Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 9.7 %

Procedure:
To a 500 mL flask, equipped with mechanical stirrer and under inert atmosphere, was added acetanilide (50 g, 370 mmol), succinic anhydride (37 g, 370 mmol), and 200 mL carbon disulfide. The reaction vessel was cooled with an external ice bath while aluminum (III) trichloride (185 g, 1390 mmol) was added over 1 hour. Additional carbon disulfide (75 mL) was added, the reaction stirred for 1 hour with external ice bath, and then stirred at room temperature for 18 hours. The reaction vessel was cooled with an external ice bath and ice (75 mL) was added to the reaction to quench. The mixture was transferred to a 2 L beaker and ice was added until the final volume was 1400 mL. The insoluble material was collected by suction filtration and washed with 2×100 mL of water. The solid was then dissolved in 1000 mL of 8% aqueous sodium bicarbonate and stirred for 3 hours, diluted with an additional 200 mL of water, and filtered to remove insoluble impurities. The filtered solution was acidified with 1 M aqueous hydrochloric acid until pH=2. The crude product precipitate was collected by filtration and was re dissolved in hot (80-85° C.) water (1250 mL), insoluble material removed by decanting and the mixture cooled to 4° C. The product (8.45 g, 10%) was isolated by filtration as yellow off-white crystals. Found: C, 61.20, H, 5.63%, N, 5.94%; C12H23NO4 requires C, 61.27; H, 5.58%, N, 5.96%; 1H NMR (d6-DMSO): δ 12.2, s, 1H (COOH); δ 10.3, s, 1H(NH); δ 7.9, d, 2H (aryl H's); δ 7.7 d, 2H (aryl H's); 3.2, t, 2H(CH2 α to carbonyl); δ 2.6, t, 2H(CH2 α to COOH); δ 2.1, s, 3H(CH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[S:18][C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:30]=[C:29]([C:31]5[CH:32]=[N:33][N:34]([CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])[CH:35]=5)[CH:28]=[CH:27][C:24]=4[C:25]=3[N:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[Cl:46]N1C(=O)CCC1=O.Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([N:12]2[C:16]([Cl:46])=[CH:15][N:14]=[C:13]2[C:17]2[S:18][C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:30]=[C:29]([C:31]5[CH:32]=[N:33][N:34]([CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])[CH:35]=5)[CH:28]=[CH:27][C:24]=4[C:25]=3[N:26]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nccn4C4CN(C(=O)OC(C)(C)C)C4)nc2-3)cn1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncc(Cl)n4C4CN(C(=O)OC(C)(C)C)C4)nc2-3)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of 3-(2-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (90.0 mg, 0.179 mmol) in N,N-Dimethylformamide (3.35 mL, 43.3 mmol) was added N-Chlorosuccinimide (19 mg, 0.14 mmol) and 1.00 M of Hydrogen chloride in Water (0.018 mL). The reaction was stirred at rt 4 h. the reaction was quenched with water then extracted with EtOAc 3×. The organic layer was dried Na2SO4, concentrated. The crude product was purified by isco column to give 3-(5-Chloro-2-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (EtOAc/Hep eluted at 75%). MS: (ESI+)=483.1
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=CC=CC=1.N[C@H:14](C(O)=O)C(C)C.N[C@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[C@H:3]([CH2:4][CH3:9])[CH3:14]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
Phe 0.61; Val 0.54; Leu 0.53; Trp 0.37;
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(S(=O)(=O)c3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and benzenesulfonyl chloride in the same manner as in Example 32.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[CH3:13][O:14][C:15]1[CH:22]=[CH:21]C(CN)=[CH:17][CH:16]=1.C(Cl)Cl>O1CCCC1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:11]([CH2:12][NH:8][C:1]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[O:2])=[CH:17][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)n2ccnc2)cc1

