Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][CH2:17][C:16]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:23]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[C:13]([I:23])=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][CH2:17][C:16]3([O:19][CH2:20][CH2:21][O:22]3)[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(Cc2cccc(N3CCC4(C3)OCCO4)n2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccc(N2CCC3(C2)OCCO3)nc1Cc1ccccc1
Yield: 71.2 %

Procedure:
A mixture of 6.6 g of 2-benzyl-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine and 60 ml of N,N-dimethylformamide was stirred in an ice bath. Into the mixture were added dropwise 5.5 g of N-iodosuccinimide, followed by stirring at room temperature overnight as it was. 10 ml of an aqueous solution containing one mol of sodium thiosulfate was added thereto, and the mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 5-10% ethyl acetate/hexane, to give 6.7 g of the target compound.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@@H:11]([CH2:15][NH2:16])[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:18][C:19](=[CH2:21])[CH3:20].OS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[C:19]([C@:11]([NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=1)(=[O:8])=[O:9])([CH2:15][NH2:16])[C:12]([OH:14])=[O:13])([CH3:21])([CH3:20])[CH3:18]
Reactant: C=C(C)C
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CN)C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N[C@@](CN)(C(=O)O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Acid 14-3 (5.0 g, 19.4 mmol) was suspended in dioxane (100 ml) in a 1-L pressure bottle. The bottle was cooled to -15° and isobutylene (100 ml) was condenced into the dioxane. Concentrated H2SO4 (5 ml) was added and the bottle sealed and stirred at room temperature for 36 h. The bottle was opened and the excess isobutylene carefully vented. The solution was diluted with ethyl acetate (200 ml) and washed with 1N NaOH (200 ml). The organic layer was dried (Na2SO4), filtered and evaporated to give 14-4 as a white crystaline solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[Br:18]Br.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C.C1(C)C=CC=CC=1.O>[Br:18][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:3]=1[N:2]([CH3:17])[CH3:1])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CN(C)c1ccc(C(=O)c2ccccc2)cc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CN(C)c1ccc(C(=O)c2ccccc2)cc1Br
Reaction time: 1 h

Procedure:
22.5 g (0.1 mol) of 4-dimethylaminobenzophenone were dissolved in 60 ml of acetic acid, and then a solution of 5.3 ml (0.105 mol) of bromine in 20 ml of acetic acid was added dropwise thereto over a period of one hour, while stirring. The mixture was then stirred for 30 minutes more, and some water and some sodium bisulfite for decolorization were added. The greasy substance thus obtained was shaken with toluene/water, the toluene phase was washed twice more with water and dried, and the toluene was distilled off in vacuo. Yield: 24.4 g (80% of theory); viscous oil.
Reaction SMILES: [N:1]1([CH:5]2[CH2:8][N:7](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[ClH:22]>C(OCC)(=O)C>[ClH:22].[ClH:22].[N:1]1([CH:5]2[CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCC3)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C1CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(azetidin-1-yl)-1-benzhydrylazetidine (643 mg) in ethyl acetate was added a 4N solution of hydrochloric acid in ethyl acetate (1.16 ml), followed by concentration. The resultant residue was dissolved in methanol (65 ml), and 20% palladium hydroxide (811 mg) was added thereto. This was stirred at room temperature under a pressurized hydrogen atmosphere (0.3 to 0.4 MPa) for 4 hr. The catalyst was removed by filtration, and the filtrate was concentrated. Hexane was added to the residue to suspend a solid. The residue after removing a supernatant by a pipette was concentrated under reduced pressure to provide a crude product of the titled compound as a pale yellow oil (471.2 mg).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](=O)[NH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Br:1][C:2]1[C:6]2[C:7]([Cl:14])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2scc(Br)c12
Product: Clc1nccc2scc(Br)c12
Temperature: 25 °C

Procedure:
A suspension of Example 1A (35.91 g, 0.156 mol) in POCl3 (80 mL) was heated to reflux for 2.5 hours, cooled to room temperature, poured onto 800 g of ice, and extracted repeatedly with dichloromethane. The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 0 to 5% methanol/dichloromethane to provide 29.3 g of 3-bromo-4-chlorothieno[3,2-c]pyridine (mp 158-159° C.), which was diluted with dioxane (500 mL) and concentrated aqueous NH3 (500 mL), heated to 150° C. under pressure (260 psi) for 20 hours, and concentrated. The residue was triturated from MTBE then from methanol to provide 20.29 g of the desired product. m.p. 153-155° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[NH2:13][C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)=[O:17]>CCO>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:16](=[O:17])[C:15]3[C:14](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=[C:5]2[C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)=[CH:20][CH:21]=1
Reactant: Cc1cc(C=O)ccc1[N+](=O)[O-]
Reactant: Nc1ccccc1C(=O)Nc1ccc(Br)cc1
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Br)cc2)ccc1[N+](=O)[O-]
Yield: 61.7 %

