Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[H-].[Na+].[CH3:8][N:9]([CH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][CH:13]=1)[CH3:10]>CN(C)C=O.C(O)C>[CH3:8][N:9]([CH2:11][C:12]1[N:17]=[C:16]([S:5][CH2:4][CH2:3][NH2:2])[CH:15]=[CH:14][CH:13]=1)[CH3:10]
Reactant: NCCS
Reactant: CN(C)Cc1cccc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(C)Cc1cccc(SCCN)n1
Temperature: 80 °C
Yield: 44.2 %

Procedure:
Cysteamine hydrochloride (3.43 g, 0.030 mol) is added to a suspension of 60% sodium hydride in mineral oil (2.5 g, 0.0625 mol) in dry dimethylformamide (30 ml) and is warmed to 80° C. A solution of 6-dimethylaminomethyl-2-chloropyridine (5.0 g, 029.4 mol) in 30 ml of dry dimethylformamide is added dropwise and the reaction temperature is increased to 125° C. for 2 hours. The reaction is cooled, diluted with ethanol (60 ml) and the salts are removed by filtration before evaporating to dryness. This residue is dissolved in chloroform, washed with water and extracted into dilute hydrochloric acid. The acidic extract is neutralized with sodium carbonate and the product is extracted into chloroform, dried and evaporated to give 4.4 g. This residual oil is distilled to give 2.74 g of pure product, bp: 109°-114° C./0.25 mm.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)([CH3:7])[CH3:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:32]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[C:17]4[CH:35]=[CH:36][C:14]([CH:11]5[CH2:10][CH2:9][N:8]([C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])[CH2:13][CH2:12]5)=[CH:15][C:16]=4[O:25][CH2:24][CH2:23][N:22]3[CH:21]=2)=[N:30][C:29]([CH3:31])=[N:28]1)([CH3:34])[CH3:33]
Reactant: CCOC(=O)C(C)(C)N1CCC(c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(C)(C)CO)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
A solution of 2-{4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionic acid ethyl ester (47 mg, 0.092 mmol) in anhydrous THF (3 mL) was cooled to 0° C. and treated with lithium aluminium hydride (1M solution in THF, 0.3 mL, 0.3 mmol), the mixture stirred and allowed to warm to RT before quenching by the addition of saturated aqueous sodium hydrogen carbonate. The resultant mixture was extracted twice with ethyl acetate, the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to RPHPLC (C18 column, gradient 0 to 60% methanol in water+0.1% formic acid) to give 358 as a white solid (20 mg, 47%). LCMS: RT=2.74 min, [M+H]+=465. 1H NMR 400 MHz (DMSO-d) δ: 8.33 (1 H, d, J=8.28 Hz), 8.26 (1 H, s), 7.87 (1 H, s), 7.05 (1 H, dd, J=8.35, 1.77 Hz), 6.90 (1 H, d, J=1.71 Hz), 5.82-5.81 (1 H, m), 4.49 (4 H, m), 3.38 (2 H, s), 3.21 (2 H, d, J=11.33 Hz), 2.58 (1 H, t, J=11.87 Hz), 2.47 (2 H, d, J=11.47 Hz), 2.26 (3 H, s), 1.85 (2 H, d, J=12.54 Hz), 1.72 (2 H, m), 1.46 (6 H, d, J=6.60 Hz), 1.07 (6 H, s)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: COCCOc1ncc(C(=O)O)cc1-c1ccc(F)c(F)c1
Product: COCCOc1ncc(C(=O)NCc2nc(C(F)(F)F)no2)cc1-c1ccc(F)c(F)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(3,4-difluorophenyl)-6-(2-methoxyethoxy)-nicotinic acid (example CE) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 87.6%, 459.1 (M+H)+.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:17][C:18]1[S:22][C:21]([C:23](=[O:25])[CH3:24])=[CH:20][C:19]=1[CH3:26].CC(OC)(C)C>C1COCC1>[Br:17][C:18]1[S:22][C:21]([C:23](=[O:25])[CH2:24][C:11]([C:6]2[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=2)([OH:16])[C:12]([F:13])([F:14])[F:15])=[CH:20][C:19]=1[CH3:26]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1cc(C)c(Br)s1
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)sc1Br
Reaction time: 2 h
Yield: 111.4 %

