21
Yield: 59.5 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144), 0.05 g (0.17 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.04 g (0.22 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75) to give 0.051 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-165).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH:25]([CH:27](OS(C)(=O)=O)[CH3:28])[CH3:26])(=O)=O>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]3[O:13][CH:25]([CH3:26])[CH:27]([CH3:28])[N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(OS(C)(=O)=O)C(C)OS(C)(=O)=O
Reactant: Oc1cc(-c2ccc(F)cc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1Oc2cc(-c3ccc(F)cc3)nn2C1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazol-5-ol (3 g, 16.8 mmol) in DMF (15 mL) was added K2CO3 (9.3 g, 67.4 mmol) and butane-2,3-diyl dimethanesulfonate (4.8 g, 18.5 mmol) (prepared as described in US2010/41748) at room temperature and then stirred for 16 h at 60° C. Thereafter, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get the crude product. Purification by column chromatography over silica gel (eluent 5-10% ethyl acetate in petrol ether) yielded 6-(4-fluorophenyl)-2,3-dimethyl-2,3-dihydropyrazolo[5,1-b][1,3]oxazole (2.8 g, 71%) as yellow oil and a mixture of diastereoisomers.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3]2([CH2:10][CH:9]3[CH2:11][N:6]2[CH2:7][CH2:8]3)[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].Br[C:65]1[CH:66]=[C:67]([O:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH:68]=[N:69][CH:70]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:71]([C:67]1[CH:66]=[C:65]([N:1]2[CH2:5][CH2:4][C:3]3([CH2:10][CH:9]4[CH2:11][N:6]3[CH2:7][CH2:8]4)[CH2:2]2)[CH:70]=[N:69][CH:68]=1)[C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1
Reactant: Brc1cncc(Oc2ccccc2)c1
Reactant: C1CC2(CN1)CC1CCN2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Oc2cncc(N3CCC4(CC5CCN4C5)C3)c2)cc1
Temperature: 160 °C
Yield: 57.9 %

Procedure:
A mixture of spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (50 mg, 0.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.009 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (12 mg, 0.018 mmol), potassium tert-butoxide (147 mg, 1.3 mmol), and 5-bromo-3-phenoxypyridine (90 mg, 0.36 mmol) in dry toluene (5 mL) was heated in a sealed tube under argon at 160° C. for 17 h. The reaction was cooled to 0° C. and the contents transferred to a 100 mL round bottom flask. The solvent was removed by rotary evaporation and the residue was dissolved in a saturated solution of NaHCO3 (10 mL) and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to give a dark colored syrup. This was purified by column chromatography, using MeOH:CHCl3:NH4OH (8:2:0.01, v/v) as the eluent, to afford 55.8 mg of 1′-(5-phenoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (52%) as a viscous tan oil.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:25][CH2:26][S:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)(=O)=O)=CC=1.O>CN(C=O)C>[CH3:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[S:1][CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cn1ccnc1S
Reactant: Cc1ccc(S(=O)(=O)OCCSc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccnc1SCCSc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
2-mercapto-1-methylimidazole (0.81 g) was dissolved in DMF (16.2 ml), potassium carbonate (1.37 g) was added to the mixture, 2-[(4-nitrophenyl)thio]ethyl 4-methylbenzene sulfonate (3.0 g) was added to the mixture, and the mixture was stirred for 12 hours at 60° C. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 1-methyl-2-[[2-[(4-nitrophenyl)thio]ethyl]thio]imidazole (1.3 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]1[CH2:10][C@H:9]([O:11]C(=O)C)[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O.C(Cl)(Cl)Cl>C1COCC1.CO.O>[C:1]([O:5][C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH:8]=[CH:7]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O[C@@H]1C=C[C@H](OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)O[C@H]1C=C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
Dissolve (-)-acetic acid cis-4-tert-butyloxy-cyclopent-2-enyl ester (90 mg, 0.45 mmol, prepared in example 14) in THF/methanol/water (1.5/0.5/0.5 mL). Add lithium hydroxide monohydrate (23.7 mg) with stirring. After stirring for about 2 hours at room temperature, dilute the reaction with water (10 mL) and extract with tert-butyl methyl ether. Combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, 2 g, 40% diethyl ether/hexane, 1.5×2.5 cm column) to provide the title compound (71 mg, quantitative yield, 76% ee) as a pale yellow oil, [α]20D =+14.6°, (c 1.03, chloroform).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([NH2:14])=[S:13])=[CH:6][CH:5]=1.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:27][CH:26]=1)=O>>[CH:15]1([N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:20])=[CH:5][CH:6]=2)[C:12]2[S:13][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C@H:32]4[CH2:37][CH2:36][C@@H:35]([CH3:38])[CH2:34][CH2:33]4)=[CH:27][CH:26]=3)[N:14]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1CCC(Oc2ccc(C(=O)CBr)cc2)CC1
Reactant: COC(=O)c1ccc(CN(C(N)=S)C2CCCC2)cc1
Product: C[C@H]1CC[C@@H](Oc2ccc(-c3csc(N(Cc4ccc(C(=O)O)cc4)C4CCCC4)n3)cc2)CC1
Yield: 36.7 %

