Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:14])=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[CH:2].I[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:14][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(O)c(C(=O)OCC)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O

Procedure:
Tetrakis(triphenylphosphine)palladium (0.29 g, 0.25 mmol) and copper(I)iodide (0.095 g, 0.5 mmol) were, added to a solution of ethyl 5-ethynyl-2-hydroxybenzoate (10.5 g, 55 mmol) and 4-iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide (18.7 g, 50 mmol) in tetrahydrofuran (75 ml) and triethylamine (75 ml) at 55° C. After 2 h the solid product was collected with filtration and washed with hydrochloric acid (1M). The material was boiled in formic acid (300 ml) for 15 nun. and filtered. Water (200 ml) was added and the product crystallized upon cooling. Yield 17.3 g (79%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:16]([CH3:23])[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2].[Br-:24].[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.S(=O)(=O)(O)O>CO.C1COCC1.[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>[Br:24][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([N:16]([CH3:23])[C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])[CH:7]=[C:8]([S:10]([F:14])([F:15])([F:13])([F:12])[F:11])[CH:9]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1cc(N(C)C(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)C(F)(F)F)c1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 164.6 %

Procedure:
N-[3-Acetyl-5-(pentafluorosulfanyl)phenyl]-2,2,2-trifluoro-N-methylacetamide (O2.075; 1.03 g) was dissolved in a mixture of methanol (20 ml) and THF (20 ml). Phenyltrimethylammonium tribromide (1.05 g) was added while stirring. After stirring at RT for 5 h, the mixture was left to stand overnight, then further phenyltrimethylammonium tribromide (100 mg) was added and the mixture was heated to 60° C. for 2 h. After cooling, the reaction mixture was added to 2 N sulfuric acid and stirred for 10 min. Then the aqueous phase was extracted three times with EA. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 1.2 g of the title compound were obtained, which had sufficient purity for the next reactions.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.[CH3:54][N:55]1[C:59]([CH:60]=O)=[N:58][C:57]([CH3:62])=[N:56]1.CC1C=C(C)N2N=C(C=O)N=C2N=1>O>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:60][C:59]3[N:55]([CH3:54])[N:56]=[C:57]([CH3:62])[N:58]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(C=O)n(C)n1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Solvent: O
Product: Cc1nc(CC2=C(O)CC(CCc3ccc(C(C)(C)C#N)c(F)c3)(C3CCCC3)OC2=O)n(C)n1

