Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH2:14][N:13]2[C:30]([O:32]C(C)(C)C)=[O:31])(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH2:14][N:13]2[C:30]([OH:32])=[O:31])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)C2=CCN(C(=O)OC(C)(C)C)N(S(=O)(=O)c3ccc(OC)cc3)C=C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)C2=CCN(C(=O)O)N(S(=O)(=O)c3ccc(OC)cc3)C=C2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The t-butyl 1,5-di-[(4-methoxyphenyl)sulfonyl]-diazepine-2-carboxylate (0.45 g, 0.8 mmol) is dissolved in methylene chloride (1.5 mL) and cooled down in an ice bath. Trifluoroacetic acid (1.5 mL, 19.0 mmol) is added and the resulting solution is stirred at 0° C. for 3 hours. The reaction mixture is warmed to room temperature and an additional 1 mL of trifluroacetic acid is added. The resulting solution is stirred for an additional hour and the mixture is concentrated under reduced pressure. The residue is carried forward without further purification. MS (ESI): 485 (M+H+), 502 (M+NH4+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].CO>C1COCC1.C(OCC)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])=[O:26]
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4cccc(Cl)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added 3-chlorobenzoyl chloride (0.51 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid which was slurried in diethyl ether (20 ml) and filtered to give 0.82 g (100%) of product as an off-white solid: mp 257-259° C.; 1H NMR (DMSO-d6) d 11.06 (s, 1H), 10.43 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 7.99-7.88 (m, 3H), 7.75-7.61 (m, 3H), 5.17 (dd, J=5.5 and 12.7 Hz, 1H), 2.99-2.84 (m, 1H), 2.67-2.49 (m, 2H), 2.12-2.07 (m, 1H); 13C NMR (DMSO-d6) d 172.36, 169.78, 169.36, 167.59, 166.39, 163.57, 135.99, 135.31, 133.59, 132.11, 131.33, 130.73, 127.07, 126.76, 125.78, 118.93, 118.55, 48.91, 30.77, 21.85; Anal. Calcd. For C20H14ClN3O5: C, 58.33; H, 3.43; N, 10.20. Found: C, 58.38; H, 3.23; N, 9.95.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[F:25][C:24]([F:27])([F:26])[C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)[CH:23]=1
Reactant: OCCc1ccc(O)cc1
Reactant: Fc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: OCCc1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
2-(4-Hydroxyphenyl)ethanol (4.0 g, 29 mmol), K2CO3 (8.0 g, 58 mmol) and 2-fluoro-4-trifluoromethylpyridine (3.6 g, 22 mmol) were combined in DMSO (30 mL) and stirred at 25° C. for 20 h. The mixture was poured into H2O and extracted twice with Et2O. The combined Et2O extracts were washed with 1M NaOH, H2O, brine, and concentrated in vacuo to give 2-[4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethanol (4.7 g; 57%), mp 78-79° C.; EIMS m/z 283; 1H NMR (300 MHz, DMSO-d6) δ 8.38 (d, J=5.3 Hz, 1H), 7.0-7.5 (m, 8H), 4.67 (t, J=5.0 Hz, 2H), 2.74 (t, J=5.2 Hz, 2H).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1.[Cl:23][C:24]1[N:29]=[C:28](Cl)[N:27]=[C:26]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:23][C:24]1[N:25]=[C:26]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:27]=[C:28]([N:7]2[C:6]3[CH:8]=[C:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:10]=[C:11]([O:12][CH3:13])[C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:22])[N:29]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2[nH]c(C(F)F)nc12
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
A mixture of tert-butyl 2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (0.47 g, 1.5 mmol), 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine (0.35 g, 1.5 mmol), and powdered K2CO3 (0.83 g, 6 mmol) in DMF (10 mL) was stirred at room temperature for 30 min. The reaction mixture was then diluted with water. The resulting precipitate was collected, washed with water and then MeOH, and dried to give 0.45 g (59% yield) of tert-butyl 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate: mp (CH2Cl2/MeOH)>300° C.; 1H NMR (CDCl3) δ 8.45 (d, J=0.6 Hz, 1H), 7.57 (t, JHF=53.6 Hz, 1H), 6.67 (br, exchangeable with D2O, 1H), 6.63 (d, J=0.9 Hz, 1H), 4.11 (m, 2H), 4.02 (s, 3H), 3.97 (m, 2H), 3.88 (m, 2H), 3.82 (m, 2H), 1.52 (s, 9H); Anal. Calcd. for C21H24ClF2N7O4: C, 49.3; H, 4.7; N, 19.15. Found: C, 49.4; H, 4.8; N, 19.2%.