Procedure:
23.6 g of carbonyldiimidazole are added in portions to a solution of 20 g of 4-methoxybenzylamine in 100 ml of anhydrous tetrahydrofuran, the temperature being kept below 10° C. When the addition is complete, the mixture is allowed to return to room temperature and stirring is maintained for three hours. After filtration, the tetrahydrofuran phase is evaporated under vacuum and the residue obtained is taken up with methylene chloride, washed with water and then dried. The oil obtained after evaporation of the methylene chloride is crystallized from ether. The crystals obtained are filtered off and then dried. 22.7 g of N-(4-methoxybenzyl)imidazolecarboxamide are thus recovered in the form of crystals melting at 117° C.
Reaction SMILES: CI.[O:3]=[C:4]([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])[CH2:24][CH2:23]1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[OH:21])=[O:8].[C:40]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:3]=[C:4]([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:37])([F:38])[F:36])[CH2:24][CH2:23]1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][C:10]=1[O:21][CH3:40])=[O:8]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(-c2ccccc2)ccc1C(=O)NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.84 %

Procedure:
Methyl iodide (21 mg, 0.009 ml, 0.148 mmol) was added to a stirred solution of 3-hydroxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (prepared by the method as described above) (51 mg, 0.1 mmol) and K2CO3 (20 mg, 0.144 mmol) in DMF (3 mL) and the resulting mixture was stirred at 80° C. for 2 hrs. The mixture was filtered, the filtrate was diluted with cold water and filtered the solid precipitated out, dried to afford 41 mg (78.84% yield) of 3-methoxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. 1H NMR: (DMSO-d6): δ 8.8-8.7 (bs, 1H), 8.04-7.98 (bs, 1H), 7.88-7.74 (dd, 4H), 7.72-7.64 (t, 1H), 7.58-7.46 (m, 3H), 7.46-7.34 (m, 3H), 4.32-4.18 (bs, 1H), 4.04 (s, 3H), 3.8-3.66 (bd, 2H), 3.66-3.54 (bt, 3H), 3.22-3.04 (bs, 1H).
Reaction SMILES: CS(C(S(C)(=O)=O)=[N:6][CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH2:32])[C:8](N1C2CC3C(C)(C)C2(CC3)CS1(=O)=O)=[O:9])(=O)=O.Cl.[O:38]1CCCC1>>[NH2:6][CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH2:32])[C:8]([OH:9])=[O:38]
Reactant: C1CCOC1
Reactant: C=Cc1ccccc1CC(N=C(S(C)(=O)=O)S(C)(=O)=O)C(=O)N1C2CC3CCC2(CS1(=O)=O)C3(C)C
Agent: Cl
Product: C=Cc1ccccc1CC(N)C(=O)O

Procedure:
For example, the appropriate 2-(bis-methylsulfonyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo[5.2.1.0 1,5]dec-4-yl)-3-(2-vinyl-phenyl)-propan-1-one derivative of structure (5) is treated with a suitable acid such as aqueous hydrochloric acid in a suitable organic solvent such as tetrahydrofuran. The reaction is conducted at a temperature range of from -10° C. to room temperature and for a period of time ranging from 30 minutes to 20 hours. Evaporation of the solvent followed by treatment with inorganic base such as aqueous lithium hydroxide in a suitable organic solvent, such as tetrahydrofuran. The reaction is conducted at a temperature range of from -10° C. to room temperature and for a period of time ranging from 30 minutes to 10 hours. After acidification, the corresponding 2-amino-3-(2-vinyl-phenyl)-propionic acid derivative of structure (6) was isolated by evaporation of solvents.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6](N2C=NC=C2)=[O:7])[CH:2]=1.[CH3:13][C:14]1[N:15]=[C:16]([NH2:31])[S:17][C:18]=1[C:19]1[N:20]=[C:21]([C:24]2([C:27]([F:30])([F:29])[F:28])[CH2:26][CH2:25]2)[S:22][CH:23]=1>C(Cl)Cl>[CH3:13][C:14]1[N:15]=[C:16]([NH:31][C:6]([N:3]2[CH:2]=[CH:1][N:5]=[CH:4]2)=[O:7])[S:17][C:18]=1[C:19]1[N:20]=[C:21]([C:24]2([C:27]([F:30])([F:29])[F:28])[CH2:25][CH2:26]2)[S:22][CH:23]=1
Reactant: Cc1nc(N)sc1-c1csc(C2(C(F)(F)F)CC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(C2(C(F)(F)F)CC2)n1
Reaction time: 3 h

