Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17](OCC)=[O:18])[NH:14][N:13]=2)=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(O)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:16]=[C:15]([CH2:17][OH:18])[NH:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCO
Product: OCc1cc(-c2ccc(F)cc2)n[nH]1

Procedure:
In a further embodiment, a pyrazole cyclization reaction is provided in Scheme 14A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The pyrazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydrazine hydrate to provide ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol and glacial acetic acid for about 2 to 16 hours. Ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate is then reduced with lithium aluminum hydride to provide 3-(4-fluorophenyl)-1H-pyrazol-5-yl-methanol. In one embodiment, the reduction is performed in THF at a temperature of about 0° C. to about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde is then formed by oxidizing 3-(4-fluorophenyl)-1H-pyrazole-5-methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: [CH3:1][C:2]([CH:4]([CH3:6])[CH3:5])=[CH2:3].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17]Cl)(=[O:16])=[O:15])=[CH:12][CH:13]=1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(#N)C>[CH:2]([C:4]1([CH3:6])[CH2:5][N:17]1[S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)(=[O:15])=[O:16])([CH3:1])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Reactant: C=C(C)C(C)C
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CC2(C)C(C)C)cc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 51.7 %

Procedure:
To a solution of 2,3-dimethyl butene (300 ml, 2.42 mol) in 7.8 L of dry acetonitrile was added Chloramine-T (749.9 g, 1.1 eq) portionwise over 90 min. The temperature was maintained at approximately 20° C. To this reaction mixture was added phenyltrimethylammonium tribromide (91.4 g, 0.1 eq) in 10 g portions over 90 min. The temperature increased to 26° C. during the addition. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated down to approximately 15% of the initial volume and was them filtered, washing the solid with 1 L of acetonitrile. The organic liquid phase was concentrated and the residue dissolved in 2.5 L of EtOAc. The resulting solution was washed twice with water, dried over MgSO4, and concentrated to give a solid. The crude was purified on a large plug of celite using gradient elution 5% to 25% EtOAc/heptanes to afford 317 g of 2-isopropyl-2-methyl-1-[(4-methylphenyl)sulfonyl]aziridine as a solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][C:26]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(C(F)(F)F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-(3-trifluoromethyl-phenyl)thiazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24][O:25]S(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24][O:25][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)CCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-methoxycarbonylbutyl)propanamide (65.7 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-methoxycarbonylbutyl)-3-(pyridin-3-yloxy)propanamide (64.3 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[Cl:7].O1CCCC1.[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[Cl:7]
Reactant: CCOC(=O)C(=O)c1c(C)sc(Cl)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(C)sc(Cl)c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a mixture of compound ethyl 2-(4-bromo-5-chloro-2-methylthiophen-3-yl)-2-oxoacetate (44b) (340 mg, 1.09 mmol), tetrahydrofuran (7 mL) and ethanol (1.7 mL) was added sodium tetraborohydride (37.2 mg, 0.98 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours. The mixture was quenched with hydrochloric acid 1N and extracted with ethyl acetate twice. The organic extract was washed with brine twice, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude alcohol (44c) as a colorless oil (335 mg, 1.07 mmol, 98%).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]#[C:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CC1CCN(CCC#Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1CCN(CCC#Cc2ccccc2)C1

Procedure:
The ester (0.0126 mole) is hydrolyzed in 200 ml. of methanol and 25 ml. of 1.0 N sodium hydroxide (0.025 mole), treated with 13 ml. of 1.0 N hydrochloric acid, evaporated and the residue is recrystallized to give 1-(4-phenyl-3-butynyl)-3-pyrrolidineacetic acid.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].N(CNC(N)=O)=O.[O:11]([C:18]1[CH:19]=[C:20]([C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][N:26]=1)[C:21](Cl)=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[O:11]([C:18]1[CH:19]=[C:20]([C:21](=[O:22])[CH:3]=[N+:1]=[N-:2])[C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][N:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)CCc1cnc(Oc2ccccc2)cc1C(=O)Cl
Agent: NC(=O)NCN=O
Solvent: CCOCC
Product: CCOC(=O)CCc1cnc(Oc2ccccc2)cc1C(=O)C=[N+]=[N-]

