Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](Br)=[CH:11][C:10]=1[C:24]1[N:25]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[N:35]([CH3:39])[CH:34]=[CH:33]3)[C:26]([OH:29])=[N:27][N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH:45]=[CH2:46].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:46]=[CH:45][C:44]2[CH:47]=[CH:48][C:49]([O:50][CH3:51])=[C:42]([O:41][CH3:40])[CH:43]=2)=[CH:11][C:10]=1[C:24]1[N:25]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[N:35]([CH3:39])[CH:34]=[CH:33]3)[C:26]([OH:29])=[N:27][N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(OC)c(OC)c1
Reactant: Cn1ccc2cc(-n3c(O)nnc3-c3cc(Br)c(OCc4ccccc4)cc3OCc3ccccc3)ccc21
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C=Cc2cc(-c3nnc(O)n3-c3ccc4c(ccn4C)c3)c(OCc3ccccc3)cc2OCc2ccccc2)cc1OC
Temperature: 135 °C
Yield: 66 %

Procedure:
A flask was charged with 5-(2,4-Bis-benzyloxy-5-bromo-phenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-ol (290 mg; 0.50 mmol), 3,4-dimethoxystyrene (98 mg; 0.60 mmol), tris(dibenzylideneacetone)dipalladium(0) (11 mg; 0.025 eq.), tris-tert-butylphosphine (10 mg; 0.10 eq.), diisopropylethylamine (77 mg; 0.60 mmol), and dimethylformamide (2 mL). The reaction was heated at 135° C. overnight, and then cooled. The solution was diluted with ethyl acetate (40 mL) and washed with water (3×40 mL). The organic layer was dried with sodium sulfate, evaporated, and purified by column chromatography to give 5-{2,4-bis-benzyloxy-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-phenyl}-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-ol (220 mg; 0.33 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(C1C=C(C)C(C(N)=O)=NC=1)#[N:14]>>[Cl:1][C:2]1[C:3]([C:10]([NH2:14])=[O:12])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: Cc1cc(C#N)cnc1C(N)=O
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Product: N#Cc1cnc(C(N)=O)c(Cl)c1

