Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Br:10][C:8]1[CH:7]=[C:6]([F:11])[C:3]([C:4]#[N:5])=[C:2]([N:1]=[CH:14][N:15]([CH3:17])[CH3:16])[CH:9]=1
Reactant: N#Cc1c(N)cc(Br)cc1F
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1cc(Br)cc(F)c1C#N
Temperature: 25 °C

Procedure:
17.0 g (79.1 mmol) 2-amino-4-bromo-6-fluoro-benzonitrile in 140 ml of N,N-dimethylformamide dimethyl acetal are heated to 120° C. for 2 h. After cooling RT the solvent is evaporated and the residue taken up in diethyl ether, filtered and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:29]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3cccc(Br)c3)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3cccc(-c4cccnc4)c3)n2)cc1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.20) (0.525 g, 1.0 mmol) and commercially available 3-pyridineboronic acid (0.16 g, 1.3 mmol) according to the general procedure VI. Obtained as a white solid (0.083 g, 19%). MS (ISP) 445.2 [(M+H)+]; mp 164-166° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:20][CH2:21][O-:22].[Na+]>>[CH2:21]([O:22][C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:20]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cnn2c1c(Cl)nc1ccccc12
Agent: [Na+]
Product: CCOC(=O)c1cnn2c1c(OCC)nc1ccccc12

Procedure:
5.5 g. of 4-chloropyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester is heated for two hours with 10 ml. of a 2 molar sodium ethylate solution. The hot reaction solution is filtered and, upon cooling, 4-ethoxypyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester crystallizes in the form of white needles. The product is recrystallized from ethanol to obtain 3.4 g. of white crystals, m.p. 88°-90°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].O>C1(C)C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:3]=[CH:4][C:5]=1[Cl:11])(=[O:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(N)ccc1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc(NS(C)(=O)=O)ccc1Cl
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
1-(5-Amino-2-chlorophenyl)ethanone (411 mg; synthesized by the process reported by Radziejewski et al., Heterocycles, vol. 26, pp. 1227-1238, 1987) was dissolved in toluene (5 mL), and pyridine(235 μL) and methanesulfonyl chloride (225 μL) were added. The resulting mixture was stirred at room temperature for 50 minutes. After adding water (50 mL), the reaction mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with an aqueous 1 N hydrochloric acid solution (50 mL) and saturated brine (50 mL) and then dried over anhydrous sodium sulfate (5 g). The solvent was distilled off under reduced pressure to yield N-(3-acetyl-4-chlorophenyl)methanesulfonamide (595 mg) as a colorless crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[C:27]2[CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:28][CH:25]2[CH2:26][C:27]3[N:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][CH2:24]2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: NC1CCc2cccnc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(CNC2CCc3cccnc3C2)cc1
Reaction time: 0.03 h
Yield: 100.2 %

Procedure:
Using general procedure B: Reaction of (4-Formyl-benzyl)-carbamic acid tert-butyl ester (356 mg, 1.51 mmol), 5,6,7,8-Tetrahydro-quinolin-7-ylamine (224 mg, 1.51 mmol) in anhydrous MeOH (5 mL) at room temperature overnight under N2 and 2 min of stirring after addition of sodium borohydride (115 mg, 3.00 mmol), followed by purification of crude material using chromatography on silica gel (2:2:96 CH3OH—NH3 H2O—CH2Cl2) afforded the title compound (556 mg, 100%) as a white foam.
Reaction SMILES: [ClH:1].Cl.[C:3]1([NH:9][C:10]2([C:23]([OH:25])=[O:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[ClH:1].[ClH:1].[C:3]1([NH:9][C:10]2([C:23]([O:25][CH2:31][CH3:32])=[O:24])[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO
Reactant: O=C(O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 19 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylic acid dihydrochloride, 14.4 parts of sulfuric acid and 64 parts of ethanol is stirred and refluxed for 16 hours. The solvent is decanted. The residue is dissolved in water. The aqueous solution is alkalized with ammonium hydroxide and extracted with a mixture of methylbenzene and 2,2'-oxybispropane. The combined organic layers are dried over mangnesium sulfate, filtered and evaporated. The oily residue is dissolved in 200 parts of 2,2'-oxybispropane and gaseous hydrogen chloride is introduced into the solution. The precipitated hydrochloride is filtered off, washed with 2-propanol, filtered off again and dried, yielding 11.5 parts of ethyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate dihydrochloride; mp. 212°-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:5](Cl)=[O:6].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH:33][C:34](=[O:36])[CH3:35].[H-].[Na+]>O1CCCC1>[C:34]([N:33]([CH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=1)[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:2]([Cl:1])[CH:3]=1)(=[O:36])[CH3:35]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1Cl
Reactant: CC(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1Cl

