Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12])[CH3:2].[Br:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([NH2:24])=[CH:17][C:16]=1[CH3:25]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:24][C:18]1[CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:15]([Br:14])=[C:16]([CH3:25])[CH:17]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)CCCCCN=C=O
Reactant: Cc1cc(N)cc([N+](=O)[O-])c1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(Br)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 36 %

Procedure:
6-Isocyanato-hexanoic acid ethyl ester (370 μL, 2.16 mmol) was added to a solution of 4-bromo-3-methyl-5-nitro-phenylamine (250 mg, 1.08 mmol, Example 135: step a) in CH2Cl2 (5 mL, anhydrous) at rt. The reaction mixture was stirred overnight, then diluted in EtOAc and washed with saturated NH4Cl solution, water, and brine. The organic layer was dried over magnesium sulfate. Removal of solvents in vacuo was followed by flash chromatography (50–75% EtOAc/hexanes) to afford the title compound as a brown oil (162 mg, 36%). 1H-NMR (CDCl3): δ 7.59 (d, 1H, J=2.56 Hz), 7.42–7.48 (m, 1H), 4.10–4.17 (m, 2H), 3.20–3.28 (m, 2H), 2.39 (s, 3H), 2.29–2.35 (m, 2H), 1.47-1.68 (m, 4H), 1.23–1.41 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=3)[NH:25][C:24]=2[C:33]2[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:20][CH2:21][CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=3)[NH:25][C:24]=2[C:33]2[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCNC(=O)CCCc2ccc(OCc3ccccc3)cc2)c1
Agent: B
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCNCCCCc2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a stirred solution of 4-(4-benzyloxyphenyl)-N-{2-[2-(3,5-dimethylphenyl)-5-hydroxy-1H-indol-3-yl]ethyl]butyramide(241 mg in 10 mL dry tetrahydrofuran) was added 4 mL of a 1M solution of borane in tetrahydrofuran and the mixture heated slowly to reflux on an oil bath. After 2 hours the mixture was cooled to room temperature and the excess borane quenched by the careful addition of methanol. The mixture was concentrated to half-volume, treated with N,N-dimethylethanolamine (1.4 mL) and heated to reflux on an oil bath. After 3 hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 92:8) gave the title compound (234 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2C)[C@H:6]([OH:20])[C@@H:5]1[OH:21].ClC[C@H]1O[C@@H:27]([N:29]2C3N=CN=C(N)C=3N=C2NC)[C@H](O)[C@@H]1O>CN.C(O)C>[CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[NH:29][CH3:27])[C@H:6]([OH:20])[C@@H:5]1[OH:21]
Reactant: CNc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: CN
Solvent: CCO
Product: CNC[C@H]1O[C@@H](n2c(NC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 4c was prepared by the same procedure as described for the preparation of 4a using 3c (1.00 g, 3.17 mmol) and 33% methylamine/ethanol solution (30 mL). After column chromatography (elution with 7:1:0.4 chloroform:methanol:NH4OH), a yellow glassy solid was obtained: 505 mg (51%); MS m/z 310 (M+H)+; 1HNMR (DMSO-d6) δ 7.89 (bs and q, 2H, H-2 and 8CH3—NH), 6.44 (bs, 2H, 6-NH2), 5.84 (d, 1H, H-1′, J1′,2′=7.0 Hz), 5.22 (d, 1H, 2′-OH, J2′-2′OH=6.4 Hz), 5.12 (d, 1H, 3′-OH, J3′-3′OH=4.0 Hz), 4.66 (ddd, 1H, H-2′, J1′,2′=7.0 Hz, J2′,3′=5.4 Hz, J2′-2′OH=6.4 Hz), 4.14 (bm, 1H, H-3′), 3.94-4.0 (bm, 1H, H-4′), 2.90 (d, 3H, 8NH—CH3, J=4.4 Hz), 2.77-2.83 (m, 1H, 5′-CH2), 2.57-2.62 (m, 1H, 5′-CH2), 2.35 (s, 3H, 5′NH—CH3).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:19]2[CH:18]=[C:17]([NH:20]CC3C=CC(OC)=CC=3)[N:16]=[CH:15][C:14]=2[N:13]=[CH:12]1)([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([N:11]1[C:19]2[CH:18]=[C:17]([NH2:20])[N:16]=[CH:15][C:14]=2[N:13]=[CH:12]1)([CH3:10])[CH3:9]
Reactant: COc1ccc(CNc2cc3c(cn2)ncn3C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1cnc2cnc(N)cc21