Procedure:
3-Chloro-5-cyano-pyridine-2-carboxylic acid amide was prepared from 3-chloro-5-cyano-pyridine-2-carboxylic acid (CAS 1200497-81-9) in analogy to the procedure described for Amide 1.
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:13]1[CH:18]=[C:17]2[C:19]([N:21]([CH2:24][C:25](O)=[O:26])[C:22](=[O:23])[C:16]2=[CH:15][CH:14]=1)=[O:20].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>CN(C1C=CN=CC=1)C.ClCCl>[O:20]=[C:19]1[C:17]2[C:16](=[CH:15][CH:14]=[CH:13][CH:18]=2)[C:22](=[O:23])[N:21]1[CH2:24][C:25]([O:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:26]
Reactant: CC(C)(O)C(=O)c1ccccc1
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: CN(C)c1ccncc1
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)(OC(=O)CN1C(=O)c2ccccc2C1=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 2-hydroxy-2-methylpropiophenone (2.0 g, 12.2 mmol), N-phthaloylglycine (2.7 g, 13.2 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (10.3 g, 24.3 mmol) and DMAP (0.34 g, 2.8 mmol) was dissolved in dichloromethane (100 mL) and stirred 5 days at room temperature. The mixture was diluted with dichloromethane and washed with 1 M HCl (2×), saturated NaHCO3 and brine, then filtered through cotton and concentrated to give 1,1-dimethyl-2-oxo-2-phenylethyl 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetate.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH3:2].C1COCC1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[CH2:1]([C:3]1[N:4]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCc1cc2cc(OC)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1cc2cc(OC)ccc2n1Cc1ccccc1
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
2-Ethyl-5-methoxy-1H-indole (5.6 g, 21.5 mmol) was dissolved in 150 mL of DMF and 20 mL of THF and 1.0 g (25 mmol) of 60% sodium hydride was added. After stirring for 0.17 hours, 3.0 mL (25 mmol) of benzyl bromide was added. The mixture was stirred at room temperature for 10 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with water, saturated NaCl solution, and dried (Na2SO4). The EtOAc was evaporated and the residue was chromatographed on silica gel eluting with a gradient, 5% EtOAc/hexane→15% EtOAc/hexane to give 4.6 g (82% yield) of 2-ethyl-5-methoxy-1-(phenylmethyl)-1H-indole.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:24][C:13]1=[CH:14][C:15]3[N:16]=[C:17]([CH:22]=O)[CH:18]=[N:19][C:20]=3[CH:21]=[C:12]1[CH2:11]2.[NH:25]1[C:35]2[C:36]3[CH:27]([CH2:28][C:29](=[O:37])[NH:30][C:31]=3[CH:32]=[CH:33][CH:34]=2)[CH2:26]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:37]=[C:29]1[CH2:28][CH:27]2[CH2:26][N:25]([CH2:22][C:17]3[CH:18]=[N:19][C:20]4[CH:21]=[C:12]5[CH2:11][C:3]6([C:4]7[C:5](=[N:6][CH:7]=[CH:8][CH:9]=7)[NH:10][C:2]6=[O:1])[CH2:24][C:13]5=[CH:14][C:15]=4[N:16]=3)[C:35]3[C:36]2=[C:31]([CH:32]=[CH:33][CH:34]=3)[NH:30]1
Reactant: O=C1CC2CNc3cccc(c32)N1
Reactant: O=Cc1cnc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1CC2CN(Cc3cnc4cc5c(cc4n3)CC3(C5)C(=O)Nc4ncccc43)c3cccc(c32)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (±)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoxaline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde from Step B (16 mg, 0.051 mmol), 1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one, enantiomer B (11 mg, 0.061 mmol, described in Intermediate 19), and AcOH (0.029 mL, 0.51 mmol) in DCE (0.4 mL) was added sodium triacetoxyborohydride (16 mg, 0.076 mmol) and the mixture was stirred for 4 h at ambient temperature. The solvent was removed in vacuo and the residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Saturated aqueous NaHCO3 (1 mL) was added to the tubes in the fraction collector in order to rapidly neutralize to eluted solvent. The pure, product-containing fractions were combined and extracted with CH2Cl2, and the organic extract was dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound. MS: m/z=475 (M+1). HRMS: m/z=475.1878; calculated m/z=475.1877 for C28H23N6O2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1Br)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].[Br-].[CH:20]1([Zn+])[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.CO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:5]([OH:7])=[O:6]
Reactant: O=C(OCc1ccccc1)c1ccc(Br)c(F)c1
Reactant: [Zn+]C1CCCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C2CCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.45 g (1.45 mmol) of benzyl 3-fluoro-4-bromobenzoate (0.45 g, 1.45 mmol) in 4.4 mL of 0.5 M cyclopentylzinc bromide solution in THF was treated with ˜5 mg of bis(tri-t-butylphosphine)palladium(0) and the resulting mixture was stirred at rt for 24 h. The reaction mixture was directly purified on a Biotage 40S cartridge using 1:1 hexanes/EtOAc as the eluant. A mixture of the resulting solid (0.27 g, 0.91 mmol) and 10% Pd/C in 5 mL of MeOH was stirred under 1 atm of H2 for 3 h. The reaction was filtered and concentrated. Purification by HPLC B afforded the title compound: 1H NMR δ 1.58-1.90 (m, 6H), 2.05-2.14 (m, 2H), 3.30 (m, 1H), 7.36 (t, J=7.7, 1H), 7.72 (dd, J=1.6, 10.5, 1H), 7.83 (dd, J=1.6, 8.0, 1H).
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=[CH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)[CH2:5][CH2:4]1.[Br:24]Br>C(O)(=O)C>[BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:10]3[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=3[CH:12]([Br:1])[CH:13]([Br:24])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)[CH2:5][CH2:4]1
Reactant: BrBr
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCC(=C2c3ccccc3C(Br)C(Br)c3ccccc32)CC1
Temperature: 25 °C

