Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[NH:5][C:6]=1[C:7]([N:9]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]1)=[O:8].[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>C1COCC1.C(OCC)(=O)C>[C:17]([C:4]1[NH:5][C:6]([C:7]([N:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]2)=[O:8])=[C:2]([NH:1][C:30]([NH:29][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=2[Cl:21])=[O:31])[CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)c1cc(N)c(C(=O)N2CCNC(=O)CC2)[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)c(C(=O)N2CCNC(=O)CC2)[nH]1
Temperature: 70 °C
Yield: 50 %

Procedure:
The previously prepared 1-(4-amino-2-tert-butyl-1H-pyrrole-5-carbonyl)-1,4-diazepan-5-one (8 mg, 0.03 mmol) and 2,3 dichlorophenyl isocyanate (5 mg, 0.03 mmol) were dissolved in THF (2 mL) and heated at 70° C. for 2 hours. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried and the solvent eliminated under vacuum. The crude product was purified by preparative thin layer chromatography using a mixture of dichloromethane:methanol 9:1 as elution solvent to afford 7.0 mg of 1-(5-tert-butyl-2-(5-oxo-1,4-diazepane-1-carbonyl)-1H-pyrrol-3-yl)-3-(2,3-dichloro-phenyl)urea as a white solid. 1H NMR (400 MHz, acetone-d6): δ (ppm) 9.60 (bs, 1H); 8.60 (d, 2H); 8.26 (d, 1H); 7.30 (t, 1H); 7.20 (d, 1H); 6.84 (t, 1H); 6.59 (d, 1H); 3.76 (m, 2H); 3.70 (m, 2H); 3.40 (m, 2H); 2.61 (m, 2H); 1.37 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:12]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cc(Cl)ccc2C1=O
Yield: 36 %

Procedure:
A solution of 25 g of 5-chloro-1-indanone, 31 ml of 3-buten-2-ol and 250 mg of p-toluenesulfonic acid in 31 ml of 2,2-dimethoxy-propane and 250 ml of anhydrous toluene was boiled under reflux for 17 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 11.9 g (36%) of (RS)-2-(2-buten-1-yl)-5-chloro-1-indanone were obtained as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[C:21](Cl)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.P(=O)([O-])[O-]>C(Cl)Cl>[C:21]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13]([O:14][CH2:15][CH3:16])([O:17][CH2:18][CH3:19])=[O:20])(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CCOP(=O)(CCCCCCCCCCCO)OCC
Agent: O=[PH]([O-])[O-]
Solvent: ClCCl
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)C=Cc1ccccc1)OCC
Reaction time: 2 h
Yield: 41 %

Procedure:
The diethyl 11-hydroxyundecylphosphonate (1.00 g, 3.24 mmol) was combined with TEA (0.48 mL, 3.40 mmol) in 15 mL dry DCM in a 50 mL round-bottomed flask (rbf) and the mixture was brought down to 0° C. Cinnamoyl chloride (566 mg, 3.40 mmol) was added dropwise. The reaction was stirred for 2 hours and then stopped once most of the starting phosphonate was consumed. TLC in ethyl acetate showed several new spots. The reaction mixture was then washed 3× (20 mL) NaOH followed by sodium thiosulfate and water washes. The organic layer was then dried over magnesium sulfate and the solvent removed. A chromatography column in ethyl acetate was run and the desired product was isolated as a yellow-tinted oil with Rf=0.60 (580 mg, 41% yield). 1H NMR (400.13 MHz, CDCl3) δ 7.68 (d, J=16.02 Hz), 7.53 (m, 2H), 7.38 (m, 3H), 6.44 (d, J=16.02 Hz), 4.20 (t, J=6.74 Hz, 2H), 4.08 (m, 4H), 1.79-1.49 (m, 6H), 1.43-1.22 (m, 20H). 13C{1H} NMR (100.61 MHz, CDCl3) δ 167.02, 144.48, 134.39, 130.14, 128.79 (2C), 127.97 (2C), 118.21, 64.65, 61.28 (d, J=6.54 Hz, 2C), 30.54 (d, J=16.94), 29.42 (2C), 29.28, 29.20, 29.02, 28.65, 25.90, 25.62 (d, J=140.40 Hz), 22.33 (d, J=5.21 Hz), 16.42 (d, J=5.92 Hz, 2C). 31P{1H} NMR (161.98 MHz, CDCl3): δ 33.32. Analysis found (calculated) %: C, 65.39 (65.73); H, 9.05 (8.96). MS (ESI, m/z): 439 ([M+H]+, 100%). Exact mass found (calculated for [M+H]+, m/z): 439.25720 (439.26079).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Nitrophenol (25.0 g, 180 mmol) and ethyl bromoacetate (20.0 ml, 180 mmol) were dissolved in N,N-dimethylformamide (40 ml), and potassium carbonate (27.4 g, 198 mmol) was added. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (100 ml) and extracted with an equivalent mixture of n-hexane and ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to quantitatively give 40.5 g of ethyl 4-aminophenoxyacetate as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:35]OC1C=CC(C)=CC=1S(Cl)(=O)=O>>[CH3:35][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:24])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C(=O)O)c(Cl)c3)cc21
