Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[O:35]>Cl>[CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N:14]([CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[O:35])[S:15]([C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH3:2]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1NS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C=Cc1ccc(Cl)cc1N(CC(=O)c1ccc(Cl)cc1)S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of 3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylic acid ethyl ester (3.00 g, 7.90 mmol) in NN-dimethylacetamide (15.0 ml) was added potassium carbonate (2.18 g, 15.8 mmol) and 2-bromo-4′-chloroacetophenone (2.03 g, 8.69 mmol). The reaction was stirred for 30 minutes, poured into 1N hydrochloric acid (30 ml) and extracted with methyl f-butyl ether (2×30 ml). The organic extracts were dried over magnesium sulfate, filtered, concentrated to a low volume. Hexanes was added and a solid precipitated. The precipitate was filtered to provide 3-{4-chloro-2-[[2-(4-chloro-phenyl)-2-oxo-ethyl]-(toluene-4-sulfonyl)-amino]-phenyl}-acrylic acid ethyl ester (3.19 g, 76%). mp=162-165° C. 1H NMR (300 MHz, CDCl3) d 1.38 (t, 3, J=7.2), 2.47 (s, 3), 4.28 (q, 2, J=7.2), 5.00 (bs, 2), 6.23 (d, 1, J=16.0), 7.29-7.36 (m, 4), 7.47 (d, 2, J=8.7), 7.54 (d, 1, J=8.4), 7.59 (d, 2, J=8.3), 7.74 (d, 1, J=16.0), 7.88 (d, 2, J=8.7). 13C NMR (75 MHz, CDCl3) d 14.33, 21.62, 57.72, 60.66, 112.49, 120.69, 128.07, 129.21, 129.58, 129.70, 131.22, 132.80, 133.83, 134.80, 135.84, 138.55, 139.28, 140.38, 144.46, 166.02, 191.70. IR 1720, 1698, 1590, 1338, 1313, 1179, 1161, 1089 cm−1. Analysis calculated for C26H23Cl2NO5S: C, 58.65; H, 4.35; N, 2.63. Found: C, 58.74; H, 4.56; N, 2.72.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[CH:6][C:7]([NH:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8].B([O-])([O-])O[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]([NH:9][C:10]2[CH:22]=[CH:21][C:13]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:29][CH:30]=1
Reactant: [O-]B([O-])Oc1ccc(F)cc1
Reactant: O=C(C=Cc1cccc(Br)c1)Nc1ccc(CN2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(C=Cc1cccc(-c2ccc(F)cc2)c1)Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A suspension of 1-(4-(3-bromocinnamoylamino)-benzyl)piperidine (0.4 g), 4-fluorophenyl borate (0.14 g), 1M potassium carbonate (2 ml) and ethanol (1 ml) in toluene (5 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the suspension was added tetrakistriphenylphosphinepalladium (0.05 g), and the mixture was refluxed over night. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1-(4-(3-(4-fluoro-phenyl)-cinnamoylamino)benzyl)piperidine (Compound 83) (0.35 g) as colorless crystals.
