Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH2:14][CH2:15][N:7]([C:8]=23)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4]1)#[N:2].[H-].C([Al+]CC(C)C)C(C)C.[H-].CO>ClCCl>[CH2:15]1[N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][C:9]=3[CH:3]([CH2:1][NH2:2])[NH:4][C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=32)[CH2:14]1
Reactant: N#CC1Nc2ccccc2N2CCc3cccc1c32
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: NCC1Nc2ccccc2N2CCc3cccc1c32
Reaction time: 3 h
Yield: 50.5 %

Procedure:
6-Cyano-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (15 g) was added to 300 ml of a 1M solution of diisobutylaluminium hydride in dichloromethane at -78° C. The reaction mixture was stirred for 3 hours at low temperature and thereafter diluted to 1 liter with dichloromethane. The excess hydride was slowly decomposed with methanol (50 ml). The gelatinous solution was washed with 5% sodium hydroxide (500 ml) and brine (2×500 ml) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to a solid-oil mixture (15.2 g). Purification was effected by flash chromatography over silica gel (145 g, eluted with 3.5% methanol/dichloromethane) to afford 7.7 g of product. Recrystallization from hot ethanol (65 ml) yielded 6.2 g of crystals, m.p. 171.5°-172.5° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:30][C:31]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34]>N1C=CC=CC=1.CN(C)C=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]([C:10]2[NH:40][C:39]3[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]=3[N:30]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1cccc(CC2OCCO2)c1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3cccc(CC4OCCO4)c3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(1,3-dioxolan-2-ylmethyl)benzoic acid (1.0 g, 4.80 mmol) in a mixture of pyridine (5 mL) and N,N-dimethylformamide (5 mL) was treated with 1,1′-carbonyldiimidazole (0.856 g, 5.28 mmol) at 45° C. for 2 hours. 2,3-diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, column 11, EXAMPLE 2, step (e), 1.08 g, 4.80 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the residue purified by flash chromatography on silica gel with 10% methanol in 2:1 ethyl acetate/hexane. The product was dissolved in acetic acid (20 mL) and the solution heated at 60° C. for 2 hours and at 80° C. for 1.5 hours, cooled and concentrated and the residue partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase was concentrated and the residue purified on silica gel with 10% methanol in 2:1 ethyl acetate/hexane to give 1.13 g of the title compound. MS (APCI) m/z 324 (M+H)+.
Reaction SMILES: I[C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1I.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([O:16][CH:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][N:11]3[C:5]2=[N:4][C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:8]=2)=[C:2]3[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:19]1
Reactant: OB(O)c1ccccc1
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(I)c3I)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3-c2ccccc2)CC1
Temperature: 105 °C

Procedure:
To a solution of 1,2-diiodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 219A) (212 mg, 0.386 mmole) in THF (3 mL) are added benzeneboronic acid (120 mg, 1 mmole), water (3 mL), Ba(OH)2 (460 mg, 2 mmoles) and PdCl2(dppf)2 (40 mg). The flask is evacuated and filled with argon. The reaction mixture is heated at 105° C. for 48 hours. AcOEt is added and the organic phase is washed with water, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) (100:0) to (95:5) to give 4-(1-methylpiperidin-4-yloxy)-1,2-diphenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C1C=CC=CC=1.[CH3:25][C:26]([N:29]1[C:33]([NH2:34])=[CH:32][C:31]([CH3:35])=[N:30]1)([CH3:28])[CH3:27]>C(O)(=O)C>[CH3:28][C:26]([N:29]1[C:33]2[N:34]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:32]=2[C:31]([CH3:35])=[N:30]1)([CH3:25])[CH3:27]
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nc2c1c(C)nn2C(C)(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-[4-(methyloxy)phenyl]-2,4-dioxobutanoate (327 mg, 1.305 mmol), benzene (8 mL), 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (200 mg, 1.305 mmol), and acetic acid (2 mL). The crude product was purified using column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 0.41 g (85%) of product. LCMS E-S (M+H)=368.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81 (s, 9 H), 2.55 (s, 3 H), 7.11 (d, J=8.84 Hz, 2 H), 7.89 (s, 1 H), 8.16 (d, J=8.84 Hz, 2 H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH3:15])[C:10]([OH:12])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1>>[Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH3:15])[C:10]([NH:23][C:20]1[CH:19]=[N:18][C:17]([CH3:16])=[CH:22][N:21]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: Cc1cnc(N)cn1
Product: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1cnc(C)cn1