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 501.26 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 2-methoxy-5-methyl-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.C=O.[OH-].[Na+].CCCCCC.[C:34]([O:37][CH2:38]C)(=[O:36])[CH3:35]>CC(O)=O>[C:34]([O:37][CH2:38][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[CH3:23])(=[O:36])[CH3:35]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(=O)OCc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1C
Temperature: 52.5 °C
Yield: 22 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (500 mg, 2.87 mmol) in AcOH (5 ml), formaldehyde (0.22 ml, 40% solution in water, 2.87 mmol) was added. After heating at 50-55° C. for 90 minutes, the reaction mixture was cooled and poured over ice. The solution was made alkaline with 2N NaOH and extracted with methylene chloride. The organic fractions were washed with water and with brine, dried (MgSO4), filtered and concentrated to give the crude product (780 mg) as a yellowish liquid. Chromatography (silica gel, hexane/ethyl acetate, 6/4) gave [1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]methyl acetate (250 mg, 22%) as a white solid: mp (DSC) 151° C. Anal Calc'd. for C21H20NSFO4 : C, 62.83; H, 5.02; N, 3.49. Found: C, 62.48; H, 5.16; N, 3.37.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Si:33]([O:50][CH2:51][C@@H:52]1[CH2:57][O:56][CH2:55][CH2:54][NH:53]1)([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Si:33]([O:50][CH2:51][C@H:52]1[N:53]([C:11](=[O:12])[CH2:10][C@@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:22])(=[O:24])=[O:23])=[CH:17][C:16]=2[S:25]([C:28]([F:30])([F:31])[F:29])(=[O:27])=[O:26])[CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:54][CH2:55][O:56][CH2:57]1)([C:46]([CH3:47])([CH3:48])[CH3:49])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)[Si](OC[C@@H]1COCCN1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
(R)-4-(Phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoic acid (INTERMEDIATE 8, 0.8 g, 1.60 mmol) was added to a solution of (S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholine, hydrochloride salt (INTERMEDIATE 103, 0.57 g, 1.60 mmol), DIPEA (0.84 ml, 4.81 mmol) and HATU (0.92 g, 2.41 mmol) in DCM (10 ml) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with H2O (2×), 1N aq. NaHSO4 and saturated aq. NaHCO3. The organic layer was dried (Na2SO4), concentrated under reduced pressure and purified by column chromatography (ISCO, eluting with 0→100% DCM/10% MeOH in DCM) to provide the title product (0.5 g, yield: 37%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[C:9]1([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClC(Cl)C>[C:5]([C:12]1[CH:13]=[CH:14][C:9]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:10][CH:11]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)NCc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)NCc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of aluminum chloride (22.3 g) in dichloroethane (40 ml) was added acetylchloride (7.1 ml). Thereto was added a solution of N-phenylmethylacetamide (10 g) in dichloroethane (20 ml) at 10-15° C. over 20 min. This reaction mixture was stirred at room temperature for 6 hr and poured into ice water (100 ml). The mixture was extracted with chloroform (100 ml×3). The chloroform layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a black brown oil (15.5 g). The obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give the title compound (6.48 g) as a black brown solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[O:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccccc1/C=C/COCc1ccccc1
Solvent: ClCCl