Procedure:
The title compound was prepared analogously to example A(1), where 2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl-2-methyl-propionitrile.from step 3 below, was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2,5-Dimethyl-2H-[1,2,4]triazole-3-carbaldehyde was substituted instead of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (300 MHz, DMSO-d6): δ 1.49–1.69 (m, 8 H), 1.72 (s, 6 H), 2.06 (s, 3 H), 2.11 (s, 3 H), 2.12–2.13 (m, 2 H), 2.34–2.42 (m, 1H), 2.55–2.66 (m, 3H), 2.80 (d, J=17 Hz, 1 H), 3.42–3.65 (m, 2 H), 7.08–7.18 (m, 2 H), 7.35–7.40 (m, 1 H). Anal. Calcd. For C27H33FN4O3.0.25 H2O: C, 66.85; H, 6.96; N, 11.55; Found: C, 66.88; H, 6.99; N, 11.60. ESIMS (MH+): 481.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.Br[C:33]1[CH:34]=[C:35]([S:39]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])(=[O:41])=[O:40])[CH:36]=[N:37][CH:38]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH2:45]([N:42]([CH2:43][CH3:44])[S:39]([C:35]1[CH:34]=[C:33]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)[CH:38]=[N:37][CH:36]=1)(=[O:40])=[O:41])[CH3:46]
Reactant: CCN(CC)S(=O)(=O)c1cncc(Br)c1
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCN(CC)S(=O)(=O)c1cncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg) was placed in a microwave vial with Pd(PPh3)4 (10 mg) and 5-bromo-N,N-diethyl-3-pyridinesulfonamide (29 mg) was added. DMF (2 ml) was added and the reaction was heated under microwave irradiation for 15 min at 120° C. The reaction was evaporated to dryness and the residue was dissolved in IPA (2 ml) and 2M NaOH (aq) (1 ml). The reaction was stirred at RT for 3 h then evaporated to dryness. The residue was purified by MDAP (method E). The residue obtained was further purified on silica, eluting with 0-100% EtOAc/cyclohexane over 15 min followed by 0-20% MeOH/DCM, to give the title compound (13 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:20])([F:19])[C:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:21]([OH:27])[CH2:22][O:23][CH2:24][CH2:25][OH:26]>>[OH:27][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:20])([F:19])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:27][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])=[CH:14][CH:13]=2)([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(F)(F)C(F)(F)c2ccc(F)cc2)cc1
Reactant: OCCOCCO
Product: OCCOCCOc1ccc(C(F)(F)C(F)(F)c2ccc(OCCOCCO)cc2)cc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
700 ml of diethylene glycol and 65 g of 1,2-bis(4-fluorophenyl)-1,1,2,2-tetrafluoroethane* are heated to 130° C. in a stirred flask and 57 g of potassium tert.-butylate are added in portions. The mixture is then heated to 150° C. and stirred at this temperature for 2 hours. The mixture is cooled, poured onto 4 liters of ice-water and mixed thoroughly with a homogenizer (Ultraturax), until crystals precipitate. The precipitate is filtered off with suction, stirred again with 3 liters of water, acidified with hydrochloric acid, filtered off with suction again, dried and recrystallized from toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([OH:6])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([OH:6])=[CH:4][C:3]=1[O:10][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CBr
Reactant: Oc1cc(O)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(O)c(Cl)cc1Cl
Temperature: 80 °C
Yield: 23.2 %

Procedure:
A mixture of 4,6-dichlororesorcinol (2 g), potassium carbonate (1.54 g) and methyl bromoacetate (1.71 g) in DMF (10 ml) was heated at 80° C. for 24 h. The resulting mixture was cooled and water (200 ml) added. Solid (bis-alkylated product) was filtered off, then the aqueous was acidified with aq. HCl, which was extracted with ether and the organics were dried and concentrated in vacuo. Purification by RPHPLC (Xterra, gradient 95-5%, ammonia (0.2% aq.) in acetonitrile) gave the subtitle compound (0.65 g) as a solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.CI>O1CCCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([CH3:1])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1
Reactant: CC(C)NC(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To N,N-diisopropylamine (13 mL, 93 mmol, Aldrich) in tetrahydrofuran (200 mL) at −78° C. was added 1.6 M n-butyllithium in hexanes (55 mL, 88 mmol, Aldrich). The reaction mixture was warmed to 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was cooled to −78° C., and 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (17.1 g, 58.4 mmol, from Step 1) in tetrahydrofuran (86 mL) was added dropwise over 30 minutes. The reaction mixture was then stirred for 1 hour at −78° C., and methyl iodide (7.3 mL, 120 mmol, Aldrich) was added dropwise over 5 minutes. The reaction was allowed to warm to 5° C. over 3 hours, then cooled to −20° C. and quenched by the addition of 1 N HCl. EtOAc was added, and the solution was stirred for 15 minutes and left at ambient temperature overnight. The layers were separated and the organic layer was washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a wet orange solid that was then triturated with MeOH (18 mL). The solid was isolated by filtration, washed and dried at 40° C. under high vacuum for 2.2 h to give 14.4 g of product. Additional amount of product was obtained by flash chromatography of the filtrate (eluting with a gradient from 0-40% EtOAc in hexanes) afforded 1.87 g. (Yield: 16.3 g, 91%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC3CCN(C)C3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(NS(=O)(=O)c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)C1
Yield: 29.1 %

