Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@@H:6]2[CH2:8][C@:5]32[C@H:9]2[C@H:18]([CH2:19][CH2:20][C@:3]13[CH3:4])[C@@H:17]1[C:12]([CH2:13][C:14](=[O:21])[CH2:15][CH2:16]1)=[CH:11][CH2:10]2.C(=O)(O)[O-].[Na+].O>CC(C)=O.Cl>[OH:1][C@H:2]1[CH2:7][C@@H:6]2[CH2:8][C@:5]32[C@H:9]2[C@H:18]([CH2:19][CH2:20][C@:3]13[CH3:4])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4CC(=O)CC[C@@H]43)[C@@]13C[C@H]3C[C@@H]2O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@]13C[C@H]3C[C@@H]2O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution that consists of 2 g of 17β-hydroxy-14α,15α-methylenestr-5-en-3-one in 95 ml of acetone and 5 ml of 5% aqueous hydrochloric acid is stirred for 2.5 hours at room temperature. Then, 10 ml of saturated aqueous sodium bicarbonate solution and 200 ml of water are added in succession. This solution is concentrated by evaporation in a vacuum rotary evaporator, whereby crystallization is used. The crystals are filtered off, dried, dissolved in acetone and applied to a silica gel column (0.063-0.2 mm, Merck). Chromatography with cyclohexane ethyl acetate 7:3 (v/v) as an eluant yields 17β-hydroxy-14α,15α-methylenestr-4-en-3-one.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:19][C:18]([C:20]([F:23])([F:22])[F:21])=[N:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[CH:13][CH:14]=1.[CH3:34][Si:35]([CH3:42])([CH3:41])[CH2:36][CH2:37][O:38][CH2:39]Cl>CCCCCC>[CH3:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]([CH2:39][O:38][CH2:37][CH2:36][Si:35]([CH3:42])([CH3:41])[CH3:34])[C:18]([C:20]([F:22])([F:23])[F:21])=[N:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(-c2[nH]c(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1cccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)nc(C(F)(F)F)n2COCC[Si](C)(C)C)c1
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
Sodium hydride (60% in oil, 1.06 mmol, 42 mg) was washed with hexane (ca 2×1 ml), then covered with N,N-dimethyformamide (2.1 ml). 5-(3-Methylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-trifluoromethyl-1H-imidazole (Example 59) (0.70 mmol, 268 mg) was added, with stirring. After 15 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (1.06 mmol, 0.19 ml) was added and the mixture was stirred overnight. The reaction was quenched with saturated ammonium chloride (ca. 4 drops), and concentrated in vacuo. The residue was subjected to chromatography (2:1 hexane: ethyl acetate) and concentrated to afford the title compound (284 mg, 79%) as an oil as a mixture of the two possible N alkylated isomers (by NMR).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[N+:26]([C:25]1[C:20]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3ccc(Nc4ncccc4[N+](=O)[O-])cc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.247 g, 1.02 mmol), 2-chloro-3-nitropyridine (0.325 g, 2.05 mmol), and 4-dimethylaminopyridine (0.062 g, 0.51 mmol) were combined in dry DMF (0.15 mL). The solution was refluxed 4 hours then 0.5 mL more DMF was added and the mixture was allowed to stir at ambient temperature overnight. 2-Chloro-3-nitropyridine (0.105 g, 0.69 mmol), and 4-dimethylaminopyridine (0.062 g, 0.51 mmol) were added and the mixture was refluxed 2 hours more. The solvent was removed in vacuo and the residue was taken up in methylene chloride. This organic phase was washed with 0.5N sodium hydroxide and brine; then it was dried over calcium sulfate and concentrated to a red oil which was flash chromatographed on silica gel (1×4 inches). Gradient elution with 50% to 75% ethyl acetate/hexane followed by elution with 100% ethyl acetate gave a dark colored oil which crystallized upon addition of ether (2 mL) to yield 0.19 g (51%) as a dark red solid: mp 127.5°-129° C. Analysis calculated for C20H21N5O2 ; C, 66.10; H, 5.82; N, 19.27. Found: C, 66.04; H, 5.81; N, 19.02.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[CH:13]1([C:16](O)=O)[CH2:15][CH2:14]1.Cl.[OH-].[Na+]>>[Br:1][C:2]1[C:3]2[N:12]=[C:16]([CH:13]3[CH2:15][CH2:14]3)[NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=C(O)C1CC1
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(Br)c2nc(C3CC3)[nH]c2c1
Temperature: 105 °C
Yield: 88.4 %