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Trifluoroacetic acid (2.42 ml, 31.4 mmol) was added to a solution of 1-isopropyl-N-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-6-amine (intermediate 25, 596 mg, 2.01 mmol) in DCM (12 ml) and then the mixture was stirred at 40° C. for 24 h. The reaction mixture was diluted with DCM and washed with sat. aq. NaHCO3 (strong gas evolution) and H2O. The aqueous phase was extracted with DCM (2×). The combined organic layers were dried over Na2SO4 and evaporated. The crude material was applied to a 24 g RediSep® silica column and purified by normal phase chromatography, eluting with 9:1 CH2Cl2/MeOH. Product-containing fractions were combined and evaporated to give the title compound as a beige solid. (UPLC-MS 6) tR 0.33; ESI-MS 177.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](Br)[CH:9]=2)[CH:4]=1.[Li]CCCC.[F:19][C:20]([F:29])([F:28])[CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:24]1([OH:27])[CH2:23][CH2:22][CH:21]([C:20]([F:28])([F:29])[F:19])[CH2:26][CH2:25]1)[CH:7]=[CH:6]2
Reactant: O=C1CCC(C(F)(F)F)CC1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C3(O)CCC(C(F)(F)F)CC3)ccc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) anhydrous solution of 2-methoxy-6-bromonaphthalene (1.52 g, 6.40 mmol) in THF (40 mL) was added n-BuLi (6.9 mL of a 2.5 M solution in hexanes, 6.9 mmol). The mixture was stirred at −78° C. under a nitrogen atmosphere for 15 min, then 4-(trifluoromethyl)cyclohexanone (0.88 g, 5.3 mmol) was added slowly to the reaction mixture. The bath was allowed to warm to room temperature and the reaction mixture was quenched with saturated NH4Cl (aq). The resultant mixture was extracted with EtOAc/hexanes. The organic layer was evaporated in vacuo and the crude residue was purified by flash chromatography on silica gel using gradient elution (0% to 20% EtOAc/hexanes, 150 mL; 20% to 35% EtOAc/hexanes, 204 mL; 35% to 75% EtOAc/hexanes, 381 mL) to provide Isomer A as the faster-eluting product and Isomer B as the slower-eluting product.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.CN1C(=O)N(C)CCC1.[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:28]1)=[O:26])[CH3:23].C(Br)C=C>C1COCC1>[CH2:36]([O:35][C:33]([C:29]1([CH2:7][CH:5]=[CH2:6])[CH2:30][CH2:31][CH2:32][CH:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:28]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)C1CCCC(C(=O)OCC)C1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: C=CCBr
Product: C=CCC1(C(=O)OCC)CCCC(C(=O)OCC)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a cooled solution (−78° C.) of N,N-diisopropylamine (272 mL, 1.94 mol) in anhydrous THF (1.4 L) was added n-BuLi (1.6 M in hexane, 1.21 L, 1.94 mol) over the period of one hour and 20 minutes. The mixture was stirred at 0° C. for one hour and again cooled down to −78° C. DMPU (834 mL, 6.92 mol) was added dropwise, followed by the addition of the solution of cyclohexane-1,3-dicarboxylic acid diethyl ester from step 1 (316 g, 1.38 mol) in THF (400 mL). The mixture was stirred at −78° C. for 2.5 hours, and then allyl bromide (132 mL, 1.52 mol) was added. The mixture was warmed up to rt slowly and stirred at rt overnight. The mixture was quenched with ice-cold aqueous HCl (1 N, 1 L), diluted with ethyl acetate (30 mL) and extracted. The organic layer was washed with water (4×1.5 L), brine, dried over Na2SO4 and concentrated under reduced pressure to afford 371 g of the title compound as a thick oil, which was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[N:15][C:14]([O:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:13][N:12]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.CO.[Pd]>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[CH2:19][CH2:18][O:17][C:14]1[N:15]=[CH:16][C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: O=C(Nc1cnc(OCCC2CCCCO2)cn1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cnc(OCCC2CCCCO2)cn1

