Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[NH:7][CH2:6][CH2:5][CH:4](C)[N:3]1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH3:18].[Cl:20][C:21]1[CH:32]=[CH:31][C:24]2[NH:25][C:26]([C@@H:28]([NH2:30])[CH3:29])=[N:27][C:23]=2[CH:22]=1.[CH3:33]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:20][C:21]1[CH:32]=[CH:31][C:24]2[NH:25][C:26]([C@@H:28]([NH:30][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][C:9]([N:3]4[CH2:4][CH2:5][CH2:6][N:7]([CH3:33])[S:2]4(=[O:1])=[O:19])=[C:10]([CH3:18])[CH:11]=3)[CH3:29])=[N:27][C:23]=2[CH:22]=1
Reactant: Cc1cc(C(=O)O)ccc1N1C(C)CCNS1(=O)=O
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCN(C)S1(=O)=O

Procedure:
Prepared analogously to Example 1f from 4-(1,1-dioxo-3-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]2[C:29]([O:31][C:32](=O)[C:22]=2[CH:21]=1)=[O:30]>>[C:26]([C:25]1[CH:24]=[C:23]2[C:22](=[CH:21][CH:20]=1)[C:32](=[O:31])[N:1]([C:2]1[CH:3]=[C:4]([C:8]3[O:9][C:10]4[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:11]=4[N:12]=3)[CH:5]=[CH:6][CH:7]=1)[C:29]2=[O:30])([OH:28])=[O:27]
Reactant: Nc1cccc(-c2nc3ccc(C(=O)O)cc3o2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4ccc(C(=O)O)cc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)benzoxazole-6-carboxylic acid (70 mg, 0.27 mmol) and 1,2,4-benzenetricarboxylic anhydride (53 mg, 0.27 mmol) the title compound was obtained (34 mg, 29%). 1H NMR (DMSO) δ 8.38(m, 1H), 8.31(m, 2H), 8.06(dd, 1H), 7.92(m, 2H), 7.86(s, 1H), 7.78(m, 3H). MS 429 m/z (M+H)+.
Reaction SMILES: C[C:2]([CH3:5])([O-])C.[K+].[C:7]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:15](I)[CH3:16]>>[CH2:15]([C:8]1([CH2:2][CH3:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]1=[O:14])[CH3:16]
Reactant: CC(C)(C)[O-]
Reactant: CCI
Reactant: O=C1CCCCCC1
Agent: [K+]
Product: CCC1(CC)CCCCCC1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of potassium tert-butoxide (1M in tBuOH) (160 mL, 160 mmol) was treated with cycloheptanone (5.4 mL, 45.8 mmol). The mixture stirred at room temperature for 5 minutes and was then put into an ice bath. Then, ethyl iodide (24 mL, 300 mmol) was added all at once. The reaction mixture stirred in the ice bath for 30 minutes and at room temperature overnight. After this time, the mixture was filtered, then the filtrate was evaporated to ˜15 mL. This crude mixture of mono and gem di-substituted products was combined with another 160 mL (160 mmol) of 1M potassium tert-butoxide, then after 5 minutes the mixture was put into an ice bath. Ethyl iodide (24 mL, 300 mmol) was added, and the reaction mixture was again stirred in the ice bath for 30 minutes and at room temperature overnight. The mixture was filtered after this time, and the filtrate was evaporated to ˜15 mL. This was partitioned between ether and water, and the ether layer was washed three times with water. The combined aqueous washes were then extracted three times with ether, then the combined organics were finally dried over Na2SO4 and evaporated. Chromatography on silica gel (3 to 20% EtOAc-hexane, eluant) afforded the title compound. 1H NMR (300 MHz, CDCl3) δ 2.50 (m, 2H), 1.86 (m, 1H), 1.57-1.69 (m, 6H), 1.33-1.49 (m, 4H), 1.23 (m, 1H), 0.75 (t, J=7.5 Hz, 6H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH:29]([CH2:33][OH:34])[C:30](O)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:28][CH:29]([CH2:33][O:34][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:30]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:31])(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: O=C(O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: C1=COCCC1
Reactant: COC(=O)CCCCCN
Agent: Cl