Procedure:
4-[(Cyclopentyl-{4-[4-(cis-4-methyl-cyclohexyloxy)-phenyl]-thiazol-2-yl}-amino)-methyl]-benzoic acid (90 mg) was prepared following procedure B using 4-[(1-cyclopentyl-thioureido)-methyl]-benzoic acid methyl ester (150 mg, 0.5 mmol) and 2-bromo-1-[4-(4-methyl-cyclohexyloxy)-phenyl]-ethanone (0.5 mmol). Purification (Silica gel, ethyl acetate/hexane 5:95) provided the ester, which was hydrolyzed following procedure T. Sodium 4-[(cyclopentyl-{4-[4-(cis-4-methyl-cyclohexyloxy)-phenyl]-thiazol-2-yl}-amino)-methyl]-benzoate was made following procedure J. LCMS m/z: 492 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:2].Cl[CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[CH:32]=[CH:31][CH:30]=[CH:29]2)[CH2:18][CH2:17]1)[CH3:2]
Reactant: ClCCCCn1cccc1
Reactant: CCOCCn1c(CN2CCCNCC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOCCn1c(CN2CCCN(CCCCn3cccc3)CC2)nc2ccccc21

Procedure:
A mixture of 2.42 g (8 mmol) of 1-(2-ethoxyethyl)-2-(homopiperazin-1-yl-methyl)benzimidazole, 1.39 g (8.8 mmol) of 1-(4-chlorobutyl)pyrrole, 1.65 g (12 mmol) of potassium carbonate and 1.65 g (11 mmol) of sodium iodide in 40 ml of methyl ethyl ketone is refluxed for 16 hours. The mixture is cooled, filtered and the filtrate evaporated to dryness. The residue is taken up in chloroform and washed with water, dried, filtered and evaporated under vacuum. The resulting product is purified on a silica chromatographic column (eluent: chloroform-methanol 92:8) and 1.9 g (56%) of 1-(2-ethoxyethyl)-2-{4-[4-(pyrrol-1-yl)butyl]homopiperazin-1-yl-methyl}benzimidazole are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[O:6]
Reactant: CC(C)(N)CO
Reactant: Cc1ccc(C(=O)Cl)cc1Br
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)(C)CO)cc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred 0° C. cooled solution of 3-bromo-4-methylbenzoyl chloride (prepared from the corresponding carboxylic acid; 1.40 g, 6.04 mmol, 1.0 eq) in DCM (10 mL), was added a solution of 2-amino-2-methylpropanol (1.44 mL, 15.11 mmol, 2.5 eq) in DCM (10 mL) drop wise for 15 min and then warmed to room temperature. After stirring for 24 h at room temperature, the reaction mixture was diluted with DCM (50 mL) and the organic layer was washed with water (20 mL) followed by brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford the 1.7 g of the desired product as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 8.00 (d, J=1.0 Hz, 1H), 7.70 (dd, J=1.0, 8.0 Hz, 1H), 7.62 (s, 1H, D2O exchangeable), 7.40 (d, J=8.0 Hz, 1H), 4.85 (t, J=6.0 Hz, 1H, D2O exchangeable), 3.49 (d, J=6.0 Hz, 2H), 2.37 (s, 3H), 1.28 (s, 6H); ESI-MS (m/z) 286, 288 [(MH)+, Br79,81].
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[I:14]I.S([O-])(O)=O>O.CCCCCC.C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([I:14])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: II
Reactant: Nc1ccccc1F
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: Nc1ccc(I)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
2-Fluoroaniline (54 g, 486 mmol) was added to a vigorously stirred solution of sodium bicarbonate (41 g, 486 mmol) in water (250 mL). The suspension was warmed to 60° C. on an oil bath and iodine (123 g, 486 mmol) was added portion-wise. After complete addition, the dark mixture was stirred for an additional 3 h at 60° C. After cooling to rt, methylene chloride (300 mL) was added followed by saturated hydrogensulfite solution (300 mL). The biphasic system was vigorously stirred for an additional 10 min. The mixture was poured into a 2 L separatory funnel and the organic layer was released. The aqueous was further extracted with methylene chloride (3×200 mL) and the combined organics were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the solvent was removed to give a black crystalline solid. Hexane (300 mL) was added and the mixture was heated to reflux. The hexane was decanted from a black, insoluble syrup. The product crystallized from the hexane on cooling as fine yellow needles. 65 g (274 mmol) was isolated as a fine yellow solid. Yield: 56%; mp 53° C.; 1H NMR (400 MHz, CDCl3) δ 8.1 (t, J=8 Hz, 1H), 7.4 (d, J=6 Hz, 1H), 7.2 (d, J=6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5]O.[CH2:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:9]=1)[O:11][CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][CH2:5]2
Reactant: OCc1cc(Cl)cc(Cl)c1O
Reactant: C=Cc1ccccc1
Product: Clc1cc(Cl)c2c(c1)CCC(c1ccccc1)O2

Procedure:
3,5-Dichloro-2-hydroxybenzyl alcohol (4.0 g) and styrene (2.19 g) were heated together at 190° C. for 3 hr. The required 6,8-dichloroflavan was obtained on chromatography of the crude reaction mixture on alumina, eluting with toluene-petroleum ether (b.p. 60°-80° C.) 1:1, and recrystallised from petroleum ether (b.p. 60°-80° C.) to yield 2.60 g, m.p. 74°-76° C.