Procedure:
A solution of {5-[2-(tetrahydro-pyran-2-yl)-ethoxy]-pyrazin-2-yl}-carbamic acid benzyl ester (560 mg, 1.5 mmol) in tetrahydrofuran (5 mL) and methanol (15 mL) was treated with 10% palladium on activated carbon (110 mg) in methanol (5 mL). The reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) at 25° C. for 2 h, at which time, thin layer chromatography indicated complete removal of the protection group. The reaction mixture was filtered and concentrated in vacuo to afford 5-[2-(tetrahydro-pyran-2-yl)-ethoxy]-pyrazin-2-ylamine as an oil which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[C:8]([CH3:13])[CH:7]=1)(=[O:5])=[O:4].C([O-])(=O)C.[K+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][CH2:29][C:30]2[NH:39][C:33]3=[N:34][CH:35]=[C:36](I)[CH:37]=[C:32]3[N:31]=2)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][CH2:29][C:30]2[NH:39][C:33]3=[N:34][CH:35]=[C:36]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:14])[CH3:1])(=[O:5])=[O:4])=[CH:7][C:8]=4[CH3:13])[CH:37]=[C:32]3[N:31]=2)[CH:23]=1
Reactant: Cc1cc(S(=O)(=O)N(C)C)ccc1Br
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N(C)C)cc4C)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 43.1 %

Procedure:
A mixture of 0.417 g of N,N-dimethyl-4-bromo-3-methylbenzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 6 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 17 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30-25:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate gives 0.19 g of the title compound as a solid of m.p. 179-180° C. The mass spectrum shows the molecular peak MH+ at 452.2 Da.
Reaction SMILES: [CH3:1][N:2]([N:9]=O)C(N[N+]([O-])=O)=N.[OH-].[K+].[Si:13]([O:20][C@H:21]1[CH2:25][N:24]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C@H:23]([CH:39]=[CH2:40])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[N+](=[CH2:43])=[N-].C([O-])(O)=O.[Na+]>CCOCC.[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[N+:2](=[CH2:1])=[N-:9].[Si:13]([O:20][C@H:21]1[CH2:25][N:24]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C@H:23]([CH:39]2[CH2:43][CH2:40]2)[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: C=C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C2CC2)N(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
An ethereal solution of diazomethane was prepared by adding 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) (2.84 g, 19.3 mmol) to a biphasic solution (10 ml 40% KOH/5 ml ether) and stirring at 0° C. for 5 minutes. The biphasic solution was cooled to −78° C. to freeze the aqueous layer. The diazomethane solution was decanted into a vial containing a solution of (6) (0.841 g, 1.93 mmol) in 5 ml of ether. Palladium (II) acetate (43.3 mg, 0.193 mmol) was added and the reaction was stirred for 30 min. This procedure of adding diazomethane solution followed by palladium catalyst was repeated 2 more times to produce a greater yield. Dichloromethane (10 ml) was added followed by sat. NaHCO3 (5 ml). The catalyst was filtered off and the organic layer was isolated and dried over sodium sulfate. The organic layer was concentrated in vacuo and purified via column chromatography using ethyl acetate/hexane gradients to yield (2S,4R)-4-(tert-butyldimethylsilyloxy)-2-cyclopropyl-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidine (10) (0.520 g, 60%) as a clear oil. This was a mixture of (R) (64%) and (S) (36%) isomers. MS m/z 449.1 (M+H)+; retention time=7.069 min ((R)-isomer) and 7.292 ((S) isomer); method [10].
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)#[N:12].[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:2]3[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=3[CH3:8])[CH2:21][CH2:20]2)=[CH:17][CH:18]=1)#[N:12]
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Br
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1[nH]c(=O)[nH]c(=O)c1N1CCN(c2ccc(C#N)cc2)CC1
Temperature: 140 °C
Yield: 29.9 %