Procedure:
In a 250 mL round-bottom flask a mixture of 3-bromo-5-nitrobenzene-1,2-diamine (4 g, 17.24 mmol) and cyclopropanecarboxylic acid (14.06 ml, 155 mmol) in 3M HCl (40 ml, 120 mmol) was heated to 105° C. for 5 days. The mixture was allowed to cool to room temperature and was poured into chilled 5M NaOH (25 ml, 125 mmol) solution. The resulting mixture was allowed to stand in an icebath and the brown solid that precipitated was collected by filtration. The solid was washed several times with H2O and then dried in a vacuum oven at 50° C. The resulting dark solid 4-bromo-2-cyclopropyl-6-nitro-1H-benzo[d]imidazole (4.3 g, 15.24 mmol, 88% yield) will be used as is in the next step. MS (ES+) m/e: 280.9, 281.8 [M+H]+
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7]C(=O)OCC2C=CC=CC=2)[C:3]1([CH3:19])[CH3:18]>[Pd].CO>[NH2:7][C@H:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[C:3]1([CH3:19])[CH3:18]
Reactant: CC1(C)[C@@H](NC(=O)OCc2ccccc2)CC[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: CC1(C)[C@@H](N)CC[C@@H]1O
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of benzyl trans-3-hydroxy-2,2-dimethylcyclopentylcarbamate (1.60 g, 6.08 mmol, isomer A from Step 1) and 10% palladium on carbon (0.323 g) in methanol (30 mL) was stirred under hydrogen at 20 psi for 2 h. The mixture was filtered to remove the catalyst. The filtrate was concentrated to give trans-3-amino-2,2-dimethylcyclopentanol (800 mg, 100% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 3.65-3.91 (1H, m), 2.95-3.17 (1H, m), 1.98-2.37 (2H, m), 1.28-1.63 (2H, m), 0.98 (3H, s), 0.84 (3H, s).
Reaction SMILES: C(OC[C:5]1([CH3:16])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1([CH3:15])[CH3:14])C.C[CH:18]1C(C)(C)C2C(=CC=CC=2)[CH:19]1[OH:29].[H-].[Na+].S(OCC)(OCC)(=O)=O>>[CH2:19]([O:29][CH:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:14])([CH3:15])[CH:5]1[CH3:16])[CH3:18]
Reactant: CC1C(O)c2ccccc2C1(C)C
Reactant: CCOCC1(C)Cc2ccccc2C1(C)C
Agent: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC1c2ccccc2C(C)(C)C1C
Yield: 45 %

Procedure:
The protocol described for 2-Ethoxymethyl-1,1,2-trimethylindan (Example 3) was repeated with 2,3,3-Trimethylindan-1-ol (1.76 g, 10 mmol), NaH (870 mg at 55%, 20 mmol, 2 equiv.) and diethyl sulphate (3.08 g, 20 mmol, 2 equiv.). The crude product obtained was purified by column chromatography on SiO2 (hexane/MTBE 19:1) followed by a bulb-to-bulb distillation at 0.15 mbar/80° C. to obtain the product as a colourless liquid in 45% yield. Only the major 1,2-trans isomer was isolated and characterised.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH:12]1([C:18]([NH:20][NH2:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(=O)C1CCCCC1
Product: CCCCCCN1C(=O)/C(=N\NC(=O)C2CCCCC2)c2ccccc21
Yield: 45 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and cyclohexanecarbohydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 45%. 1NMR (DMSO-d6): δ δ 0.85 (t, J=6.8 Hz, 3H), 1.24-1.83 (m, 19H), 3.74 (t, J=6.9 Hz, 2H), 7.15 (t, J=7.5 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.59 (d, 3H), 12.34 (br s, isomer 1: 50%, 0.5H ), 13.00 (br s, isomer 2: 50%, 0.5H), both isomer are in the same proportion. 13C NMR (DMSO-d6): δ 14.33(CH3), 22.42 (CH2), 25.48 (CH2), 26.34 (CH2), 25.83 (CH2), 27.37 (CH2), 31.29 (CH2), 39.64 (CH2), 110.52 (CH), 119.78 (C), 123.48 (CH), 131.79 (CH), 143.27 (C═N), (C═O). HRMS (ES+) calcd for C21H30N3O2 (M+H+), m/e, 356.2328; found, 356.2333.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH2:15]O)[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH2:15][F:27])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO)CN(C(=O)OCc2ccccc2)C1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CF)CN(C(=O)OCc2ccccc2)C1
Yield: 45 %

