Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(CC2C=C(C=CC=2)OCCCN)CCCCC1.C(N=C(SC)SC)#N.[CH3:27][S:28][C:29](=[N:48][C:49]#[N:50])[NH:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]2[CH2:47]CCC[CH2:43]2)[CH:36]=1>>[C:49]([N:48]=[C:29]([S:28][CH3:27])[NH:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]([CH3:47])[CH3:43])[CH:36]=1)#[N:50]
Reactant: CSC(=NC#N)NCCCOc1cccc(CN2CCCCC2)c1
Agent: CSC(=NC#N)SC
Agent: NCCCOc1cccc(CN2CCCCC2)c1
Product: CSC(=NC#N)NCCCOc1cccc(CN(C)C)c1

Procedure:
Similarly prepared from 3-[3-(1-piperidinylmethyl)phenoxy]propanamine] (10 g) and cyanocarbonimidodithioic acid, dimethyl ester (5.84 g) was N'-cyano-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]carbamimidothioic acid methyl ester (11.5 g) m.p. 89°-90°.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:14]2)=O)(C)(C)C.[Cl:23]N1C(=O)CCC1=O>>[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:23])=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:14]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc2cc(S(=O)(=O)O)ccc12
Product: Nc1ccc(Cl)c2cc(S(=O)(=O)O)ccc12
Yield: 100.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 31B, 5-(tert-butoxycarbonylamino)naphthalene-2-sulfonic acid (Intermediate 31A, 3.70 g, 11.44 mmol) and N-chlorosuccinimide (1.60 g, 12.01 mmol) were converted to the title compound (2.95 g, 90%). MS(ESI+) m/z 275.1 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[CH3:16])[CH2:5][C:6]1([OH:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH:31]([CH2:33]Br)[CH2:30][C:29]=2[CH:35]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[CH3:16])[CH2:5][C:6]1([OH:12])[CH2:11][CH2:10][N:9]([CH2:33][CH:31]2[CH2:30][C:29]3[CH:35]=[C:25]([O:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:26]=[CH:27][C:28]=3[O:32]2)[CH2:8][CH2:7]1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1C
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Product: Cc1ccc(CC2(O)CCN(CC3Cc4cc(OCc5ccccc5)ccc4O3)CC2)cc1C