Procedure:
3-methyl-4-nitrobenzaldehyde (0.85 g, 5.20 mmol) and anhydrous CuCl2 (2.1 g, 15.5 mmol) were added to a solution of 2-amino-N-(4-bromophenyl)benzamide (1.5 g, 5.20 mmol) in anhydrous EtOH (60 mL). After heating at reflux temperature for 3.5 hours, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 15% to 60% EtOAc in heptane, afforded 3-(4-bromophenyl)-2-(3-methyl-4-nitrophenyl)quinazolin-4(3H)-one (1.4 g, 62%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])[C:6](=[O:21])[C:5]1=[O:22].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])[C:6](=[O:21])[C:5]1=[O:22])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CN2CCN(CCBr)C(=O)C2=O)c(OC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(CCN=[N+]=[N-])C(=O)C2=O)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A mixture of 4.5 g of 1-(2-bromoethyl)-4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, 1.03 g of sodium azide and 45 ml of N,N-dimethylformamide was stirred at 80° C. for 1 hour and then distilled under reduced pressure to remove the solvent. To the resulting residue were added 60 ml of ethyl acetate and 30 ml of water, and the pH was adjusted to 3 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with two 30-ml portions of ethyl acetate. The combined organic layer was washed with 20 ml of water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, 5 ml of diisopropyl ether and 5 ml of diethyl ether were added to the resulting residue and the crystals were collected by filtration to obtain 3.7 g of 1-(2-azidoethyl)-4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine as colorless crystals.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.Cl.[N:88]1([CH2:93][C:94](O)=[O:95])[CH:92]=[CH:91][N:90]=[N:89]1>>[N:88]1([CH2:93][C:94]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:95])[CH:92]=[CH:91][N:90]=[N:89]1
Reactant: O=C(O)Cn1ccnn1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cn3ccnn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 1H-1,2,3-triazole-1-acetic acid hydrochloride was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 639.5 (M+H)+, 2.04 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.94 (d, J=0.9 Hz, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.77 (d, J=0.9 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 6.93 (s, 1H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 5.15 (s, 2H), 4.75 (d, J=1.5 Hz, 1H), 4.64 (br. s., 1H), 2.63-2.57 (m, 1H), 2.57-2.50 (m, 1H), 2.37 (dd, J=8.1, 12.7 Hz, 1H), 2.12 (dd, J=6.4, 17.1 Hz, 1H), 1.94-1.83 (m, 1H), 1.78-1.72 (m, 3H), 1.70 (s, 3H), 1.69-1.64 (m, 1H), 1.58-1.39 (m, 8H), 1.38-1.29 (m, 3H), 1.24 (dd, J=3.7, 10.4 Hz, 1H), 1.15-1.06 (m, 2H), 1.02 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]Br)=[CH:4][CH:3]=1.C1COCC1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: BrCCc1ccc(Br)cc1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CCc2ccc(Br)cc2)cc1

Procedure:
4-Bromophenethyl bromide (261.4 mg, 1.0 mmol) and a THF solution (1.42 mL, 1.06 M, 1.5 mmol) of 4-methoxyphenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of 4-methoxyphenylmagnesium bromide was added dropwise at 40° C. over 3 hours. After thin-layer chromatography (hexane/ethyl acetate=92/8), the title compound was obtained as a colorless liquid (0.226 g, yield 78%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17]C)[CH:16]=[C:11]2[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br.CC(O)=O>[CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([OH:17])[CH:16]=[C:11]2[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2cn1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(O)ncc2n1Cc1ccccc1