Procedure:
The title compound is prepared by the procedure of Example 27 using 1.31 g of product from Example 38, 0.535 g of product from Example 12, 0.171 g of washed 50% sodium hydride and 12 ml of tetrahydrofuran. The residue is purified by column chromatography (silica gel:35% ethyl acetate/hexane) to give 0.067 g of product as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](F)=[CH:6][C:5]=1[F:14].[CH3:16][NH2:17]>CN(C=O)C>[F:14][C:5]1[CH:6]=[C:7]([NH:17][CH3:16])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([OH:2])=[O:15]
Reactant: CN
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: CN(C)C=O
Product: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
2-Fluoro-4-methylamino-5-nitro-benzoic acid (375 mg) was prepared by following General Procedure A starting from 2,4-difluoro-5-nitro-benzoic acid methyl ester (440 mg) and methylamine (2 M in THF, 1.01 mL) in DMF.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[C:22]([CH:26]([CH:34]2[CH2:36][CH2:35]2)[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:23]=[N:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[C:22]([CH:26]([CH:34]3[CH2:36][CH2:35]3)[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:29])=[O:30])[CH:23]=[N:24][CH:25]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)S(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
A mixture of 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (198 mg, 0.75 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)propane-2-sulfonamide (250 mg, 0.75 mmol), PdCl2(PPh3)2 (43 mg, 0.06 mmol) and Na2CO3 (2 M in water, 0.94 mL, 1.88 mmol) in DMF(6 mL) was heated at 100° C. for 2 h. After concentration, the resulting residue was dissolved in DCM and filtered. The filtrates were concentrated and purified by flash column (EtOAc/Heptane, v/v, 0-40%) to give the title compound (195 mg, 67%); ESI-MS m/z: 390 [M+1]+; 1H-NMR (MeOD, 400 MHz) δ 8.84 (1H, s), 8.71 (1H, s), 8.25 (1H, s), 8.05 (1H, bs), 7.98 (1H, d, J=8.0 Hz), 7.86 (1H, d, J=8.0 Hz), 3.97 (1H, d, J=9.2 Hz), 3.16-3.09 (1H, m), 1.37-1.33 (1H, m), 1.36 (3H, d, J=7.2 Hz), 1.29 (3H, d, J=7.2 Hz), 0.81-0.76 (1H, m), 0.66-0.63 (2H, m), 0.53-0.48 (1H, m); Enantiomers were separated by chiral HPLC (ChiralPak IA-H, EtOH/Heptane, v/v, 60/40) to give the first peak (enantiomer 1, t=10.11 min) and the second peak (enantiomer 2, t=12.95 min).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 7 h
Yield: 75 %

Procedure:
1-Benzylpiperazine (2.8 ml; 16 mmol) and potassium carbonate (2.3 g; 17 mmol) were added to a solution of 1-chloro-4-nitrobenzene (2.0 g; 13 mmol) in dimethylformamide (0.5 ml), and the mixture was stirred for 7 hours in a bath controlled at 100° C. Water was added to the reaction mixture to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 2.9 g (yield: 76%) of 4-(4-benzyl-1-piperazinyl)-1-nitrobenzene as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]C)=O)[CH2:4][CH2:3]1.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:13][NH2:14])=[O:10])[CH2:4][CH2:3]1
Reactant: NN
Reactant: COC(=O)C1CCN(C)CC1
Solvent: CCO
Solvent: O
Product: CN1CCC(C(=O)NN)CC1
Temperature: 120 °C
Yield: 72.5 %