Procedure:
LiH (2.06 g) is added to a solution of 3′,5′-dichloro-2,2,2-trifluoroacetophenone (48.0 g) and 1-(5-bromo-4-methyl-thiophen-2-yl)-ethanone (30.3 g) in THF (1000 ml). After 2 hours at 60° C. MTBE is added (300 ml) and the reaction mixture is poured onto water (500 ml) at 0° C. The organic phase is extracted with water and a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo to yield 71.2 g of 1-(5-bromo-4-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-butan-1-one. The crude product is used without further purification.
Reaction SMILES: N1CCCCC1.[CH:7]1([CH2:13][C@H:14]([NH:22][C:23](=[O:43])[C@@H:24]([NH:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH2:34])[CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)[C@@H:15]([OH:21])[C@H:16]([CH:18]2[CH2:20][CH2:19]2)[OH:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[N:44]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50][CH2:49][C@@H:45]1[C:46](O)=[O:47]>C(Cl)Cl>[C:55]([O:54][C:52]([N:44]1[CH2:51][CH2:50][CH2:49][C@@H:45]1[C:46](=[O:47])[NH:34][C@H:33]([C:32](=[O:42])[NH:31][C@H:24]([C:23](=[O:43])[NH:22][C@@H:14]([CH2:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C@@H:15]([OH:21])[C@H:16]([CH:18]1[CH2:19][CH2:20]1)[OH:17])[CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:53])([CH3:58])([CH3:57])[CH3:56]
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described in Example 19, by condensing (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide with Fmoc-Phe-OH there was obtained 9H-fluoren-9-ylmethyl [(S)-α-[[(S)-1-[[(1S,2R, 3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate which, by reaction with piperidine in methylene chloride, was converted into (S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-α-[(3-phenyl-L-alanyl)amino]imidazole-4-propionamide. Further condensation with Boc-D-Pro-OH, analogously to Example 19, yielded (R)-2-[[(S)-α-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1-pyrrolidinecarboxylic acid tert-butyl ester as an amorphous solid, MS: 709 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([CH:22]=C)[N:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[O:25]1CCCC1.O.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([CH:22]=[O:25])[N:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: C=Cc1cc2c(cn1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C=O)ncc1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-10-vinyl-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (0.500 g, 0.00155 mol) was dissolved in Tetrahydrofuran (30 mL, 0.4 mol) and Water (20 mL, 1 mol). Osmium tetraoxide 4% (wt) in water (0.758 mL, 0.000124 mol) was added. Followed by sodium metaperiodate (0.664 g, 0.00310 mol). The reaction mixture was stirred overnight at room temperature. LC-MS analysis of the reaction mixture showed complete conversion to desired product [C]. The crude reaction mixture was quenched with saturated sodium thiosulfate, diluted with EtOAc, and extracted 3×. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness to give 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-10-carbaldehyde.
Reaction SMILES: [CH2:1]([N:5]([CH2:34][CH2:35][CH2:36][CH3:37])[C:6]1[N:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][C:13]=2[C:22]([N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:23])[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:5]([CH2:34][CH2:35][CH2:36][CH3:37])[C:6]1[N:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[C:22]([N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:23])[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1cccc(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(CCCC)c1cccc(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-(6-(dibutylamino)pyridin-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (75 mg, 0.15 mmol) in THF (1.0 mL) and MeOH (1.0 mL) was added 2N NaOH (0.75 mL, 1.50 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. At 0° C., the reaction mixture was neutralized to pH 4-5 with 1N HCl. The solution was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give the title compound (69 mg, 95%). MS(ESI+) m/z 486.4 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=O)[CH:3]([CH2:4]2)[CH2:2]1.C(N(CC)CC)C.[NH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[C:23]#[N:24]>C(Cl)Cl>[NH2:24][C:23]1[C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=2[N:16]=[C:7]2[C:6]=1[CH:5]1[CH2:4][CH:3]2[CH2:2][CH2:1]1
Reactant: N#CC1=C(N)CCCC1
Reactant: O=C1CC2CCC1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c2c(nc3c1C1CCC3C1)CCCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 12.8 %

Procedure:
To a stirred solution of norcamphor (0.9 g, 8.2 mmole) in methylene chloride (8.0 ml) at -20° C., a mixture of triethylamine (1.7 g, 16.4 mmole) and 2-amino-1-cyano-1-cyclohexene (1.0 g, 8.2 mmole) in methylene chloride (24 ml) was added and the resulting mixture was stirred at 25° C. for 15 hours. The reaction mixture was then quenched with 12% aqueous NaCH (60 ml) and was stirred vigorously with methylene chloride (60 ml). The reaction mixture was then filtered through a 2" pad of diatomaceous earth (Celite (trademark)). The organic phase was separated, washed with water (2×50 ml) and then dried (anhydrous MgSO4). Methylene chloride was then removed under reduced pressure to afford an oil which was triturated with pentane to give the title compound as a off-white solid (225 mg, 13%, m.p. 131°-133° C.). 1H-NMR (CDCl3, 300 MHz, δ): 2H, m, 1.15-2.38 ppm; 1H, d, 1.5 ppm; 7H, m, 165-2.0 ppm; 2H, bs, 2.4 ppm; 2H, bd, 2.8 ppm; 2H, bd 3.3 ppm; 2H, s, 3.95 ppm. HRMS: Calculated--214.3096; Found--214.1466. TLC: (90:10:1-methylene chloride: methanol:28% aqueous ammonia) Rf =0.25
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[N:10]([CH3:18])[C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:5][CH:4]=1)=O.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>C(O)C>[CH3:18][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[N:17]=[C:9]1[CH2:8][O:7][C:6]1[CH:19]=[CH:20][C:3]([CH:1]=[C:25]2[S:21][C:22](=[O:27])[NH:23][C:24]2=[O:26])=[CH:4][CH:5]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cn1c(COc2ccc(C=O)cc2)nc2cccnc21
Solvent: C1CCNCC1
Solvent: CCO
Product: Cn1c(COc2ccc(C=C3SC(=O)NC3=O)cc2)nc2cccnc21
Yield: 79.2 %