Procedure:
The title compound MS: m/e=458.6 (M+H+) was prepared from 4-(3,4-dimethyl-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[C:9]([C:15]2[O:19][C:18]([C:20]3[CH:21]=[C:22]([CH2:26][NH:27]C(=O)OC(C)(C)C)[CH:23]=[CH:24][CH:25]=3)=[N:17][N:16]=2)=[N:10][C:11](Br)=[CH:12][N:13]=1.[CH:35]([S:38]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)(=[O:40])=[O:39])([CH3:37])[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(C(F)(F)F)=O>O1CCOCC1.[Pd]>[NH2:27][CH2:26][C:22]1[CH:21]=[C:20]([C:18]2[O:19][C:15]([C:9]3[C:8]([NH2:7])=[N:13][CH:12]=[C:11]([C:44]4[CH:43]=[CH:42][C:41]([S:38]([CH:35]([CH3:37])[CH3:36])(=[O:40])=[O:39])=[CH:46][CH:45]=4)[N:10]=3)=[N:16][N:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2nnc(-c3nc(Br)cnc3N)o2)c1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CN)c4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
Sodium carbonate (335.4 μL of 2 M, 0.6708 mmol) was added to a solution of tert-butyl N-[[3-[5-(3-amino-6-bromo-pyrazin-2-yl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]carbamate (100 mg, 0.2236 mmol), (4-isopropylsulfonylphenyl)boronic acid (66.30 mg, 0.2907 mmol), palladium; triphenylphosphane (25.84 mg, 0.02236 mmol) in dioxane (5 mL) and the resulting mixture heated at 110° C. under microwave conditions for 90 min. The mixture was placed directly onto silica gel pad and washed through with diethyl ether and followed by 50% EtOAc/ petroleum ether. Product fractions were combined and concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL) and TFA (764.9 mg, 516.8 μL, 6.708 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo to leave an oil. This was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were combined and lypholised to give the product as a yellow solid (36.05 mg, 35% yield); 1H NMR (400 MHz, DMSO) d 1.3 (d, 6H), 3.45-3.55 (m, 1H), 4.24-4.3 (m, 2H), 7.7-7.8 (m, 2H), 7.95 (d, 2H), 8.25 (d, 1H), 8.3-8.4 (br s, 2H), 8.4 (s, 1H), 8.45 (d, 2H) and 9.1 (s, 1H) ppm; MS (ES+) 451.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:18]([CH2:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:17](=[O:26])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:27])[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:29][CH2:30][CH2:31][Cl:32].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:18]([CH2:19][C:20]([NH:22][CH:23]([CH3:24])[CH3:25])=[O:21])[C:17](=[O:26])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:27][CH2:29][CH2:30][CH2:31][Cl:32])[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(O)cc2c1=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(OCCCCl)cc2c1=O
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A mixture of 2-[2-(3-chloro-4-fluorophenyl)-6-hydroxy-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (INTERMEDIATE IV.1) (373 mg, 0.96 mmol), 3-bromo-1-chloropropane (0.28 mL, 2.87 mmol) and K2CO3 (662 mg, 4.80 mmol) in acetonitrile (5 mL) was heated at reflux temperature for 24 h. The mixture was cooled to room temperature and then poured into ice water (40 mL). The resultant white solid was collected by filtration and washed with additional portions of cold water (3×20 mL) followed by washing with cold diethyl ether (3×10 mL) and cold hexane (2×10 mL) to remove residual 3-bromo-1-chloropropane. In this way 2-[2-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (391 mg, 0.84 mmol, 87%) was obtained.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:15][C@H:14]2[N:16]([CH3:17])[C@H:11]([CH2:12][CH2:13]2)[C@H:10]1[C:18](OC)=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:15][C@H:14]2[N:16]([CH3:17])[C@H:11]([CH2:12][CH2:13]2)[C@H:10]1[CH2:18][OH:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2CC[C@H]1N2C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: ClCCl
Product: CN1[C@H]2CC[C@@H]1[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2
Temperature: -78 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
The TBDMS-protected compound of Example 1 (900 mg, 2.88 mmol) was dissolved in 12 mL of methylene chloride. The solution was cooled to -78° C., and a 1M solution of diisobutylaluminum hydride in hexanes (11.5 mL, 11.5 mmol) was added. The reaction mixture was stirred at -78° C. for 4 hr. A saturated solution of K2CO3 was added to quench the reaction. The aqueous layer was extracted with chloroform. The combined organic layers were washed with water and brine and dried over MgSO4. The solvent was evaporated in vacuo, and the residue was chromatographed using methanol as eluent to give 650 mg of the title alcohol 3 (79% yield): IR (thin film) 3453, 2947, 2899, 2857, 1472, 1252, 1098, 837 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 4.12-3.85 (m, 3H), 3.45-3.37 (m, 1H), 3.21-3.17 (m, 1H), 2.22 (s, 3H), 2.20-1.50 (m, 8H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3, 75.46 MHz) δ 66.9, 65.7, 63.6, 61.5, 46.5, 41.2, 40.6, 26.0, 25.4, 18.3, 6.6, 6.3; mass spectrum m/z 285 (M+), 228, 154, 126, 83; HRMS (FAB) calcd for C15H32NO2Si (MH+) 286.2194, found 286.2215.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)[S:6][C:7]=1[C:8]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=1)=[O:2].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=1.CCOCC>O1CCCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:1]([OH:2])[C:3]2[N:4]=[C:5]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=3)[S:6][C:7]=2[C:8]2[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=2)=[CH:34][CH:33]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(=O)Nc1cc(-c2nc(C=O)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)Nc1cc(-c2nc(C(O)c3ccc(Cl)cc3)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
N-{4-[4-formyl-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.250 g, 0.564 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled at 0° C. 1.0 M 4-Chlorophenylmagnesium bromide in ether (1.41 mL, 1.41 mmol) was added and the solution was stirred at 0° C. for 30 minutes. The reaction was quenched by the addition of MeOH (10 mL), and was evaporated under reduced pressure. The residue was purified using column chromatography (20 to 100% ethyl acetate in hexane) to give the title compound (0.150 g, 48%). LCMS: (FA) ES+, 556, 558. 1H NMR (400 MHz, CDCl3) δ: 8.69 (s, 1H), 8.34 (d, J=5.23 Hz, 1H), 8.21 (s, 1H), 7.65 (dd, J=5.23, 1.55 Hz, 1H), 7.31 (d, J=8.28 Hz, 2H), 7.21-7.16 (m, 3H), 7.07 (d, J=1.31 Hz, 1H), 6.26-6.15 (m, 1H), 5.30 (s, 1H), 3.46-3.36 (m, 2H), 2.24 (s, 3H), 0.94-0.84 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[N:8][C:6]=2[N:7]=1.[OH-:14].[Na+]>>[Cl:1][C:2]1[NH:3][C:4](=[O:14])[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Clc1cnc2nc(Cl)nc(Cl)c2c1
Agent: [Na+]
Product: O=c1[nH]c(Cl)nc2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,4,6-Trichloro-pyrido[2,3-d]pyrimidine (360 mg, crude) was dissolved in 1N NaOH (6 ml) (ultrasonication) and stirred for 30 min at r.t. The obtained suspension was extracted with Et2O. The water layer was separated, acidified (HCl), and again extracted (EtOAc). The organic layer was dried (Na2SO4), filtered and evaporated to give crude 2,6-dichloro-3H-pyrido[2,3-d]pyrimidin-4-one (MS: m/e=214.3 [M−H−]) which was used without further purification in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1.[H-].[Na+].CI.[C:16](OCC)(=O)C>CN(C=O)C>[CH3:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1
Reactant: CCOC(C)=O
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2cccc(C=O)c21
Reaction time: 0.5 h

