Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([C:9]1[O:13][N:12]=[C:11]([C:14](Cl)=[O:15])[CH:10]=1)[CH2:7][CH3:8].O>ClCCl>[C:1]([NH:5][C:14]([C:11]1[CH:10]=[C:9]([CH2:6][CH2:7][CH3:8])[O:13][N:12]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CCCc1cc(C(=O)Cl)no1
Solvent: O
Solvent: ClCCl
Product: CCCc1cc(C(=O)NC(C)(C)C)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
At 5° C., 9.3 g (126.8 mmol) of tert-butylamine in 20 ml of dichloromethane was dripped into 10.0 g (57.6 mmol) of 5-n-propyl-isoxazole-3-carboxylic chloride in 250 ml of anhydrous dichloromethane. The mixture was stirred for 12 hours at room temperature, 200 ml of water was added, the phases were separated, the organic phase was washed once with 150 ml of saturated sodium bicarbonate solution and once with 150 ml of saturated sodium chloride solution, followed by drying over magnesium sulfate and stripping off the solvent under reduced pressure. There was obtained 11.5 g (95%) of 5-n-propylisoxazole-3-carboxylic acid-tert-butylamide as a solid of melting point 34°-37° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:15][C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:19]([OH:21])[N:20]=1>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH:18]2[S:17][C:16]([NH:15][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])=[N:20][C:19]2=[O:21])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: Nc1nc(O)c(-c2ccc(Cl)cc2)s1
Solvent: O
Product: O=C(NC1=NC(=O)C(c2ccc(Cl)cc2)S1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.280 g) of Preparation 1 and 2-amino-5-(4-chlorophenyl)-4-hydroxy-1,3-thiazole (0.340 g) in 50 mL xylenes is heated to reflux. To this is added dropwise PCl8 (0.103 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is triturated with HOAc to yield 0.236 g of the title product as a gold solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[N:16]O)[C:6]2=[O:15].C1(C)C=CC(S(Cl)(=O)=[O:25])=CC=1>>[Cl:1][C:2]1[C:3]([CH2:4][C:5]#[N:16])=[C:7]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:6]([OH:15])=[O:25]
Reactant: COc1cc2c(c(Cl)c1OC)CC(=NO)C2=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1cc(C(=O)O)c(CC#N)c(Cl)c1OC

Procedure:
Similar procedure as described in example 9B was used, starting from 4-Chloro-5,6-dimethoxy-indan-1,2-dione 2-oxime and p-Toluenesulfonyl chloride to give 3-Chloro-2-cyanomethyl-4,5-dimethoxy-benzoic acid. LC-MS: m/e 254 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([O:12][CH3:13])[C:5]([O:14][CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.C(O)(=O)C.[CH:22](N)=[NH:23]>COCCO>[CH3:13][O:12][C:6]1[C:5]([O:14][CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=[C:2]2[C:7]=1[C:8](=[O:9])[N:23]=[CH:22][NH:1]2
Reactant: COC(=O)c1c(N)cc(OC)c(OC)c1OC
Reactant: N=CN
Solvent: COCCO
Solvent: CC(=O)O
Product: COc1cc2[nH]cnc(=O)c2c(OC)c1OC
Yield: 35.6 %

Procedure:
A solution of methyl 6-amino-2,3,4-tris(methyloxy)benzoate (2.87 g, 11.90 mmol) and formamidine acetate (3.72 g, 35.7 mmol) in 2-methoxyethanol (25 mL) was stirred at 125° C. for 2 hrs before being concentrated. The residue was suspended in water and the solid was collected by filtration, washed with water, and dried under vacuum (45° C.) to give 5,6,7-tris(methyloxy)-4(1H)-quinazolinone (1 g, 34%) as a light brown solid. MS (m/z) 237.1 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7]>>[CH2:6]([N:8]([CH2:2][C:3]([OH:5])=[O:4])[CH2:9][CH3:10])[CH3:7]
Reactant: CCNCC
Reactant: O=C(O)CCl
Product: CCN(CC)CC(=O)O
Yield: 104.8 %