Procedure:
1-Methyl-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrobromide, 18.40 g. (0.05 mole) is dissolved with warming in 750 ml. of glacial acetic acid. This solution is cooled to room temperature and 8.0 g., 2.6 ml., (0.05 mole) of bromine dissolved in 75 ml. of glacial acetic acid is added dropwise with stirring. After completion of the addition the mixture is stirred overnight. The crystals are collected, washed with a small amount of cold glacial acetic acid, then with dry ether, and then dried for 2 hours in a vacuum oven at 70° to give 1 methyl-4-(10,11-dibromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrobromide. Recrystallization from acetonitrile gives an analytical sample, m.p. 185°-186°C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:12])[O-:11])[CH:6]=[CH:5][CH:4]=1.[CH3:13][C:14]([CH3:17])([O-])[CH3:15].[K+].Br[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C.C(OCC)(=O)C.O>[CH:22]1([CH2:21][CH2:20][N:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][OH:1])[N:8]=2)[C:10](=[O:11])[O:12][C:14]([CH3:17])([CH3:15])[CH3:13])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C([O-])Nc1cccc(CO)n1
Reactant: CC(C)(C)[O-]
Reactant: BrCCC1CCCCC1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCC1CCCCC1)c1cccc(CO)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
To a stirred solution of [6-(hydroxymethyl)pyridin-2-yl]carbamate (200 mg, 1.07 mmol) in DMF, cooled to 0° C. with a brine/ice bath, was added potassium tert-butoxide (126 mg, 1.07 mmol). The mixture was stirred 5 minutes at 0° C. then 1-bromo-2cyclohexylethane (205 mg, 1.07 mmol) was added. After stirring at room temperature for 4 h, the reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, dried over MgSO4 and concentrated in vacuo. Purification on silica gel afforded tert-butyl (2-cyclohexylethyl)[6-(hydroxymethyl)pyridin-2-yl]carbamate as a yellow oil [240 mg, yield 64%; HPLC/MS: m/z=335 (M+H); logP(HCOOH)=4.49]
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[CH3:15][O:16][C:17]([CH3:30])([CH3:29])[CH2:18][CH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22](=[O:28])[CH2:21]1>O1CCCC1>[CH3:15][O:16][C:17]([CH3:30])([CH3:29])[CH2:18][CH2:19][CH:20]1[CH2:25][C:24]([CH3:26])([CH3:27])[CH2:23][CH:22]([OH:28])[CH2:21]1
Reactant: COC(C)(C)CCC1CC(=O)CC(C)(C)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(C)(C)CCC1CC(O)CC(C)(C)C1
Reaction time: 16 h

Procedure:
To lithium tri-sec-butylborohydride (2.7 mL of a 1.0 M solution in tetrahydrofuran, 0.0027 mol) cooled to -65~C. was added 3-(3-methoxy-3-methylbutyl)-5,5-dimethylcyclohexan-1-one (0.5 g, 0.0022 mol) dissolved in tetrahydrofuran (3.5 mL). The mixture was allowed to stir at 25~C. for 16 hours. Workup yielded 3-(3-methoxy-3-methylbut-1-yl)-5,5-dimethylcyclohexan-1-ol, bp1.0 210-212~C. (0.31 g). This compound was determined to possess a warm woody note. NMR(CDCl3))δ 0.9(s,3H), 1.1 (s,3H), 1.2(s,6H), 1.2-1.4(m,4H), 1.4-1.7(m,6H), 1.7-1.9(m,2H), 3.2(s,3H), 4.2(m, 1H); IR(neat) 3425, 2970, 2940, 1470, 1365, 1080 cm-1 ; MS(m/e) 43, 55, 73, 125, 163, 213, 214.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([C@@H:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>N1C=CC=CC=1.CCOC(C)=O>[CH3:17][CH:16]([CH3:18])[C:15]([O:13][C@H:10]([C@H:8]1[O:7][C@@H:5]2[O:6][C:2]([CH3:1])([CH3:14])[O:3][C@@H:4]2[CH2:9]1)[CH2:11][CH3:12])=[O:19]
Reactant: CC[C@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a cooled solution of (1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 6e, 505.6 mg, 2.5 mmol) in pyridine was added isobutyryl chloride (0.39 mL, 3.72 mmol) dropwise while cooled with an ice-water bath. After the addition, the mixture was warmed to room temperature and stirred at room temperature overnight. The resulting mixture was diluted with EtOAc and washed with a saturated NH4Cl solution. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to afford 470 mg of [(1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl] 2-methylpropanoate (compound 42a).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:7]=1[F:16])(=O)C.[OH-].[Na+]>CO>[F:16][C:7]1[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: COc1ccc(COC(C)=O)c(F)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CO)c(F)c1OC

