Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C1(C)C=CC=CC=1.[CH3:19][CH2:20][O:21]C(C)=O>>[C:20]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])(=[O:21])[CH3:19]
Reactant: CCOC(C)=O
Reactant: O=C1Nc2ccccc2C1=O
Solvent: Cc1ccccc1
Product: CC(=O)N1C(=O)C(=O)c2ccccc21

Procedure:
T.L.C. (PhCH3 /AcOEt=75/25): slightly impure for isatin.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][OH:7])[CH2:3][C:4]#[N:5].[S:8](Cl)([CH3:11])(=[O:10])=[O:9].Cl>N1C=CC=CC=1.C(Cl)Cl>[OH:1][C@H:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][C:4]#[N:5]
Reactant: N#CC[C@H](O)CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H](O)CC#N
Temperature: 0 °C
Reaction time: 6 h

Procedure:
(3S)-3,4-Dihydroxybutyronitrile (16.2 g, 160 mmol) was dissolved in pyridine (26.0 ml). To the resulting solution, a solution of mesyl chloride (14.8 ml) in methylene chloride (160 ml) was added at 0° C. and stirred at 0° C. for 6 hours. Then, the pH of the mixture was adjusted at 2 with 6N hydrochloric acid, and the mixture was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated off. The residue was purified with silica gel column chromatography (acetone:chloroform=5:95) to obtain (3S)-3-hydroxy-4-methanesulfonyloxybutyronitrile (15.2 g). Yield, 53 %.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C@@H:41]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:42]Br)=[C:34]2[C:39]=1[NH:38][C:37](=[O:40])[CH:36]=[CH:35]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>CS(C)=O.O>[C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:42][C@@H:41]([C:33]4[CH:32]=[CH:31][C:30]([O:29][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[C:39]5[C:34]=4[CH:35]=[CH:36][C:37](=[O:40])[NH:38]5)[O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: NCCc1cccc(OCC23CC4CC(CC(C4)C2)C3)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1cccc(OCC23CC4CC(CC(C4)C2)C3)c1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 41 (0.117 g, 0.41 mmol) in dimethyl sulfoxide (0.8 mL) and a solution of (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)-ethyl)quinolin-2(1H)-one (0.2 g, 0.41 mmol) in dimethyl sulfoxide (0.8 mL) was added sodium hydrogen carbonate (0.103 g, 1.23 mmol) and sodium iodide (0.092 g, 0.61 mmol). The resulting reaction mixture was stirred at 150° C. for 1 hour. The mixture was poured into water and the precipitate was collected by filtration and washed with ether and ethyl acetate. The title compound was obtained as a brown solid (0.231 g, 57%) and was used in the next step without further purification. MS (M+): 694.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([C:34](Cl)=[O:35])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([N:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:34](=[O:35])[C:31]1[CH:32]=[CH:33][C:28]([CH3:37])=[CH:29][CH:30]=1)[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(C(=O)c1ccc(C)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.8 %

Procedure:
3-Benzyl-2-(1-cyclohexylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 28, 26.3 mg, 0.072 mmol) in CHCl3 (1.5 mL) at 25° C. was treated with p-toluoyl chloride (38.3 mg, 0.248 mmol) and triethylamine (16.8 mg, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (5.5 mg, 15.8%) as a colorless film: LC/MS 89% at 4.48 min (ESI+) 483 (M++H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Si:13]([O:20][CH2:21][CH:22]=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[C:16]([Si:13]([CH3:15])([CH3:14])[O:20][CH2:21][CH2:22][NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCNCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Tryptamine (3.34 g, 20.85 mmol) and t-butyldimethylsilyloxylacetaldehyde (2.44 g, 13.99 mmol) is dissolved in dichloromethane (200 ml) for 10 minutes. The mixture is cooled to 0° C. and it is added sodium triacetoxyborohydride (5.38 g, 25.38 mmol). The mixture is warmed slowly to room temperature and stirred for 18 hours. Then water is added and the mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated. The crude product is purified by a silica gel flash chromatograph using dichloromethane-methanol eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:19]=[CH2:18]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCNc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Yield: 78.2 %