Procedure:
To a solution of indole-7-carboxaldehyde (500 mg, 3.45 mmol) in DMF (8 mL) was added sodium hydride (152 mg of 60% dispersion in oil, 3.8 mmol). The mixture was stirred for 30 mins. Methyl iodide (0.98 g, 6.9 mmol) was then added and the mixture was stirred for 2 hrs. Ethyl acetate (200 mL) was added and solution was washed with H2O (3×20 mL) and brine (25 mL) dried over MgSO4 and concentrated to afford N-methylindole-7-carboxaldehyde as a brown oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:43][NH:44][CH2:45][CH2:46][N:47]([CH3:49])[CH3:48]>C1COCC1.C(N(CC)CC)C>[CH3:48][N:47]([CH3:49])[CH2:46][CH2:45][N:44]([CH3:43])[C:19](=[O:21])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CNCCN(C)C
Reactant: O=C(O)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCN(C)C(=O)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of (4-(((benzyloxy)carbonyl)amino)-phenyl)acetic acid (6 g) in THF (100 ml) were added WSC (4 G), HOBt (3 g), and N,N,N-trimethylethylenediamine (2.1 g) sequentially. Triethylamine (3 ml) was added to the reaction mixture. After stirring at room temperature overnight, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. The residue was recrystallized from IPE/ethyl acetate to obtain the titled compound (7 g).
Reaction SMILES: [NH2:1][C:2]([NH2:22])=[N:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([CH:15]2[CH2:19][CH2:18][CH:17]=[CH:16]2)=[CH:7][C:6]=1[CH3:20].[CH3:23][S:24]([OH:27])(=[O:26])=[O:25]>CC(C)=O>[NH2:22][C:2]([NH2:1])=[N:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:12])=[O:13])[C:8]([CH:15]2[CH2:19][CH2:18][CH:17]=[CH:16]2)=[CH:7][C:6]=1[CH3:20].[CH3:23][S:24]([O-:27])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)O
Agent: Cc1cc(C2C=CCC2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Solvent: CC(C)=O
Product: CS(=O)(=O)[O-]

Procedure:
700 mg of N-diaminomethylene-2-methyl-4-(1-cyclopenten-3-yl)-5-methylsulfonylbenzamide [which can be prepared according to Example 1; m.p. 212°-214°] are dissolved in 20 ml of acetone, and 6.1 ml of methanesulfonic acid are added, while stirring. Filtration and lyophilization give N-diaminomethylene-2-methyl-4-(1-cyclopenten-3-yl)-5-methylsulfonylbenzamide, methane-sulfonate, m.p. 202°-204°.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[Br:29][C:30]1[N:31]=[C:32]([O:37][CH3:38])[C:33]([NH2:36])=[N:34][CH:35]=1.C(N(C(C)C)CC)(C)C>C(#N)CCC>[Br:29][C:30]1[N:31]=[C:32]([O:37][CH3:38])[C:33]2[N:34]([C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:36]=2)[CH:35]=1
Reactant: COc1nc(Br)cnc1N
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(Br)cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 125 °C