Reaction SMILES: I.CNC(=N)SC.CNC.C(N1C[CH2:22][N:21]([C:24]2[N:28]([CH3:29])[C:27]([CH:30]=[O:31])=[CH:26][N:25]=2)[CH2:20]C1)C1C=CC=CC=1.C(N1C[CH2:43][N:42]([C:45]2[N:46]([CH3:52])[CH:47]=[C:48]([CH:50]=[O:51])[N:49]=2)[CH2:41]C1)C1C=CC=CC=1>>[CH3:20][N:21]([CH3:22])[C:24]1[N:28]([CH3:29])[C:27]([CH:30]=[O:31])=[CH:26][N:25]=1.[CH3:41][N:42]([CH3:43])[C:45]1[N:46]([CH3:52])[CH:47]=[C:48]([CH:50]=[O:51])[N:49]=1
Reactant: Cn1cc(C=O)nc1N1CCN(Cc2ccccc2)CC1
Reactant: Cn1c(C=O)cnc1N1CCN(Cc2ccccc2)CC1
Agent: CNC
Agent: CNC(=N)SC
Agent: I
Product: CN(C)c1nc(C=O)cn1C
Product: CN(C)c1ncc(C=O)n1C

Procedure:
2-Dimethylamino-3-methyl-3H-imidazole-4-carbaldehyde and 2-dimethylamino-1-methyl-1H-imidazole-4-carbaldehyde were prepared from 1,2-dimethyl-isothiourea hydroiodide and dimethylamine in the same manner as 2-(4-benzyl-piperazin-1-yl)-3-methyl-3H-imidazole-4-carbaldehyde and 2-(4-benzyl-piperazin-1-yl)-1-methyl-1H-imidazole-4-carbaldehyde (Example 57 and Example 58).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)\[CH3:11].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)\[CH2:11][Br:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C(=C\c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(/C(=C/c2ccc(Cl)cc2Cl)CBr)cc1
Yield: 69.5 %

Procedure:
104 g of E-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)-prop-1-ene were refluxed with 62.3 g of N-bromosuccinimide and 5 g of 2,2'-azoisobutyrodinitrile in 1 liter of carbon tetrachloride, the precipitated succinimide was filtered off and the filtrate was evaporated down under reduced pressure. Treatment of the residue with methanol gives 91.5 g (69.4%) of Z-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)-3-bromoprop-1-ene of melting point 128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][C:15]([C:20]#[N:21])=C(C#N)[N:17]=1.[OH2:22].[CH2:23]([OH:25])[CH3:24]>Cl>[C:20]([C:15]1[NH:14][C:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=2[Cl:12])=[N:17][C:24]=1[C:23]([OH:22])=[O:25])#[N:21]
Reactant: O
Reactant: CCO
Reactant: N#Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1C#N
Agent: Cl
Product: N#Cc1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(=O)O

Procedure:
A solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4,5-dicyanoimidazole (25.3 g, 0.08 mol) in absolute ethanol (80 ml) and concentrated hydrochloric acid (30 ml) was heated at reflux for 69 hours. The mixture was poured into cold water (200 ml) and extracted with dichloromethane (2×150 ml). The combined organic layers were extracted with saturated aqueous sodium bicarbonate (2×200 ml) which was acidified carefully to pH 3 and extracted with dichloromethane (100 ml). The aqueous layer was acidified to pH 1 and extracted with ethyl acetate (2×100 ml), washed with water (100 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The gummy residue was treated with dichloromethane (50 ml) and evaporated to dryness to give 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole-4-carboxylic acid (6.31 g) as an off-white solid which decomposed at 80°-130° C.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH3:41][O:42][C:43]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:44]=1[CH2:45][CH2:46][N:47]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C@@H:60]([NH2:62])[CH3:61])=[CH:56][CH:55]=1)[CH2:48]2>CN(C=O)C>[CH3:41][O:42][C:43]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:44]=1[CH2:45][CH2:46][N:47]([CH2:53][C:54]1[CH:55]=[CH:56][C:57]([C@@H:60]([NH:62][C:6]([C:5]3[S:1][CH:2]=[N:3][CH:4]=3)=[O:8])[CH3:61])=[CH:58][CH:59]=1)[CH2:48]2
Reactant: COc1cccc2c1CCN(Cc1ccc([C@H](C)N)cc1)C2
Reactant: O=C(O)c1cncs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1CCN(Cc1ccc([C@H](C)NC(=O)c3cncs3)cc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
37 mg (0.29 mmol) Thiazole-5-carboxylic acid, 83 μl (0.48 mmol) DIPEA and 154 mg (0.481 mmol) TBTU in 0.5 mL DMF are stirred for 10 min at r.t. Then 80 mg (0.24 mmol) (S)-1-[4-(5-methoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-ethylamine hydrochloride (example XXXIII.2) in 1.0 mL DMF and 102 μl (0.601 mmol) DIPEA are added and the resulting mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by the addition of 200 μL water and purified by HPLC.