Procedure:
C6a was prepared in an analogous fashion to C4d from (S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropanoic acid C4c and 5-methylpyrazine-2-amine (CAS 5521-58-4).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[N:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:11].Cl[O-].[Na+]>C(#N)C>[C:1]1([CH2:7][C:8]([Cl:11])=[N:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=CCc1ccccc1
Reactant: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Product: ON=C(Cl)Cc1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Phenylacetaldehyde oxime (40.5 g, 300 mmol) was dissolved in acetonitrile (100 ml). To the solution, a 6.7% aqueous hydrochloric acid (145 g) and then an 8.5% so aqueous sodium hypochlorite (262 g, 299 mmol) were added dropwise at -10° C. over 2.3 hours. The mixture was stirred at -5° C. for 30 minutes and then combined with toluene (200 ml) for extraction. The separated organic layer was washed twice with water (200 ml). Reversed phase HPLC revealed that the extract contained 40.3 g (238 mmol, yield 79%) of the desired compound. The solution was used in the next step without concentration.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[O:19][CH3:20])=[O:5])[CH3:2]>CO.C(=O)(O)[O-].[Na+].[Pt]=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[O:19][CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2cc(OC)ccc2OC)CCC1
Agent: O=[Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCCC1c1cc(OC)ccc1OC
Yield: 89.8 %

Procedure:
Dissolve 2-(2,5-dimethoxy-phenyl)-cyclopent-1-enecarboxylic acid ethyl ester (5 g, 18 mmol) in methanol (150 ml) exchange with N2 3×, add platinum oxide (1.6 g 7.2 mmol), add 60 psi of H2 for 24 hours at room temperature. Filter off catalyst, concentrate the filtrate to give the title compound (4.5 g, 89%): 1H NMR (CDCl3) δ 6.77-6.67 (m, 3H), 3.81 (s, 3H), 3.74 (s, 3H), 3.71-3.57 (m, 3H), 3.32-3.27 (m, 1H), 2.13-1.96 (m, 4H), 1.89-1.83 (m, 1H), 1.70-1.62 (m, 1H), 0.83-0.79 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:18]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[C:30]([Cl:37])[C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:32][C:20]=3[N:19]=2)[CH:17]=1)=[O:12])[CH3:9]>N1C=CC=CC=1>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:18]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[C:30]([Cl:37])[C:31]([S:33](=[O:35])(=[O:34])[NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:32][C:20]=3[N:19]=2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)Cl)c(Cl)cc3n2COCCOC)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)Nc4ccccc4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 42.9 %

Procedure:
Aniline (15.8 μL, 0.173 mmol) was added to a solution of 1-[6-chloro-5-chlorosulfonyl-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (75.0 mg, 0.157 mmol) in pyridine (0.79 mL) and the reaction mixture was allowed to stir at 23° C. for 1.5 h. At this point it was partitioned between EtOAc (20 mL) and water (20 mL). The aqueous layer was further extracted with EtOAc (20 mL) and the combined organic layers were washed with brine (10 mL), dried, filtered, and concentrated. The residue was purified via FCC (5-80% EtOAc/hexanes) to yield the titled compound (36.0 mg, 43% yield). MS (ESI/CI): mass calcd. for C23H24ClN5O6S, 533.1; m/z found, 534.1 [M+H]+.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[C:34]1[S:35][CH:36]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:38]=1)(=O)C1C=CC=CC=1.CC[O-].[Na+]>C(O)C>[C@@H:11]1([C:34]2[S:35][CH:36]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:38]=2)[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: CCOC(=O)c1csc([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1csc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 2-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)thiazole-4-carboxylate 8 (3.01 g, 5.00 mmol) in dry ethanol (50 ml) under argon atmosphere was added NaOEt (1.02 g, 15 mmol) powder. The reaction mixture was stirred at room temperature overnight, neutralized with Dowex 50W-X8 H+ resin and filtere. The resin was washed with ethanol (20 ml) and the filtrate evaporated to dryness. The residue was dissolved in salt free water (50 ml) and washed with CHCl3 (2×50 ml). The water extract was evaporated to dryness under reduced pressure to an oil. The oil was dissolved in minimum amount of warm ethyl acetate (10 mL). The solution was seeded with authentic 5 and once crystallization had begun the mixture was refrigerated (5° C.) for 16 h. The solid was collected by filtration, washed with cold (5° C.) ethyl acetate (5 mL), and dried (40° C., 1 mm); 1.2 g (83%), mp 74-78° C. 1H NMR (DMSO-d6): d 1.31 (t, 3H), 3.46-3.64 (m, 2H), 3.8-4.12 (m, 3H), 4.30 (q, 2H), 4.84 (t, 1H) 4.94 (d, 1H), 5.04 (d, 1H), 5.4 (d,1H) and 8.49 (s,1H).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[CH:19])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:21]([O:23][C:24](=[O:36])[CH2:25][NH:26][S:27]([C:30]1[S:31][C:32](Br)=[CH:33][CH:34]=1)(=[O:29])=[O:28])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.[Pd](Cl)Cl>[CH2:21]([O:23][C:24](=[O:36])[CH2:25][NH:26][S:27]([C:30]1[S:31][C:32]([C:19]#[C:18][C:16]2[CH:15]=[N:14][C:12]3[N:13]=[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[N:9]=[C:10]([OH:20])[C:11]=3[CH:17]=2)=[CH:33][CH:34]=1)(=[O:29])=[O:28])[CH3:22]
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CNS(=O)(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)s1
Yield: 93.2 %