Procedure:
To a stirred solution of methyl 3,3-dimethyl-2-(3-(N-(1-methylpyrrolidin-3-yl)sulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (140 mg, 0.31 mmol) in methanol/tetrahydrofuran (5 mL/5 mL) was added 1N sodium hydroxide (4.59 mL). The resultant mixture was heated to reflux for 2.5 h. Organic solvent was removed and the residue was dissolved in water. The aqueous layer was acidified to pH=4. The precipitates were filtered, and dissolved in tetrahydrofuran, dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed, and after evaporation, the residue was treated with ethyl acetate to afford 40 mg of 3,3-dimethyl-2-(3-(N-(1-methylpyrrolidin-3-yl)sulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. (Yield: 29%). MS (ESI+APCI) M+1=444.2.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH3:11].C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[C:3]([NH:15][CH:12]([CH2:13][CH3:14])[CH2:10][CH3:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CCC(N)CC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (4.56 g, 20 mmol) in ethanol (9 mL) is added 1-ethylpropylamine (2.6 mL, 22 mmol) and N,N-diisopropylethylamine (7 mL, 40 mmol) at ambient temperature. The reaction mixture is stirred at ambient temperature for 16 h and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, EtOAc/hexane 3:97 to 30:70) to give (5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine. LCMS: 280 (M+H)+
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCl
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCC(Cc2ccccc2)CC1
Temperature: 110 °C
Yield: 40.7 %