Procedure:
To an ethereal solution of diazomethane prepared from nitrosomethylurea (2.0 g) and ether (25 ml), a solution of the said 2-phenoxy-5-ethoxycarbonylethylisonicotinoyl chloride (1.05 g) in anhydrous ether (10 ml) is added dropwise at 0° to 3°C, and the resultant mixture is stirred at 10° to 15°C for 1 hour. The reaction mixture is evaporated under reduced pressure to remove the ether. The residue is chromatographed on a column of neutral alumina/50 % benzene-n-hexane, whereby 2-phenoxy-4-diazoacetyl-5-ethoxycarbonylethylpyridine (830 mg) is obtained. This substance is recrystallized from ether/n-hexane to give crystals melting at 77° to 79°C (decomp.). IR (CCl4): 2120, 1745 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].C(Cl)Cl.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:29][CH2:30][N:31]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:32][CH2:33]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(N4CCNCC4)ccc2OCC3)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.7 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperazin-1-yl-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (150 mg, 0.3 mmol) was dissolved in THF, DIPEA (155 mg, 1.2 mmol) was added. Methanesulfonyl chloride (41 mg, 0.36 mmol) was added dropwise into the solution, and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo, and then dissolved in DCM. The mixture was washed by water, dried over Na2SO4, concentrated in vacuo, and purified by prep. TLC (DCM/EtOAc=10:1) to give 130 (42.0 mg, yield: 26%). 1HNMR (Acetone, 400 MHz): δ8.00 (s, 1H), 7.73-7.71 (m, 1H), 7.36-7.10 (m, 2H), 7.12 (s, 2H), 6.69 (d, J=9.2 Hz, 1H), 4.14 (s, 1H), 3.49 (s, 4H), 3.22 (s, 4H), 3.00 (s, 2H), 2.79 (s, 3H). ESI-MS: m/z=545 [M+H+]
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH:7]1([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:7]1([C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1
Reactant: COCC(=O)Cl
Reactant: Nc1ccc(C2CC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methoxyacetyl chloride (0.55 mL, 6.0 mmol) was added to a solution of 4-cyclopropylaniline (800 mg, 6.0 mmol) and DIEA (1.05 mL, 6.0 mmol) in DCM, and the reaction was stirred at r.t. for 2 h. The reaction was washed with brine, dried (MgSO4), and concentrated to give crude N-(4-cyclopropylphenyl)-2-methoxyacetamide.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][C:17]([OH:24])([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH:10]=1)=O.[NH4+].[OH-]>CO>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]([OH:24])([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH:12]=[CH:13][CH:14]=1
Reactant: CCCC(O)(C#Cc1cccc(CCCNC(=O)C(F)(F)F)c1)CCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCCC(O)(C#Cc1cccc(CCCN)c1)CCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propyl)acetamide (2.6 g, 7.0 mmol) in MeOH (50 mL) was added concentrated aqueous NH4OH (ca. 25 mL) and the solution was stirred at room temperature overnight. More concentrated aqueous NH4OH (5 mL) was added and the mixture was stirred overnight. The volatiles were removed by concentration under reduced pressure and the residue was extracted twice with EtOAc. The organic solution was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (0 to 20% (20% 7M NH3 in MeOH-EtOAc)-EtOAc gradient) gave 4-((3-(3-aminopropyl)phenyl)ethynyl)heptan-4-ol as a clear oil. Yield (1.58 g, 83%): 1H NMR (400 MHz, DMSO-d6) δ 7.14-7.26 (m, 4H), 5.12 (s, 1H), 2.56 (t, J=7.2 Hz, 2H), 2.47 (t obs, J=7.2 Hz, 2H), 1.42-1.63 (m, 12H), 0.90 (t, J=7.2 Hz, 6H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](Cl)=[O:11].[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([C:21]1[CH:22]=[CH:23][C:18]([O:24][CH3:25])=[CH:19][CH:20]=1)=[O:11]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Aluminium chloride (15.5 g) was added over 2 hours in small portions to an ice-cooled solution of 3-trifluoromethylbenzoyl chloride (21.7 g) and anisole (12.5 g) in dichloromethane. After a further 2 hours at room temperature, the mixture was poured on to ice, extracted with dichloromethane and the extracts washed with water and dried (MgSO4). Removal of solvent gave a solid which was recrystallised first from light petrol (b.p. 60°-80°) and then from ethanol-water, giving white prisms of the ketone, m.p. 62.5°-63.5°, (17.5 g, 60%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:13]([CH:21]2[CH2:23][CH2:22]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=2)[CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH:21]1([N:13]([C:4]2[C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=[C:2]([C:43]3[CH:44]=[CH:32][CH:33]=[C:34]([CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:42]=3)[N:3]=2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2cccc(CN3CCOCC3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N(c1nc(Br)cn2c(C=O)cnc12)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(c1nc(-c2cccc(CN3CCOCC3)c2)cn2c(C=O)cnc12)C1CC1
Yield: 48.3 %