Product: Clc1ccccc1C1OC1COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a solution of (E)-1-(3-(benzyloxy)prop-1-enyl)-2-chlorobenzene(Preparation example 367, 4.94 g, 22 mmole) in CH2Cl2 (110 mL) was added 3-chloroperoxybenzoic acid (70˜75%, 8 g, 33 mmole) portionwise at 0° C. The mixture was stirred for 18 hr at room temperature. The TLC showed complete consumption of SM. The reaction mixture was quenched with H2O at 0° C. then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with sat′ NaHCO3, H2O, then dried over MgSO4 and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (4.3 g, 60˜80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:7]=1.C(N(C(C)C)CC)(C)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:7]=1)[NH:8][CH2:9][CH2:10][CH2:11][O:12][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-((5-bromo-2-nitrophenyl)amino)propan-1-ol (6.73 g, 24.45 mmol) was dissolved in dry dichloromethane (50 mL), and diisopropylethyl amine (6.41 mL, 36.7 mmol) and tert-butyldimethylsilyl chloride (4.42 g, 29.3 mmol) were added. This mixture was stirred at room temperature for 3 h. The organic layer was washed with water, then saturated aqueous ammonium chloride, and then brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give crude 5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-nitroaniline as an orange oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6](=[S:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-])=O)=[O:4].O>CO>[NH2:17][C:9]1[CH:10]=[C:11]([S:14][C:15]#[N:16])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[S:20]
Reactant: COC(=O)NC(=S)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Solvent: CO
Solvent: O
Product: COC(=O)NC(=S)Nc1ccc(SC#N)cc1N
Yield: 26.6 %

Procedure:
A stirred mixture of 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-thiocyanatobenzene (27.0 g.), ferrous chloride tetrahydrate (5.85 g.), methanol (450 ml.) and water (100 ml.) was brought to reflux and treated with reduced iron powder (29.7 g.) portionwise during 5 minutes. The mixture was heated at reflux for one hour, methanol (250 ml.) was added, and the boiling solution was filtered hot. The filtrate was evaporated to dryness and the residue was extracted with boiling methanol (3× 500 ml.). The extract was evaporated and the residue was recrystalised from methyl ethyl ketone (removing some undissolved material by filtration of the hot solution) to give 2-amino-1-(3-methoxycarbonyl-2-thioureido)-4-thiocyanatobenzene (6.5 g.), m.p. 174°-176° C. (with decomposition).
Reaction SMILES: CC(=[N:4][OH:5])C.CC(C)([O-])C.[K+].[C:12]([C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][C:39]=1F)[C:17]([NH:19][C:20]1[C:21]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:18])#[N:13]>CN(C=O)C.C1COCC1>[NH2:13][C:12]1[C:14]2[CH:15]=[C:16]([C:17]([NH:19][C:20]3[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:18])[CH:37]=[CH:38][C:39]=2[O:5][N:4]=1
Reactant: CC(C)=NO
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(F)c(C#N)c2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3onc(N)c3c2)cc1
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To a stirring solution of acetone oxime (94 mg, 1.28 mmol) in DMF (2 mL) was added a 1 M solution of potassium t-butoxide (1.28 mL, 1.28 mmol) in THF. After 30 min, N1-(3-cyano-4-fluorobenzoyl)-N2-(4-methoxybenzoyl)-1,2-benzenediamine (100 mg, 0.26 mmol) was added and stirring continued for 72 h. The solvents were removed in vacuo and the residue was dissolved in methanol (20 mL). To this stirring solution was added water (15 mL) and conc HCl (3 mL), and the solution was heated to reflux. After 2 h, the solvents were removed in vacuo and the residue was dissolved in methanol. Silica gel was added and then the solvents were removed in vacuo. This dry pack was loaded onto a silica gel column and eluted with 1:1 ethyl acetate/dichloromethane. The product containing fractions were combined and concentrated to give 48 mg (46%) of white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CCOC(C)=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:31][CH:28]3[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:26][CH2:27]3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