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.C(N(CC)CC)C.BrCC[CH2:21][CH2:22][C:23](Cl)=[O:24].[CH2:26]([Cl:29])[CH2:27]Cl>>[Cl:29][CH2:26][CH2:27][CH2:21][CH2:22][C:23]([NH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)=[O:24]
Reactant: ClCCCl
Reactant: O=C(Cl)CCCCBr
Reactant: Nc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Product: O=C(CCCCCl)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Part A. A solution of 2-amino-1H-benzimidazole (5.00 g, 57.5 mmol) and triethylamine (7.50 mL, 53.8 mmol) in ethylene dichloride (150 mL) was treated with a solution of 5-bromovaleryl chloride (5.00 mL, 37.6 mmol) in ethylene dichloride (50 mL) with stirring, for 20 hours at ambient temperature. The solution was washed with water (2×200 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to afford a solid. The solid was recrystallized from methanolacetonitrile to afford pure 5-chloro-N-(1H-benzimidazol-2-yl)-pentanamide, m.p. 161°-163° C. (2.98 g, 11.8 mmol). 1H NMR (d6 -DMSO): 12.14 (1H, br s); 11.56 (1H, br s); 7.44 (2H, dd, J=5.9, 3.0 Hz); 7.08 (2H, dd, J=5.8, 2.9 Hz); 3.58 (2H, t, J=6.6 Hz); 2.49 (2H, t, J=6.9 Hz); 1.96-1.71 (4H, m). Successive crops of solid from the mother liquor proved to be 5-bromo-N-(1H-benzimidazol-2-yl)-pentanamide (2.85 g, 9.62 mmol; total yield of products 58%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH:23][C:31](=[O:32])[CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)Cc1ccccc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)Cc2ccccc2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and 2-phenylacetyl chloride, gave 5-formyl-6-methoxy-3′-nitro-N-(2-phenylacetyl)-biphenyl-3-sulfonamide.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH:1]1([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[N:9]2[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NN(CC2CCCCC2)C(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)C(c2ccc(Cl)c(Cl)c2)C(c2ccncc2)N1CC1CCCCC1
Temperature: 0 °C

Procedure:
In a 100 mL round bottom flask, was added 0.4 g 1-Cyclohexylmethyl-4-(3,4-dichloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one and 20 mL THF, stirred at 0° C. under nitrogen. 1.32 mL 1 M LHMDS in THF was added drop wise. After stirred at 0° C. for 30 min. 0.11 mL iodomethane was added drop wise. The resulted mixture was stirred from 0° C. to rt for 2 hour, quenched with 50 mL sat. NH4Cl, extracted with dichloromethane 3×25 mL. The organic phase was dried over anhydrous Na2SO4. After purification by flash chromatography, obtained the title compound 0.4 g as light solid. MS (ES+): 418 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)([CH3:8])[CH3:7].[C:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1>[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:23](=[O:24])[CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:8])[CH3:7]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)CCc1ccccc1
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
Add n-butyllithium (2.5 M solution in hexanes, 32 mL of, 80 mmol) to a solution of 4-(S)-isopropyloxazolidin-2-one (10.26 g, 79.4 mmol) in THF (250 mL) at −78° C. Stir 30 min. Add 3-phenylpropionyl chloride (13.2 mL, 89 mmol) over 4 min. Stir 2.5 h at −78° C., then warm to −55° C. and stir 2 h. Add saturated aqueous ammonium chloride (75 mL) and warm to room temperature. Extract with dichloromethane and wash extract with 1 N NaOH (200 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate. Add hexanes (50 mL), filter solids and dry under vacuum to give a white solid (18.94 g, 91%).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19].N[C@H:21]1[CH2:28][CH2:27][CH2:26][NH:25][C:23](=[O:24])[CH2:22]1.C(#[N:31])C>>[CH2:17]([O:16][C:14]([CH2:13][N:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][CH2:8][CH:2]([NH:31][C@H:22]2[CH2:21][CH2:28][CH2:27][CH2:26][NH:25][C:23]2=[O:24])[C:3]1=[O:19])=[O:15])[CH3:18]
