Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:18])[C:6]([C:15]([OH:17])=[O:16])=[CH:7][N:8]3[CH2:13][CH3:14])=[CH:3][C:2]=2[Cl:1])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(Cc4ccccc4)CC3)cc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of 4.3 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 10.5 g of 1-benzylpiperazine in 45 cm3 of DMSO was stirred and heated to 110° C. After 2 hours, the amount of Cl- ions in the reaction mixture corresponded to 94% of the amount calculated for the removal of one halogen atom. After evaporation of the solvent, the reaction product was isolated as in the preceding example; it was purified by recrystallisation from methyl cellosolve. 3.2 g of 7-(4-benzylpiperazinyl)-6-chloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 228° C., were obtained.
Reaction SMILES: C(NCC)C.CC(O)(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH2:20][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1ccc(C(C)=O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: COc1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a vigorously stirred mixture of zinc chloride (5 g, 36.6 mmol) in anhydrous toluene (200 mL) is added a mixture of diethylamine (2.82 mL, 27.5 mmol) and t-BuOH (2.61 mL, 27.5 mmol) under Argon. After 1 h, 4′-methoxyacetophenone (4.12 g, 27.45 mmol) and 2-bromoacetophenone 1 (3.64 g, 18.3 mmol) are added sequentially. The mixture is stirred for 3 days at room temperature. The mixture is washed with 5% H2SO4 (200 mL) and the organics separated. The aqueous layer is washed with ethyl acetate (2×100 mL). The organics are combined, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (hexane/ethyl acetate (5→15%)) afforded 1-(4-Methoxy-phenyl)-4-phenyl-butane-1,4-dione (1.8 g), characterized by LCMS (Obs: 269.09, Cal: 268.11) and 1H NMR.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:30][C:28]([F:31])([F:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:62][C@H:60]([OH:61])[CH2:59][O:58][C:55]3[CH:56]=[CH:57][C:52]([OH:51])=[CH:53][CH:54]=3)=[CH:33][CH:32]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccccc3C(F)(F)F)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccccc1C(F)(F)F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 22.4 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[2-(trifluoromethyl)benzyl]-1-piperidinecarboxamide formate (0.50 g, 1.07 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.433 g, 1.07 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.211 g, 0.24 mmol).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]([CH:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:20](=[O:31])NCC(OC(OC)=O)(C)C)[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1.CC(C)([O-])C.[K+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:20](=[O:31])[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)CC(=O)N(c1ccc2[nH]cnc2c1)C(C(=O)NCC(C)(C)OC(=O)OC)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)C1C(=O)C(c2ccccc2)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from ethyl 2-[(1H-benzo[d]imidazol-5-yl)[phenyl({2-[(methoxycarbonyl)oxy]-2-methylpropyl}carbamoyl)methyl]-carbamoyl]-acetate (which may be prepared in accordance with the procedure described for Intermediate 1; 0.3 g, 0.588 mmol) and potassium tert.-butoxide solution (1M, 1.18 ml, 1.176 mmol) according to the method described in step 2.
Reaction SMILES: Cl[C:2]1[S:3][N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.Cl.Cl.[CH2:13]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[OH:26])[NH2:22])[CH2:16][CH3:17])[CH3:14].COCCOCCOC>O>[CH2:13]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[S:3][N:4]=[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[CH:23]=[CH:24][C:25]=1[OH:26])[CH2:16][CH3:17])[CH3:14]
Reactant: CCN(CC)Cc1cc(N)ccc1O
Reactant: Clc1snc2ccccc12
Agent: Cl
Solvent: COCCOCCOC
Solvent: O
Product: CCN(CC)Cc1cc(Nc2snc3ccccc23)ccc1O

