Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.C(N(CC)CC)C.[C:18]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(O)C>[C:21]([O:20][C:18](=[O:19])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[N:7]=[CH:6][N:5]=[C:4]3[NH:8][N:9]=[CH:10][C:3]=23)[CH2:28][CH2:27]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 80 °C
Yield: 26.5 %

Procedure:
To a solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (J. Amer. Chem. Soc. 1957, 79, 6407-6413) (59 mg, 0.38 mmol) in ethanol (2 ml) was added triethylamine (100 μl, 0.72 mmol) and 4-(N-Boc-amino)piperidine (134 mg, 0.67 mmol). The solution was heated at 80° C. for 3 hours, and then cooled to room temperature. The solution was evaporated to dryness and the residue purified by recrystallisation (isopropanol) to yield the product (32 mg, 26% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH2:15][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)([C:12]([NH2:14])=[O:13])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)C.C(OCC)(OCC)OCC.[OH-].[NH4+]>C1(C)C=CC=CC=1.O>[CH2:1]([N:8]1[CH2:16][CH2:15][C:11]2([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[CH:25]=[N:14][C:12]2=[O:13])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(OCC)OCC
Product: Cc1cccc(N2C=NC(=O)C23CCN(Cc2ccccc2)CC3)c1

Procedure:
To a mixture of 1-benzyl-4-(3-methylphenylamino)-isonipecotamide (4.3 g, 13.5 mmol) and glacial acetic acid (1.0 mL) in toluene (20 mL) heated under reflux, triethyl orthoformate (2.0 g, 13.5 mmol) was added over a period of 3 h using a syringe pump. The resultant mixture was refluxed for 38 h., and treated with a mixture of concentrated ammonium hydroxide (1.3 mL) and water (3.4 mL). The organic extract was isolated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to column chromatography on silica gel eluting with 5% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH2:9]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C#CCCc1nc2ccccc2o1
Product: Fc1ccc(C#CCCc2nc3ccccc3o2)nc1
Yield: 4.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-5-fluoropyridine (200 mg, 1.14 mol) and 2-(but-3-ynyl)benzo[d]oxazole (195 mg, 1.14 mmol, Example 8(A)). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM/MeOH 100:0 to 94:6, DCM/MeOH/NH4OH 94:5:1 to 90:8:2) to yield 15 mg (56 μmol, 5%) of 2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]#[N:16])=[CH:4][CH:3]=1.[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:21]2[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]2)=[NH:16])=[CH:6][CH:7]=1
Reactant: N#CNc1ccccc1-c1ccc(F)cc1
Reactant: OC1CCNCC1
Solvent: CCO
Product: N=C(Nc1ccccc1-c1ccc(F)cc1)N1CCC(O)CC1

Procedure:
A mixture of 4'-fluoro-2-biphenylylcyanamide (1 g) and 4-hydroxypiperidine (0.6 g) in ethanol (10 ml) was heated at 90°-95° C. for 3 hours to give N-(4'-fluoro-2-biphenylyl)-4-hydroxypiperidine-1-carboxamidine as a colourless solid (m.p. 132°-133° C.) which was recrystallised from ethylacetate.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[O:13])=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1.Br[C:35]1[C:40]([Cl:41])=[CH:39][C:38]([Cl:42])=[CH:37][N:36]=1>C1(C)C=CC=CC=1.CCO.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[O:13])=[CH:10][C:9]=1[C:35]1[C:40]([Cl:41])=[CH:39][C:38]([Cl:42])=[CH:37][N:36]=1
Reactant: COc1ccccc1NC(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1cnc(Br)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccccc1NC(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Temperature: 100 °C
Yield: 67.1 %

Procedure:
A solution of 2N Na2CO3 (5.85 mL) and Pd(PPh3)4 (340 mg, 0.29 mmol) was added to a degassed mixture of 4-chloro-N-(2-methoxy-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (2.2 g, 5.85 mmol) and 2-bromo-3,5-dichloro-pyridine (1.47 g, 6.44 mmol) in toluene (30 mL) and EtOH (6 mL). The mixture was heated at 100° C. for 12 hrs. Upon cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water and brine, and was dried over Na2SO4. After filtration and concentration the mixture was taken up in EtOAc, filtered, washed with EtOAc (3×), MeOH and ether to yield 1.6 g of 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide. MS [M+H]+: 406.9; tR=3.03 min. (method 1)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O)=O.[CH3:13][NH:14][NH2:15]>CCO>[CH3:13][N:14]1[C:10](=[O:12])[CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[N:15]1
Reactant: O=Cc1ccccc1CC(=O)O
Reactant: CNN
Solvent: CCO
Product: CN1N=Cc2ccccc2CC1=O
Yield: 50 %