Reaction SMILES: NC[C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([C:14]3[C:15]([NH2:32])=[N:16][CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=4)[N:19]=3)=[N:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.CI.C(=O)([O-])[O-].[K+].[K+].[CH3:41][N:42]([CH:44]=O)[CH3:43]>C(OCC)(=O)C>[CH3:43][N:42]([CH2:44][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([C:14]3[C:15]([NH2:32])=[N:16][CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([S:26]([CH:29]([CH3:30])[CH3:31])(=[O:27])=[O:28])=[CH:22][CH:21]=4)[N:19]=3)=[N:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:41]
Reactant: CN(C)C=O
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CN)c4)o3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CN(C)C)c4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
3-[5-[3-(aminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (12 mg, 0.02108 mmol) was added to a solution of MeI (8.976 mg, 3.937 μL, 0.06324 mmol) and potassium carbonate (8.740 mg, 0.06324 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (3 mL) and washed successively with water (1×5 mL) and brine (1×5 mL). The organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were combined and lypholised to give the product as a yellow solid (3.0 mg, 24% yield); 1H NMR (400 MHz, MeOD) d 1.35-1.4 (m, 6H), 2.95 (s, 6H), 4.65 (s, 2H), 7.8-7.85 (m, 2H), 8.05-8.1 (m, 2H), 8.4-8.5 (m, 4H) and 9.95 (s, 1H) ppm; MS (ES+) 479.3
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-])=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.[Pd]>[C:1]([O:5][C:6](=[O:20])[N:7]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH2:17])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ccc(N)c(N(C)C(=O)OC(C)(C)C)c1
Reaction time: 8 h

Procedure:
To a solution of N-(2-nitro-5-methylthiophenyl)-N-methylcarbamic acid t-butyl ester (obtained in Reference Example 3) in anhydrous methanol (120 ml) and anhydrous tetrahydrofuran (30 ml) was added 10% palladium on carbon (3.0 g). The resulting mixture was vigorously stirred under a hydrogen atmosphere. Further 10% palladium on carbon (1.5 g) was added after 2.5 hours and 4.5 hours of the reaction respectively. The resulting mixture was stirred at room temperature for 1.5 hours and allowed to stand overnight. 10% palladium on carbon (0.7 g) was further added to the reaction mixture, which was then stirred under a hydrogen atmosphere for 1 hour. At the end of this time the 10% palladium on carbon was filtered off and the filtrate concentrated in vacuo. The residue was chromatographed on a silica gel column using ethyl acetate/n-hexane (⅓) as the eluant to afford the desired compound (3.61 g). Rf=0.24 (thin-layer chromatography on a silica gel plate using ethyl acetate/n-hexane (⅓) as the eluant).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:2]2.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:2]2[C@@H:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]3[CH2:5][CH2:6][CH:1]2[CH2:8][CH2:7]3)(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1NC2CCC1CC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1C2CCC(CC2)N1S(=O)(=O)c1ccc(OC)cc1
Yield: 37.5 %

Procedure:
To a solution of ethyl (3R)-2-azabicyclo[2.2.2]octane-3-carboxylate (362 mg, 1.97 mmol) in chloroform (4.0 ml) were added triethylamine (0.30 ml, 2.17 mmol) and 4-methoxybenzenesulfonyl chloride(448 mg, 2.17 mmol) while being cooled with ice. After a reaction at room temperature for 2 hours, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized (hexane/ethyl acetate), to give ethyl (3R)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.2]octane-3-carboxylate (261 mg). Further, mother liquid was concentrated, and the resulting residue was purified by silica gel column chromatography (1%–5% methanol/chloroform), to give the same compound (137 mg, total 399 mg, 57%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=2[CH3:20])=[C:7]([F:23])[CH:6]=1)[CH:2]=[CH2:3].[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>>[CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:25]=2[F:24])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=2[CH3:20])=[C:7]([F:23])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CNc2cccc([N+](=O)[O-])c2C)c(F)c1
Reactant: Fc1ccc(CBr)c(F)c1
Product: C=CCOc1ccc(CN(Cc2ccc(F)cc2F)c2cccc([N+](=O)[O-])c2C)c(F)c1

Procedure:
The product from Example 53C and 2,4-diflurobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 443 (M+H)+.