Product: COC(=O)CCCCCNC(=O)C(COC1CCCCO1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 1 was repeated, except that dihydropyran (2.56 ml) and methyl 6-aminohexanate hydrochloride (3.41 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (4.94 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(tetrahydropyran-2-yloxy)propanamide (0.87 g).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[N:3]1.C([Li:15])CCC.CCCCCC.[S:22](=O)([OH:24])[OH:23]>C(OCC)C>[CH3:1][N:2]1[C:10]([S:22]([O-:24])=[O:23])=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[Li+:15]
Reactant: Cn1cc2ccccc2n1
Reactant: [Li]CCCC
Reactant: O=S(O)O
Solvent: CCCCCC
Solvent: CCOCC
Product: Cn1nc2ccccc2c1S(=O)[O-]
Product: [Li+]
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution containing 9.5 g (72 mmol) of 2-methyl-2H-indazole in 200 ml of ethyl ether, was cooled to -30° C., and 61.4 g (144 mmol) of n-butyl lithium (a 15% hexane solution) was dropwise added thereto. The mixture was stirred for one hour at the same temperature, and then an excess amount of sulfurous acid gas was blown thereinto for 3 hours at a temperature of not higher than -20° C. After completion of the reaction, the mixture was returned to room temperature, stirred for 12 hours and then diluted with ethyl ether. The product was subjected to filtration. The crystals were dried to obtain crude lithium 2-methyl-2H-indazole-3-sulfinate. This product was used for the subsequent reaction without purification. 48.8 g (430 mmol) of hydroxylamine-O-sulfonic acid was gradually added to a solution containing 17.2 g (430 mmol) of sodium hydroxide in water (300 ml) under cooling with ice (not higher than 10° C.). This solution was added all at once to a solution containing the crude lithium 2-methyl-2H-indazole-3-sulfinate previously prepared in water (100 ml), and then the mixture was stirred for 12 hours at room temperature. Formed crystals were collected by filtration to obtain 8.8 g (yield: 58%) of 2-methyl-2H-indazole-3-sulfonamide (slightly yellow granular crystals). Melting point: 181°-183° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([Cl:12])=[C:4]([C:13]#N)[CH:3]=1.[OH-:15].[Na+].[OH2:17]>CCO>[Br:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([Cl:12])=[C:4]([C:13]([OH:17])=[O:15])[CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: CC1Cc2c(Cl)c(C#N)cc(Br)c2O1
Agent: [Na+]
Solvent: CCO
Product: CC1Cc2c(Cl)c(C(=O)O)cc(Br)c2O1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a suspension of compound 87 (2.1 g, 7.71 mmol) in EtOH (40 mL) and H2O (20 mL) was added NaOH (11 g, 270 mmoL). The mixture was stirred at 100° C. for 15 hours. The mixture was cooled to r.t. and evaporated in vacuo to remove EtOH. The mixture was diluted with H2O (100 mL) and cooled to 0° C. To the mixture was added conc. HCl to acidify the reaction mixture with stirring. The product was precipitated, filtered and washed with H2O (150 mL). The desired product was dried under high vacuum at 45° C. for 12 hours (2.4 g, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]2[CH2:21][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:9]1[CH:10]=[CH:11]2)[C:2]1C=CC=CC=1.[H][H].C(C1C2CC(C(OCC)=[O:46])C(C=C2)N1)C1C=CC=CC=1.C(Cl)(=O)C>[Pd].N1C=CC=CC=1>[C:1]([N:8]1[CH:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]2[CH2:21][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:9]1[CH:10]=[CH:11]2)(=[O:46])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1CC2C=CC1NC2Cc1ccccc1
Reactant: CCOC(=O)C1CC2C=CC1N(Cc1ccccc1)C2Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1CC2C=CC1N(C(C)=O)C2Cc1ccccc1

Procedure:
Reduction of the ethyl 2,3-dibenzyl-2-azabicyclo[2.2.2]-oct-5-ene-7-carboxylate described in Example 1AE in the form of the hydrochloride salt with one molar equivalent of hydrogen over a palladium-on-charcoal catalyst at ambient temperature and reaction of the resulting ethyl 3-benzyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate with acetyl chloride in the presence of pyridine affords ethyl 2-acetyl-3-benzyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH3:32][NH:33][CH3:34]>>[CH3:32][N:33]([CH3:34])[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: CNC