Reactant: CCOC(=O)CN1C(=O)C(Br)CCc2ccccc21
Reactant: N[C@H]1CCCNC(=O)C1
Reactant: CC#N
Product: CCOC(=O)CN1C(=O)C(N[C@H]2CCCCNC2=O)CCc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 15.3 g of 3-bromo-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one and 30 g of 3-(S)-amino-ε-caprolactam [L-(-)-3-aminocaprolactam] in 400 ml of acetonitrile is heated under reflux for 48 hours. The reaction mixture is cooled to room temperature, filtered, and the filtrate is evaporated to dryness. The residue is dissolved in 200 ml methylene chloride, the methylene chloride solution is washed with 2×200 ml of water and then extracted with 2×100 ml of 2N hydrochloric acid. The acidic extract is neutralized to pH 8 by addition of solid potassium carbonate. Extraction with methylene chloride yields 1-ethoxycarbonylmethyl-3-[(2-oxo-(3S)-2,3,4,5,6,7-hexahydro-1H-azepin-3-yl)-amino]-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one as a mixture of diastereoisomers. The crude product is recrystallized from methanol to yield 1-ethoxycarbonylmethyl-3-[(2-oxo-(3S)-2,3,4,5,6,7-hexahydro-1H-azepin-3-yl)-amino]-2,3,4,5-tetrahydro-1H-1-(3S)-benzazepin-2-one, m.p. 148°- 150°, the compound of formula IIa wherein COR represents carboxy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([N+:24]([O-])=O)[CH:16]=1.N[CH:28]([CH3:32])[CH2:29][C:30]#[N:31]>C(#N)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:7][C:2]=2[Cl:1])=[CH:16][C:17]=1[NH:24][CH:28]([CH3:32])[CH2:29][C:30]#[N:31])([O-:23])=[O:22]
Reactant: CC(C)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c(Cl)c1
Reactant: CC(N)CC#N
Solvent: CC#N
Product: CC(CC#N)Nc1cc(Oc2ccc(S(=O)(=O)C(C)C)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A solution of 4.0 g of 2-chloro-4-isopropylsulphonyl-(3,4-dinitrophenoxy)benzene and 2,5 g of 3-aminobutyronitrile in 30 ml of acetonitrile was refluxed for 13 hours. After evaporation the residue was recrystallized from methanol. The desired product was obtained in a yield of 3.3 g; m.p. 132° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:26]=[CH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17](=[O:27])[C:16]=3[CH:15]=2)[CH2:9]1)(OC(C)(C)C)=O.O.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>CCOC(C)=O>[C:29]1([CH3:39])[CH:30]=[CH:31][C:32]([S:35]([OH:38])(=[O:36])=[O:37])=[CH:33][CH:34]=1.[NH:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:26]=[CH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17](=[O:27])[C:16]=3[CH:15]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc3c(c2)C(=O)c2ccccc2-3)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2-c2ccc(O[C@H]3CCNC3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A solution of 2-[(S)—N-Boc-pyrrolidin-3-yloxy]-fluoren-9-one (315 mg, 0.863 mmol; Example 4A) and p-toluenesulfonic acid monohydrate (165 mg, 0.868 mmol; Aldrich) in EtOAc (15 mL) was heated to reflux. A precipitate began to form after about 30 min of heating. After 18 h, the mixture was cooled to room temperature and the yellow crystals were collected by filtration to afford the title compound (334 mg, 0.763 mmol; 88% yield): 1H NMR (300 MHz, CD3OD) δ ppm 7.67-7.73 (m, J=8 Hz, 2H), 7.55-7.63 (m, 3H), 7.52 (dt, J=7, 1 Hz, 1H), 7.27 (dt, J=7, 1 Hz, 1H), 7.20-7.24 (m, J=5, 3 Hz, 3H), 7.14 (dd, J=8, 3 Hz, 1H), 5.24-5.30 (m, 1H), 3.44-3.63 (m, 4H), 2.29-2.39 (m, 5H); MS (DCI/NH3) m/z 266 (M+H)+; Anal. C17H15NO2.C7H8O3S: C, H, N.