Procedure:
CDI (0.13 g) was added to a stirred solution of 4′-methyl-2-(1-trifluoromethyl-cyclopropyl)-[4,5]bithiazolyl-2′-ylamine (Step 10.2) (0.16 g) in CH2Cl2 (5 mL) at rt. The reaction mixture was then stood for 3 h at 25° C. and the title compound isolated by filtration.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([NH2:33])[CH:27]=2)=[O:22])[CH3:19].N1C=CC=CC=1C(NC(C1C=NC2C(C=1)=CC=C(N)C=2)=O)C1C=CC=CN=1>>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([NH:33][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[O:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:27]=2)=[O:22])[CH3:19]
Reactant: O=C(O)c1ccccc1OCC1CCCCC1
Reactant: CCOC(=O)c1cnc2cc(N)ccc2c1
Agent: Nc1ccc2cc(C(=O)NC(c3ccccn3)c3ccccn3)cnc2c1
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3OCC3CCCCC3)ccc2c1
Yield: 58 %

Procedure:
The title compound was prepared following the procedure of Example 134 but using 2-cyclohexylmethoxybenzoic acid and 7-aminoquinoline-3-carboxylic acid ethyl ester in the place of 2-benzyloxy-3-methoxybenzoic add and 7-amino-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide, respectively.
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[F-:23].[K+]>CS(C)=O.O>[F:23][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: [F-]
Reactant: N#Cc1c(Cl)cncc1-c1ccc(Oc2ccccc2)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1c(F)cncc1-c1ccc(Oc2ccccc2)cc1
Temperature: 120 °C
Yield: 68.5 %