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCN(C)C)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (−)-2-(2-Bromo-ethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 24b) and dimethylamine as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16]([S:27][CH3:28])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:29].[OH:30]OS([O-])=O.[K+]>C1COCC1.O.CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2=[N:15][C:16]([S:27]([CH3:28])=[O:30])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:29]
Reactant: O=S([O-])OO
Reactant: CSc1nc(-c2ccc(F)cc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reaction time: 2 h

Procedure:
The product of example 2 (204 mg, 0.49 mmol) in THF was treated dropwise with Oxone® (0.307 g, 0.5 mmol) in H2O (10 mL). The mixture was stirred at 23° for 2 h, diluted with EtOAc (100 mL) and washed with H2O (2×25 mL) and satd aq NaCl (25 mL), dried (Na2SO4), and concentrated. The residue was purified by prep hplc to afford the sulfoxide as a white powder. LC MS m/z=433 (MH+), Rt=1.70 min
Reaction SMILES: [Br-].FC1(F)OC2C=C(C)C(C3N=[CH:14][C:15]([NH:18][C:19](=O)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4F)=[N:16]C=3)=CC=2O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.[C:44](#N)C.O>>[CH3:39][C:40]1[O:41][C:42]2[CH:43]=[CH:21][CH:22]=[CH:23][C:24]=2[C:25]=1[C:20]1[CH:44]=[CH:14][C:15]([NH2:16])=[N:18][CH:19]=1
Reactant: CC#N
Reactant: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)OC(F)(F)O2
Reactant: C1COCCO1
Agent: O=P([O-])([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: Cc1oc2ccccc2c1-c1ccc(N)nc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
Palladium tetrakis-triphenylphosphine (68 mg, 0.1 mmol) was added to a degassed solution of bromide 244 (250 mg, 1.2 mmol) and boronate 11 (521 mg, 2.4 mmol) in dioxane: acetonitrile:water (9:9:2, 6 mL) and potassium phosphate (376 mg, 1.8 mmol). The resulting mixture was heated under argon at 90° C. with stiffing for 18 hours. The mixture was then cooled, extracted with dichloromethane (3×15 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 245 (202 mg, 76%) as an solid: LRESIMS m/z 225.2 [M+H]+, calcd. for C14H13N2O1 225.1.
Reaction SMILES: C(O[C:4]([C:6]1[C:22]2[C:10](=[C:11]([CH3:25])[C:12]3[N:13]([CH3:24])[C:14]4[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=4[C:20]=3[CH:21]=2)[CH:9]=[CH:8][N:7]=1)=[O:5])C.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[O:33]1[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][CH2:27][NH:26][C:4]([C:6]2[C:22]3[C:10](=[C:11]([CH3:25])[C:12]4[N:13]([CH3:24])[C:14]5[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=5[C:20]=4[CH:21]=3)[CH:9]=[CH:8][N:7]=2)=[O:5])[CH2:31][CH2:32]1
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)c1nccc2c(C)c3c(cc12)c1cc(O)ccc1n3C
Product: Cc1c2ccnc(C(=O)NCCCN3CCOCC3)c2cc2c3cc(O)ccc3n(C)c12
Temperature: 120 °C

Procedure:
0.36 g (1. 078 mmol) of the ester obtained in Step A of Example 11 are dissolved in 10 ml of 4-(3-aminopropyl) morpholine under an argon atmosphere. The mixture is heated at 120° C. for 19 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]([Cl:19])([Cl:18])[CH2:13][O:14][C:15](Cl)=[O:16].[CH3:20][C:21]1[NH:22][C:23](=[O:27])[CH2:24][S:25][CH:26]=1>>[CH3:20][C:21]1[NH:22][C:23](=[O:27])[CH2:24][S:25][C:26]=1[CH:9]1[CH:8]=[CH:7][N:6]([C:15]([O:14][CH2:13][C:12]([Cl:19])([Cl:18])[Cl:11])=[O:16])[CH:5]=[C:4]1[C:3]([O:2][CH3:1])=[O:10]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COC(=O)c1cccnc1
Reactant: CC1=CSCC(=O)N1
Product: COC(=O)C1=CN(C(=O)OCC(Cl)(Cl)Cl)C=CC1C1=C(C)NC(=O)CS1
Yield: 48 %

Procedure:
A mixture of methylnicotinate (2.74 g), 2,2,2-trichloroethylchloroformate (3.44 ml) and 5-methyl-2H-1,4-thiazin-3(4H)-one (1.29 g) was treated in the same manner as described in Example 2 (i) to give the titled compound (2.1 g, yield 48%) as pale yellow crystals. Ethyl acetate-n-hexane (=1:1) was used as a developing eluant.