Procedure:
A mixture of 20.5 g (0.10 mole) of 5-bromo-6-methyl-2,4(1H,3H)-pyrimidinedione, 18.1 g (0.10 mole) of 4-(4-cyanophenyl)piperazine, 6.4 g (0.11 mole) of anhydrous potassium fluoride, 15.2 g (0.1 mole) of powdered potassium carbonate in 100 ml of hexamethyl phosphoramide was heated at 140° C. for 24 hours. The mixture was cooled and poured into 500 ml of ice water. The solid was collected and washed with 100 ml of water. Recrystallization from N,N-dimethylformamide and drying in vacuo at 78° C. for 16 hours gave 9.3 g of the product as a dull solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:6][C:7]=1[O:8][CH3:9].[CH3:20][S-:21].[Na+]>C1COCC1>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=[N:3][C:2]=1[S:21][CH3:20]
Reactant: C[S-]
Reactant: COc1cc(-c2cccc(C(F)(F)F)c2)nnc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(C(F)(F)F)c2)nnc1SC
Yield: 88.3 %

Procedure:
3-Chloro-4-methoxy-6-[3-(trifluoromethyl)phenyl]pyridazine (2.0 g, 0.0069 mole, Compound No. 48) and sodium thiomethoxide (0.5 g, 0.0069 mole) were refluxed overnight under N2 in THF (50 mL). After this time no starting material was present by TLC. The mixture was partitioned between EtOAc-water. The aqueous layer was extracted again with EtOAc. The EtOAc layers were combined, washed with brine, dried (MgSO4), filtered and evaporated to give a crude oil. The oil was chromatographed on a Prep-500 using EtOAc-cyclohexane (3:17) to give 4-methoxy-3-(methylthio)-6-[3-(trifluoromethyl)phenyl]pyridazine (1.83 g, 88% yield, Compound No. 64) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C[Al](C)C.[O:10]1[CH:14]=[C:13]([C:15]([O:17]C)=O)[N:12]=[CH:11]1.Cl.C(Cl)Cl>ClC(Cl)C>[O:10]1[CH:14]=[C:13]([C:15]([N:4]([CH3:5])[O:3][CH3:2])=[O:17])[N:12]=[CH:11]1
Reactant: COC(=O)c1cocn1
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CON(C)C(=O)c1cocn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.1 %

Procedure:
To a suspension of methoxy-methylamine hydrochloride (2.3 g, 23.6 mmol) in 30 mL of dichloroethane at 0° C. was added dropwise 11.8 mL (23.6 mmol) of trimethylaluminum. The mixture was stirred at 0° C. for 20 min, and methyl 4-oxazolecarboxylate (1 g, 7.9 mmol) in 20 mL of dichloroethane was added in one portion. The mixture was poured into an ice-cold solution of 0.5N HCl/methylene chloride (2:1) and stirred for 10 min. The aqueous layer was extracted with methylene chloride (2×50 mL), and the combined organic layer was washed with saturated ammonium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by chromatography on silica (methylene chloride/ethyl acetate/methanol 6:3:1) to afford 1.0 g (81.9%) of 4-oxazolyl-N-methyl-N-methoxy-carboxamide.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[CH:10][C:9]1([CH3:23])[CH3:22])=O)(C)(C)C.Br[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([F:33])[CH:32]=1)[C:28]#[N:29]>>[C:28]([C:27]1[CH:26]=[C:25]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][C:9]([CH3:22])([CH3:23])[CH:10]=[C:11]3[CH3:21])[CH:32]=[C:31]([F:33])[CH:30]=1)#[N:29]
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Reactant: N#Cc1cc(F)cc(Br)c1
Product: CC1=CC(C)(C)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Yield: 38.6 %