Reaction SMILES: [NH2:1][C@H](C1N(C2C=CC=CC=2)C(=O)C2C(C=1)=CC=CC=2C)C.ClC1N=C(Cl)C(Cl)=CN=1.C(N(CC)CC)C.[Cl:38][C:39]1[N:44]=[C:43]([NH:45][C@H:46]([C:48]2[N:49]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:50](=[O:59])[C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[CH3:58])[CH3:47])[C:42]([Cl:66])=[CH:41][N:40]=1>CCCCO>[NH2:1][C:39]1[N:44]=[C:43]([NH:45][C@H:46]([C:48]2[N:49]([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:50](=[O:59])[C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[CH3:58])[CH3:47])[C:42]([Cl:66])=[CH:41][N:40]=1.[Cl:38][C:39]1[N:44]=[C:43]([NH:45][C@H:46]([C:48]2[N:49]([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:50](=[O:59])[C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[CH3:58])[CH3:47])[C:42]([Cl:66])=[CH:41][N:40]=1
Reactant: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: Cc1cccc2cc([C@H](C)Nc3nc(Cl)ncc3Cl)n(-c3ccccc3)c(=O)c12
Agent: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1cccc2cc([C@H](C)Nc3nc(N)ncc3Cl)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
A mixture of 3-(1-aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (150 mg, 0.54 mmol), 2,4,5-trichloropyrimidine (119 mg, 0.65 mmol) and triethylamine (137 mg, 1.35 mmol) in n-BuOH (10 mL) was stirred at reflux for 2 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (MeOH:CH2Cl2=1:100) to afford the desired product, (S)-3-(1-(2,5-dichloropyrimidin-4-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (2H)-one (compound 5101) (170 mg, 74% yield) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:29][C:30](=[O:45])[C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=1.CO.[OH-].[Li+]>O1CCCC1>[C:20]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:22][C:17](/[CH:16]=[N:15]/[O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:46])=[O:2])=[C:5]([NH:29][C:30](=[O:45])[C:31]3[CH:36]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:34]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:32]=3)[CH:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)ccc1C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 22 %

Procedure:
This compound was produced using similar methods as those used in Step 6, example 28, starting with 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[3,5-bis(trifluoromethyl)benzoyl]amino}benzoic acid methyl ester (0.25 g, 0.39 mmol), 1:1 methanol:tetrahydrofuran (10 mL) and 4N aqueous lithium hydroxide solution (0.29 mL). The crude material was crystallized from hot chloroform (10 mL) by the addition of room temperature hexanes (100 mL), and allowing the mixture to sit for 2 hours. The product was isolated and then triturated with hexanes to give 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[3,5-bis(trifluoromethyl)benzoyl]amino}benzoic acid (0.054 g, 22%) as a white solid. mp=205-206° C. (dec). 1H NMR (500 MHz, DMSO-d6); δ 13.70 (bs, 1H), 12.70 (bs, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 8.32 (d, 2H), 8.00 (d, 1H), 7.67-7.64 (AA′BB′, 4H), 7.45 (t, 2H), 7.37 (t, 1H), 6.84 (d, 1H), 4.31 (t, 2H), 4.22 (t, 2H), 2.18 (m, 2H). Mass spec (MW 630.54); (ES+) m/z 630.96, (ES−) m/z 629.39. Elemental analysis; Calculated for C32H24F6N2O5: C, 60.96; H, 3.84; N, 4.44. Found: C, 60.10; H, 3.57; N, 4.18.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[Cl:29][C:30]1[CH:37]=[C:36]([C:38]2[NH:39][C:40]3[C:45]([CH:46]=2)=[C:44]([F:47])[CH:43]=[CH:42][CH:41]=3)[C:33]([CH:34]=O)=[CH:32][N:31]=1>C1COCC1.O>[Cl:29][C:30]1[CH:37]=[C:36]([C:38]2[NH:39][C:40]3[C:45]([CH:46]=2)=[C:44]([F:47])[CH:43]=[CH:42][CH:41]=3)[C:33]([CH:34]=[C:3]([CH3:4])[CH3:2])=[CH:32][N:31]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