Procedure:
A mixture of 3-chloro-5-(4-phenoxyphenyl)isonicotinonitrile (11.8 g, 38.5 mmol) and potassium fluoride (11.17 g, 192 mmol) in DMSO (500 mL) was heated to 120° C. for 10 days. The mixture was diluted with water (1 L) and extracted with ethyl acetate (3×400 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-15% ethyl acetate in dichloromethane-hexanes (1:2), gave 3-fluoro-5-(4-phenoxyphenyl)isonicotinonitrile as tan solid (7.66 g, 69% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.67 (1H, s), 8.64 (1H, s), 7.52-7.62 (2H, m), 7.36-7.46 (2H, m), 7.20 (1H, t, J=7.42 Hz), 7.05-7.17 (4H, m); MS (ES+) m/z: 291 (M+H); LC retention time: 4.118 min (analytical HPLC Method A).
Reaction SMILES: [C:1]([Cu])#[N:2].CN(C)C=O.[CH2:9]([O:17][C:18]1[CH:41]=[CH:40][C:21]([C:22]([O:24][C:25]2([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=3)[CH:30]=[CH:29][CH:28]=[CH:27][CH2:26]2)=[O:23])=[CH:20][CH:19]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N)CN>O.C1C=CC=CC=1>[CH2:9]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][C:25]2([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:1]#[N:2])=[CH:35][CH:34]=3)[CH:26]=[CH:27][CH:28]=[CH:29][CH2:30]2)=[O:23])=[CH:40][CH:41]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(C(=O)OC2(CCc3ccc(Br)cc3)C=CC=CC2)cc1
Reactant: N#C[Cu]
Solvent: c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C(=O)OC2(CCc3ccc(C#N)cc3)C=CC=CC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The following are successively charged into an Erlenmeyer flask: 0.24 g (≃0.0027 mole) of CuCN, 1.5 ml of dimethylformamide (DMF) and 1 g (>0.002 mole) of 1-(4'-octyloxybenzoyloxy) phenyl-2-(4-bromophenyl) ethane. The whole is brought to 160° C. fot six hours while stirring briskly. The mixture is then allowed to cool to ambient temperature. It is poured into a solution of 0.7 g of ethylene diamine in 10 ml of water. It is stirred again for an hour. Benzene is poured into the solution in order to dissolve and extract the cyano product. Filtering is carried out on infus orial earth. The liquid is poured off. The aqueous fraction is washed with benzene. The organic fractions are placed together. They are washed with water until neutral. Drying is carried out on anhydrous Na2SO4. The solvent is evaporated, and chromatography is performed on a column with the mixture of 50% benzene and 50% hexane as an eluent. The product obtained is recrystallised in this mixture of solvents. 600 mg of product are obtained. The molar efficiency is 66%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:40])=[C:5]([C:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([O:33]C3CCCCO3)=[CH:29][CH:28]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[CH3:1][C:2]1[NH:3][C:4]([CH3:40])=[C:5]([C:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(OC3CCCCO3)cc2)C1c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(O)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.4 Grams of methyl 3-(4-tetrahydropyranyloxy-phenyl)2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate was dissolved in 50 ml of methanol, then 0.2 g of p-toluenesulfonic acid was added to the solution and the whole mixture was stirred at a room temperature for 4 hours. The reaction mixture was neutralized by adding sodium hydrogen carbonate, and methanol was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: chloroform), recrystallized from benzene-ether to yield 2 g of methyl 3-(4-hydroxyphenyl)-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate as in the form of light yellow powdery substance. Melting point: 137.5°-139° C.
Reaction SMILES: C([O:8][C:9]1[C:26]([F:27])=[CH:25][C:24]2=[CH:28][C:10]=1[CH2:11][N:12]([CH3:61])[C:13](=[O:60])[C@H:14]([NH:34][C:35]1[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=1)[C:41]([N:45]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[N:40][CH:39]=[CH:38]3)[C:15]1[CH:32]=[C:31]([CH3:33])[C:18]([C@@H:19]([CH3:30])[CH2:20][O:21][C:22](=[O:29])[NH:23]2)=[CH:17][CH:16]=1)C1C=CC=CC=1>CO.[Pd]>[C:48]([O:47][C:46]([N:45]([C:41]1[C:42]2[C:37](=[CH:36][C:35]([NH:34][C@H:14]3[C:13](=[O:60])[N:12]([CH3:61])[CH2:11][C:10]4[CH:28]=[C:24]([CH:25]=[C:26]([F:27])[C:9]=4[OH:8])[NH:23][C:22](=[O:29])[O:21][CH2:20][C@H:19]([CH3:30])[C:18]4[C:31]([CH3:33])=[CH:32][C:15]3=[CH:16][CH:17]=4)=[CH:44][CH:43]=2)[CH:38]=[CH:39][N:40]=1)[C:53](=[O:54])[O:55][C:56]([CH3:58])([CH3:59])[CH3:57])=[O:52])([CH3:49])([CH3:50])[CH3:51]
Reactant: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(OCc3ccccc3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(O)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
17I (0.227 g, 0.272 mmol) was dissolved in methanol (10 mL), degassed (3× Ar/vacuum). Then, Pd—C (0.029 g, 0.027 mmol) was added, and the reaction mixture was degassed again (3× Ar/vacuum). The resulting suspension was stirred under hydrogen (1 atm, balloon) for 1 h. The reaction mixture was filtered though a membrane filter, washed with MeOH (2×2 mL). MeOH was removed under reduced pressure to give 17J (0.199 g, 0.268 mmol, 98% yield) as a yellowish glass, which was lyophilized to give as a yellow solid. MS (ESI) m/z: 744.3 [M+1]+. 1H NMR: (400 MHz, CD3OD) δ ppm 8.04 (1H, d, J=5.77 Hz), 7.58-7.69 (2H, m), 7.50 (1H, d, J=6.02 Hz), 7.43 (1H, d, J=7.78 Hz), 7.24-7.30 (2H, m), 6.86 (1H, d, J=2.01 Hz), 6.50 (1H, dd, J=11.29, 2.01 Hz), 5.71 (1H, s), 5.56 (1H, br. s.), 5.36 (1H, d, J=17.32 Hz), 4.67 (1H, t, J=10.92 Hz), 3.86-3.99 (2H, m), 3.65 (2H, s), 3.41-3.55 (1H, m), 3.28 (3H, br. s.), 2.34 (3H, s), 1.23-1.36 (21H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=1.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COc1cc(-c2cccc(O)c2)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
To a solution of 6-bromo-4-(3-methoxy-phenyl)-2-methoxy-quinoline (1.31 g, 3.81 mmol) in dichloromethane (CH2Cl2. 30 ml) was added a solution of BBr3 in CH2Cl2 (1M, 11.4 ml, 11.4 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. It was poured into water. The organic layer was washed with brine, dried over MgSO4 and concentratred to give the tiltle compound of example 34A (640 mg, 41% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]2[CH:13]=[CH:12][N:11]([C@@H:14]3[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@:15]3([CH3:32])[O:16][C:17](=[O:19])[CH3:18])[C:7]=2[N:8]=[CH:9][N:10]=1)(=[O:3])[CH3:2].[Br:33]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([NH:4][C:5]1[C:6]2[C:13]([Br:33])=[CH:12][N:11]([C@@H:14]3[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@:15]3([CH3:32])[O:16][C:17](=[O:19])[CH3:18])[C:7]=2[N:8]=[CH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncnc2c1ccn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@]1(C)OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncnc2c1c(Br)cn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@]1(C)OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a pre-cooled (0° C.) solution of the compound from Step A (460 mg, 1.00 mmol) in DMF is added N-bromosuccinimide (178 mg, 1.0 mmol) in DMF. The resulting solution is stirred at 0° C. for 30 min then at room temperature for another 30 min. The reaction is quenched by addition of methanol and evaporated in vacuo. The resulting crude mixture is purified on silica gel using ethyl acetate/hexane as the eluent. Fractions containing the desired product are pooled and evaporated in vacuo to give the desired product.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:10])([CH3:9])[CH2:4][C:5](=[O:8])[O:6]2.[CH3:11][C:12]([CH3:15])([OH:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:11][C:12]([CH3:15])([O:14][CH:7]1[O:6][C:5](=[O:8])[CH2:4][C:3]([CH3:10])([CH3:9])[CH:2]1[OH:1])[CH3:13]
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(=O)OC2OC21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC1OC(=O)CC(C)(C)C1O
Temperature: 25 °C
Reaction time: 41 h

