Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[C:50]1=[O:63]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:11])[NH:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[C:50]1=[O:63])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccccc1N1CCCC[C@H](N)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccccc4C)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-1-o-tolylazepan-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (45 mg, 0.080 mmol) and Intermediate 69 (27 mg, 0.080 mmol) to give a white solid (35 mg, 57% yield). Anal. Calcd. for C44H54N4O6S m/z 766.7. found: 767.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.38-6.86 (m, 14H), 5.38-5.23 (m, 1H), 5.19-5.07 (m, 1H), 5.04-4.90 (m, 1H), 4.82-4.66 (m, 1H), 4.14 (s, 3H), 4.04-3.83 (m, 1H), 3.68 (s, 3H), 3.59-3.46 (m, 1H), 3.31 (dd, J=15.0, 4.9 Hz, 1H), 3.10 (dd, J=24.7, 11.2 Hz, 1H), 2.95-2.63 (m, 4H), 2.53-2.26 (m, 3H), 2.19 and 2.13 (2s, 3H), 2.07-1.92 (m, 3H), 1.91-1.42 (m, 12H), 1.44-1.27 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:9](=[O:22])[C:10]1[CH:15]=[C:14]([F:16])[C:13]([Cl:17])=[C:12]([N+:18]([O-:20])=[O:19])[C:11]=1Cl)[C:4]([O:6][CH2:7][CH3:8])=[O:5]>O1CCOCC1>[Cl:17][C:13]1[C:12]([N+:18]([O-:20])=[O:19])=[C:11]2[C:10]([C:9]([OH:22])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:2]=[N:1]2)=[CH:15][C:14]=1[F:16]
Reactant: CCOC(=O)C(=CN)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2c([N+](=O)[O-])c(Cl)c(F)cc2c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.0 g of the product from Example 8 are initially introduced into 100 ml of dioxane. 4.7 g of potassium tert.-butylate are added to this in portions. The mixture is stirred for 24 hours at room temperature, poured onto ice, and neutralized. The precipitated solid is isolated and dried. Yield: 5.3 g, melting point: 224°-7° (decomposes)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13](O)[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1.C(N(S(F)(F)[F:27])CC)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13]([F:27])[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1C2CC(O)CCN2C(=O)N1c1ncc(Cl)cc1F
Solvent: O
Solvent: ClCCl
Product: O=C1C2CC(F)CCN2C(=O)N1c1ncc(Cl)cc1F
Reaction time: 1 h

Procedure:
2.6 g of 2-(5-chloro-3-fluoro-pyridin-2-yl)-7-hydroxitetrahydroimidazo-[1,5-a]-pyridin-1,3-dione (isomer B, Example H10) in 80 ml dichloromethane is treated at −55° C. to −65° C. with 1.9 ml of diethylaminosulfur trifluoride (DAST) and stirred at the same temperature for 1 hour. The reaction mixture is then allowed to stir at 20° C. over night. The resulting brownish solution is treated with ice and water and extracted with ethyl acetate. The combined extracts are washed with water, dried, filtered through a small silicagel column and evaporated to give the desired product with m.p. 154-157° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][C:14]1[C:3]2[C:4](=[N:5][C:6]3[C:11]([C:2]=2[N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=1
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(N3CCOCC3)c12
Temperature: 100 °C
Yield: 36.5 %

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.47 g, 5.00 mmol), morpholine (0.87 g, 10.0 mmol) and potassium carbonate (1.38 g, 10.0 mmol) in N,N-dimethylformamide (20 mL) was heated under reflux at 100° C. for 12 hours. The solution was cooled to room temperature, and concentrated under reduced pressure. The residue was poured into water and organic matter was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:chloroform=3:1) to give the title compound (0.63 g, 36% yield).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].CS[C:17](=[NH:22])[NH:18][N+:19]([O-:21])=[O:20]>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:17]([NH2:22])=[N:18][N+:19]([O-:21])=[O:20])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CCCCN)cs1
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CCO
Product: N=C(N)Nc1nc(CCCCNC(N)=N[N+](=O)[O-])cs1
Temperature: 25 °C

Procedure:
To a solution of 2-guanidino-4-(4-aminobutyl)thiazole (0.426 g.) in ethanol (10 ml.) was added 2-methyl-1-nitroisothiourea (0.270 g.). The mixture was heated under reflux for 4 hours, allowed to cool to room temperature, evaporated to dryness and the residue triturated with alcohol. The product was filtered off and dried to give 2-guanidino-4-[4-(2-nitroguanidino)butyl]thiazole, m.p. 180°-181° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1.[CH:15]([PH:18][CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].C(N(CC)CC)C>CO>[CH:15]([P:18]([CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1)[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]
Reactant: ClCc1cccc(-c2ccccn2)n1
Reactant: CC(C)PC(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)P(Cc1cccc(-c2ccccn2)n1)C(C)C
Temperature: 50 °C