Procedure:
In a 25 mL sealed tube, methyl 1-methylpiperidine-4-carboxylate (0.2 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (0.127 g, 2 eq.) was introduced dropwise at RT and the reaction mixture was heated at 120° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 1-methylpiperidine-4-carbohydrazide (0.145 g) which was used without further purification in the following step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[Cl:11].C([O-])([O-])=O.[K+].[K+].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C)C(=O)C.O>[Cl:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH2:2][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH:7]=[O:8]
Reactant: Nc1ccccn1
Reactant: O=Cc1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1ccc(CNc2ccccn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.6 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (2 g, 9 mmol) in N,N-dimethylacetamide (DMA; 20 mL) was added K2CO3 (2.36 g, 17.16 mmol) and 2-aminopyridine (0.84 g, 8.58 mmol), and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as off-white solid (1.05 g, 50%): mp 122-123° C.; 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.4 (m, 1H), 6.64 (d, J=3.9 Hz, 1H), 6.38 (d, J=6.3 Hz, 1H), 5.04 (br s, 1H), 4.71 (s, 2H); ESIMS m/z 246.97 ([M+H]+).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)N[Si](C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CSc1ncc2ncnc(O)c2n1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CSc1ncc2ncnc(Nc3ccc(F)c(Cl)c3)c2n1
Temperature: 100 °C

Procedure:
148 g of 4-hydroxy-6-methylthiopyrimido[5,4-d]pyrimidine, 286 ml of hexamethyldisilazane, 333 g of 3-chloro-4-fluoroaniline and 15 g of p-toluenesulphonic acid are heated at 140° C. for 23 hours. The reaction mixture is cooled and, after addition of 4 1 of methanol, heated at 100° C. for one hour. The methanol is distilled off and the residue is triturated three times with diethyl ether and filtered off with suction.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].O>N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[O:6][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[N:23][C:15]=2[N:14]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: Nc1ncccc1C(=O)O
Solvent: c1ccncc1
Solvent: O
Product: O=c1oc(-c2ccccc2C(F)(F)F)nc2ncccc12
Temperature: 25 °C
Yield: 59.4 %

Procedure:
2-(Trifluoromethyl)benzoyl chloride (4.2 ml, 29.2 mmol) is added dropwise to a solution of 2-aminonicotinic acid (2.04 g, 14.76 mmol) in 20 ml of pyridine. The reaction mixture is heated at 158 C. for 30 min then cooled to room temperature. The reaction is poured into 200 ml of water and an oil forms which solidifies upon stirring. The solid is collected by vacuum filtration and washed with water and diethyl ether. The product is dried to give 2-(2-trifluoromethyl-phenyl)-pyrido[2,3-d][1,3]oxazin-4-one (2.56 g, 60% yield) which may be used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[NH:3]1.Cl.[NH:18]1[CH:22]=[N:21][C:20]([S:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[C:31]([CH2:33][NH2:34])[CH:30]=[CH:29][N:28]=2)=[N:19]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:34][CH2:33][C:31]2[CH:30]=[CH:29][N:28]=[C:27]([O:26][CH2:25][CH2:24][S:23][C:20]3[N:21]=[CH:22][NH:18][N:19]=3)[CH:32]=2)=[O:14])[NH:3]1
Reactant: NCc1ccnc(OCCSc2nc[nH]n2)c1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(NCc1ccnc(OCCSc2nc[nH]n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 15 h
Yield: 35 %

Procedure:
A suspension of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (200 mg, 0.917 mmol), 1-(2-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}pyridin-4-yl)methanamine hydrochloride obtained in Reference Example is (343 mg, 1.19 mmol) and diisopropylethylamine (462 mg, 3.57 mmol) in DMA (5 mL) was stirred at 90° C. for 15 hr. After cooling the mixture to room temperature, the resulting solid was collected by filtration, and washed with ethanol. The obtained crude powder was recrystallized from ethanol to give the title compound as a white powder (135 mg, 35%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.[OH-].[Na+].C1COCC1>CN(C=O)C>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccc(COc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Yield: 23.4 %