Procedure:
A 250 mL round-bottom flask, equipped with a magnetic stir bar, was charged with methyl 4-aminobenzoate (1) (6.04 g, 40 mmol), K2CO3 (11.06 g, 80 mmol) and 85 mL anhydrous DMF. The mixture was cooled to 0° C. and allyl bromide (3.13 mL, 36 mmol) was added dropwise with stirring. After the reaction mixture was heated at 60° C. for 12 hours, DMF was removed under high vacuum. The residual was extracted with CH2Cl2/H2O=150 mL/200 mL, the organic phase was removed and the aqueous phase was then extracted again with CH2Cl2 (150 mL). The combine organic phases were dried over MgSO4. After removal of solvent, the crude product was purified by silica gel chromatography (eluent: Hexane/Ethyl acetate from 100/0 to 100/7) to give compound 2 as a white solid (5.38 g, 78.2% yield). 1H NMR (400 MHz, CDCl3): δ 3.72 (d, 2H), 3.76 (s, 3H), 5.16 (dd, 1H), 5.21 (dd 1H), 5.80-5.85 (m, 1H), 6.50 (d, 2H), 7.80 (d, 2H); 13C NMR (400 MHz, CDCl3): δ 45.89, 51.53, 111.72, 116.80, 118.66, 131.51, 134.29, 144.91, 151.67. MP: 71-73° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:22]2[O:26][C:25]([CH3:28])(C)C(C)(C)[O:23]2)=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:31](C)([O-:33])=[O:32].[OH-].[Na+].C1COCC1>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:22]([OH:23])[O:26][CH:25]([CH2:28][N+:31]([O-:33])=[O:32])[C:15]=2[CH:18]=[CH:19][C:20]=1[F:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2c(C=O)ccc(F)c2OCCCOCc2ccccc2)OC1(C)C
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])CC1OB(O)c2c1ccc(F)c2OCCCOCc1ccccc1
Yield: 93.8 %

Procedure:
Synthesized according to the methods of general procedure 8 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-benzyloxy-propoxy)-4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (0.40 g, 0.966 mmol), nitromethane (0.15 mL, 2.89 mmol), NaOH (0.038 g, 0.96 mmol), THF (10 mL), water (10 mL). This generated 0.34 g (94% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.83 (s, 1H), 7.32-7.02 (m, 7H), 5.78-5.75 (m, 1H), 5.28-5.23 (m, 1H), 4.60-4.56 (m, 1H), 4.42 (s, 2H), 4.37 (brs, 2H), 3.57 (brs, 2H), 1.92 (brs, 2H). 19F NMR (376 MHz, DMSO-d6 with D2O) δ (ppm): −132.3 (1F).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)C>O1CCOCC1>[N:12]1([C:2]2[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1csc(Cl)n1
Agent: CCN(CC)C(C)C
Solvent: C1COCCO1
Product: O=C(O)c1csc(N2CCCC2)n1
Temperature: 60 °C
Yield: 68 %

Procedure:
A mixture of ethyl 2-chlorothiazole-4-carboxylate (500 mg, 2.6 mmol), pyrrolidine (210 mg, 2.98 mmol) and diethylisopropyl amine (1 mL) in p-dioxane (5 mL) was heated to 60° C. for 2 h. After cooling to room temperature, the solvent was concentrated in vacuo and the residue purified by flash chromatography (SiO2, 2 to 5% MeOH in CH2Cl2 as eluent) to give the desired compound as a foam (400 mg, 68% yield, which was used directly for the next step). MS: (ES) m/z 227.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:21](OC(=O)C)(=[O:23])[CH3:22]>C([O-])(=O)C.[Na+].O>[CH2:1]([NH:11][C:12]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:21](=[O:23])[CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)CCCOCCO
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCNC(=O)CCCOCCOC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
In a glass reaction vessel 17.7 grams (0.0616 mole) of N-decyl-4-(2-hydroxyethoxy)butyramide was admixed with 25.3 grams (0.25 mole) of acetic anhydride in the presence of 4 grams sodium acetate catalyst. This mixture was heated to 100° C. on a steam bath until a reaction was completed within a period of 3 hours. The mixture was then drowned in water, salted out and phase separated. The upper liquid phase was dried to 17.8 grams of liquid product having a refractive index ηd25 =1.4586 and an IR of 6.09 mu.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.[Br:17][C:18]1[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[C:20](Br)[CH:19]=1>>[Br:17][C:18]1[CH:19]=[C:20]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:21]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:23]=1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: FC(F)(F)Oc1cc(Br)cc(Br)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(Br)cc(OC(F)(F)F)c3)cc21

Procedure:
6-(3-Bromo-5-trifluoromethoxy-phenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]-oxazin-2-one was prepared, using (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1,3-dibromo-5-trifluoromethoxybenzene according to the procedure of Example 5, as a white solid: mp 214-216° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.68-7.62 (m, 3H), 6.97 (d, 1H, J=8.0 Hz), 1.68 (s, 6H); MS (ESI) m/z 414 ([M−H]−, 100%); Anal. Calcd. For C17H13BrF3NO3: C, 49.06; H, 3.15; N, 3.37. Found: C, 49.16; H, 3.05; N, 3.30.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]([Br:15])[C:12]([CH3:16])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:14]=[C:13]([Br:15])[C:12]([CH2:16][Br:24])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C)c(Br)cc1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)c(Br)cc1OC(C)=O
Temperature: 85 °C