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (203 mg, 0.38 mmol, 1.0 eq), 5-bromo-3-methoxypyrazin-2-amine (74.6 mg, 0.38 mmol, 1 eq.; Jiang, B. et al. Bioorg. Med. Chem. (2001), 9, 1149-1154.) and diisopropylethylamine (0.064 mL, 0.38 mmol, 1.0 eq) in 2.3 mL butyronitril was heated to 120° C. for 17 hours and to 125° C. for 6 h. The reaction mixture was concentrated in vacuo. The crude mixture was purified via preparative HPLC under basic conditions (column: Waters X-Bridge, eluent: ACN/water (15/85)→ACN/water 55/45) to deliver 9 mg (4%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O1CCCC1>>[CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:9])[CH3:2]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(O)c1ccccc1
Yield: 87 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde (1.0 g) and 1N phenylmagnesium bromide-tetrahydrofuran solution (8.0 mL) to give the title compound (1.2 g, 87%) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[CH:14]=[CH:13][N:12]=2)[S:5][C:6]=1[Si](C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH:14]=[CH:13][N:12]=2)[S:5][CH:6]=1
Reactant: CN1CCN(c2ccnc(-c3cc(Cl)c([Si](C)(C)C)s3)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN1CCN(c2ccnc(-c3cc(Cl)cs3)c2)CC1
Reaction time: 10 h

Procedure:
A solution of 1-[2-(4-chloro-5-trimethylsilanyl-thiophen-2-yl)-pyridin-4-yl]-4-methyl-piperazine (20 mg, 0.05 mmol) in THF (1 mL) was treated with TBAF (1 M in THF, 0.2 mL). After 10 h, the resulting mixture was concentrated, diluted with water, and extracted with CH2Cl2. The organic layer was dried and concentrated, and the resulting residue was purified by preparative TLC (CH2Cl2/MeOH) to yield the title compound as a solid.
Reaction SMILES: [CH3:1][C@H:2]([NH2:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[CH2:8]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]=1[F:21])[C:9]#[CH:10]>>[CH3:1][C@H:2]([NH:7][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:8][C:9]#[CH:10])=[C:13]([F:21])[CH:14]=1)[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@H](N)C(C)(C)C
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Product: C#CCOc1ccc(C(=O)N[C@@H](C)C(C)(C)C)cc1F

Procedure:
According to the same method as that of Production Example 1, (1S)-1,2,2-trimethylpropylamine was used in place of 2,2-dimethylpropylamine, and 4-(2-propynyloxy)-3-fluorobenzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-((1S)-1,2,2-trimethylpropyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 25 of the present invention) represented by the formula:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:15]1([C:13]([C:6]2[C:7]([CH3:12])=[N:8][C:9]3[C:4]([C:5]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:3][C:2]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:11][CH:10]=3)=[O:14])[CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C1CC1
Product: Cc1nc2ccc(N3CCCCC3)cc2c(-c2ccccc2)c1C(=O)C1CC1
Yield: 64 %