Procedure:
stirring bar was added 6-chloromethyl-2,2′-bipyridine (BPy-CH2Cl) (1.03 g, 5.00 mmol), di-iso-propyl phosphine (710 mg, 6.00 mmol), and 15 mL MeOH in nitrogen glove box. The flask was sealed and heated at 50° C. for 48 hrs with stirring outside the glove box. After cooling, it was reintroduced to the glove box, triethylamine (910 mg, 9.00 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr. The solvents were removed under reduced pressure to obtain a white solid. The residue was washed with ether (2×10 mL), filtered and was removed under reduced pressure to yield a pale yellow liquid. It was further purified by basic alumina chromatography under the glove box using hexane as an eluent to yield pure 6.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=2[F:22])[NH:4][CH:3]=1.C([Li])CCC.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=2[F:22])[N:4]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1ccc(Oc2ccnc3[nH]cc(Br)c23)c(F)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Oc2ccnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3.23 g (8.87 mmol) of N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluorophenyl}acetamide are dissolved in 500 ml of THF and cooled to −78° C. 3.90 ml (9.76 mmol) of a 2.5M n-butyllithium solution are added, and the mixture is stirred for 15 min. 1.86 g (9.76 mmol) of p-toluenesulfonyl chloride are then added dropwise as a solution in 20 ml of THF. The reaction solution is allowed to warm to RT and stirred for one hour. Sodium bicarbonate solution is then added, and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10]([O:12][C:13]1[C:14](=O)[C:15](=[O:20])[C:16]=1[O:17]CC)[CH3:11]>C(O)C>[O:17]=[C:16]1[C:15](=[O:20])[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[C:13]1[O:12][CH2:10][CH3:11]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: N#Cc1cccc(N)c1
Solvent: CCO
Product: CCOc1c(Nc2cccc(C#N)c2)c(=O)c1=O

Procedure:
3-Aminobenzonitrile (2.06 g, 17.4 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.97 g, 17.5 mmol) in absolute ethanol (50 mL). The mixture was heated at reflux overnight. The mixture was cooled and the resulting yellow precipitate was collected by vacuum filtration. Yield: 3.40 g (81%): 1H NMR (DMSO-d6): δ 10.95 (s, 1H), 7.75-7.40 (m, 4H), 4.73 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([Cl:9])=[N+:6]([O-])[CH:7]=1.[Si]([C:15]#[N:16])(C)(C)C.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:7]([C:15]#[N:16])=[N:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(Cl)[n+]([O-])cc1Br
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Cl)nc(C#N)c1Br
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-2-chloro-4-methylpyridine 1-oxide (from step 1) (1.0 eq.) in acetonitrile (0.2 M) was added TMSCN (4.0 eq.) and triethylamine (3.0 eq.). The reaction was heated at 100° C. overnight. After cooling to room temperature, the solvent was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane to give 3-bromo-6-chloro-4-methylpicolinonitrile.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.[C:28]1([N:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)N)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:25][CH:23]([CH3:24])[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:6]3[C:29]4[C:28](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:2]=3)[CH2:10][CH2:11]2)[CH:16]=1)=[O:26]
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCCO3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCc3cn(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:30][CH:31]=3)[NH:26][CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].O.[OH-].[Li+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:31]=3)[NH:26][CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: CCOC(=O)CCc1ccc2c(c1)NCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(CC(=O)N2CCNc3cc(CCC(=O)O)ccc32)ccc1NC(=O)Nc1ccccc1C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution of ethyl 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro -quinoxalin-6-yl)-propanoate (0.16 g, Reference Example 1) in anhydrous ethanol (3 ml), at 25° C., was treated dropwise with a solution of lithium hydroxide monohydrate (22 mg) in distilled water (1 ml). After stirring for 4 hours at 25° C. a further portion (10 mg) of lithium hydroxide monohydrate was added and stirring was continued for 16 hours at 25° C. The reaction mixture was evaporated under reduced pressure (2.7 kPa) at 40° C. and the residue was treated with distilled water (40 ml). The resulting solution was washed twice with diethyl ether (20 ml), then acidified to pH 3 by addition of hydrochloric acid (1.3 ml, 1N) and then extracted three times with ethyl acetate (25 ml). The combined organic extracts were washed twice with water (5 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. to give the title compound (132 mg) as a foamy solid. 1H NMR [400 Hz, (CD3)2SO]: δ2.2 (s, 3H); 2.5 (bq, 2H); 2.7 (broad t, 2H); 3.2 (broad s, 2H); 3.65 (broad s, 2H); 3.8 (s, 5H); 6.1 (broad s, 1H); 6.4 (broad s, 1H); 6.45 (broad s, 1H); 6.7 (very broad s, 1H); 6.9 (t, J=8 Hz, 1H); 7.15 (m, 3H); 7.8 (d, J=8 Hz, 1H); 8 (broad s, 1H); 8.45(s, 1H); 8.6(s, 1H); 12.1 (broad s, 1H. MS (LSIMS: glycerol+thioglycerol): 503 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].[CH2:11](I)[CH3:12]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH2:11][CH3:12])=[CH:4][C:3]=1[CH3:10]
Reactant: CCI
Reactant: Cc1cc(O)nc(C)c1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCOc1cc(C)c(Br)c(C)n1