Procedure:
A mixture of 5.0 g (0.025 mol) 4-phenoxymethylphenol, 5.35 g (0.025 mol) 2-chloromethylquinoline hydrochloride and 30 ml (2N, NaOH) in 50 ml DMF and 100 ml THF was stirred at 60° C. bath temperature for a period of 3 hours. The reaction mixture was poured into wast and extracted with ether. The ether extract was washed with water, dried and concentrated to dryness to obtain solid. Recrystallization from acetonitrile yielded (2.0 g) product, m.p. 100°-111° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:17]=[CH:18][N:19]([CH3:21])[CH3:20])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.N1CC[CH2:24][CH2:23]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([N:17]=[CH:18][N:19]2[CH2:21][CH2:24][CH2:23][CH2:20]2)=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CN(C)C=Nc1nc(OCc2ccc(F)cc2)ncc1F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: Fc1ccc(COc2ncc(F)c(N=CN3CCCC3)n2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
To a solution of N′-[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-N,N-dimethylformamidine (0.10 g, 0.36 mmol) in toluene (2 mL) was added pyrrolidine (0.051 g, 0.72 mmol) and a catalytic amount of camphorsulfonic acid. The vented vial was placed on an orbital shaker, agitated at 90° C. for 16 h, cooled, and evaporated to dryness. Purification by reverse phase chromatography afforded the title compound (0.060 g, 53% yield) as a white solid: mp 102-103° C.; 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.06 (d, J=2.7 Hz, 1H), 7.49-7.42 (m, 2H), 7.09-7.01 (m, 2H), 5.32 (s, 2H), 3.73-3.62 (m, 4H), 2.07-1.96 (m, 4H); HPLC-MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.[CH3:18][C:19]([OH:23])([C:21]#[CH:22])[CH3:20]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:23][C:19]([CH3:20])([CH3:18])[C:21]#[C:22][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: CN1Cc2c(I)ncn2-c2ccccc2C1=O
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2ccccc2C1=O

Procedure:
3.40 g (10 mmol) of 4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 1.5 hours with 0.925 g (11 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The solvent was then evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 168°-169°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[NH:22][C:21]2[C:23]([F:36])=[C:24]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:25]([C:27](O)=[O:28])=[CH:26][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[F:68][C:69]([F:78])([F:77])[C@H:70]1[CH2:75][CH2:74][C@H:73]([NH2:76])[CH2:72][CH2:71]1>CN(C=O)C>[F:68][C:69]([F:77])([F:78])[C@H:70]1[CH2:71][CH2:72][C@H:73]([NH:76][C:27]([C:25]2[C:24]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[C:23]([F:36])[C:21]3[NH:22][C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:26]=2)=[O:28])[CH2:74][CH2:75]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)O)c(OCC(F)(F)F)c(F)c3[nH]2)c1Cl
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)(F)F)c(F)c3[nH]2)c1Cl
Reaction time: 0.5 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]phenylamino}-6-(2,2,2-trifluoroethoxy)-7-fluoro-1H-benzimidazole-5-carboxylic acid (60 mg, 0.109 mmol), TBTU (36.7 mg, 0.114 mmol), DIPEA (66 μl, 0.38 mmol) and DMF (1 mL) is stirred for 30 min, then trans-4-trifluoromethyl-cyclohexylamine (24 mg, HCl salt) is added and it is stirred for 1 h.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[O:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:30][C:31]([Si](C)(C)C)([F:33])[F:32]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:11])[C:31]([F:33])([F:32])[F:30]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cc2ccccc2o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cc2ccccc2o1)C(F)(F)F
Yield: 43.8 %

Procedure:
According to Reference Example 8-12, by use of benzofuran-2-carbaldehyde (300 mg, 2.05 mmol) dissolved in tetrahydrofuran (6 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (1.03 mL, 1.03 mmol) and (trifluoromethyl)trimethylsilane (0.516 mL, 3.49 mmol), the mixture was stirred and reacted at room temperature for 5 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=100/1) was performed to give 1-(benzofuran-2-yl)-2,2,2-trifluoroethanol (Compound DR) (194 mg, yield: 44%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][OH:20])=[CH:23][CH:24]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1ccc(CO)cc1
Temperature: 80 °C
Yield: 26.3 %

Procedure:
Nitrogen was bubbled through a mixture of 1-bromo-4-chloro-2-nitro-benzene (1.25 g, 5.3 mmol), bis(triphenylphosphine)palladium(II) chloride (90 mg, 0.13 mmol) and potassium phosphate tribasic (4.2 g, 19.7 mmol) in anhydrous 1,2-dimethoxyethane (30 mL) for 15 minutes. A solution of 4-(hydroxymethyl)phenylboronic acid (0.8 g, 5.3 mmol) in anhydrous 1,2-dimethoxyethane (1.5 mL) was added and the resulting mixture was heated at 80° C. overnight. The reaction mixture was then poured into water and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 70/30) to give 0.367 g of (4′-chloro-2′-nitro-biphenyl-4-yl)-methanol as a solid.