Procedure:
A solution of cis(+/−)-benzyl 3-(tert-butoxycarbonylamino)-5-(hydroxymethyl)piperidine-1-carboxylate (1 eq.), perfluorobutanesulfonylfluoride (2 eq.), triethylamine-HF (4 eq.) and triethylamine (6 eq.) in tetrahydrofuran at a concentration of 0.16 M was stirred for 36 hours. Upon dilution with ethyl acetate (50×) the solution was washed with 1N HCl, NaHCO3(sat.) and brine, was dried over MgSO4, filtered, concentrated and purified by column chromatography (25-40% ethyl acetate/hexanes) to yield cis(+/−)-benzyl 3-(tert-butoxycarbonylamino)-5-(fluoromethyl)piperidine-1-carboxylate (45% yield). LCMS (m/z): 267.1 (MH+); LC Rt=4.23 min.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]2[C:16](=[O:27])[NH:17][C:18]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=2)[CH:5]=1.[OH-].[Na+].O>CO>[C:23]([C:21]1[O:20][N:19]=[C:18]([NH:17][C:16]([C@@H:11]2[CH2:12][CH2:13][C:14](=[O:15])[N:10]2[C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:28])=[O:2])=[O:27])[CH:22]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1cccc(N2C(=O)CC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCC(=O)N2c2cccc(C(=O)O)c2)no1

Procedure:
To a solution of 3-[(S)-2-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-5-oxo-pyrrolidin-1-yl]-benzoic acid methyl ester (870 mg, 2.23 mmol) in methanol (30 mL) a 2 M solution of sodium hydroxide in water (5 mL, 10 mmol) is added at room temperature. After 18 h solvent is evaporated in vacuo, the concentrate is cooled in an ice-bath and acidified to pH 2 using 1 N sulfuric acid. Precipitated white solid is filtered, washed with water and dried to give the title compound, ESI m/z 372 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:20](=[O:21])[O:19][C:18]4[CH:17]=[C:16]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)[N:15]=[CH:14][C:13]=4[CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:20](=[O:21])[O:19][C:18]4[CH:17]=[C:16]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[N:15]=[CH:14][C:13]=4[CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3oc(=O)c(-c4nc5c(Cl)cccc5s4)cc3cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1oc2cc(N3CCNCC3)ncc2cc1-c1nc2c(Cl)cccc2s1
Reaction time: 6 h
Yield: 147.5 %