Procedure:
A mixture of 500 mg of 5,6-epoxy-4,4-dimethyl-tetrahydro-pyr-2-one, 5 ml of 1,1-dimethyl ethanol and 2.5 mg of p-toluene sulfonic acid was stirred for 41 hours at room temperature and 1 ml of pyridine was then added. The mixture was evaporated to dryness under reduced pressure to obtain 6-(1,1-dimethylethoxy)-5-hydroxy-4,4-dimethyl-tetrahydro-pyr-2-one which was used as is for the next step.
Reaction SMILES: [CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28]NC(=O)CCC(N)=O.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([Cl:28])[C:18]([OH:20])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(O)cc2C1
Reactant: NC(=O)CCC(=O)NCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(Cl)c(O)cc2C1
Reaction time: 9 h
Yield: 51.8 %

Procedure:
Under nitrogen, a suspension of N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (300 mg) and N-chlorosuccinamide (110 mg) in 1,4-dioxane (5 ml) was stirred at 10020 C. for 9 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (toluene:ethyl acetate=50:1 to 10:1) to give N-benzyl-N-(2-chloro-3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (152 mg) .
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[N+:5]([C:8]([CH3:38])([CH3:37])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[CH:13][C:12]=1[C:30]1[N:31]([CH3:36])[N:32]=[CH:33][C:34]=1[Cl:35])([O-])=O>CO.[Zn]>[Cl:35][C:34]1[CH:33]=[N:32][N:31]([CH3:36])[C:30]=1[C:12]1[CH:13]=[C:14]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][C:8]([NH:5][CH2:1][CH3:2])([CH3:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Product: CCNC(C)(C)COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (388 μl, 5.44 mmol) was added dropwise to a solution of N-(4-(2-nitro-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide (270 mg, 0.544 mmol) in methanol (5.0 mL). Zinc dust (356 mg, 5.44 mmol) was added, and the mixture was stirred at 23° C. After 1 hour, the mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in ammonium hydroxide (35%), diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, filtered, and evaporated to dryness to afford the title compound as a colorless foam which was used without further purification. LCMS m/z (%) 469.4 (M+H, 37Cl 46.9), 467.2 (M+H, 35Cl 86.1), 452.2 (51.6%), 450.1 (100.0%).