Procedure:
To a solution of methyl 2-(acetyloxy)-4-bromo-5-methylbenzoate (may be prepared as described in Description 15; 705 mg, 2.46 mmol) in carbon tetrachloride (10 ml) was added NBS (437 mg, 2.46 mmol) and benzoyl peroxide (47.6 mg, 0.15 mmol). The solution was heated at 85° C. overnight, cooled and the solvent was removed in vacuo to give a residue. Purification by column chromatography (SiO2, 6:1 cyclohexane/ethyl acetate) yielded the title compound as an oil. 741 mg.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11](O)[CH3:12]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: CCO
Product: CCOC(=O)c1cnc(C)cn1
Yield: 93 %

Procedure:
The reaction was carried out, under nitrogen, in a 2 L×4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor was charged with 5-methylpyrazinecarboxylic acid (300.84 g), an acidic cation exchange resin (60.17 g), and ethanol (1004 g). The mixture was stirred at reflux for about 16 h after which the reaction was found to be complete by GC or GC/MS. The resin was removed by pressure filtration and rinsed with ethanol. The rinse was added to the alcohol solution of the ester. Evaporation of the solvent under reduced pressure gave 336.7 g (93%) of 5-methylpyrazinecarboxylic acid, ethyl ester that was suitable for use in the following examples. It was also possible to pass the material through a thin film evaporator at 125° C./3 mm. The material from this distillation was almost colorless and crystallizes at about 20° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:44]=[CH:43][C:32]3[N:33](C(OC(C)(C)C)=O)[CH:34]=[N:35][C:31]=3[CH:30]=2)O1.CC1(C)C(C)(C)OB(C2C=CC3N=CN(C(OC(C)(C)C)=O)C=3C=2)O1>>[NH:33]1[C:32]2[CH:43]=[CH:44][C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])=[CH:30][C:31]=2[N:35]=[CH:34]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(C)(C)OC(=O)n1cnc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: CC(C)(C)OC(=O)n1cnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]cnc4c3)ccn2c1=O

Procedure:
Methyl 8-(1H-benzo[d]imidazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (75 mg, 0.26 mmol) and a mixture of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate (141.5 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title BOC-deprotected compound as a yellow solid (69.9 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[C:8](=[N:10]/[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])/[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH3:20][Al](C)C.[OH-].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[C:12]([CH3:19])=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])([CH3:20])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: C/C(=N\c1c(C)cc(C)cc1C)c1cccc(Br)n1
Reactant: C[Al](C)C
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(NC(C)(C)c2cccc(Br)n2)c(C)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
In argon atmosphere, to a solution of 5.59 g (17.61 mmol) of N-[(1E)-1-(6-bromopyridin-2-yl)ethylidene]-2,4,6-trimethylaniline in 140 ml of dry toluene cooled to 0° C., a solution of 2.53 g (35.2 mmol) AlMe3 in 20 ml of dry toluene was added dropwise for 10 min. This mixture was slowly warmed to room temperature, stirred for 25 min at 40° C., cooled to 0° C., and then 140 ml of 5% KOH was added dropwise for 1 h. The aqueous layer was separated, the organic layer was washed with 100 ml of water, then 100 ml of brine, dried over Na2SO4, and then evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane-ethyl acetate=20:1, vol.). Yield 2.80 g (47%) of yellow crystalline solid. Anal. calc. for C17H21BrN2: C, 61.27; H, 6.35; N, 8.41. Found: C, 61.14; H, 6.26; N, 8.31. 1H NMR (CDCl3): δ 7.63 (dd, J=8.0 Hz, J=0.6 Hz, 1H, 5-H in pyridine), 7.49 (t, J=7.6 Hz, 1H, 4-H in pyridine), 7.32 (dd, J=8.0 Hz, J=0.6 Hz, 1H, 3-H in pyridine), 6.78 (s, 2H, 3, 5-H in mesityl), 3.65 (br.s, 1H, NH), 2.21 (s, 3H, 4-Me in mesityl), 2.01 (s, 6H, 2, 6-Me in mesityl), 1.46 (s, 6H, CMe2).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH2:19]1[O:21][C@H:20]1[CH2:22]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.O>CN(C)C=O>[S:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:22][CH:20]3[CH2:19][O:21]3)=[CH:12][CH:13]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: Oc1ccc(-c2csc3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
Cool a mixture of sodium hydride (585 mg, 60% dispersion in mineral oil, 14.6 mmol) in dimethylformamide (20 mL, anhydrous), with an ice bath, under a nitrogen atmosphere. Add a solution of 4-benzo[b]thiophen-3-yl-phenol (3.0 g, 13.3 mmol) in dimethylformamide (20 mL) over a period of 5 minutes. Reaction mixture has noticeable gas evolution and is a yellow mixture. Stir at room temperature for 0.5 hours and cool via an ice bath to give a yellow solution. Rapidly, add a solution of (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (3.78 g, 14.6 mmol) in dimethylformamide (20 mL) and stir at 0° C. for 35 minutes. The reaction mixture is a red-orange color. Stir reaction mixture at room temperature overnight. Pour the reaction mixture into cold (0° C.) water (300 mL) and extract with ethyl acetate (3×100 mL). Combine the organic layers, wash with water (100 mL), saturated sodium chloride (100 mL), dry (MgSO4) and concentrate (in vacuo) to give a brown oil. The brown oil is purified by column chromatography (dichloromethane) to give a light green/clear, viscous oil. The oil is dried (0.5 mm Hg) at room temperature for 3 hours to give the title compound as a solid (3.19 g, 85% Yield).
Reaction SMILES: [CH2:1]1[CH2:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C@H:4]2[CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].[Cl-].[NH4+]>>[C:12]([CH:9]1[CH2:8][CH2:7][CH:5]2[CH:4]([CH2:3][CH2:2][CH2:1][CH2:6]2)[C:10]1=[O:11])(=[O:14])[CH3:13]
Reactant: O=C1CCC[C@H]2CCCC[C@H]12
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)C1CCC2CCCCC2C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 19.8 %