Procedure:
The title compound was prepared from [(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-cyclopropyl-methanone [example 55] and piperidine according to the procedure of example 51. Yield: 64%; MS: m/z=371 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:33]1[C:46]2[C:37](=[N:38][C:39]3[C:44]([C:45]=2[NH:47][C:48]2[CH:49]=[C:50]([NH:56][C:57](=[O:61])[CH:58]([NH2:60])[CH3:59])[CH:51]=[C:52]([CH2:54][OH:55])[CH:53]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][CH:34]=1>>[CH:43]1[C:44]2[C:39](=[N:38][C:37]3[C:46]([C:45]=2[NH:47][C:48]2[CH:49]=[C:50]([NH:56][C:57]([CH:58]([NH:60][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:24]=[C:25]([O:31][CH3:32])[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:59])=[O:61])[CH:51]=[C:52]([CH2:54][OH:55])[CH:53]=2)=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:40]=[CH:41][CH:42]=1
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 49.1 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-dimethoxyphenyl)-piperazine-1-carbonyl]-amino}-6-meth oxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([SiH2][O:28][C:29](C)(C)[C@@H:30]1[N:35]([CH2:36][C:37]2[NH:45][C:44]3[CH:43]=[CH:42][N:41]=[CH:40][C:39]=3[CH:38]=2)[C:34](=[O:46])[CH2:33][N:32]([S:47]([CH:50]=[CH:51][C:52]2[S:53][C:54]([Cl:57])=[CH:55][CH:56]=2)(=[O:49])=[O:48])[CH2:31]1)(C)(C)C>C1COCC1>[Cl:57][C:54]1[S:53][C:52]([CH:51]=[CH:50][S:47]([N:32]2[CH2:31][C@H:30]([CH2:29][OH:28])[N:35]([CH2:36][C:37]3[NH:45][C:44]4[CH:43]=[CH:42][N:41]=[CH:40][C:39]=4[CH:38]=3)[C:34](=[O:46])[CH2:33]2)(=[O:48])=[O:49])=[CH:56][CH:55]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)CC(=O)N1Cc1cc2cnccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)C[C@H](CO)N1Cc1cc2cnccc2[nH]1
Reaction time: 4 h
Yield: 48.5 %

Procedure:
Glacial acetic acid (3 mL, 0.046 mmol) and tetrabutylammonium fluoride (92 mL, 0.092 mmol) is added to a solution of 6-(R)-(tert-butyl-dimethyl-silanyloxymethyl)-4-[2-(5-chloro-thiophen-2-yl)-ethenesulfonyl]-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one (0.019 g, 0.033 mmol) in THF (0.5 mL). The resulting solution is stirred for 4 h then concentrated in vacuo. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN and the appropriate product fractions are lyophilized to provide the title compound (0.009 g, 0.016 mmol) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ14.50 (bs, 1H), 12.60 (bs, 1H), 9.18 (s, 1H), 8.38 (d, 1H), 7.89 (d, 1H), 7.61 (d, 1H), 7.50 (d, 1H), 7.21 (d, 1H), 7.08 (d, 1H), 6.90 (s, 1H), 5.03 (s, 2H), 4.63 (d, 2H), 3.70-3.90 (AB, 2H), 3.75 (m, 1H), 3.21 (m, 2H). Ion spray MS, [M+H]+467, 469, Cl pattern.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)([O:6][CH3:7])[O:4][CH3:5].[CH2:17]([S:19][C:20]1[C:21]([C:26](O)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>C1C=CC2N(O)N=NC=2C=1.N1C=CC=CC=1>[CH2:17]([S:19][C:20]1[C:21]([C:26]([NH:12][C:11]2[CH:13]=[CH:14][C:8]([C:3]([O:6][CH3:7])([O:4][CH3:5])[C:2]([F:15])([F:16])[F:1])=[CH:9][CH:10]=2)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18]
Reactant: CCSc1cccnc1C(=O)O
Reactant: COC(OC)(c1ccc(N)cc1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CCSc1cccnc1C(=O)Nc1ccc(C(OC)(OC)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
A mixture of 0.38 g of 4-(2,2,2-trifluoro-1,1-dimethoxyethyl)aniline, 0.22 g of 3-ethylsulfanylpicolinic acid, 0.29 g of EDCI hydrochloride, 0.01 g of HOBt and 5 mL of pyridine was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.43 g of 3-ethylsulfanyl-N-[4-(2,2,2-trifluoro-1,1-dimethoxyethyl)phenyl]picolinamide (Compound of Present Invention 58).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[NH:14][C:15]2[C:16]3[C:23]([CH3:24])=[C:22]([C:25](O)=[O:26])[S:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:28]>CO>[CH:1]1([O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[NH:14][C:15]2[C:16]3[C:23]([CH3:24])=[C:22]([C:25]([NH2:28])=[O:26])[S:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCCC3)c12
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCCC3)c12

Procedure:
Prepared analogously to example 1.4 from 4-(2-cyclopentoxy-4-fluoro-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (59 mg) and 7 M ammonia in MeOH (0.5 ml).