Procedure:
A mixture of 5-bromo-4,6-dimethylpyridin-2-ol obtained in Preparation Example 23(1) (50 mg), ethyl iodide (2.0 mL) and silver carbonate (1.4 g) was stirred in a chloroform solvent (10 mL) at room temperature for 36 hours. The reaction mixture was subjected to silica gel pad and eluted with a mixed solvent of (ethyl acetate/n-heptane, 10%). The resulting solution was concentrated under reduced pressure to give the title compound (550 mg).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].CCO>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CN(Cc2ccccc2)C3)nc1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CNC3)nc1
Yield: 11.9 %

Procedure:
Combine 6-(2-benzyl-2,3-dihydro-1H-isoindol-5-yloxy)-nicotinamide (230.0 mg, 0.67 mmol), EtOH (5 mL), and 10% Pd—C (45.0 mg) and place under a hydrogen balloon. Stir the reaction at room temperature for 168 hours at atmospheric pressure. Filter the reaction mixture through a pad of Celite® using MeOH eluent and then concentrate the filtrate under reduced pressure. Add the mixture to a 2 g SCX column, wash with MeOH, and elute using 1.0 N NH3-MeOH. After concentrating under reduced pressure, purify the mixture by flash chromatography using 10% 1.0 N NH3-MeOH/DCM eluent to afford 19.2 mg, 0.08 mmol (11% yield) of the title compound as a white solid: 1H NMR (500 MHz, CD3OD); 4.1-4.3 (4H, br m), 6.9-7.1 (3H, m), 7.3-7.4 (1H, m), 8.2-8.3 (1H, m), 8.6 (1H, s); MS m/z 254 (M−1).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([CH2:24][CH:25]=[O:26])=[CH:20][CH:19]=1>C1COCC1>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([OH:26])[CH2:14][C:13]([O:16][CH3:17])=[O:15])=[CH:22][CH:23]=1
Reactant: O=CCc1ccc(-c2ccccc2)cc1
Reactant: COC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)CC(O)Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A solution of diisopropylamine (0.241 mL, 1.72 mmol) in anhydrous THF (1.5 mL) was treated with n-BuLi (1.6 M in hexane, 0.7 mL, 1.72 mmol) at −78° C. The mixture was kept at this temperature for 1 h, and then a solution of methyl acetate (0.137 mL, 1.72 mmol) in anhydrous THF (1 mL) was added at −78° C. The reaction mixture was stirred for 1 h at −78° C., and a solution of 2-(biphenyl-4-yl)acetaldehyde (S90, 282 mg, 1.43 mmol) in anhydrous THF (2 mL) was added. The reaction mixture was stirred for another hour, then quenched by the addition of saturated aqueous NH4Cl, which was extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography (SiO2, 50% Et2O-hexanes) yielded the title compound (226 mg, 58%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.64 (dd, 2H, J=7.2 Hz), 7.58 (dd, 2H, J=8.0 Hz), 7.49 (t, 2H, J=7.6 Hz), 7.38 (t, 1H, J=7.0 Hz), 7.34 (d, 2H, J=8.0 Hz), 4.38-4.34 (m, 1H), 3.71 (s, 3H), 3.35 (s, 1H(—OH)), 2.97-2.82 (m, 2H), 2.61-2.43 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 172.7, 140.5, 139.1, 136.6, 129.6, 128.5, 126.9, 126.7, 68.7, 51.4, 42.3, 40.3.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.N1C=CC=CC=1.[C:39]1([S:49](Cl)(=[O:51])=[O:50])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:49]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)(=[O:51])=[O:50])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4cccc5ccccc45)ccc3N2)=C(O)c2ccccc21
Yield: 101.6 %