Procedure:
To a suspension of t-butyl 4-(3-(4-chlorobenzo[d]thiazol-2-yl)-2-oxo-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate (96 mg, 0.19 mmol) in CH2Cl2 (2 mL) was added 4N HCl in dioxane (1 mL). The mixture was stirred for 6 hours, and filtered. The solid was washed with ether and dried under nitrogen to give 61 mg (82%) of 3-(4-chlorobenzo[d]thiazol-2-yl)-7-(piperazin-1-yl)-2H-pyrano[3,2-c]pyridin-2-one hydrochloride used in the next step without further purification. MS m/z 399.1 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.34 (2H, br), 9.13 (1H, s), 8.96 (1H, s), 8.16 (1H, d, J=6.94 Hz), 7.66 (1H, d, J=6.62 Hz), 7.46 (1H, t, J=7.88 Hz), 7.00 (1H, s), 4.01 (4H, m), 3.22 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[H-].[Na+].I[CH3:33].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[N:19]([CH3:33])[C:18]3=[O:23])=[CH:14][N:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1ccc(-c2nn(-c3ccccc3)cc2C=C2SC(=O)NC2=O)cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(-c2nn(-c3ccccc3)cc2C=C2SC(=O)N(C)C2=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
5-[3-(3-Bromo-4-ethoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl-methylene]-thiazolidine-2,4-dione (Compound No. 77, 0.10 g, 0.21 mmol) was dissolved in 1.00 mL of anhydrous dimethylformamide. Sodium hydride (12.74 mg, 0.32 mmol) was added under nitrogen atmosphere and iodomethane (19.78 μL, 0.32 mmol) was added 5 minutes later. The mixture was stirred at room temperature for 2 hours. When the reaction was completed, 10 mL of water was added and the solution was extracted with dichloromethane (10 mL×2 times). The organic layer was washed with brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The product was purified with silica gel chromatography (n-hexane/ethyl acetate=4:1) to obtain 48 mg (46.7%) of the target product in yellow solid form.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:24][C:25](=[O:40])[O:26][CH2:27][C:28]1([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29]1)[CH:12]([OH:23])[C:13](=[O:22])[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:5])=[O:4].OC([C@@H](NC(=O)OCC1(CC2C=CC=CC=2)CCCCC1)CCCCNC(N1CCOCC1)=O)C(=O)N[C@@H](C1C=CC=CC=1)C>>[CH3:41][N:2]([CH3:1])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:24][C:25](=[O:40])[O:26][CH2:27][C:28]1([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH2:31][CH2:30][CH2:29]1)[C:12](=[O:23])[C:13](=[O:22])[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)NCCCC[C@H](NC(=O)OCC1(Cc2ccc(F)cc2)CCC1)C(O)C(=O)NCc1cccnc1
Agent: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccccc2)CCCCC1)c1ccccc1
Product: CN(C)S(=O)(=O)NCCCC[C@H](NC(=O)OCC1(Cc2ccc(F)cc2)CCC1)C(=O)C(=O)NCc1cccnc1

Procedure:
[1-(4-Fluorobenzyl)cyclobutyl]methyl(1S)-5-{[(dimethylamino)sulfonyl]amino}-1-{oxo[(3-pyridinylmethyl)amino]acetyl}pentylcarbamate was prepared as in example 9j except that [1-(4-fluorobenzyl)cyclobutyl]methyl(1S)-5-{[(dimethylamino)sulfonyl]amino}-1-{1-hydroxy-2-oxo-2-[(3-pyridinylmethyl)amino]ethyl}pentylcarbamate was substituted for (1-benzylcyclohexyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate. 1H NMR (300 MHz, 80° C., DMSO-d6) δ 9.07 (m, 1H), 8.52 (s, 1H), 8.47 (d, J=5 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.33 (m, 1H), 7.21 (m, 2H), 7.08 (t, J=9 Hz, 2H), 6.82 (m, 1H), 4.85 (m, 1H), 4.40 (d, J=6 Hz, 2H), 3.81 (s, 2H), 3.10 under water peak (m, 2H), 2.92 (m, 2H), 2.70 (s, 6H), 1.70-1.95 (m, 6H), 1.37-1.65 (m, 6H). ES-LCMS m/z 592 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[Br:13]Br.C(=O)([O-])[O-].[K+].[K+].O>CO>[Br:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:1][CH3:2])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: CCc1ccccc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1ccc(Br)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The above methyl 2-ethylbenzoate was mixed with molecular sieve 13× (powder, 70 g), and while stirring the mixture, bromine (5.2 ml) was added dropwise thereto at 80° C. The mixture was further stirred at the same temperature for 1.5 hours. The mixture was cooled to room temperature, and added thereto were potassium carbonate (7.4 g), water (70 ml) and methanol (350 ml), and the mixture was stirred for 8 hours. Insoluble materials were filtered off, and suspended in a mixed solution of methanol (500 ml)-water (500 ml), and the mixture was stirred at room temperature overnight. Insoluble materials were filtered off and the filtrate was combined with the previously obtained filtrate, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure, to give methyl 5-bromo-2-ethylbenzoate (2.44 g). APCI-Mass m/Z 260/262 (M+NH4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[CH3:13][O:14][NH2:15].O>N1C=CC=CC=1>[CH3:13][O:14][N:15]=[CH:7][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[S:10][CH3:11]
Reactant: CON
Reactant: CSc1ccc(Br)cc1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON=Cc1cc(Br)ccc1SC
Yield: 96.1 %

Procedure:
(Step 2) 5-Bromo-2-(methylsulfanyl)benzaldehyde obtained in Step 1 (11.0 g) and O-methylhydroxylamine hydrochloride (4.37 g) were stirred in pyridine (30 ml) at room temperature for 14 hr. The reaction solution was treated with water, and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid (twice) and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-(methylsulfanyl)benzaldehyde O-methyloxime (11.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH2:31]=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:31])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Reactant: C=O
Product: CN1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2Cl)CC1