Procedure:
A solution of chloroacetic acid (30 g, 0.32 mol) in diethylamine (230 mL, 2.2 mol) was stirred overnight. The obtained white precipitate was removed by filtration. The filtrate was evaporated to dryness to afford yellow oil to which EtOAc (300 mL) was added. The obtained precipitate was again removed by filtration. The filtrate was evaporated to afford yellow solid residue (44 g) that was washed with hexane (2×100 mL), EtOAc (2×50 mL) and again with hexane (50 mL), and then dried in vacuo to afford title Intermediate 2 (38 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:30][CH:31]=C)[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C.C(OCC)(=[O:35])C>CC(O)C.O.O=[Os](=O)(=O)=O>[CH3:1][O:3][C:4]([C:6]1([CH2:30][CH:31]=[O:35])[CH2:7][CH2:8][CH:9]([O:12][Si:13]([C:26]([CH3:27])([CH3:28])[CH3:29])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:11]1)=[O:5]
Reactant: C=CCC1(C(=O)OCC)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C1(CC=O)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
1-Allyl-4-(tert-butyl-diphenyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (5 g, 11.1 mmol) was dissolved in 2-propanol (100 mL) and water (50 mL). To this was added an aqueous solution of NaIO4 (5.94 g, 27.8 mmol) in water (50 mL), followed by addition of OsO4 (0.025 g, crystals, in one portion). The reaction mixture was allowed to stir for 16 hours at rt. The reaction mixture was poured into ice water (50 mL) and ethyl acetate (EtOAc) (60 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, and concentrated to dryness. The material was then purified over silica gel column eluting with ethyl acetate in heptanes (0-60%) to afford 4.45 g (87%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>O1CCCC1>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[CH:7]=2)=[CH:10][C:11]=1[Cl:16]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)Oc3ccccc3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (707 mg) as disclosed in WO 02/32872 was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere, and then triethylamine (0.523 ml) and phenyl chloroformate (0.470 ml) were added dropwise thereto while cooling in an ice bath, followed by raising the temperature gradually to room temperature while stirring. After 6 hrs, the reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:2) to provide a crude product of 4-(4-amino-3-chlorophenoxy)-2-phenoxycarbonylaminopyridine (920 mg). The crude product was dissolved in N,N-dimethylformamide (9 ml), and then 2 M solution of ethylamine in tetrahydrofuran (4.5 ml) was added thereto, followed by stirring at room temperature for 23 hrs. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2). Fractions containing the target compound were concentrated to give a residue, to which hexane-ethyl acetate (5:1) was added to precipitate crystals. The crystals were filtered, and dried under aeration to provide the titled compound (298 mg, 32%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)=[O:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To an ice-cooled solution of 1-(4-nitro-phenyl)-piperazine (prepared as described in Reference Example 29; 5 g, 24 mmol) in DCM (40 mL) was added pivaloyl chloride (4.36 g, 36.2 mmol) and triethylamine (8.73 mL, 60 mmol) at 0-5° C. The mixture was warmed to room temperature and stirred for 1 hour then diluted with DCM (150 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate and concentrated to dryness to afford 2,2-dimethyl-1-[4-(4-nitro-phenyl)-piperazin-1-yl]-propan-1-one (6 g, 85.7%) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.C(O)(=O)C.[Br-:21].[Li+]>C1COCC1>[Br:21][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2
Reactant: [Br-]
Reactant: O=C1CCc2cc(OCC3CO3)ccc2N1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1CCc2cc(OCC(O)CBr)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10085.3 %

Procedure:
To a stirred solution of 6-(oxiran-2-ylmethoxy)-3,4-dihydroquinolin-2(1H)-one (0.2 g, 0.909 mmol) in dry THF (5 mL) was added acetic acid (0.162 g, 2.272 mmol) and lithium bromide (0.118 g, 1.363 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to remove solvent and water was added (25 mL). The solid was filtered and dried to give crude 6-(3-bromo-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one as an off-white solid (0.25 g, 91.675 mmol). LCMS: RT 0.65 min; LCMS (ES-API), m/z 300.0 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:10]Br>C(O)(=O)C>[CH2:2]([Br:10])[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1