Procedure:
Tert-butyl 6-bromo-3-formylimidazo[1,2-a]pyrazine-8-yl(cyclopropyl)carbamate (100 mg, 0.26 mmol), 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (118 mg, 0.39 mmol), 3M Na2CO3 (1.3 mL, 2.60 mmol) and DME (3.5 mL) were combined. The solution was degassed with a stream of N2 for 10 min. Pd(PPh3)4 was added and the solution was refluxed for 2 h. The solution was partitioned between dichloromethane (25 mL) and water (25 mL). The aqueous layer was further extracted with dichloromethane (2×25 mL). The organics were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via preparative TLC (5% MeOH/dichloromethane) to afford tert-butyl cyclopropyl(3-formyl-6-(3-(morpholinomethyl)phenyl)imidazo[1,2-a]pyrazin-8-yl)carbamate (60 mg, 48%). LCMS (ES): >95% pure, m/z 478 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:20][C:21]#[N:22])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=2)=O)C.[H][H]>CCO.O=[Pt]=O>[CH2:18]([O:17][C:15]([C:10]1[CH:11]=[CH:12][C:13]2[CH:14]=[C:6]3[C:4](=[O:3])[NH:22][CH2:21][CH2:20][N:7]3[C:8]=2[CH:9]=1)=[O:16])[CH3:19]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC#N)c2c1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)c1ccc2cc3n(c2c1)CCNC3=O
Yield: 109.2 %

Procedure:
To 1-cyanomethyl-1H-indole-2,6-dicarboxylic acid diethyl ester (500 mg, 1.66 mmol) in 20 mL of absolute EtOH was added PtO2 (Adams' catalyst). The reaction mixture was hydrogenated at 50 psi of hydrogen overnight. The reaction mixture was filtered through a pad of diatomaceous earth, the solid cake was washed with dichloromethane several times. The solvent was evaporated to dryness to give 468 mg of 1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid ethyl ester as a light yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([NH:26][CH2:25][CH2:24][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Reactant: NCCN1CCCC1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: c1ccc(CN2CCc3nc(NCCN4CCCC4)ccc3C2)cc1
Temperature: 150 °C