Procedure:
A mixture of 0.35 g of 2-(4-formylphenoxymethyl)-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 112), 0.31 g of 2,4-thiazolidinedione, 0.26 ml of piperidine and 10 ml of ethanol was heated under reflux for 4 hours. At the end of this time, the solvent was removed by distillation under reduced pressure and the residue was crystallized by trituration with water. The crystals were collected by filtration and washed with water and then with ethyl acetate, to give 0.38 g of the title compound, melting at 279°-281° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH2:20]Br)=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:20][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[O:19])[CH:8]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-chloropyrimidin-2-one hydrochloride (502 mg), α-bromo-4-methoxyacetophenone (687 mg), triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 2 hours, during which the suspension formed a solution from which a solid crystallised out. The solid was crystallised from acetone to give the title pyrimidinone: yield. 449 mg; m.p. 212°-214° C.: λmaxEtOH 222.5 nm (ε 19850), 277 nm (ε 18000), 330 nm (ε 3725).
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]1[CH2:10][CH2:9]CC1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>O>[CH2:13]([NH:1][C@@H:2]([CH:6]1[CH2:10][CH2:9]1)[C:3]([OH:5])=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@H](C(=O)O)C1CCCC1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H](NCc1ccccc1)C1CC1
Yield: 69.9 %

Procedure:
(S)-2-amino-2-cyclopentylacetic acid (1) (66.0, 0.46 mol, 1.0 eq) was added in portions into 2N NaOH (230 mL, 0.46 mol, 1.0 eq) with stirring. After complete dissolution of the amino acid, benzaldehyde (49.0 g, 0.46 mol, 1.0 eq) was added all at once. The reaction mixture was allowed to stir at room temperature for 1 h. Sodium borohydride (17.5 g, 0.46 mol, 1.0 eq) was added slowly in portions at 0° C., and the reaction mixture was stirred at room temperature for 4 h. Then the reaction mixture was diluted with water (250 mL) and extracted twice with diethyl ether (250 mL). The clear aqueous layer was neutralized with 4N HCl (aq) to pH=7 and the white suspension were stirred at rt for 0.5 h. After filtration, the solid was washed with water (250 mL), the filter cake was dried to yield the product 2 (66 g, 59%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: O=C(O)C=Cc1cc(F)ccc1F
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cc(F)ccc1F
Yield: 73.3 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2,5-difluorocinnamic acid (2.2 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (2.8 g, 74%) as crystals.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[C:12](=[O:16])[NH:13][N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]2[C:10]=1[CH:15]=[N:14][NH:13][C:12]2=[O:16]
Reactant: BrBr
Reactant: O=c1[nH]ncc2cnc(-c3ccccc3)n12
Solvent: ClC(Cl)Cl
Product: O=c1[nH]ncc2c(Br)nc(-c3ccccc3)n12
Temperature: 25 °C