Procedure:
This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (46.4 mg, 0.14 mmol) and 3-bromo-5-fluorobenzonitrile (29.1 mg, 0.14 mmol). The crude material was purified to recrystallization from hexane to afford 15.8 mg (37%) of Compound 271. Data for Compound 271: 1H NMR (400 MHz, acetone-d6) 7.83 (app t, J=1.3, 1 H), 7.68 (dd, J=10.6, 4.0, 1 H), 7.43 (d, J=2.0, 1 H), 7.41 (dd, J=2.2, 1.2 1H) 7.35 (dd, J=8.3, 2.2, 1 H), 6.59 (d, J=8.4, 1 H), 5.35 (br s, 1 H), 5.39 (s, 1 H), 2.04 (s, 3 H), 1.28 (s, 6 H).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[Cl:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1>>[Cl:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][N:28]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:16])=[CH:15][CH:14]=3)=[O:13])[CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1)N1CCN(c2ncc(Cl)cc2Cl)CC1
Yield: 75.7 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (253 mg) described in Preparation Example 16 and 1-(3,5-dichloropyridin-2-yl)piperazine (229 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (340 mg) was obtained.
Reaction SMILES: [CH3:1][CH2:2][N:3](C(C)C)C(C)C.[CH:10]1[C:23]2[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:15][C:14]=2[CH:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.Cl.C(N)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOCC.CCOC(C)=O>[CH2:2]([NH:3][C:24]([C:11]1[CH:12]=[CH:13][C:14]2[S:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:22][C:23]=2[CH:10]=1)=[O:26])[CH3:1]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc2c(c1)Nc1ccccc1S2
Agent: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCNC(=O)c1ccc2c(c1)Nc1ccccc1S2
Temperature: 0 °C
Reaction time: 15 h

Procedure:
5.8 ml (3.3 eq.) of DIEA is added dropwise to a solution of 2.43 g (10 mmoles) of 10H-phenothiazine-2-carboxylic acid, 1.79 g (2.2 eq.) of ethylamine hydrochloride and 4.17 g (1.1 eq.) of HBTU in 50 ml of DMF, cooled down to 0° C. The reaction mixture is stirred for 15 hours at 23° C., and then poured into a mixture of 100 ml of a saturated solution of NaHCO3 and 100 ml of AcOEt. After stirring for a few minutes, the precipitate formed is removed by filtration and the filtrate is decanted. The organic phase is successively washed with water, a 1M solution of citric acid and salt water. The organic solution is dried over sodium sulphate, filtered and concentrated to dryness under vacuum. The solid obtained is suspended in Et2O, triturated and filtered. A beige solid is obtained with a quantitative yield. Melting point: 150-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.Cl.[CH3:26][NH2:27]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:27][CH3:26])=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(OC)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and methylamine hydrochloride in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [CH2:1]([N:4]1[CH:13]2[C:8]3=[C:9]([C:22]([OH:27])=[C:23]([O:25][CH3:26])[CH:24]=[C:7]3[CH2:6][CH2:5]1)[C:10]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:11]=1[CH2:12]2)[CH:2]=[CH2:3].[C:28]1(C)C=CC=CC=1.CN(C)C=O.[OH-].C1([N+](C)(C)C)C=CC=CC=1>CO>[CH2:1]([N:4]1[CH:13]2[C:8]3=[C:9]([C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=[C:7]3[CH2:6][CH2:5]1)[C:10]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:11]=1[CH2:12]2)[CH:2]=[CH2:3]
Reactant: C=CCN1CCc2cc(OC)c(O)c3c2C1Cc1cc(OC)c(OC)cc1-3
Reactant: Cc1ccccc1
Agent: C[N+](C)(C)c1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCN1CCc2cc(OC)c(OC)c3c2C1Cc1cc(OC)c(OC)cc1-3

Procedure:
4.5 g. (12.2 mmol) (+)-6-Allyl-5,6,6a,7-tetrahydro-1-hydroxy-2,9,10-trimethoxy-4H-dibenzo(de,g)quinoline are reacted in 230 ml. of a mixture of toluene and dimethylformamide (9:1 v/v) with 20 ml. of a 1N solution of phenyltrimethylammonium hydroxide in methanol as described in Variant 1. After appropriate working up, there is obtained (+)-6-allyl-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-4H-dibenzo(de,g)quinoline, which is identical in every respect to the product obtained according to Variant 1. [α]DRT (hydrochloride): +117.7° (c=0.5, methanol).