Procedure:
5.4 g of 2-fluoro-3,4-dimethoxybenzyl acetate are heated to 80° for 1.5 hours together with 50 ml of methanol and 50 ml of 1N sodium hydroxide solution. After evaporation of the methanol the residue is extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 80 g of silica gel with methylene chloride/methanol (95:5), 2-fluoro-3,4-dimethoxybenzyl alcohol is obtained as an oil.
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[CH2:12][NH:11][CH2:10][CH2:9]2.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(O)C>O.C(O)(C)C>[Cl:18][C:19]1[CH:24]=[C:23]([N:11]2[CH2:10][CH2:9][C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH3:4])[CH:7]=3)[CH2:12]2)[N:22]=[CH:21][N:20]=1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)O
Solvent: O
Product: COc1cc2c(cc1OC)CN(c1cc(Cl)ncn1)CC2

Procedure:
Sodium hydroxide solution (80 ml, IN) was added to a suspension of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride in water (20 ml) followed by 4,6-dichloropyrimidine (5.95 g) and the mixture was heated on a steam bath for 5 hours. The solvent was evaporated in vacuo to give a brown oil which solidified on standing. Re-crystallization from aqueous ethanol followed by isopropanol gave 4-chloro-6-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)pyrimidine (6.0 g). An analytical sample re-crystallized from isopropanol, m.p. 88°-89°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([O:14]CC)=[O:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCOC(=O)c1ncc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 3 h
Yield: 84.5 %

Procedure:
423 g of ethyl 3-chloro-5-trifluoromethyl-2-pyridinecarboxylate (Example H2) is initially introduced into a mixture of 800 ml of water and 160 ml of ethanol. 800 ml of a 2N sodium hydroxide solution are added dropwise at a temperature below 35° C. After 3 hours, the mixture is washed twice with methylene chloride and then rendered acid with an excess of concentrated hydrochloric acid, while cooling in an ice-bath. The slurry formed is filtered and the solid is washed with water and dried in vacuo. 318 g of the desired product are obtained as a white solid of melting point 135° C. (decomposition).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][N:11]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].[CH2:26]([O:33][C:34]([NH:36][CH2:37][C:38](O)=[O:39])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[Br:16][C:13]1[CH:14]=[CH:15][N:11]([NH:10][C:38](=[O:39])[CH2:37][NH:36][C:34](=[O:35])[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]=1[C:17](=[O:18])[NH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Nn1ccc(Br)c1C(=O)Nc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)OCc1ccccc1)Nn1ccc(Br)c1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
DIEA (10.5 ml, 60 mmol) was added at 0° C. over a mixture of 1-amino-3-bromo-N-phenyl-1H-pyrrole-2-carboxamide (5.1 g, 18 mmol) and 2-(benzyloxycabonylamino)acetic acid (5.33 g, 25 mmol) in anhydrous ethyl acetate (100 ml). After 15 min T3P® solution (50% AcOEt, 15 ml) was slowly added and stirred 20 min at 0° C. and then at room temperature overnight. Further DIEA (5 ml, 30 mmol), 2-(benzyloxycabonylamino)acetic acid (2.66 g, 25 mmol) and T3P® solution (50% AcOEt, 7 ml) were added and the reaction mixture was stirred at room temperature overnight. More ethyl acetate was added and the reaction crude was washed with water and brine, dried over magnesium sulphate and the solvent was removed under vacuum. The residue was purified by flash chromatography using Isolera® Purification System (0-40%, hexane-AcOEt) to give 7.81 g (41% yield) of the final product with a purity of 45% that was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][N:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[C:10]2=[O:30])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:31]1([C:2]2[C:7]([CH2:8][N:9]3[N:18]=[CH:17][C:16]4[C:11](=[CH:12][C:13]([C:19]5[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=5)=[CH:14][CH:15]=4)[C:10]3=[O:30])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: OB(O)C1CC1
Reactant: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1Cc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1Cc1cccnc1C1CC1
Temperature: 100 °C