n-BuLi (3.15 mL, 7.88 mmol, 2.5 M in hexane) was added dropwise to a mixture of isopropyltriphenylphosphonium iodide (3.55 g, 8.21 mmol) in THF (30 mL) at −78° C. under N2 atmosphere. The mixture was stirred at −78° C. for 1 hour. Then a solution of 6-chloro-4-(4-fluoro-1H-indol-2-yl)nicotinaldehyde (900 mg, 3.28 mmol) in THF (10 mL) was added dropwise to the mixture at −78° C. The mixture was stirred at room temperature overnight. The mixture was then diluted with water (100 mL) and extracted with EA (50 mL*3). The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EA=4:1) to give the product of 2-(2-chloro-5-(2-methylprop-1-en-1-yl)pyridin-4-yl)-4-fluoro-1H-indole (500 mg, yield: 50.6%). 1H-NMR (CDCl3, 400 MHz) δ 8.66 (br s, 1H), 8.17 (s, 1H), 7.51 (s, 1H), 7.12 (br s, 2H), 6.96 (d, J=1.6 Hz, 1H), 6.70˜6.81 (m, 1H), 6.22 (br s, 1H), 1.97 (s, 3H), 1.68˜1.70 (m, 1H), 1.74 (s, 3H). MS (M+H)+: 301/303.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C@H:3]([CH3:4])[CH2:2][CH:1]=[O:5])=[CH:7]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: C/C=C/C=O
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC(C)O
Product: C[C@H](CC=O)c1c[nH]c2ccccc12
Reaction time: 3 h
Yield: 71.8 %

Procedure:
Prepared according to general procedure from crotonaldehyde (100 μL, 1.25 mmol), indole (146 mg, 1.25 mmol), 2,4-dinitrobenzoic acid (53 mg, 0.25 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (62 mg, 0.25 mmol) in CH2Cl2 (2.25 mL) and isopropanol (0.25 mL) at −60° C. for 19 h at which time an additional 30 μL (0.36 mmol) of crotonaldehyde was added. The reaction was allowed to continue stirring for an additional 3 h to provide, after silica gel chromatography (20:80 EtOAc/hexanes), the title compound as a colorless oil (168 mg, 72% yield, 91% ee). IR (film) 3408, 2962, 2875, 2833, 2729, 1716, 1617, 1451, 1420, 1337, 1223, 1099, 1010, 772, 741 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.77 (dd, J=2.1, 2.1 Hz, 1H, CHO), 8.15 (s, 1H, NH), 7.68 (dt, J=0.6, 7.8 Hz, 1H, ArH), 7.35 (dt, J=1.5, 7.8 Hz, 1H, ArH), 7.27-7.15 (m, 2H, ArH), 6.94 (d, J=2.4 Hz, 1H, NCH), 3.68 (dt, J=7.2, 21 Hz, 1H, ArCH), 2.91 (ddd, J=2.4, 6.9, 16.2 Hz, 1H, CH2CO); 2.73 (ddd, J=2.1, 7.2, 16.2 Hz, 1H, CH2CO); 1.47 (d, J=6.9 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 203.0, 136.5, 126.1, 122.1, 120.7, 120.1, 119.3, 118.9, 111.4, 50.9, 26.0, 21.6; HRMS (CI) exact mass calcd for (C12H13NO) requires m/z 187.0997, found m/z 153.0993. [α]D=−2.2 (c=CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel OD-H and OD guard column (10:90 ethanol/hexanes, 1 mL/min); S isomer tr=20.2 min and R isomer tr=17.6 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=O>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:21]([CH2:20][CH3:19])=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Product: CCOC(=O)C=C(CC)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and ethyl 3-oxo-n-valerate and finely powdered Amberlyst®-15 (an organic polymeric resin featuring free sulphone groups) as catalyst there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-ethylvinyl]ureido}-benzoate, m.p. 123°-126° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:13][CH2:12][C:11]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([S:20](=[O:25])(=[O:24])[N:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=3)=[CH:9][C:8]3[C:26](=[O:30])[C:27](=[O:29])[NH:28][C:7]=3[C:6]=2[CH2:5]1.[CH3:31]I.O>CN(C)C=O>[CH3:31][N:28]1[C:7]2[C:6]3[CH2:5][N:4]([CH3:3])[CH2:13][CH2:12][C:11]=3[C:10]([C:14]3[CH:19]=[CH:18][C:17]([S:20](=[O:25])(=[O:24])[N:21]([CH3:22])[CH3:23])=[CH:16][CH:15]=3)=[CH:9][C:8]=2[C:26](=[O:30])[C:27]1=[O:29]
Reactant: CI
Reactant: CN1CCc2c(-c3ccc(S(=O)(=O)N(C)C)cc3)cc3c(c2C1)NC(=O)C3=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2c(-c3ccc(S(=O)(=O)N(C)C)cc3)cc3c(c2C1)N(C)C(=O)C3=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