Procedure:
A solution of 1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (Compound 9, 7.0 mg, 0.016 mmol) in HBr (48%, 0.5 ml) and HOAc (1.0 ml) was heated to 120° C. for 5 h. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (PTLC) on silica gel (10% MeOH—CH2Cl2) to yield the title compound.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Na].[CH2:15](Br)[CH:16]=[CH2:17]>CO>[C:1]([CH:9]([CH2:17][CH:16]=[CH2:15])[C:10]([O:12][CH3:13])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: C=CCBr
Reactant: COC(=O)CC(=O)c1cccnc1
Agent: [Na]
Solvent: CO
Product: C=CCC(C(=O)OC)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-(nicotinoyl)acetate (17.9 g, prepared by the method of E. Wenkert et al, J. Org. Chem., 1983, 48, 5006) was added under argon to a solution of sodium metal (2.3 g) in methanol (200 ml) and the resulting mixture was stirred at 25° C. for 30 mins. Allyl bromide (12.0 g) was then added and stirring was continued overnight. A further amount (about 2 g) of allyl bromide was added, the mixture was stirred for 48 hours, and then concentrated. The residual oil was partitioned between water and ether and the aqueous layer was extracted three times with ether. The combined extracts were washed with saturated brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography, eluting with a mixture of petroleum ether (b.p. 60°-80°) and ethyl acetate (1:1, v/v) to give methyl 2-nicotinoyl-4-pentenoate (B) as a pale yellow oil (13.8 g); NMR 2.6-2.9(2H,m), 3.7(3H,s), 4.4(1 H,m), 4.9-5.2(2H,m), 5.5-6.0(1H,m), 7.2-7.5(1H,m), 8.1-8.3(1H,m), 8.7-8.8(1H,m) and 9.1-9.2(1H,m).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH2:2]1.[CH2:16]=[CH:17][CH:18]=[CH2:19]>>[CH:10]1[C:5]2[C:4]3([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:16][CH:17]=[CH:18][CH2:19][CH:3]3[CH2:2][S:1][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1=CCSc2ccccc21
Reactant: C=CC=C
Product: CCOC(=O)C12CC=CCC1CSc1ccccc12
Yield: 44 %

Procedure:
In an manner similar to that described in Example 16 the product of Example 17 was reacted with butadiene to give the title compound as a yellow oil (8.57 g, 44%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:7][C:8]([CH3:10])=O>ClC1C=CC=CC=1>[CH3:10][C:8]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[S:6][CH:7]=1
Reactant: CC(=O)CSc1cccs1
Solvent: Clc1ccccc1
Product: Cc1csc2sccc12
Yield: 41.6 %

Procedure:
A 1M solution of 1-(2-thienylthio)acetone (2.6 g, 15.1 mmol) in chlorobenzene (15 mL) was heated to 110° C. under nitrogen and hot polyphosphoric acid (3 mL) was added. The reaction was heated to reflux overnight. The chlorobenzene layer was decanted off and further chlorobenzene (15 mL x2) was added to the polyphosphoric acid residue and stirred at reflux for 30 minutes. The combined chlorobenzene extracts were concentrated in vacuo and purified by flash column chromatography on silica, eluting with 40% dichloromethane/isohexane, to give 3-methylthieno[2,3-b]thiophene (0.97 g, 42%). 1H NMR (500 MHz, CDCl3) δ 7.34 (1H, dd, J=1.0, 5.2 Hz), 7.16 (1H, d, J=5.2 Hz), 6.94 (1H, t, J=1.1 Hz), 2.40 (3H, d, J=1.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([Cl:23])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(N=C(Cl)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
Using the procedure of Step A of Example 1, 13 g of N-(4-methoxyphenyl)-3-nitrobenzamide prepared as in Step A of Example 1 and melting at 170° C. and 40 ml of thionyl chloride were reacted at reflux for 12 hours to obtain 14.5 g of N-(4-methoxyphenyl)-3-nitrobenzene-carboximidoyl chloride melting at 108° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH3:4].[Mg].I[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1>O1CCCC1.C1C=CC=CC=1.O.[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>[Br:1][C:2]1[CH:12]=[CH:7][C:8]([CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCCBr
Agent: [Pd]
Agent: [Mg]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 1414.8 %