Procedure:
A mixture of 2-((2-bromopyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (25 mg, 0.053 mmol), cyclopropyl boronic acid (14 mg, 0.16 mmol), dppf(Pd)Cl2 (6 mg, 0.0079 mmol), potassium carbonate (29 mg, 0.021 mmol) in degassed dioxane (1 mL) was heated at 100° C. for 3 hours. The layers were separated, the organic layer was concentrated and the residue was purified by reverse phase HPLC to provide 2-((2-cyclopropylpyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white powder. C2-4H18F3N3O2. 438.1 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:7][C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13](I)=[N:12][N:11]3[CH:17]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[CH:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[CH3:25])[O:26][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:17]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][CH:1]3[CH2:3][CH2:2]3)[N:9]=2)[N:12]=1
Reactant: Cc1ccc(O)cc1N
Reactant: O=C(CC1CC1)Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CC4CC4)cn3n2)cc1N
Yield: 46.6 %

Procedure:
Using 2-cyclopropyl-N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (300 mg, 0.877 mmol), 3-amino-4-methylphenol (216 mg, 1.754 mmol), potassium carbonate (182 mg, 1.316 mmol) and N,N-dimethylformamide (3 mL), and by a reaction in the same manner as in Example 191, the title compound (138 mg, 47%) was obtained as a orange powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:24][C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][N:13]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1.S(=O)(=O)(O)O.[C:30](=O)([O-])O.[Na+].C(Cl)(Cl)Cl>CO>[CH3:30][O:1][CH2:2][C:3]1[S:24][C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][N:13]([C:17]4[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=4)[C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(-n2nc3c(cc2=O)CCCc2sc(CO)cc2-3)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COCc1cc2c(s1)CCCc1cc(=O)n(-c3ccc(C)cc3)nc1-2

Procedure:
To a suspension of 0.75 g of 9-hydroxymethyl-2-(4-methylphenyl)2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one in methanol was added 0.1 ml of conc. sulfuric acid at room temperature and the mixture was refluxed under heating for 3 hours. The mixture was poured into aqueous sodium hydrogen carbonate solution and extraced with chloroform. The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using chloroform as an eluent. The solid was recrystallized from a mixed solvent of ethanol and isopropyl ether to give 0.7 g of 9-methoxymethyl-2-(4-methylphenyl)-2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one as a white powder, melting at 109°-110° C.
Reaction SMILES: [CH2:1]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:22]([N:29]1[C:34]([CH3:36])([CH3:35])CC(O)[CH2:31][C:30]1([CH3:39])[CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:40]1([CH3:47])[C:41](C)=[CH:42][CH:43]=[CH:44][CH:45]=1.[Li]N>C(O)C>[CH2:22]([N:29]1[C:30]([CH3:38])([CH3:39])[CH2:31][CH:20]([O:19][C:17]([CH2:1][C:2]([C:12]([O:14][CH:15]2[CH2:31][C:30]([CH3:39])([CH3:38])[N:29]([CH2:47][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]([CH3:36])([CH3:35])[CH2:16]2)=[O:13])([C:7]([O:9][CH:10]2[CH2:39][C:30]([CH3:31])([CH3:38])[N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:34]([CH3:35])([CH3:36])[CH2:11]2)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:18])[CH2:21][C:34]1([CH3:35])[CH3:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCC(CC(=O)OCC)(C(=O)OCC)C(=O)OCC
Reactant: Cc1ccccc1C
Reactant: CC1(C)CC(O)CC(C)(C)N1Cc1ccccc1
Agent: [Li]N
Solvent: CCO
Product: CCCCC(CC(=O)OC1CC(C)(C)N(Cc2ccccc2)C(C)(C)C1)(C(=O)OC1CC(C)(C)N(Cc2ccccc2)C(C)(C)C1)C(=O)OC1CC(C)(C)N(Cc2ccccc2)C(C)(C)C1
Reaction time: 3 h

Procedure:
30.2 g (0.1 mol) of triethyl hexane-1,2,2-tricarboxylate, 74.2 g (0.3 mol) of 1-benzyl-2,2,6,6-tetramethyl-4-hydroxypiperidine and 50 ml of xylene are warmed to 130° and mixed with 0.8 g of LiNH2. The ethanol formed is distilled off continuously. The solution is kept at the above temperature for 3 hours, so that it can then be kept at 150° for a further 2 hours. After cooling, the residue is taken up in toluene, a little glacial acetic acid is added to the solution and the latter is washed with H2O. After drying over Na2SO4, the solvent is distilled off in vacuo. Tris-(1-benzyl-2,2,6,6-tetramethyl-4-piperidinyl)hexane-1,2,2-tricarboxylate is obtained as a powdery residue. (Compound No. 1).