Procedure:
Synthesis of 2-amino-4-arylimidazolamine of the formula (48) (wherein R4, R5, R6, R7 R8 and R9 are as defined above) is described in Scheme 9. Thus, reaction of acetophenone derivative of formula (45) with bromine in acetic acid gives phenacyl bromide, which on reaction with acetyl guanidine in acetonitrile at reflux temperature gives N-acetyl imidazole of the formula (47). The N-deacetylation of (47) under acidic conditions affords 2-amino-4-arylimidazoles of the formula (48). This is similar to the procedure reported by Thomas, L. et al in J. Org. Chem., 1994, 59, 7299-7305.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4cnc(OC)nc4OC)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12m and 4-bromoanisole
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[C-]#N.[Na+].C(C1C=CC=CN=1)#N.[NH:19]1[C:29]2[C:23](C=[CH:25][CH:26]=[C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]3=2)=[CH:22][CH:21]=[CH:20]1>>[O:6]=[C:7]1[C:23]2[CH:22]=[CH:21][CH:20]=[N:19][C:29]=2[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[CH:26]=[CH:25]1
Reactant: C1=CNC2=c3ccccc3=CC=CC2=C1
Reactant: COS(=O)(=O)OC
Agent: [C-]#N
Agent: [Na+]
Solvent: N#Cc1ccccn1
Product: O=c1ccc2ccccc2c2ncccc12

Procedure:
In a process described in U.S. Pat. No. 3,326,924, 3-(2-phenethyl)-2-cyanopyridine is prepared by reacting 3-(2-phenethyl)pyridine-1-oxide with dimethylsulfate and then with aqueous sodium cyanide. A process to convert the cyanopyridine to an aza-dibenzocycloheptene by cyclizing to give the 5-keto-aza-dibenzocycloheptene, then reacting with a Grignard reagent. e.g., 1-methyl-4-piperidinyl magnesium chloride, to give a 5-(1-methyl-4-piperidinyl)aza-dibenzocycloheptene-5-ol, which is dehydrated to give the exocyclic 5-(1-methylpiperidylidenyl) compound, e.g., azatadine, is also described in U.S. Pat. No. 3,326,924.
Reaction SMILES: C([NH:9][C:10]1[O:11][C@@H:12]2[C@H:14]([C@@:15]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=3[F:30])[C:23]([O:25]C)=O)([CH:17]([F:19])[F:18])[N:16]=1)[CH2:13]2)(=O)C1C=CC=CC=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1O>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]2[N:31]=[C:23]([C:22]3[CH:27]=[CH:28][C:29]([F:30])=[C:20]([C@@:15]4([CH:17]([F:18])[F:19])[C@H:14]5[C@H:12]([CH2:13]5)[O:11][C:10]([NH2:9])=[N:16]4)[CH:21]=3)[O:25][C:33]=2[CH:34]=1
Reactant: Nc1ccc(Cl)cc1O
Reactant: COC(=O)c1ccc(F)c([C@]2(C(F)F)N=C(NC(=O)c3ccccc3)O[C@H]3C[C@H]32)c1
Product: NC1=N[C@](c2cc(-c3nc4ccc(Cl)cc4o3)ccc2F)(C(F)F)[C@@H]2C[C@@H]2O1
Temperature: 170 °C
Yield: 10.7 %