Procedure:
Following a procedure similar to that described in Example 14 but reacting 10 g. of 3-chloro-2,1-benzisothiazole with 21 g. of 3-(diethylamino)methyl-4-hydroxyaniline dihydrochloride in 30 ml. of diglyme and 20 ml. of water there was obtained 3-{[3-(diethylamino)methyl-4-hydroxyphenyl]amino}-2,1-benzisothiazole, m.p. 164°-165° C.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5]C=C(C)C=1.[CH2:9]([O:13]CC1OC1)[CH:10]1[O:12][CH2:11]1.C1(CN)C=CC=C(CN)C=1.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>C(O)CO.C(C1OC1)Cl>[CH2:9]([O:13][CH2:5][CH2:6][CH2:1][CH3:8])[CH:10]1[O:12][CH2:11]1
Reactant: C(OCC1CO1)C1CO1
Reactant: Cc1cccc(C)c1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: NCc1cccc(CN)c1
Solvent: OCCO
Solvent: ClCC1CO1
Product: CCCCOCC1CO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 210 %

Procedure:
In the same reaction vessel as in Example 1 was fed 270 g of the modified polyamine synthesized in Production Example 1 (corresponding to the modified polyamine based on 1 mol of metaxylene, 0.125 mol of methoxypolyethylene glycol and 0.14 mol of epichlorohydrin), and then 186 g (1 mol) of 2-ethylehexyl glycidyl ether (epoxy equivalent of 186, produced by NOF Corporation, the trademark "Epiol EH") was added dropwise thereto over one hour at 80° C. in an atmosphere of nitrogen under stirring. After the completion of the dropwise addition, the reaction was carried out for one hour at a reaction temperature raised 100° C. Then, the vessel interior was cooled to 80° C., and then 231 g (1.70 mol) of metaxylylenediamine was added thereto. Then, a mixture of 307 g (0.807 mol) of epoxy resin in a liquid form of bisphenol A type (epoxy equivalent 190, produced by Yuka Shell Epoxy Co., Ltd., the trademark "Epicoat 828) with 278 g (2.1 mol) of butyl glycidyl ether (epoxy equivalent of 132, produced by NOF Corporation, the tradmark "Epiol B") was added dropwise thereto over one hour at 80° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.C(N(CC)CC)C.[C:19]1([C:25](Br)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.CCOC(C)=O.O>[CH3:2][O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:10]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1c[nH]cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 24 h

Procedure:
To a solution of the product from Step A (24.85 g, 0.141 mol) in dimethylformamide (DMF) (115 ml) was added triethylamine (57.2 ml, 0.412 mol) and triphenylmethyl bromide(55.3 g, 0.171 mol) and the suspension was stirred for 24 hr. After this time, the reaction mixture was diluted with EtOAc (1 l) and water (350 ml). The organic phase was washed with sat. aq. NaHCO3 (350 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (SiO2, 0-100% ethyl acetate in hexanes; gradient elution) to provide the title compound as a solid.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[ClH:27]>>[OH:1][C:3]1([CH2:2][Cl:27])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1
Reactant: Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CCl)CC3)c(F)c2)C(=O)O1
Temperature: 55 °C

Procedure:
A mixture of (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (18.0 mmol) and aqueous hydrochloric acid was heated at a temperature 50-60° C. for 12 hours to provide crude (S)-N-{3-[4-(4-hydroxy-4-chloromethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide which was purified by silica gel column chromatography and used further.
Reaction SMILES: [CH:1]([OH:5])=[C:2]([OH:4])[CH3:3].[CH3:6][Si:7](Cl)([CH3:9])[CH3:8]>C[Si](N[Si](C)(C)C)(C)C>[Si:7]([O:4][CH:2]([CH2:1][O:5][Si:7]([CH3:9])([CH3:8])[CH3:6])[CH3:3])([CH3:9])([CH3:8])[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: CC(O)=CO
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CC(CO[Si](C)(C)C)O[Si](C)(C)C