Procedure:
Using alkylation method B, 3-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (300 mg, 0.67 mmol) and paraformaldehyde (201 mg, 6.7 mmol) afforded, after purification (SiO2: 10:10:1 hexane:EtOAc:isopropylamine), 175 mg (57%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:19]O)[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH:7]=1.S(Cl)([Cl:23])=O.O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:19][Cl:23])[CH:3]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1
Reactant: OCc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Oc2cc(Br)cc(CCl)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of (3-bromo-5-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methanol (5.5 g, 15.8 mmol) in dry THF (30 mL) cooled to 0° C. was added thionyl chloride (3.22 mL, 44.3 mmol) dropwise. The reaction was warmed to RT and stirred for 2 h. The reaction mixture was then cooled and water was added. The mixture was extracted with ethyl acetate three times. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, and evaporated to dryness to give the title compound (4.7 g). 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.29 (s, 1H), 7.15 (s, 1H), 7.05 (d, J=8.5 Hz, 1H), 4.54 (s, 2H).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].[CH3:14][O:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CN(C=O)C>[CH3:14][O:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=1[CH2:26][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]1=[O:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(Cc2c(C(=O)OC)cccc2[N+](=O)[O-])c2ccccc21
Yield: 97.8 %

Procedure:
To a solution of 1-isopropenyl-2-benzimidazolidinone (200 mg, 1.1 mmol) in DMF (10 mL) were added methyl-2-bromomethyl-3-nitrobenzoate (472 mg, 1.7 mmol) and K2CO3 (317 mg, 2.3 mmol) at room temperature. The solution was heated to 80 C for 2 hours. The solution was cooled down and sat. NH4Cl solution was added. The solution was extracted with EtOAc. The combined organic layer was dried with MgSO4 and was filtered. The filtrate was concentrated and the residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 2-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-3-nitro-benzoic acid methyl ester (395 mg, 94%) as a pale yellow foam.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25]CC)=[O:24])[CH:16]=[N:15]3)[N:9]=2)=[CH:6][C:5]([C:28]([F:31])([F:30])[F:29])=[CH:4][N:3]=1.[CH3:32][C:33]1[CH:34]=[C:35]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH:36]=[CH:37][C:38]=1[CH2:39][OH:40]>>[CH3:32][C:33]1[CH:34]=[C:35]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:48])([F:49])[F:50])=[CH:43][CH:42]=2)[CH:36]=[CH:37][C:38]=1[CH2:39][O:40][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:18]([C:19]([F:22])([F:20])[F:21])=[C:17]([C:23]([OH:25])=[O:24])[CH:16]=[N:15]3)[N:9]=2)=[CH:6][C:5]([C:28]([F:30])([F:31])[F:29])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C(F)(F)F)cnc3F)n2)c1C(F)(F)F
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ncc(C(F)(F)F)cc1-c1cccc(-n2ncc(C(=O)O)c2C(F)(F)F)n1

Procedure:
The title compound was prepared according to the procedure described in Example 237 Step B, by reaction of the title compound from Example 240 Step A with [3-methyl-4′-(trifluoromethyl)biphenyl-4-yl]methanol (PCT Publication WO2005118542): LCMS m/z 666.8 [M+H]+; 1H NMR (500 MHz, acetone-d6) δ (ppm) 8.78 (d, J=2.3 Hz, 1H), 8.71 (s, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.26 (m, 2H), 8.22 (m, 1H), 7.92 (d, J=8.2 Hz, 2H), 7.88 (m, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.66 (s, 1H), 7.59 (dd, J=7.9, 1.7 Hz, 1H), 5.80 (s, 2H), 2.54 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[Pt]=O.CO>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(/C=C/C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: O=[Pt]
Solvent: CO
Product: CC(=O)N1CCC(CCC(=O)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To 6.74 g of (E)-4-[3-(1-acetylpiperidin-4-yl)propenoyl]nitrobenzene were added 300 ml of methanol and 0.30 g of platinum oxide, and under a hydrogen stream, the mixture was stirred at room temperature for 3 hours. Then, the solid was removed by filtration, the solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 4.81 g of the title compound as brownish white powder.