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:42][CH2:43][CH3:44])[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)[C:19](=[O:26])[C:20]=1[CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23])[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:42][CH2:43][CH3:44])[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:3][C:4](=[O:7])[O:5][N:41]=3)=[CH:32][CH:33]=2)[C:19](=[O:26])[C:20]=1[CH:21]([OH:25])[CH:22]([CH3:23])[CH3:24])[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)c(C(O)C(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(C(O)C(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.53 g), sodium hydrogen carbonate (0.75 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-(1-hydroxy-2-methylpropyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.38 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.13 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1ccccc1F
Product: COc1ccc(NC(=O)Nc2ccccc2F)cc1-c1c(Cl)cnn1C
Yield: 26.7 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (20 mg, 0.08 mmol) was treated with 2-Fluorophenyl isocyanate (10 μL, 0.09 mmol) in a similar manner to Example 1.53, providing 8.0 mg (26%) of Compound 97: LCMS m/z (%)=375 (M+H35Cl, 100), 377 (M+H37Cl, 43). 1H NMR (400 MHz, CDCl3) δ: 8.26 (t, 1H), 7.73 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.69 (s, 1H), 7.36 (t, 1H), 7.35 (d, J=4 Hz, 1H), 7.29 (t, 1H), 7.24 (d, J=8 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 3.97 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[F:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl.O>[Cl:25][CH2:26][C:27]([N:15]1[CH2:16][CH2:17][C@H:13]([F:12])[CH2:14]1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: F[C@H]1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCl)N1CC[C@H](F)C1

Procedure:
A mixture of Step 3 intermediate (563 mg, 1.48 mmol) and triethylamine (196 mg, 1.93 mmol) in dry dichloromethane (20 ml) was added drop wise (10 min) to a stirred and cooled (0° C.) solution of chloroacetyl chloride (186 mg, 1.63 mmol) in dry dichloromethane (5 ml) over 20 min. The resulting mixture was stirred at 0° C. for 2 h and diluted with water (50 ml). The organic layer was separated, washed with water (2×50 ml), brine and dried (Na2SO4). The solvent was evaporated under reduced pressure to give 124 mg of the desired compound as an off white solid; 1H NMR (CDCl3, 300 MHz) δ 1.35 (brs, 2H), 1.20-2.41 (m, 2H), 3.52-4.11 (m, 4H), 5.19-5.43 (m, 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH2:9][CH2:10][Cl:11])=[O:7])[CH:2]([CH3:4])[CH3:3].C(O)C.[N:15]([O-])=[O:16].[Na+]>Cl.O>[CH2:1]([NH:5][C:6]([N:8]([CH2:9][CH2:10][Cl:11])[N:15]=[O:16])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNC(=O)NCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)CNC(=O)N(CCCl)N=O
Reaction time: 2 h
Yield: 70 %

Procedure:
A 2 g (11.2 mmol) quantity of 1-isobutyl-3-(2-chloroethyl) urea was dissolved in 25 ml of concentrated HCl:ethanol, 2:1, and cooled to 5° C. A solution of 773 mg (11.2 mmol) of sodium nitrite in 5 ml of water was added in portions and the mixture was stirred at this temperature for 2 hrs. The crystalline yellow solid was filtered and dried in vacuo overnight giving 1.6 g (70%) of the product, MP 51° C. (decomposes). IR analysis showed peaks at 1705/cm (C=O) and 1525/cm (C--N=O). NMR: Doublet (6H, J=6.8 Hz) at 0.9 ppm, multiplet (1H) at 2.0 ppm, multiplet (6H) at 3.7 ppm.