Procedure:
To a solution of o-formylphenylacetic acid (10 g, 61 mmol) (Bleasdale et al., J. Chem. Soc. Perkin Trans. I 1991, 1683) in 60 mL of EtOH was added N-methylhydrazine (4.2 g, 91 mmol) and refluxed for 1 h. The reaction mixture cooled, solvent removed and transferred the crude reaction mixture to a vaccum sublimation apparatus. The imine was heated at 140° C. under high vaccum for 1 h and collected the cyclized product by extracting with hot 20% ethyl acetate in hexane (Nagarajan et al., J. Med. Chem., 1972, 15(10), 1091). The product was crystallized from 20% ethyl acetate in hexane. 4,5-dihydro-3-methyl-3H-2,3-benzodiazepin-4-one was obtained in 50% yield.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([NH:10][C:11]1[C:12]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25](OC)=[O:26])=[CH:21][N:20]=2)=[O:18])=[CH:13][S:14][CH:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:3]([O:7][C:8]([NH:10][C:11]1[C:12]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][N:20]=2)=[O:18])=[CH:13][S:14][CH:15]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(C(=O)Nc2cscc2NC(=O)OC(C)(C)C)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Under ice cooling, lithium tetrahydroborate (1.5 g, 70 mmol) was added to a mixed solution of N-(4-t-butoxycarbonylaminothiophen-3-yl)-5-methoxycarbonylpyridine-2-carboxylic acid amide (Reference Compound No. 2-1, 24 g, 64 mmol) in THF (1.3 L)-1,4-dioxane (1.3 L), and then the reaction mixture was stirred at same temperature overnight. Lithium tetrahydroborate (0.30 g, 14 mmol) was added thereto and the mixture was stirred at room temperature for 2 hours. Under ice cooling, water (0.40 L) and 10% aqueous citric acid solution (25 mL) were added thereto. The precipitates were filtered off and the filtrate was evaporated under reduced pressure. Water (0.30 L) was added thereto and the precipitates were filtered and dried under reduced pressure to give 21 g of the title reference compound as a pale yellow solid. (Yield 95%)
Reaction SMILES: S(OC)(OC)(=O)=O.[CH3:8][C:9]([C:12]1[CH:17]=[CH:16][N+:15]([O-])=[CH:14][CH:13]=1)([CH3:11])[CH3:10].C(O)C.[O-][C:23]#[N:24].[K+]>O>[C:9]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:23]#[N:24])[CH:13]=1)([CH3:11])([CH3:10])[CH3:8]
Reactant: N#C[O-]
Reactant: CC(C)(C)c1cc[n+]([O-])cc1
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CCO
Product: CC(C)(C)c1ccnc(C#N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To stirred dimethyl sulfate (6.70 g) was added slowly 4-tert-butyl-1-oxypyridine (8.0 g) at ca. 10° C. in an ice-water bath and the mixture was stirred for 3 hours at 80° C. After cooling to room temperature, to the mixture was added a mixture of ethanol and water (1:1, 60 ml) under stirring. To the mixture was added dropwise an aqueous solution of potassium cyanate (6.9 g in 20 ml of water) below 10° C. and stirring for 1 hour under the same condition, and then overnight at room temperature. To the resultant mixture was added 150 ml of water and the resultant mixture was extracted with CHCl3. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. A crude compound was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane to give 4-tert-butyl-2-cyanopyridine (4.6 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13](O)[C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH:13]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[C:14]#[N:15]
Reactant: CCOc1ccc(C(O)C#N)cc1OCC
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(C(Cl)C#N)cc1OCC