Procedure:
Boron trifluoride-acetic acid complex (5.2 mL, 37.5 mmol) was cooled to 0° C. trans-1-Decalone (3.82 g, 25 mmol) in acetic anhydride (4.7 mL, 50 mmol) was added, and the reaction was stirred at room temperature for 3.5 hours. Saturated ammonium chloride solution (95 mL) was added, and the mixture was heated to 80° C. for 45 minutes. After cooling to room temperature, the mixture was extracted with ethyl acetate. The extracts were dried over MgSO4 and concentrated. SiO2 chromatography with 10-40% ethyl acetate/hexanes gave 0.96 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[N:20]=[N:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=4)[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[F:36][C:33]1[CH:34]=[C:35]2[C:30]([CH2:29][CH2:28][N:27]2[CH:24]2[CH2:25][CH2:26][N:21]([C:18]3[N:19]=[N:20][C:15]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=4)=[CH:16][CH:17]=3)[CH2:22][CH2:23]2)=[CH:31][CH:32]=1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Fc1ccc2c(c1)N(C1CCN(c3ccc(-c4ccc(C(F)(F)F)cc4)nn3)CC1)CC2

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 4-trifluoromethylphenylboronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
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.[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][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:30][CH:31]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)(C)c1ccc(C=O)cc1
Product: CC(C)(C)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-tert-butylbenzaldehyde 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-tert-butylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8])=[O:4].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[CH3:21][S:22]([O:11][CH2:10][CH2:9][N:5]([C:3](=[O:4])[C:2]([F:12])([F:13])[F:1])[CH2:6][CH2:7][O:8][S:22]([CH3:21])(=[O:24])=[O:23])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N(CCO)CCO)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C(=O)C(F)(F)F
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
Trifluoro-N,N-bis-(2-hydroxy-ethyl)-acetamide (2.01 g, 10 mmol) of in THF (12 mL) was cooled to ice bath temperature. Triethylamine (20.1 mol, 2.3 g=1.56 mol) was added between 5-10° C. Methanesulphonyl chloride was then added to the reaction mixture at a temperature between 5-10° C. The reaction mixture was stirred for 1 h at 5-10° C. and then allowed to warm to ambient temperature overnight. The resulting precipitated solids were filtered off and the reaction flask was rinsed with THF (2×10 mL portions), then filtered. The filtrate was concentrated to yield the title compound as a clear thick oil.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1CCOCC1.[Br:17][C:18]1[CH:19]=[C:20]([C:31](Cl)=[O:32])[C:21]2[O:26][CH:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[C:22]=2[CH:30]=1>C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:19]=[C:20]([C:31]([NH:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[O:32])[C:21]2[O:26][CH:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[C:22]=2[CH:30]=1
Reactant: NC1CN2CCC1CC2
Reactant: CC1Oc2c(C(=O)Cl)cc(Br)cc2N(C)C1=O
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Br)cc2N(C)C1=O

Procedure:
To a solution of 1.6 g of 3-aminoquinuclidine and 1.35 g of N-methylmorpholine in 25 ml of chloroform is added a solution of 4.0 g of 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo -2H-1,4-benzoxazine-8-carboxylic acid chloride in 20 ml of chloroform under cooling and stirring followed by stirring at room temperature for 3 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanol-isopropyl ether to give 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide, melting at 287°-288° C.