Procedure:
A mixture of 436 mg (1.27 mmol) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 415 mg of N-(5-bromothien-2-ylsulfonyl)glycine ethyl ester, 20 mg of palladium chloride, 54 mg of triphenylphosphine, 10 mg of cuprous iodide, and 0.4 mL of triethylamine in 7 mL of acetonitrile was heated to reflux under nitrogen for 1 hour. The resulting reaction mixture was then concentrated in vacuo and the residue flash chromatographed with 4% CH3 OH/chloroform to give 610 mg of N-[5-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl)thien-2-ylsulfonyl]glycine ethyl ester as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ1.13 (t, J=7 Hz, 3H), 1.25, (s, 9H), 3.79 (d, J=5.8 Hz, 2H), 3.99 (q, J=7 Hz, 2H), 7.48 (d, J=3.6 Hz, 1H), 7.56 (d, J=3.6 Hz, 1H), 8.51 (s, 1H), 8.65 (t, J=5.8 Hz, 1H), 8.99 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][C:13]([Cl:15])=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCCCCl)cc1
Yield: 75.5 %

Procedure:
A solution of 4-hydroxybenzaldehyde (100 mmol, 12.2 g), 3-bromopropionyl chloride (101 mmol, 20 mL) and potasium carbonate (20.7 g, 150 mmol) in acetone (250 mL) was heated at reflux for overnight. The salt was filtered off. The solvent was evaporated. Reduced pressure distillation provided the title compound (15 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[C:7]([NH2:19])[CH:6]=1.N1C=CC=CC=1.[Cl:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:2][O:3][C:4](=[O:20])[C:5]1[CH:6]=[C:7]([NH:19][S:31]([CH2:30][CH2:29][CH2:28][Cl:27])(=[O:33])=[O:32])[CH:8]=[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1cc(N)cc(OCc2ccccc2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)CCCCl)cc(OCc2ccccc2)c1
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A suspension of 3-amino-5-benzyloxy-benzoic acid methyl ester hydrochloride (D50) (5.0 g, 17 mmol, 1 equiv) in CH2Cl2 (100 ml) was treated with DMAP (400 mg, 3.2 mmol) and pyridine (3.5 g, 44 mmol, 2.6 equiv) followed by 3-chloropropanesulfonyl chloride (3.54 g, 20 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred for 16 h then concentrated in vacuo. The residue was dissolved in AcOEt (200 ml) and the resulting solution was washed with 2N aqueous HCl solution (100 ml) followed by saturated aqueous NaHCO3 solution (100 ml), dried over MgSO4 and concentrated in vacuo to give 3-benzyloxy-5-(3-chloro-propane-1-sulfonylamino)-benzoic acid methyl ester (D52) (6.0 g, 97%) as a pale pink solid. [M+H]+=366.1, RT=2.34 min
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:32][CH:33]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(-c5ccccn5)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-pyridin-2-ylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-pyridin-2-ylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[OH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22](=[O:21])[CH:23]=[CH:24]2)[CH:7]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Oc1ccnc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Br)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Temperature: 85 °C
Yield: 73.5 %