Procedure:
1,2-Propenediol (58.8 g, 0.77 mol) was placed in a 500 mL 3-necked RB flask and treated with 0.2 mL trimethylsilyl chloride. A small volume of HMDS (ca. 10 mL) was added, and an exothermic reaction took place as the mixture became homogeneous. The remainder of the HMDS (170 mL) was added at a controlled rate (ca. 3-5 mL/min), maintaining the reaction temperature at ca. 50°-70° C. Heating was continued at 100° C. (1.5 h), 120° C. (1.0 h), and 140° C. (2.5 h). GC analysis (method 1) revealed excess HMDS and one product. Distillation provided 147 g of colorless oil, bp 70°-72° C./10 mm. 1H NMR (CDCl3): 3.83 (m; 1H), 3.50 and 3.38 (AB pattern with additional coupling, 2H), 1.15 (d, J=7 Hz, 3H), 0.15 (partially resolved singlets, 18H).
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=1[C:20](=O)[CH2:21][CH3:22]>CCO.O.O>[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=1[C:20](=[N:2][OH:3])[CH2:21][CH3:22]
Reactant: CCC(=O)c1c(O)cccc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(=NO)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A solution of hydroxylamine hydrochloride (510 mg, 7.3 mmol) and sodium acetate trihydrate (629 mg, 4.6 mmol) dissolved in 20 ml of a mixture EtOH/H2O (7/3) was added to a solution of 1-(2,6-dihydroxyphenyl)-1-propanone (Intermediate 28, 1.0 g) in 15 ml of a mixture EtOH/H2O (7/3). After refluxing and stirring under N2 overnight, additional hydroxylamine hydrochloride (510 mg, 7.3 mmol) and sodium acetate trihydrate (629 mg, 4.6 mmol) dissolved in 4.5 mL of water were added. The reaction mixture was heated at reflux an additional 3 hours. After cooling down to room temperature, the volatiles were removed. Then water was added and reaction mixture was extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound (1.05 g).
Reaction SMILES: [N:1]1[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[N:1]1[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([Cl:10])(=[O:13])=[O:12])[C:5]=12
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2nscc2c1
Product: O=S(=O)(Cl)c1cccc2csnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.6 %

Procedure:
Benzo[c]isothiazole 24B (1 g, 7.45 mmol) was added dropwise to chlorosulfonic acid (5.5 mmol) at 0° C. After the addition was complete, the mixture was stirred at room temperature for 0.5 h and then heated at 105° C. and stirred overnight. The resulting mixture was cooled to −10° C. and quenched by pouring on crushed ice slowly. The resulting mixture was extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 200 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 9.68 (s, 1H), 8.66 (d, J=1.9 Hz, 1H), 8.10 (d, J=9.4 Hz, 1H), 7.99 (dd, J=9.4, 2.1 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[C:8]([O:11]C)[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=1[CH2:16][C:17]([OH:19])=[O:18])([O-:3])=[O:2].B(Br)(Br)Br>ClCCl>[OH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH2:16][C:17]([OH:19])=[O:18])[C:6]([N+:13]([O-:15])=[O:14])=[CH:7][C:8]=1[OH:11]
Reactant: COc1cc([N+](=O)[O-])c(CC(=O)O)c([N+](=O)[O-])c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)Cc1c([N+](=O)[O-])cc(O)c(O)c1[N+](=O)[O-]
Temperature: -20 °C

Procedure:
The product from Example 3 (0.28 g) 3 was slurried in dichoromethane (15 ml), cooled to -20° C. and boron tribromide (0.4 ml) added under nitrogen. The reaction mixture was allowed to warm up to room temperature and then refluxed for four hours. The mixture was poured into ice-water and extracted to ethyl acetate. The product was purified by column chromatography using toluene-ethyl acetate-acetic acid 8:1:1 as the eluent. Yield: 21 mg, melting point 178-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N+:5]([O-])=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12
Reactant: [O-][n+]1c(OC2CCCC2)cc(Cl)c2c1CCC2
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: Clc1cc(OC2CCCC2)nc2c1CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
To a solution of crude 4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.49 mmol) in methylene chloride (5 mL) was added phosphorous trichloride (0.100 g, 0.74 mmol). The mixture stirred at rt for 2 h. After this time, the mixture was quenched with a saturated solution of NaHCO3 and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.029 g, 25% over two steps) as a clear oil. MW=237.73. 1H NMR (CDCl3, 300 MHz) δ 6.45 (s, 1H), 5.34-5.26 (m, 1H), 3.01-2.84 (m, 4H), 2.11 (quip; J=7.5 Hz, 2H), 2.00-1.57 (m, 8H); APCI MS m/z 238 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6]C(=O)C)([O-:3])=[O:2].Cl>CO>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: Nc1ccccc1[N+](=O)[O-]
Yield: 108.7 %