Procedure:
To a solution of 4-benzylpiperidine (0.50 mL, 2.8 mmol) in DMF (15 mL) were added 2-chloroethanol (0.25 mL, 3.70 mmol) and K2CO3 (0.79 g, 5.70 mmol). The heterogeneous mixture was heated at 110° C. for 2 h. It was then cooled to 25° C. and was diluted with water (100 mL) and extracted with ether (2×70 mL). The collected organic phase was washed with water (2×100 mL), dried and concentrated in vacuo. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound as a colorless solid (0.25 g, 40%): mp 62-64° C.; 1H NMR (CDCl3) δ1.15-1.35 (m, 2H), 1.45-1.60 (m, 1H), 1.63 (bd, J=13.8 Hz, 2H), 1.99 (t, J=11.7 Hz, 2H), 2.48 (t, J=5.7 Hz, 2H), 2.53 (d, J=6.9 Hz, 2H), 2.87 (bd, J=11.7 Hz, 2H), 2.9 (bs, 1H), 3.574 (t, J=5.4 Hz, 2H), 7.14 (d, J=7.2 Hz, 2H), 7.20 (d, J=6.9 Hz, 1H), 7.28 (t, J=6.2 Hz, 2H); MS (m/z) 219, 188, 91. Anal. Calcd for C14H21NO: C, 76.71; H 9.65; N, 6.40. Found: C, 74.49; H 9.29; N, 6.08.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15](O)[C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=3)[CH3:2].P(Cl)(Cl)([Cl:21])=O.C(N(CCC)CCC)CC>>[Cl:21][C:15]1[C:6]2[N:7]([C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=2
Reactant: CCc1nnc2c(O)nc3cc(OC)ccc3n12
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN(CCC)CCC
Product: CCc1nnc2c(Cl)nc3cc(OC)ccc3n12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame-dried reaction flask under a dry nitrogen atmosphere, there were placed 1.87 g. (0.0076 mole) of 1-ethyl-4-hydroxy-7-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline and 25 ml. of phosphorus oxychloride together with 1.8 ml. of tri-n-propylamine. The reaction mixture was then refluxed overnight for approximately 16 hours and finally cooled to room temperature prior to being slowly poured over ice/water. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and filtered, and the solid product so obtained was subsequently washed with cold water and then dissolved in chloroform. The latter organic solution was thereafter washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was finally obtained a yellow solid product which was triturated with diethyl ether and filtered to ultimately afford 1.6 g. (80%) of pure 4-chloro-1-ethyl-7-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 173°-175° C. Mass Spectrum: m/e, 262 (P); m/e, 264 (P+2); m/e, 261 (P-1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[F:28][C:24]1[CH:23]=[C:22]([C:20]2[CH:19]=[CH:18][C:14]([C:15]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:16])=[C:13]([CH3:12])[N:21]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: Cc1nc(-c2cccc(F)c2)ccc1C(=O)O
Product: Cc1nc(-c2cccc(F)c2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (28 mg, 0.20 mmol) and 6-(3-fluorophenyl)-2-methyl-nicotinic acid (D25) (50 mg, 0.33 mmol), as an off-white solid. MS(ES): MH+ 358, M-H+ 356.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]C(C)(C)C.[CH2:32]1[O:42][C:41]2[C:34](=[CH:35][C:36]([CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])=[C:37]([CH:40]=2)[CH:38]=[O:39])[O:33]1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:38]([OH:39])[C:37]1[CH:40]=[C:41]2[O:42][CH2:32][O:33][C:34]2=[CH:35][C:36]=1[CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:51])([CH3:50])[CH3:52])([CH3:47])[CH3:48])(=[O:9])=[O:10]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc2c(cc1C=O)OCO2
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2CCO[Si](C)(C)C(C)(C)C)OCO3)sc2ncccc12
Yield: 46.8 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)thieno-[2,3-b]pyridine-3-sulfonamide (0.64 g, 1.5 mmoles) [Example 4(A)], THF (10 ml), t-BuLi (1.7 M, 1.2 ml, 2.0 mmoles), and 4,5-(methylenedioxy)-2-(2-{[(1,1-dimethylethyl)dimethylsilyl]oxy}ethyl)benzaldehyde (0.71 g, 2.3 mmoles; prepared according to Lin, et al. (1994) J. Am. Chem. Soc. 116:9791-9792). Flash chromatography (40% EtOAc/hexanes) provided 0.51 g (46%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:9][C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:7][CH:6]=2)[CH2:3][CH2:2]1.[Cl:16]N1C(=O)CCC1=O>C(#N)C>[Cl:16][C:6]1[N:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:9][C:5]=1[NH:4][CH:1]1[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1cncc(-c2ncc(NC3CC3)s2)c1
Solvent: CC#N
Product: Clc1nc(-c2cccnc2)sc1NC1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine (1.00 g, 4.60 mmol) in acetonitrile (2 mL) was added 1-chloropyrrolidine-2,5-dione (645 mg, 4.83 mmol) and the mixture stirred at 0° C. for 1 h. The mixture was filtered and the filtrate was treated with excess HCl (4M in dioxane) to give 4-chloro-N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine as a brown solid: mp 56-60° C.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30](O)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(Cl)(Cl)=O)C=CC=CC=1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>O1CCCC1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: C1COCCN1
Agent: O=P(Cl)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (4.69 g.) in tetrahydrofuran (60 ml.) under a nitrogen atmosphere at 0°-5° C. was added triethylamine (1.6 ml.) followed by dropwise addition of phenylphosphonic dichloride (1.63 ml.) over 5 minutes. After stirring for 3 hours at 20° C., the reaction mixture was cooled to 0° C. and morpholine (4.0 ml.) was added dropwise over 10 minutes with the reaction temperature maintained at 0°-5° C. After stirring for 3 hours at this temperature, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in example 8.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[CH3:23][O:24][CH2:25][CH2:26][NH2:27]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][NH:27][CH2:26][CH2:25][O:24][CH3:23])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: COCCN
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: COCCNCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with 2-methoxyethylamine similarly to as in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 10-bromo-9-fluoro-3-(((2-methoxyethyl)amino)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 14 mg (16%) of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(2-methoxyethylamino)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=427.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5].P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][C:15]1[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: COCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COCC(=O)c1cnc2c(OC)cccc2c1Cl
Yield: 45.8 %

Procedure:
3-Methoxyacetyl-8-methoxy-4-(1H)-quinolone (39 g, 0.16 mol) was heated under reflux in a mixture of phosphoryl chloride (150 ml) and chloroform (200 ml) for 45 minutes. The solvent was evaporated and the mixture was partitioned between chloroform and sodium hydrogen carbonate solution. The aqueous layer was separated and extracted with chloroform. The combined organic solutions were washed with sodium hydrogen carbonate solution and brine. Evaporation gave an oil which afforded yellow crystals of 4-chloro-8-methoxy-3-methoxyacetylquinoline (19.2 g, 45.8%), m.p. 96°-8°.