Procedure:
In 60 ml of chloroform is dissolved 4.4 g of α-(3,4-diethoxyphenyl)-α-hydroxyacetonitrile and after addition of 1.5 ml of thionyl chloride, the mixture is heated under reflux for 15 minutes. After cooling, the reaction mixture is washed with a saturated aqueous solution of sodium hydrogen carbonate and water in the order mentioned, followed by drying over MgSO4. The solvent is then distilled off to give 4.8 g of a crude oil of α-chloro-α-(3,4-diethoxyphenyl)acetonitrile (quantitative yield). [If desired, this crude oil as it is can be used in the next reaction step.] The above crude oil is then purified by column chromatography (eluent: ether-n-hexane=1:5) and the resulting crystals are recrystallized from n-hexane. Colorless needles, m.p. 61°-62° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:10]2[C:11](=[O:22])[N:12]([CH2:19][CH2:20][CH3:21])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>O1CCOCC1>[CH2:1]([NH:5][C:6]1[C:10]2[C:11](=[O:22])[N:12]([CH2:19][CH2:20][CH3:21])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[N:8]([C:30]([O:31][CH3:32])=[O:33])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1n[nH]c2c1c(=O)n(CCC)c1ccccc21
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCNc1nn(C(=O)OC)c2c1c(=O)n(CCC)c1ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
In 60 ml of dioxane was suspended 1.40 g (4.7 mmol) of Compound 2, and 1.0 ml (7.2 mmol) of triethylamine and 0.73 ml (9.4 mmol) of methyl chlorocarbonate were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was dried under reduced pressure, and the residue was partitioned between chloroform and water. The chloroform layer was dried under reduced pressure, and the residue was passed through a silica gel column and eluted with a 3:1 (by volume) mixed solvent of hexane and ethyl acetate. The main fraction collected was recrystallized from hexane-ethyl acetate to obtain 0.67 g (40%) of the titled compound as a colorless crystal.
Reaction SMILES: [CH2:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[S:4](=[O:15])[CH2:3][CH2:2]1.C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:19][N:20]([CH:22]=[C:3]1[CH2:2][CH2:1][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[S:4]1=[O:15])[CH3:21]
Reactant: CCOC(OCC)N(C)C
Reactant: O=S1CCCc2c1ccc1ccccc21
Product: CN(C)C=C1CCc2c(ccc3ccccc23)S1=O

Procedure:
3-Dimethylaminomethylenebenzo[f]thiochroman-4-one was prepared from benzo[f]thiochroman-4-one (1.50 g, 7.01 mmol) and N,N-dimethylformamide diethylacetal to give the compound as a yellow solid (1.67 g) m.p. 163-165°. MS(EI) 269 (M+, 49.8%), 82 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.[Li]CCCC.[CH2:15]=[O:16]>C1COCC1>[OH:16][CH2:15][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C)ccn1
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(CCO)ccn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a stirred solution of 2-methoxy-4-methylpyridine (6 g, 49 mmol) in anhydrous THF (200 mL) at −78° C. under nitrogen was added dropwise 29.4 mL (73.5 mmol) of n-BuLi (2.5 M solution in hexanes). The mixture was stirred at −78° C. for 1 h, and then warmed slowly to 0° C. and stirred at 0° C. for 30 min. The mixture was recooled to −78° C. and paraformaldehyde (10 g) was added in one portion. The mixture was warmed slowly to room temperature and stirred at room temperature for 8 h. The reaction was quenched by addition of saturated aq. NH4Cl and extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography with hexane/EtOAc (2:1) to afford 4-(2-hydroxyethyl)-2-methoxypyridine as a colorless oil (3.8 g, 51%). 1H NMR (CDCl3) δ 8.06 (d, 1H, J=5.1 Hz), 6.77 (d, 1H, J=5.1 Hz), 6.62 (s, 1H), 3.92 (s, 3H), 3.87 (t, 2H, J=6.6 Hz), 2.81 (t, 2H, J=6.6 Hz), 1.98 (br s, 1H); 13C NMR (CDCl3) δ 164.48, 150.63, 146.71, 117.76, 110.91, 62.43, 53.34, 38.30. MS m/z (%): 153 (M, 73), 152 (100), 123 (48).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[Na].O.[CH2:23](I)[CH3:24]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([O:20][CH2:23][CH3:24])=[O:19]
Reactant: CCI
Reactant: Nc1c(CC(=O)O)cc(Cl)cc1C(=O)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Reaction time: 2 h
Yield: 4.7 %