Procedure:
A sealable vial was charged with methyl 3-((1S,5R,6S)-3-benzamido-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorobenzoate (0.100 g, 0.24 mmol), 2-amino-5-chlorophenol (0.086 g, 0.60 mmol) and polyphosphoric acid (0.50 mL). The reaction mixture was purged with nitrogen for 1 min and then heated to 170° C. for 1 h. The reaction mixture was allowed to cool to rt, neutralized with aqueous, saturated Na2CO3 solution and 1 N NaOH. The mixture was extracted three times with a solvent mixture of CHCl3:i-PrOH (3:1). The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude was purified first by silica gel chromatography 0-100% EtOAc-hexane. The collected fractions were further purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 16 min. The fractions containing the desired product were combined and neutralized with solid Na2CO3. The aqueous phase was extracted with DCM and dried over Na2SO4. The filtrate was concentrated in vacuo to obtain the title compound as a beige solid (10.5 mg, 11% yield). MS m/z=408 [M+H]+. Calculated for C19H13ClF3N3O2: 407.8.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:3]1.[CH3:14][C:15]([O:18][C:19]([NH:21][C@H:22]([C:31](O)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:20])([CH3:17])[CH3:16].C(Cl)CCl>N1C=CC=CC=1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C@H:22]([NH:21][C:19](=[O:20])[O:18][C:15]([CH3:16])([CH3:14])[CH3:17])[C:31]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[CH:5]=2)=[O:32])=[CH:25][CH:26]=1
Reactant: Cn1nc(-c2ccncc2)cc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 99.1 %

Procedure:
To a 100 ml flask was added 1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-amine 17.B (540 mg, 3.10 mmole), Boc-L-4-fluorophenylalanine (970 mg, 3.41 mmole), EDC (710 mg, 3.72 mmole), and 10 ml of pyridine. The reaction was stirred at room temperature for 5.5 hours at which time the solvent was removed by rotary evaporation. The residue was suspended in ethyl acetate, and washed successively with saturated sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 103.1.A (1.35 g, 99% yield) as colorless amorphous.
Reaction SMILES: [CH:1]([N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[N:15]=[N:16][N:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:18]=3[CH3:19])[CH:10]=2)[C:5]1=[O:26])([CH3:3])[CH3:2].[H][H]>[C].[Pd].C(O)C>[CH:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[N:15]=[N:16][N:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:18]=3[CH3:19])[CH:10]=2)[C:5]1=[O:26])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2ccc3c(=O)n(C(C)C)ccc3c2)nnn1-c1cccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-c2ccc3c(c2)CCN(C(C)C)C3=O)nnn1-c1cccnc1
Yield: 91.5 %

Procedure:
After adding 50 mg of palladium carbon to 10 ml solution of ethanol with 25 mg of 4-(2-isopropyl-1-oxo-isoquinoline-6-yl)-1-(pyridine-3-yl)-5-methyl-1H-[1,2,3]triazole, hydrogen was added under 4 atm of hydrogen pressure. 8 hours later, the reaction solution was filtrated, the solvents of the filtrate were distilled outunder reduced pressure, and the residues were separated and purified by thin-layer chromatography (chloroform/methanol=10/1) to obtain 23 mg of the above compound as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11]1.[Br:22]N1C(=O)CCC1=O>>[Br:22][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]([CH:10]3[CH2:15][CH2:14][N:13]([C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:12][CH2:11]3)[CH2:3][C:4]=2[CH:9]=1
Reactant: O=C(N1CCC(C2Cc3ccccc3O2)CC1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Product: O=C(N1CCC(C2Cc3cc(Br)ccc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from 1-[4-(2,3-dihydro-benzofuran-2-yl)-piperidin-1-yl]-2,2,2-trifluoro-ethanone and N-bromo-succinimide following a procedure analogous to that described for Intermediate 1. LC (method 2): tR=1.47 min; Mass spectrum (ESI+): m/z=378 [M+H]+.
Reaction SMILES: O1CCCCC1CC(=O)C.[CH3:11][C:12]1([CH2:25][O:26]C2CCCCO2)[CH2:21][C:20](=O)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:23]#[N:24])[CH:18]=2)[O:13]1.CC1(COC2CCCCO2)CC(O)C2[C:36](=[CH:37][CH:38]=[C:39]([C:45]#[N:46])C=2)[O:35]1.CC1(COC2CCCCO2)C=CC2C(=CC=C(C#N)C=2)O1.Cl>>[OH:26][CH2:25][C:12]1([CH3:11])[CH:21]=[C:20]([N:46]2[CH:45]=[CH:39][CH:38]=[CH:37][C:36]2=[O:35])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:23]#[N:24])[CH:18]=2)[O:13]1
Reactant: CC1(COC2CCCCO2)CC(=O)c2cc(C#N)ccc2O1
Reactant: CC1(COC2CCCCO2)CC(O)c2cc(C#N)ccc2O1
Agent: CC(=O)CC1CCCCO1
Agent: CC1(COC2CCCCO2)C=Cc2cc(C#N)ccc2O1
Agent: Cl
Product: CC1(CO)C=C(n2ccccc2=O)c2cc(C#N)ccc2O1