Reaction SMILES: CI.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH3:12])[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(S)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(SC)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Methyl iodide (14.67 ml, 0.235 mol) was added dropwise to a solution of 3-methoxy-benzenethiol (30 g, 0.214 mol) and potassium carbonate (29.6 g, 0.214 mol) in acetone (400 ml) under nitrogen at 3° C. The reaction was allowed to warm to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water (300 ml) and the aqueous layer was extracted with diethylether (3×200 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure to give 1-Methoxy-3-methylsulfanyl-benzene (32.87 g) as a pale yellow liquid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.O1CCOCC1.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>O>[C:17]1([N:23]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNc1ccccc1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: NN(C(=O)c1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.9 %

Procedure:
A solution of 44.7 g. (0.168 mole) of p-iodobenzoyl chloride in 100 ml. of dioxane was added to 18.2 g. (0.168 mole) of phenylhydrazine dissolved in 250 ml. of pyridine at 5° to 15° C. The resulting suspension was stirred at 25° C. for 3 days, poured into 2 liters of water, the solids were filtered and washed with water, dilute aqueous hydrochloric acid and then again with water. The product thus obtained was crystallized from ethanol to give 40.0 g. (70.9% yield) of p-iodobenzoic acid phenylhydrazide having a melting point of 210° to 211° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[N:10][N:9]([CH3:12])[C:8](=[O:13])[C:7]=1Cl)[CH2:2][CH2:3][CH3:4].[F:15][C:16]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:17]=1[C:18]([N:20]=[C:21]=[S:22])=[O:19]>O1CCOCC1>[CH2:1]([N:5]1[C:6]2[CH:11]=[N:10][N:9]([CH3:12])[C:8](=[O:13])[C:7]=2[S:22]/[C:21]/1=[N:20]\[C:18](=[O:19])[C:17]1[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:16]=1[F:15])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(N=C=S)c1cc(C(F)(F)F)ccc1F
Reactant: CCCCNc1cnn(C)c(=O)c1Cl
Solvent: C1COCCO1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2c(=O)n(C)ncc21
Temperature: 100 °C
Yield: 22.1 %

Procedure:
A mixture of 5-(butylamino)-4-chloro-2-methylpyridazin-3(2H)-one from Example 4A (250 mg, 1.16 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl isothiocyanate (375 mg, 1.51 mmol) in dioxane (20 mL) was heated at 70° C. for 12 hours and at 100° C. for 6 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (CH2Cl2-Et2O 19:1)) to afford 110 mg of the title compound. MS (ESI) m/z 429 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH:13]3[O:17][CH2:16][CH2:15][O:14]3)[C:6]=2[N:18]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[H-].[Na+].Cl>CN(C)C=O.O.C(OCC)(=O)C>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[CH2:12][N:7]1[C:8](=[O:11])[CH:9]=[N:10][C:5]2[CH:4]=[CH:3][C:2]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[N:18][C:6]1=2
Reactant: c1nc[nH]n1
Reactant: O=c1cnc2ccc(Cl)nc2n1CC1OCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1cnc2ccc(-n3cncn3)nc2n1CC1OCCO1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
To a solution of 0.30 g of 6-chloro-4-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-one and 78 mg of 1,2,4-triazole in 9 mL of N,N-dimethylformamide, 48 mg of 60% sodium hydride was added, and the mixture was stirred at 40 to 50° C. for 1 hour 30 minutes. Thereto was further added 78 mg of 1,2,4-triazole and 48 mg of 60% sodium hydride, and the mixture was stirred at 40 to 50° C. for 1 hour 30 minutes, and stirred at 60 to 70° C. for 20 minutes. The reaction mixture was charged with a mixed solution of ethyl acetate and water and neutralized with 2.0 mol/L hydrochloric acid, and the insoluble substance was filtered off. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=80:20 to 30:70 and washed with diisopropyl ether to obtain 77 mg of 4-(1,3-dioxolan-2-ylmethyl)-6-(1H-1,2,4-triazole-1-yl)pyrido(2,3-b)pyrazin-3(4H)-one as a light red solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:15])C2C=CC=CC=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[CH:23][N+:22]([O-:25])=[CH:21][CH:20]=1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:15][C:19]2[CH:24]=[CH:23][N+:22]([O-:25])=[CH:21][CH:20]=2)=[N:6][CH:7]=1
Reactant: OC(c1ccccc1)c1ccc(F)cn1
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [O-][n+]1ccc(OCc2ccc(F)cn2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) was dissolved in DMF (20 mL), and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes, 4-chloropyridine-N-oxide (2.03 g, 15.7 mmol) was added, and the reaction mixture was heated for 1 h at 120° C. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried and concentrated. Purification by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) provided the title compound (1.76 g, 50%) as a tan solid: 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 8.12 (d, J=7.7 Hz, 2H), 7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).