Procedure:
A solution of 1-bromopropane (1.32 g, 0.6 mmol) was added dropwise at room temperature at a rate such that a gentle reflux was maintained to a suspension of magnesium (258 mg, 12 mmol) in dry tetrahydrofuran. The cloudy suspension was stored at room temperature for an additional 30 minutes to produce a gray solution that was then added dropwise over 15 minutes to a mixture of 1-iodo-4-bromobenzene (3.0 g, 10.6 mmol) and tetrakis (triphenylphosphine) palladium (O) in 50 mL of dry benzene at room temperature. The mixture was stirred for 2 hours, diluted with 50 mL of water, the organic layer was separated and the aqueous layer was extracted with ether (2×50 mL). The combined organic extracts was dried and evaporated to yield 1.69 g (80%) of a light brown oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example B5) (5.00 g, 14.7 mmol), isobutyl-amine (7.36 mL, 73.4 mmol) in DMSO (35 mL) at RT according to the general procedure C. Obtained as a yellow solid (5.39 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([OH:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][CH:40]1[CH2:42][CH2:41]1>CC(C)=O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([O:30][CH2:39][CH:40]3[CH2:42][CH2:41]3)=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCc1ccc(Cn2c(-c3cccnc3O)nc3cc(F)c(F)cc32)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Yield: 67 %

Procedure:
To a stirred solution of 3-{4-[5,6-difluoro-2-(2-hydroxy-pyridin-3-yl)-benzoimidazol-1-ylmethyl]-phenyl}-propionic acid methyl ester (72 mg, 0.17 mmol) in acetone (10 ml) was added cesium carbonate (85 mg, 0.26 mmol) followed by bromomethyl-cyclopropane (26 mg, 0.19 mmol; CAS Reg. No. 7051-34-5) and the reaction was refluxed for 2 h. The reaction mixture was filtered and the filtrate removed under reduced pressure. The residue was purified by column chromatography using silica gel (50-60% ethyl acetate/n-hexane) to afford the desired product as a brown solid (67%). MS (Turbo Spray): m/z=478.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[N:26][C:25]=3[O:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][S:36]([CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:38])=[O:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:34])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:45]3[CH2:46][CH2:47][N:42]([CH2:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:37])=[O:38])[CH2:43][CH2:44]3)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[N:26][C:25]=3[O:32][CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC)nn1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Product: COc1cc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2C(=O)N2CCN(CCCS(C)(=O)=O)CC2)c(OC)nn1

Procedure:
In a manner analogous to the method described in examples 3, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(3,6-dimethoxy-pyridazin-4-yl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was coupled with 4-[3-(methylsulfonyl)propyl]-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C32H39Cl2N6O5S [(M+H)+] 689.2074, observed 689.2079.
Reaction SMILES: [CH3:1][SH:2].[OH-].[Na+].Cl[C:6]1[CH:7]=[CH:8][C:9]([N+:16]([O-:18])=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1>C(O)C>[N+:16]([C:9]1[CH:8]=[CH:7][C:6]([S:2][CH3:1])=[CH:11][C:10]=1[C:12]([F:15])([F:14])[F:13])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: CS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
The sodium salt of methanethiol is formed by stirring a solution of methanethiol (100 g, 2.0 mole plus a slight excess), sodium hydroxide (80 g, 2.0 mole) and ethanol (2 l.) under nitrogen at 0°-5° C. for one hour. To this solution is rapidly added 5-chloro-2-nitrobenzotrifluoride (451.2 g, 2.0 mole). The solution is allowed to warm to room temperature overnight and then refluxed four hours, cooled, filtered and the solvent evaporated off under reduced pressure. The resulting oil is poured into cold water (1 l.), extracted with methylene chloride, dried over magnesium sulfate and the solvent evaporated under reduced pressure to afford a yellow solid. Recrystallization from hexane affords a product having a melting point of 47°-50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]2[O:18][CH2:17][O:16][C:15]=12)[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O.S(=O)(=O)(O)O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:13]=[C:14]2[O:18][CH2:17][O:16][C:15]=12
Reactant: COC(=O)CC(=O)c1cc(OC)c2c(c1)OCO2
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)CCc1cc(OC)c2c(c1)OCO2
Yield: 99.9 %

Procedure:
550 mg of methyl 3-methoxy-4,5-methylenedioxybenzoylacetate (10) and 55 mg of 5% Pd/C were suspended in 10 ml of methanol containing 2 drops (about 50 mg) of concentrated sulfuric acid. The mixture was subjected to hydrogenation at normal temperature and pressure. It was confirmed by thin layer chromatography that the hydrogenation was completed when twice as much moles of hydrogen as the starting material had been absorbed. After the catalyst was filtered out and washed, the filtrate was concentrated. The resultant residue was dissolved in 15 ml of ethyl ether, then dried over anhydrous magnesium sulfate, again filtered, washed with Et2O and concentrated to obtain 519 mg of pure methyl 3-(3-methoxy-4,5-methylenedioxyphenyl)propionate (12) with a quantitative yield.