Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH2:20])=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C=O.[OH-].[Na+].[C:35](=O)([O-])[O-:36].[Na+].[Na+]>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH:20][CH2:35][OH:36])=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
To a solution of 5-[[(4-fluorophenyl)sulfonyl](2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (150 mg, 0.34 mmol) obtained in Example 39 in ethylene glycol dimethyl ether (3 ml), an aqueous solution of formaldehyde (37%, 0.1 ml) and 5% aqueous sodium hydroxide (0.4 ml) were added at 0° C., and the mixture was stirred overnight at room temperature. Sodium carbonate (20 mg) was added to the reaction mixture, and the mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure, and then the residue was dissolved in chloroform, dried over magnesium sulfate, and filtered. Subsequently, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, and then was collected by filtration, to obtain the title compound (93 mg, 0.20 mmol, 58%) as a white solid.
Reaction SMILES: [NH:1]([C:3]([O:5]C)=[O:4])[NH2:2].[CH2:7]([N:10]=[C:11]=[S:12])[CH:8]=[CH2:9].[CH3:13]CCCCC>C(Cl)Cl>[CH3:13][N:1]([C:3]([OH:5])=[O:4])[NH:2][C:11]([NH:10][CH2:7][CH:8]=[CH2:9])=[S:12]
Reactant: COC(=O)NN
Reactant: C=CCN=C=S
Reactant: CCCCCC
Solvent: ClCCl
Product: C=CCNC(=S)NN(C)C(=O)O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Into a stirred mixture of 20 g (0.2 mole) methyl hydrazinocarboxylate in 150 ml methylene chloride, 19.8 g (0.2 mole) allyl isothiocyanate in 50 ml methylene chloride was dropped in. The reaction mixture was refluxed at about 40° C. for 3.5 hours, allowed to stir overnight at ambient temperature, refluxed about 8 hours, stirred overnight at ambient temperature, refluxed 8 hours, stirred overnight at ambient temperature, and refluxed an additional 4 hours. The reaction mixture was cooled, vacuum filtered and the solids dried. The filtrate was poured back into the flask, at which point a precipitate started to form. Hexane was added. A yellow precipitate formed which was vacuum filtered and dried to give 29.6 g of the above-identified product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]([C:18]#[N:19])[S:14][C:15]=2[S:16][CH3:17])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].CO.C(Cl)(Cl)Cl>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([S:8]([C:11]3[CH:12]=[C:13]([C:18]#[N:19])[S:14][C:15]=3[S:16][CH3:17])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: CSc1sc(C#N)cc1S(=O)(=O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CSc1sc(C#N)cc1S(=O)(=O)c1cccc(N2CCN(C)CC2)c1
Temperature: 100 °C
Yield: 9.8 %