Reaction SMILES: [S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.B.CSC.B>C1COCC1>[S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C@@H:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCS(=O)(=O)c2sccc21
Agent: B
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Solvent: CSC
Solvent: C1CCOC1
Product: O=S1(=O)CC[C@@H](O)c2ccsc21
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-one-7,7-dioxide (13) (1.00 g, 4.94 mmol) in dry THF (14 mL) was added (S)-diphenylprolinol-borane complex from Example 12 (132 mg, 0.494 mmol). The solution was cooled to -15° C. and a solution of borane-dimethyl sulfide (10M, 0.4 mL, 4.0 mmol) in dry THF (6.8 mL) was added at a rate to maintain the internal temperature at -15° C. The solution was stirred at -15° C. for 1 hour then at 22° C. for 6 hours. The product was isolated by the method decribed in Example 34 Step E. The enantiomeric ratio of the purified product was 95:5.
Reaction SMILES: [C:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[CH2:14]1[O:42][C:41]2[CH:40]=[CH:39][C:18]([C:19]([N:21]3[C:30]4[C:25](=[CH:26][C:27]([C:31]5[CH:36]([CH3:37])[S:35][C:34](=[O:38])[NH:33][N:32]=5)=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:17][C:16]=2[O:15]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([N:33]1[N:32]=[C:31]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:21]([C:19](=[O:20])[C:18]2[CH:39]=[CH:40][C:41]4[O:42][CH2:14][O:15][C:16]=4[CH:17]=2)[CH2:22][CH2:23][CH2:24]3)[CH:36]([CH3:37])[S:35][C:34]1=[O:38])=[O:11]
Reactant: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CCCN2C(=O)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1SC(=O)N(C(=O)C2CC3CCC2(C)C3(C)C)N=C1c1ccc2c(c1)CCCN2C(=O)c1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
A solution of 26 g of (-)-camphanic acid chloride in 100 ml of methylene chloride is added dropwise at 0°, with stirring, to a suspension of 48 g of 5-[1- (3,4-methylenedioxybenzoyl)-1,2,3, 4-tetrahydroquinol-6- yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in 800 ml of methylene chloride to which 20 ml of triethylamine have been added, and the reaction mixture is stirred for 4 hours. It is then washed with dilute hydrochloric acid and subsequently with bicarbonate solution. The organic phase is separated off and worked up in conventional manner to give 3-[(-)-camphanoyl]-5-[1-(3,4-methylenedioxybenzoyl)-1,2,3, 4- tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4- thiadiazin-2-one as a mixture of diastereoisomers, m.p. 216°-217° .
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH2:39]([O:46][C:47](Cl)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:47]([O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:48])=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
To a solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (9.11 g, 31.1 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) in dry dichloromethane (100 mL) were added triethylamine (8.80 mL, 63.1 mmol) and dimethylaminopyridine (5 mg), followed by the dropwise addition of benzylchloroformate (4.60 mL, 30.6 mmol) over a period of 30 min. The reaction mixture was stirred for 16 h, transferred to a separatory funnel, washed with 2N HCl, brine, dried over anhydrous magnesium sulfate and concentration in vacuo. Flash chromatography yielded the product as a white solid.