Procedure:
A mixture of 1 g of 2-methyl-2-(2-tetrahydropyranyloxymethyl)-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chroman [obtainable from 1-(2-tetrahydropyranyl)2-propanone via 2-methyl-2-(2-tetrahydropyranyloxymethyl)-6-cyano-4-chromanone, 2-methyl-2-(2-tetrahydropyranyloxymethyl)-6-cyano-4-chromanol, 2-methyl-2-(2-tetrahydropyranyloxymethyl)-6-cyano-3-chromene and the corresponding 3,4-epoxide] and 15 ml of 10% methanolic HCl solution is boiled for 15 min. Cooling and customary working up gives 2-hydroxymethyl-2-methyl-4-(1,2-dihydro2-oxo-1-pyridyl)-6-cyano-3-chromene. Example 5
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1.[OH-].[CH2:18]([N+:25](C)(C)C)[C:19]1C=CC=[CH:21][CH:20]=1.CCO.C(C#N)C=C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:20]([CH3:21])[CH2:19][C:18]#[N:25])[C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: O=C1Nc2ccc(Br)cc2C12OCCCO2
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: C=CCC#N
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CC#N)N1C(=O)C2(OCCCO2)c2cc(Br)ccc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
To a solution of 5′-bromospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (2.00 g, 7.04 mmol) and benzyltrimethylammonium hydroxide (40% aqueous solution, 0.768 mL, 1.69 mmol, 0.24 mole %) in abs. EtOH (32 mL) was added allyl cyanide (1.42 mL, 17.6 mmol, 2.5 eq) all at one time at room temperature and the mixture was heated at 80° C. for 2.5 hr. Additional benzyltrimethyl-ammonium hydroxide (0.77 mL) was added and the heating continued another 24 hr. The reaction was cooled to room temperature and poured into H2O (100 mL). The reaction mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (97/2/1) to give the title compound as a white solid (0.299 g, 16% ). Anal. Calc'd for: C15H15BrN2O3: C, 51.3; H, 4.3; N, 7.98. Found: C, 51.55; H, 4.47; N 7.99. NMR (300 Mz, DMSO-d6): consistent. MS: (ES+) m/z 350/352 [M+]; one Br pattern observed. m.p.: 112-113° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: OB(O)c1cccnc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4cccnc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (42 mg, 53%), MS (ISP) m/z=317.6 [(M+H)+], mp 260° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available pyridin-3-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][OH:53]>CN(C)C=O>[OH:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][NH:47][C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:10]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: NCCOCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)NCCOCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1000-mL round bottom flask, was placed a solution of 3-(methoxycarbonyl)benzoic acid (20 g, 111.11 mmol, 1.00 equiv) in N,N-dimethylformamide (500 mL), HATU (63.2 g, 166.32 mmol, 1.50 equiv), N,N-diisopropylethylamine (21.5 g, 166.67 mmol, 1.50 equiv), and 2-(2-aminoethoxy)ethanol (23.3 g, 221.90 mmol, 2.00 equiv). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The resulting solution was dissolved in 200 mL of ethyl acetate. The resulting mixture was washed with 10×200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (100:1). This resulted in 15 g (51%) of methyl 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoate as red oil.