Procedure:
A 3.0 portion of 6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one is stirred with 100 ml. of chloroform. The mixture is heated slightly and a solution of one ml. of bromine in 10 ml. of chloroform is slowly dripped into the reaction mixture. The mixture is refluxed for one hour, cooled to room temperature, and filtered. To the solid is added aqueous Na2CO3 and chloroform and the mixture is shaken in a separatory funnel. The remaining solid and the organic phase are combined and evaporated to a steam bath. Methanol and 2-propanol are added and the mixture is treated twice with charcoal. Cooling gives the desired product as a solid, m.p. 192°-194° C.
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[C:3]=1Cl.[C:15](/[C:17](/[S-:22])=[C:18](\[C:20]#[N:21])/[S-:19])#[N:16].[Na+].[Na+].O>O1CCCC1>[O:12]=[C:11]1[C:2]2[S:19][C:18]([C:20]#[N:21])=[C:17]([C:15]#[N:16])[S:22][C:3]=2[C:4](=[O:13])[N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][N:6]12
Reactant: N#C/C([S-])=C(/[S-])C#N
Reactant: O=c1c(Cl)c(Cl)c(=O)n2n1CCCC2
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1=C(C#N)Sc2c(c(=O)n3n(c2=O)CCCC3)S1
Temperature: 40 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
An amount of 1 g (4.254 mmol) of 2,3-dichloro-6,7,8,9-tetrahydropyridazino[1,2-a]pyridazine-1,4-dione (II-1) is introduced in 20 ml of absolute tetrahydrofuran. Subsequently 0.869 g (4.254 mmol) of disodium (Z)-1,2-dicyanoethene-1,2-bis(thiolate) and 2 ml of water are added and the mixture is stirred at 40° C. for 18 hours. It is filtered with suction and extracted with methylene chloride and water, and the extract is dried and concentrated. Chromatography on silica gel (cyclohexane/ethyl acetate 0-100%) gives 0.5 g (99% purity, 38.3% of theory) of 5,12-dioxo-5,7,8,9,10,12-hexahydro[1,4]dithiino[2,3-d]pyridazino[1,2-a]pyridazine-2,3-dicarbonitrile.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[OH-].[Na+]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:8]=2[CH:9]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc2c(c1)C(Cl)Cc1ccc(C(F)(F)F)cc1S2
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(C2Cc3ccc(C(F)(F)F)cc3Sc3ccc(F)cc32)CC1

Procedure:
9 G. of 10-chloro-8-fluoro-10,11-dihydro-3-trifluoromethyldibenzo[b,f]thiepin are treated with 11 g. of N-methylpiperazine and stirred for 10 minutes at 105°-110°C. The cooled mixture is treated with 2N sodium hydroxide and extracted with ether. The ether solution is washed neutral with water and shaken with dilute methanesulfonic acid. The acidic solution is made alkaline with sodium hydroxide and extracted with ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated in a vacuum, and there is obtained 1-{8-fluoro-10,11-dihydro-3-trifluoromethyl-dibenzo[b,f]thiepin-10-yl}-4-methylpiperazine as a yellow oil which is converted into the methanesulfonate having a melting point of 224°-226°C. by treatment with methanesulfonic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[C:14]#[N:15].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:7]1[C:2]([Cl:1])=[C:3]([C:14]#[N:15])[C:4](=[O:13])[N:5]([C@H:8]([CH:10]([CH3:11])[CH3:12])[CH3:9])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[C@H](C)n1ccc(Cl)c(C#N)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](C)n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Reaction time: 20 h
Yield: 97.3 %

Procedure:
To a solution of 4-chloro-1-((2S)-3-methylbutan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (14.6 g) in N,N-dimethylformamide (120 mL) was added N-bromosuccinimide (17.4 g), and the mixture was stirred at 50° C. for 20 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (19.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[Cl:1][C:2]1[C:7]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(I)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Clc1nc(I)ccc1OCc1ccccc1
Temperature: 22 °C
Yield: 61.4 %

Procedure:
To a solution of 2-chloro-6-iodo-3-pyridinol (500 mg, 1.96 mmol), and K2CO3 (690 mg, 5.0 mmol) in methanol (5 mL) was added benzyl bromide (510 mg, 3.0 mmol). The reaction was refluxed for 60 minutes and was allowed to cool to 22° C. The mixture was then concentrated in vacuo. The remaining solids were slurried in ethyl acetate and filtered. The filtrate was dried over MgSO4 and concentrated in vacuo to yield 416 mg (61%) of 2-chloro-3-benzyloxy-6-iodo-pyridine.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([C:12]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]1([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: c1ccc(C2(c3ccccc3)NCCc3ccccc32)cc1
Reactant: O=C(Cl)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCl)N1CCc2ccccc2C1(c1ccccc1)c1ccccc1

Procedure:
Chloroacetyl chloride (0.151 mL) was added to a solution of 1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (339 mg) and p-toluenesulfonate monohydrate (11.3 mg) in toluene (5 mL). The mixture was heated under reflux for 3 hours. The solvent was evaporated under reduced pressure, and EtOAc and an aqueous 1 M HCl solution were added to the residue. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 2-(chloroacetyl)-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (452 mg).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[CH:6]=O)([O-])=O.[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CS(C)=O>[N+:12]([C:8]1[C:5]2[CH:6]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[S:15][C:4]=2[CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: O=Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1cc2c([N+](=O)[O-])cccc2s1
Temperature: 0 °C

Procedure:
1.0 g (5.10 mmol) of 2,6-dinitrobenzaldehyde, 0.54 g (5.10 mmol) of methyl mercaptoacetate and 1.42 ml (10.20 mmol) of triethylamine in 3 ml of DMSO are heated at 80° C. for 3.5 h. The reaction solution is poured into 100 ml of ice-water. The resulting precipitate is filtered off with suction, washed with water and dried at 50° C. under reduced pressure overnight. This gives 1.10 g (88.7% of theory) of the title compound.