NaH 60% (110 mg, 2.8 mmol) was added at 0° C. to a mixture of 8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1-H-pyrrolo[3,2-h]isoquinoline-2,3-dione (1 g, 2.5 mmol) in dimethylformamide (10 ml). The mixture was stirred at 0° C. for 10 min. Methyliodide (175 μl, 2.8 mmol) was added and the mixture was stirred or one hour at ambient temperature. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2×25 ml). The organic phase was dried over sodium sulphate and evaporated. Pure 1-methyl-8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)- 6,7,8,9-tetrahydro-pyrrolo[3,2-h]isoquinoline-2,3-dione was obtained after purification on silica gel using dichloromethane/acetone/methanol (8:1:1) as the eluent. Yield 160 mg, m.p. 232-240° C. (decomposes).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1CCCC1.O.CCOC(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([O:8][C:5]2[CH:6]=[CH:7][C:2](=[O:1])[NH:3][CH:4]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: Oc1ccc(O)nc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1ccc(Oc2ccc([N+](=O)[O-])cc2)c[nH]1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A suspension of 2,5-dihydroxy-pyridine (4.65 g, 41.9 mmol), 4-fluoro-nitrobenzene (2.22 ml, 21 mmol) and Cs2CO3 (13.7 g, 41.9 mmol) in N-methyl-pyrrolidine (60 ml) is stirred for 18 h at 90° C. under N2-atmosphere. The reaction mixture is diluted with water and AcOEt, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with a NaHCO3 solution and brine, dried (Na2SO4) and partially concentrated. Thereby the title compound crystallizes and can be filtered off and washed with AcOEt: m.p.: 214-217° C.; 1H-NMR (DMSO-d6): 11.6 (s, HN), 8.22 (d, 2H), 7.57 (d, 1H), 7.43 (dd, 1H), 6.14 (d, 2H), 6.46 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH2:7])=[O:5])[CH3:2].C(O)(=O)C.[CH:12]([C:15]([CH3:17])=O)([CH3:14])[CH3:13]>O>[CH2:1]([O:3][C:4]([NH:6]/[N:7]=[C:15](/[CH3:17])\[CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CC(=O)C(C)C
Reactant: CCOC(=O)NN
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)N/N=C(/C)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrazinecarboxylic acid ethyl ester (4.40 g, 42.2 mmol) and acetic acid 60 um, 1.0 mmol) were added to 20 mL (excess) of methyl isopropyl ketone, and the mixture was stirred at room temperature for 18 hours. Water (40 mL) was added, and the mixture was extracted with methylene chloride. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 7.25 g of crude N′-[1,2-dimethyl-prop-(Z)-ylidene]-hydrazinecarboxylic acid ethyl ester as an oil, which was used directly in the next step.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])(=O)=O)=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]2)=[CH:22][C:21]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]2)=[CH:22][C:21]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])=[CH:42][CH:43]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOCC(F)F)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.3 %

Procedure:
2-(2,2-difluoroethoxy)ethyl 4-methylbenzenesulfonate (53 mg, 0.19 mmol) dissolved in anhydrous DMF (3 mL) was added to a reaction flask containing (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (57 mg, 0.15 mmol) in DMF (3 mL) at room temperature. Cesium carbonate (98 mg, 0.30 mmol) was added to the flask, and the resulting mixture was stirred for 48 hr at room temperature. The reaction was diluted with diethyl ether (50 mL) and the organic layer was washed with an aqueous solution of ammonium chloride (50 mL), sodium bicarbonate (50 mL), and NaCl (50 ml), after which it was dried over sodium sulfate, filtered and concentrated en vacuo. The residue was purified by preparative TLC using 15% methanol in dichloromethane as the mobile phase to yield the title compound (4.6 mg, 5.0%). 1H NMR (CDCl3, 300 MHz): δ 7.33 (d, 1H, J=11.2 Hz), 7.15 (d, 1H, J=11.2 Hz), 7.14 (s, 1H), 7.06 (d, 2H, J=11.6 Hz), 6.79 (d, 2H, J=11.6 Hz), 5.86 (tt, 1H, J1=5.2 Hz, J2=66.4 Hz), 4.07-3.98 (m, 3H), 3.87-3.84 (m, 3H), 3.84-3.71 (m, 2H), 3.74 (td, 2H, J1=5.6 Hz, J2=18.4 Hz), 3.66-3.54 (m, 3H), 3.30-3.36 (m, 2H), 2.78 (br s, 1H), 2.42 (br s, 1H), 1.65 (s, 2H); LC/MS: theoretical mass=488.14; observed M+1=489.2, M+Na=511.4).