Procedure:
A mixture of 2-[2-(5-bromo-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (5.0 g, 14.2 mmol), 4-hydroxyquinoline (3.08 g, 21.2 mmol) and sodium ethoxide (21 wt. % solution in ethanol, 5.3 mL, 14.2 mmol) in ethanol (120 mL) was heated at 85° C. for 14 hours. The reaction was quenched with water and concentrated in vacuo to remove most of the ethanol. The residue was diluted with methylene chloride and washed with half saturated sodium bicarbonate (NaHCO3), dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was precipitated from diethyl ether-hexanes to afford 1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (5.2 g, 73% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:16]([CH2:17]/[CH:18]=[C:19](\[CH3:29])/[CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])=[C:15]([O:30][CH3:31])[C:14]([CH3:32])=[C:13]2[C:9]=1[C:10](=[O:33])[O:11][CH2:12]2>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:16]([CH2:17]/[CH:18]=[C:19](\[CH3:29])/[CH2:20][C:21]([CH3:27])([CH3:28])[C:22]([OH:24])=[O:23])=[C:15]([O:30][CH3:31])[C:14]([CH3:32])=[C:13]2[C:9]=1[C:10](=[O:33])[O:11][CH2:12]2
Reactant: CCOC(=O)C(C)(C)C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCCOCOc1c(C/C=C(\C)CC(C)(C)C(=O)O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
By following the procedure of Example ZA-6A and substituting methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate with ethyl (E)-6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,2,4-trimethyl -4-hexenoate and compounds of Formula 109, prepared e.g, as described in Example ZA-12 and converted to compounds of Formula 112 as described in Part A above, there are obtained (E)-6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,2,4-trimethyl-4-hexenoic acid, m.p. 163-165 (hexane/ethyl acetate) and the corresponding compounds of Formula I-ZA-M2 as identified in the following table.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[C:4]([CH2:11][CH3:12])[CH:3]=1.C[CH2:14][N:15](CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:15][CH3:14])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CCO
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(Br)ccc1CCNC
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.7 %

Procedure:
Mesyl anhydride (430 mg, 2.46 mmol) was added portionwise to a solution of 36B (470 mg, 2.05 mmol) in CH2Cl2 (10 mL) and Et3N (0.57 mL, 4.1 mmol) at 0° C. After stirring for 15 h at ambient temperature, the mixture was diluted with CH2Cl2 (80 mL), washed with 1.0 M HCl, NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo. The crude mesylate was dissolved in EtOAc (20 mL) and methyl amine (33%, 5 mL) and heated in a pressure tube for 2 h. The reaction mixture was concentrated in vacuo to afford 36C (500 mg, 99%) as a yellow oil. MS (ESI) m/z 242.0/244.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.O=[Pt]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2=CCCC2)cc1
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.5 %

Procedure:
A mixture of 1.04 g of 1-bromo-4-cyclopent-1-enyl-benzene (4.7 mmol) and 100 mg of PtO2 in 25 ml toluene was stirred under an atmosphere of hydrogen at RT for 6 h. The reaction mixture was then filtered and the filtrate was evaporated to dryness to give 1.0 g of 1-bromo-4-cyclopentyl-benzene (95%) as a yellow liquid.
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.[Br:14][C:15]1C(C)=[N+:17]([O-])[CH:18]=[C:19]([F:22])[C:20]=1[CH3:21]>C(Cl)Cl.C(OCC)(=O)C>[Br:14][C:15]1[C:7]([CH2:6][OH:11])=[N:17][CH:18]=[C:19]([F:22])[C:20]=1[CH3:21]
Reactant: Cc1c(F)c[n+]([O-])c(C)c1Br
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(F)cnc(CO)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
Trifluoroacetic anhydride (0.35 mL, 2.5 mmol) was added dropwise to a solution of 3-bromo-5-fluoro-2,4-dimethylpyridine 1-oxide (220 mg; 1.0 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, Silica, 0-100% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a pale yellow oil (150 mg, 68%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]CC)=[O:20])=[CH:14][CH:13]=2)[N:4]=1.[OH-].[Na+].O>C(O)C>[F:25][C:2]([F:1])([F:24])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[N:4]=1
Reactant: CCOC(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Yield: 49.6 %

Procedure:
A mixture of ethyl {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetate (0.92 g, 2.61 mmol), sodium hydroxide (114 mg, 2.85 mmol), in ethanol (10 ml) and water (10 ml) was stirred at reflux for 1 hour. The reaction mix was allowed to cool and the ethanol was removed under reduced pressure and the residue was made acidic with 5N HCl, then extracted into dichloromethane. The organic layer was added to a 5 g pre-packed column and eluted from 0-100% ethyl acetate in petroleum ether to give the title compound as a pale yellow solid (0.42 g, 50%).