Procedure:
A solution of 3.12 g (0.1 mole) of 2-amino-3-benzoyl-5-chlorobenzeneacetic acid, sodium salt.1/2 H2O in 250 ml of dry dimethylformamide was treated with 44 g of ethyl iodide (0.3 mole) under nitrogen and stirred for 2 hours. The resulting solution was then added to one liter of water and extracted several times with ethyl ether. The combined ether layers were washed with water, dried over sodium sulfate, filtered and stripped to yield a solid yellow residue. This residue was recrystallized from ethyl alcohol, yielding 1.5 g of the title compound as yellow needles, m.p. 80°-82° C.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](C=O)[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][CH:36]2[CH2:38][CH2:37]2)[C:23]=1[CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:18][CH2:19][CH3:20].O.[CH3:49]N(C)C=O>>[CH2:17]([O:21][CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][CH:36]2[CH2:38][CH2:37]2)[C:23]1(/[CH:49]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:39][NH:40][C:41]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:47])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C=O)cc12
Reactant: CN(C)C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCCOC1c2ccccc2C(=O)N(CC2CC2)C1(/C=C/C(=O)OCC)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (0.99 mL, 5 mmol) in N,N-dimethylformamide (30 mL) was added. sodium hydride (0.20 g, 5 mmol) (60% in oil) and the mixture was stirred at room temperature for 10 min. To the obtained mixture was added a solution of tert-butyl (4-butoxy-2-cyclopropylmethyl-6-formyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (Example 2 (2))(2.14 g, 5 mmol) in N,N-dimethylformamide (20 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenate (1.92 g, 77.1%) as crystals.
Reaction SMILES: C(#N)C.FC(F)(F)C(O)=O.[Br:11][C:12]1[C:13]([OH:18])=[N:14][CH:15]=[CH:16][CH:17]=1.[I:19]N1C(=O)CCC1=O>O>[Br:11][C:12]1[C:13]([OH:18])=[N:14][CH:15]=[C:16]([I:19])[CH:17]=1
Reactant: Oc1ncccc1Br
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Oc1ncc(I)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 190.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with acetonitrile (50 mL), trifluoroacetic acid (10 mL), 3-bromopyridin-2-ol (4.0 g, 11.56 mmol) and N-iodosuccinimide (5.2 g, 11.56 mmol). The mixture was stirred at room temperature for 15 h. The mixture was diluted with water (100 mL) and resulting white solid was collected by filtration to afford 214a (6.6 g, 96%) as a white solid. MS-ESI: [M+H]+ 300
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH3:24])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:31]>CO.[OH-].[OH-].[Pd+2]>[ClH:31].[CH3:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: CC1CCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1CCCN1c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 8-benzyl-3-(2-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (0.51 g) in methanol (15 mL) was added 20% Pd(OH)2/C (0.08 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (15 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (430 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (0.30 g, 71%) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[N:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([F:33])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:26]([F:33])[CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnn1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1)c1cccnn1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyridazine-3-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 62 a) and B-(4-chloro-2-fluorophenyl)-boronic acid (CAN 160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 427.0587 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[CH:25]([Mg]Cl)([CH3:27])[CH3:26].C([Mg]Cl)CC>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[CH:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (150.0 mg, 0.394 mmol) in tetrahydrofuran (3.0 mL) was added i-propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.59 mL, 0.591 mmol). The reaction mixture was stirred at 0° C. for 2 hrs. To the mixture was added 1-propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.59 mL, 0.591 mmol). The mixture was stirred at 0° C. for 1 hr. After cooling, the mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic is layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (78.8 mg, 0.186 mmol, 47%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH:11]=[CH:10][C:9](/[CH:12]=[C:13]3\[CH2:14][N:15]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:17][C:18]\3=[O:19])=[N:8]2)[N:3]=[CH:2]1.[BH4-].[Na+].O.C(OCC)(=O)C>CO>[S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH:11]=[CH:10][C:9](/[CH:12]=[C:13]3\[CH2:14][N:15]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:17][CH:18]\3[OH:19])=[N:8]2)[N:3]=[CH:2]1
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccn(Cc2cscn2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccn(Cc2cscn2)n1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of (E)-3-({1-[(1,3-thiazol-4-yl)methyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidin-4-one (2.48 g) in methanol (25 ml) was added sodium borohydride (0.09 g) at room temperature. After being stirred at the same temperature for 0.5 hour, water and ethyl acetate were added and the product was extracted. The separated organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave (E)-3-({1-[(1,3-thiazol-4-yl)methyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol (ca. 2.5 g) as a crude pale yellow amorphous solid.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:52]=[CH:51][C:42]([C:43]([N:45]([CH2:47][CH2:48][CH2:49][CH3:50])[CH3:46])=[O:44])=[C:41]([S:53]([CH:56]([CH3:58])[CH3:57])(=[O:55])=[O:54])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:52]=[CH:51][C:42]([C:43]([N:45]([CH2:47][CH2:48][CH2:49][CH3:50])[CH3:46])=[O:44])=[C:41]([S:53]([CH:56]([CH3:57])[CH3:58])(=[O:54])=[O:55])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCCN(C)C(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CCCCN(C)C(=O)c1ccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1S(=O)(=O)C(C)C

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-N-butyl-2-(isopropylsulfonyl)-N-methylbenzamide (Intermediate 253), the title compound was obtained.