Procedure:
A mixture of 1.32 g of an o-nitroacetoanilide compound having the formula (XXV), ##STR23## 5 ml of conc. hydrochloric acid and 50 ml of methanol was heated under reflux for 80 minutes. The reaction solution was concentrated, poured into ice water and alkalified with potassium carbonate. After extraction with ethyl acetate, the organic layer was washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the dried layer by distillation gave 1.1 g of an o-nitroaniline compound [compound (306)] having the formula (XXIV).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.Cl.Cl.[C:39]1([CH2:49][NH2:50])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:50][CH2:49][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][N:40]=1)=[O:25]
Reactant: NCc1nccc2ccccc12
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2nccc3ccccc23)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-isoquinolin-1-yl-methylamine dihydrochloride.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.[NH2:21][CH2:22][C:23]1[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1>>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:22][C:23]2[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(CN)o1
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1

Procedure:
The method described in Example 23 was repeated except that 4-chloro-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine was used in place of 4-chloro-2,6-dimethyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine and ethyl 5-aminomethyl-2-furancarboxylate was used in place of ethyl (4-aminomethyl)benzoate to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23]>>[F:21][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:22]#[N:23])[CH:29]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-Cyanobenzene boronic acid. MS (M+H) 378.2
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:28][CH:29]([F:39])[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1>>[F:39][CH:29]([F:28])[C:30]1[N:31]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: FC(F)c1nc2ccccc2[nH]1
Reactant: CC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(=O)N1CCC(Cc2ccc3nc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
1-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)ethanone from Example 148 (0.135 g) was reacted with 2-(difluoromethyl)-1H-benzo[d]imidazole via General Procedure D to produce 31.4 mg of 171 following reverse phase HPLC purification. MS (Q1) 522.2 (M)+
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.C(O)C>O>[CH3:22][N:13]([S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:16])[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[NH:4][C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:6]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Yield: 45.5 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.06 g), concentrated hydrochloric acid (1 ml) and ethanol (5 ml) was heated overnight under reflux. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. The obtained crystals were subjected to silica gel column chromatography to give the title compound (0.43 g, yield 46%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 164-165° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([CH2:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[N:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:28][C:25]3[CH:24]=[N:23][C:22]([C:21]([F:30])([F:20])[F:29])=[CH:27][N:26]=3)[C:3]=2[N:10]=1
Reactant: Nc1cnc(C(F)(F)F)cn1
Reactant: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2s1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cnc(Nc2ncnc3sc(Cc4c(Cl)cccc4Cl)nc23)cn1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a mixture of 7-chloro-2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidine (113 mg, 0.34 mmol), 1,2,3,4,5-pentaphenyl-1-(di-t-butylphosphino)ferrocene (49 mg, 0.07 mmol), tris(dibenzylideneacetone)dipalladium (0) (31 mg, 0.03 mmol), and 5-trifluoromethyl-pyrazin-2-ylamine (66 mg, 0.41 mmol) in toluene (3 mL) was added NaOtBu (40 mg, 0.41 mmol) at rt. The mixture was heated to 90° C. under N2. After 18 h, the reaction mixture was cooled and filtered through a pad of diatomaceous earth, eluting with MeOH (30 mL). The filtrate was concentrated and the crude residue was purified using preparative reverse-phase HPLC to afford the title compound a colorless solid (43 mg, 28%). MS (ESI): mass calcd. for C17H9Cl2F3N6S, 455.9; m/z found, 457.0 [M+H]+. 1H NMR ((CD3)2SO): 10.77 (s, 1H), 9.49 (s, 1H), 8.88-8.87 (m, 1H), 8.75 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.45 (dd, J=8.5, 7.7 Hz, 1H), 4.83 (s, 2H).