A solution of 4′-(methylsulfonyl)-4-biphenylol (0.15 g, 0.60 mmol), N-Boc-4-piperidinemethanol (0.14 g, 0.60 mmol) and Ph3P (0.16 g, 0.66 mmol) in THF (4 mL) was cooled to −20° C. Diisopropyl azodicarboxylate (0.13 g, 94%, 0.60 mmol) in THF (1 mL) was added dropwise. The reaction mixture was kept between −20° C. and 0° C. for 3 h, then allowed to warm up to ambient temperature, and stirred at ambient temperature overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by chromatography on a silica gel column eluted with 40% EtOAc/hexane to give 0.20 g (74%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.97 (d, 2H, J=7.6 Hz), 7.83 (d, 2H, J=7.3 Hz), 7.64 (d, 2H, J=7.6 Hz), 7.03 (d, 2H, J=7.8 Hz), 4.15-4.05 (m, 2H), 3.90 (d, 2H, J=6.4 Hz), 3.13 (s, 3H), 2.90-2.70 (bs, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 446 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([O:10][CH3:11])[CH2:8][C@@H:7]([NH2:12])[C@@H:6]([NH2:13])[CH2:5]1.Cl.CO[C@@H]1[C@H](OC)C[C@@H](N)[C@@H](N)C1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39]([C:44](OC1C=CC([N+]([O-])=O)=CC=1)=[O:45])=[CH:38]2>CN(C)C=O>[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39]([C:44]([NH:12][C@@H:7]1[CH2:8][C@H:9]([O:10][CH3:11])[C@H:4]([O:3][CH3:2])[CH2:5][C@@H:6]1[NH2:13])=[O:45])=[CH:38]2
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cc2cc(Cl)ccc2[nH]1
Reactant: CO[C@H]1C[C@@H](N)[C@@H](N)C[C@H]1OC
Agent: CO[C@H]1C[C@H](N)[C@H](N)C[C@H]1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](N)C[C@H]1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture (645 mg) of (1R*,2S*,4R*,5S*)-4,5-dimethoxy-1,2-cyclohexanediamine hydrochloride and (1R*,2S*,4S*,5R*)-4,5-dimethoxy-1,2-cyclohexane-diamine hydrochloride was suspended in N,N-dimethylformamide (50 ml), and triethylamine (1.10 ml) and p-nitrophenyl 5-chloroindole-2-carboxylate (920 mg) were added to stir the mixture overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to conduct extraction with dichloromethane. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:9) to obtain a mixture (330 mg) of (1R*,2S*,4R*,5S*)-N1-[(5-chloroindol-2-yl)carbonyl]-4,5-dimethoxy-1,2-cyclohexanediamine and (1R*,2S*,4S*,5R*)-N1-[(5-chloroindol-2-yl)carbonyl]-4,5-dimethoxy-1,2-cyclohexanediamine as pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])C)([CH3:4])([CH3:3])[CH3:2].Br[CH:22](CC)[CH2:23]C.C(ONC(=O)OC(C)(C)C)C1C=CC=CC=1>>[CH2:13]([O:12][N:7]([CH:8]([CH2:9][CH3:11])[CH2:22][CH3:23])[C:6](=[O:20])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCC(Br)CC
Reactant: CC(C)CN(OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NOCc1ccccc1
Product: CCC(CC)N(OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
Using the general method of Compound 54 Part B, 3-bromopentane (15.0 mL, 121 mmole) was reacted with tert-butyl N-benzyloxycarbamate (25.1 g, 112 mmole) to provide tert-butyl N-benzyloxy-N-(1-ethylpropyl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[Cl:28][C:29]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:30]=1[NH:31][C:23]([C:15]1[C:16]2[O:20][C:19]([CH3:21])([CH3:22])[CH2:18][C:17]=2[C:11]2[NH:10][C:9]([NH:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:27])=[N:13][C:12]=2[CH:14]=1)=[O:25]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cc3nc(Nc4c(Cl)cncc4Cl)[nH]c3c3c2OC(C)(C)C3)c(Cl)c1
Yield: 23.7 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 2-chloro-4-methylaniline (0.052 g, 0.361 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.030 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 2.26 (s, 3H), 3.08 (s, 2H), 7.16 (t, J=7.8 Hz, 1H), 7.30 (s, 1H), 7.36 (s, 1H), 8.43 (s, 2H), 8.46 (s, 1H), 10.09 (s, 1H), 10.99 (br s, 1H), 11.52 (br s, 1H); MS [M+H]+: 517.97.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[CH3:21][O:20][N:19]([CH3:18])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
(R)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (25 g, 0.11 mol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride, (10.5 g, 0.14 mol, 1.25 equiv) and EDCI.HCl (26.3 g, 0.14 mol, 1.25 equiv) and diisopropylethylamine (48 mL, 0.28 mol, 2.5 equiv) were dissolved in solvent (400 mL) and stirred overnight at rt. The reaction mixture was diluted with EtOAc, washed with 5% aq HCl (2×150 mL), satd aq NaHCO3 (150 mL), brine (100 mL), and dried over Na2SO4. Concentration afforded (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (24.42 g, 82%) as a clear oil. The crude product was used for next step without further purification. MS ESI +ve m/z 295 (M+Na). 1H NMR (CDCl3) δ 4.19-4.00 (m, 2H), 3.77 (m, 3H), 3.12 (s, 3H), 2.79 (m, 2H), 2.64 (m, 1H), 1.89 (m, 1H), 1.71-1.52 (m, 2H), 1.51-1.33 (m, 10H).