Procedure:
Copper (II) sulphate (70 mg) was added to a solution of 6-benzyl-2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (0.75 g, 2.9 mmol)(WO9830560 Example 33 b) in 2-pyrrolidin-1-yl-ethylamine (3 ml) and the mixture was heated in an autoclave to 150° C. for 24 hours. The reaction mixture was cooled to room temperature and was diluted with dichloromethane (50 ml). The solution was washed with 50% ammonium hydroxide solution (50 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ammonium hydroxide and methanol in dichloromethane as eluant (gradient from 0.5:5:95 to 0.7:7:93) to give the title compound as a yellow oil (0.9 g). LRMS: m/z (ES+) 337 [MH+]
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([OH:18])=O)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])=[O:3].C1C=C2N=NN(O)C2=CC=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[NH2:55][C@H:56]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C@@H:57]([OH:59])[CH3:58]>C(Cl)Cl>[OH:59][C@@H:57]([CH3:58])[C@H:56]([NH:55][C:16]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]=1[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[O:18])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: CS(=O)(=O)Nc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Reactant: C[C@H](O)[C@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](O)[C@H](NC(=O)c1c(NS(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
A solution of 3-methanesulfonylamino-2-phenyl-4-carboxylic acid (1c) (250 mg, 0.73 mmol), HOBt hydrate (148 mg, 1.1 mmol), 4-methylmorpholine (160 μL, 1.46 mmol) in methylene chloride (15 mL) was added EDCI (210 mg, 1.1 mmol) at RT under N2. A mixture of (1R,2S)-1-amino-1-phenylpropan-2-ol hydrochloride and 4-methylmorpholine (193 μL, 1.75 mmol), in methylene chloride (5 mL) was added and the reaction mixture was stirred at RT for 16 h. Solution is partitioned against water and twice extracted with methylene chloride. The combined organic extracts are washed with brine, dried over magnesium sulfate and then concentrated in vacuo with added silica. The compound is subsequently eluted off the silica and chromatographed, eluting with 15-30% ethyl acetate/dichloromethane to give the title compound (167 mg, 48%). 1H NMR (500.333 MHz, CDCl3) δ 1.10 (d, J=6.6 Hz, 3H), 2.23 (s, 3H), 2.69 (d′, J=6.7 Hz, 1H), 4.44-4.47 (m, 1H), 5.35 (dd, J=8.4, 3.3 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.39 (dd, J=6.9, 6.9 Hz, 2H), 7.44 (d, J=7.5 Hz, 2H), 7.47-7.55 (m, 4H), 7.71-7.78 (m, 4H), 8.16 (d, J=8.4 Hz, 1H) MS APCI, m/z=476.1 (M+1). LCMS: 1.86 min.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:23]1[C:36]2[NH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[S:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.Br[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46][CH3:47])=[CH:40][CH:39]=1.CC(C)([O-])C.[Na+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:44]([C:41]1[CH:42]=[CH:43][C:38]([N:35]2[C:36]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[S:28][C:29]3[C:34]2=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:39][CH:40]=1)[CH2:45][CH2:46][CH3:47]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CCCCc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCCc1ccc(N2c3ccccc3Sc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.1 %

Procedure:
A 2 L 3 neck round bottom flask equipped with overhead stirrer, reflux condensor and a nitrogen line was charged with 0.948 g (4.216 mmol) palladium acetate and 2.647 g (8.746 mmol) tri-o-tolylphosphine and 50 ml toluene. The mixture was stirred at ambient temperature for 20 minutes until an orange-red solution was formed. At that time, phenothiazine (19.93 g, 100 mmol), 1-bromo-4-butyl benzene (23.6 g, 110 mmol) and sodium t-butoxide (10.71 g, 100 mmol) along with 1000 mL toluene was added. The reaction was placed in an oil bath and heated to reflux for 15 hours. A sample was taken for HPLC showing that all starting material was gone. A major peak with the retention time of 8.6 minutes was seen. The solution was cooled. 15 mL concentrated HCl was added. The solution was stirred for an additional hour. Then the solution was passed through a neutral alumina column (750 g). The column was rinsed with toluene. The solvent was removed using a rotary evaporator to yield a yellow solid. The solid was recrystallized from toulene/MeOH. 19.6 g of white solid was obtained with 99% purity. The yield was 60.6%. MS: 331. 1H NMR (DMSO) δ0.92 (t, 3H), 1.36 (m, 2H), 1.62 (m, 2H), 2.73 (t, 2H), 6.13 (d, 2H), 6.87(m, 4H), 7.05 (d, 2H), 7.30 (d, 2H), 7.47 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:35]1C=C(S(Cl)(=O)=O)C=C(Cl)C=1>>[CH3:35][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)cc(Cl)c1)CC2
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)cc(Cl)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 525.21 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 3,5-dichloro-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:25][CH:24]([CH:33]([CH3:35])[CH3:34])[C:23]=2[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:18][CH:17]=1>C(Cl)Cl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:24]([CH:33]([CH3:35])[CH3:34])[S:25][C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1=C(c2ccc(F)cc2)C(c2ccccc2)SC1C(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C(C)C)sc(-c2ccccc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.3 %

Procedure:
To a suspension of 25 g of 2,3 dichloro-5,6-dicyanobenzoquinone in 1 liter of methylene chloride at room temperature was added slowly a solution of 40 g of the dihydrothiophene carboxylate of Step 5, above, in 125 ml of methylene chloride. The mixture was stirred at room temperature for 24 hours, filtered, and the filtrate was washed with 10% aqueous sodium bicarbonate solution. The organic phase was separated and the solvent was removed under reduced pressure. The residue was filtered through a pad of silica gel to remove any polar material. Evaporation of the solvent gave 41.5 g of the title product of this preparation.