Procedure:
A mixture of Example 39H (23.8 mg, 0.050 mmol), pyridine (31.6 mg, 0.80 mmol), and 1-naphthalenesulfonyl chloride (45.3 mg, 0.20 mmol) in acetone (1.5 mL) was stirred at rt for 72 h. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic phase was separated, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 99:1 dichloromethane/methanol to provide the title compound (32.0 mg, quant. yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=1>N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1I
Reactant: COc1nc(C)cnc1N
Solvent: c1ccncc1
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1I
Temperature: 70 °C
Yield: 44.4 %

Procedure:
2-IodobenzenesulphonyI chloride (obtained as described in J Org Chem, (1977), 42, 3265) (12.1 g) was added to a solution of 2-amino-3-methoxy-5-methylpyrazine (5.6 g) in pyridine (100 ml) and the solution was heated at 70° C. for 8 hours. Volatile material was removed by evaporation and water (200 ml) was added to the residue. The mixture was extracted with ethyl acetate (2×200 ml) and the extracts were washed with 2M hydrochloric acid (200 ml) and water (200 ml). The extracts were dried (MgSO4) and the solvent was removed by evaporation. The residue was triturated with ether to give 2-iodo- N-(3-methoxy-5-methylpyrazin-2-yl)benzenesulphonamide (7.2 g), m.p. 136°-138° C.; 1H NMR (d6 -DMSO): 2.3 (s, 3H), 3.9 (s, 3H), 7.3(dt, 1H), 7.5-7.65 (m, 2H), 8.05-8.15 (m, 2H), 10.7-10.8 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:24]C(O)C>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F

Procedure:
To a solution of ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 3 (Compound 3, 200 mg) in 2-propanol (4 ml), concentrated sulfuric acid (0.2 ml) was added and the mixture was stirred under reflux for 10 days hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with dilute brine (30 ml×2) and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1/4) and then crystallized from diisopropyl ether to yield isopropyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 25, 20 mg) as white powdery crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[C:11]([O-])([O-])=O.[Na+].[Na+]>C(O)=O>[Br:1][C:2]1[C:3]2[N:10]=[CH:11][NH:9][C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Cl)cc(Br)c1N
Agent: [Na+]
Solvent: O=CO
Product: Clc1cc(Br)c2nc[nH]c2c1
Temperature: 80 °C
Yield: 77 %

Procedure:
A mixture of 109b (4.3 g, 19.5 mmol) in formic acid (10 mL) was heated at 80° C. for 1 h. After cooled to room temperature, the reaction mixture was poured into aqueous Na2CO3 (30 mL) and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 109c as a brown solid (3.5 g, 77%). LCMS: [M+H]+ 233. 1H NMR (500 MHz, CDCl3) δ 10.05 (bs, 1H), 8.18 (s, 1H), 7.64 (bs, 1H), 7.50 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20](=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.CO>C(Cl)Cl.C(=O)=O>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([C:19]3[C:20](=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CCN2CCN(c3cccccc3=O)CC2)cc1OC
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CO
Product: O=c1cccccc1N1CCN(CCc2ccc(O)c(O)c2)CC1
Reaction time: 4 h

Procedure:
A solution of 2-[4-[2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one (1.10 g, described in Example 4) in methylene chloride (5 ml) was cooled to -65° C. in dry ice bath. A solution of boron tribromide (3.36 g) in methylene chloride (5 ml) was added dropwise to the solution of the compound. After the addition, the temperature was allowed to rise to room temperature. After 4 hr, the mixture was cooled in an ice bath and methanol (20 ml) was added dropwise. The resulting mixture was slowly brought to reflux and the solid was allowed to dissolve. The solution was then concentrated to the point at which crystals start to separate. Some diethyl ether was added, the mixture was cooled overnight, and filtered to give crude product (1.4 g). Recrystallization form methanol gave the hydrobromide salt (0.5 g) of the title compound: mp 256°-258° C.; ir(nujol) 3490, 2540 and 1522 cm-1 ; uv max(MeOH) 342 (ε=7820), 250 (ε=10720) and 222 nm(ε=11535); nmr(DMSO-d6)δ3.25 (m, 12H), 6.8 (m, 7H) and 8.7 (broad, 2H); and Anal. Calcd for C19H22N2O3.HBr: C, 56.02% H, 5.69% N, 6.88% and Found: C, 55.91% H, 5.74% N, 6.86%.