Procedure:
To a flask containing 0.15 g (0.4 mmol) of 4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carbonitrile (Example 286: step f), 44.1 μL (0.4 mmol) of N-methylpiperazine, 4.5 mg (0.02 mmol) of Pd(OAc)2, 24.8 mg (0.04 mmol) of BINAP, and 195 mg (0.6 mmol) of CsCO3 was added 2.5 mL of toluene. The flask was purged with Ar, and heated to 100° C. for 16 h. The reaction was then concentrated in vacuo and purified by preparative TLC (50%-EtOAc-Hexane), isolating the low Rf material, which was subjected to preparative TLC again (10% MeOH-CHCl3) to give 15.5 mg (10% yield) of 4-[3-(4-methyl-piperazin-1-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-2-carbonitrile in greater than 98% purity.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:18]1[CH2:22]OC[CH2:19]1>>[C:10]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:22][CH:18]=[CH2:19])[C:8]#[N:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: C=CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A solution of 2,2-diphenylacetonitrile (9.15 g) in THF (22.5 ml) was added dropwise to a stirred slurry of 80% sodium hydride (2.85 g, washed twice with hexane) and THF, under nitrogen. The mixture was stirred vigorously until the evolution of gas ceased. Allyl bromide (6.3 g) was added by syringe, and the resultant mixture was stirred at room temperature for 18 hours. The mixture was carefully poured into ice water, and the aqueous mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine (once each), dried (MgSO4), and rotary evaporated to yield 11.1 g of 2,2-diphenyl-4-pentenenitrile, as an oily product.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].ClC(N(C)C)=C(C)C.[NH2:17][C:18]1[CH:23]=[C:22]([O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([NH:35][C:36]([NH:38][C:39]3[N:43]([C:44]4[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=4)[N:42]=[C:41]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:40]=3)=[O:37])=[CH:27][CH:26]=2)[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C.N>C(Cl)Cl.CO>[C:51]([C:41]1[CH:40]=[C:39]([NH:38][C:36](=[O:37])[NH:35][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([O:24][C:22]3[CH:21]=[CH:20][N:19]=[C:18]([NH:17][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]=3)=[CH:26][CH:27]=2)[N:43]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:42]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(N)c3)c3ccccc23)cc1
Agent: CC(C)=C(Cl)N(C)C
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NC(=O)CS(C)(=O)=O)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a suspension of methanesulfonylacetic acid (40 mg, 0.29 mmol) in DCM (2.0 mL) under nitrogen was added 1-chloro-N,N,2-trimethylpropenylamine (48 μL, 0.37 mmol), and the mixture was stirred at RT for 2 hr. The resulting mixture was added to a solution of (Intermediate Q) (37 mg, 0.07 mmol) and DIPEA (51 μL, 0.29 mmol) in DCM (2.0 mL) and stirring continued at RT for 3 hr. The reaction mixture was stirred with 1% NH3 in MeOH (3.0 mL) for 45 min and then evaporated in vacuo. The residue was subjected to SCX capture and release and was then purified by flash column chromatography (SiO2, 12 g, 0-70% [5% MeOH in EtOAc] in isohexane, gradient elution) to afford the title compound (Example 51) as a white powder (13 mg, 28%): m/z 627 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.39 (3H, s), 3.10 (3H, s), 4.36 (2H, s), 6.40 (1H, s), 6.71 (1H, dd), 7.33-7.38 (3H, overlapping m), 7.47 (2H, m), 7.56 (1H, m), 7.65 (1H, m), 7.69 (1H, m), 7.85 (1H, d), 7.96 (1H, d), 8.11 (1H, d), 8.22 (1H, d), 8.91 (1H, br s), 9.23 (1H, br s), 10.96 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:13]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([NH2:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 2,4-dichloroquinazoline (2.0 g, 10 mmol) in THF (10 mL), was added ammonia (28-30% in water, 18 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated. The resulting solid was washed with EtOAc to give the title compound (1.3 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ7.52-7.48 (m, 1H), 7.6-7.58 (m, 1H), 7.8-7.76 (m, 1H), 8.22-8.20 (m, 1H), 8.32 (bs, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:20][C:5]2[CH2:6][N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Br.CCCCCC>C(O)(=O)C.O>[NH2:1][C:2]1[S:20][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCN(C(=O)OCc1ccccc1)C2
Agent: Br
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: O
Product: Nc1sc2c(c1C(=O)c1ccccc1)CCNC2
Yield: 92 %

Procedure:
To a cooled and stirred suspension of protected 2-amino-3-benzoyl-6-benzyloxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (0.01 mol) in acetic acid (2 mL), as prepared in Example 7, was added a solution of HBr (33%) in acetic acid (10 mL). After stirring at room temperature for 4 h (TLC control), n-hexane was added and the resulting suspension was evaporated under vacuum to give a solid which was dissolved in water (10 mL) and neutralized with NAOH (5% solution). The precipitated solid was chromatographed on a silica gel column eluting with an ethyl acetate and petroleum ether mixture to give 2-amino-3-benzoyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[CH2:6]1[O:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[O:7]1>>[CH3:5][O:4][CH2:3][CH2:2][O:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][CH2:6][O:10][C:9]=2[CH:11]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: COCCBr
Product: COCCOc1ccc2c(c1)OCO2

Procedure:
Starting from commercially available 1-bromo-2-methoxy-ethane and sesamol the title compound is obtained as colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:22]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[S:27][CH2:26][CH2:25][CH2:24][S:23]1)[CH:3]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4]1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]1([CH:6]2[CH2:5][CH2:4][CH:3]([CH:2]([O:1][C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:41])[C:22]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[S:27][CH2:26][CH2:25][CH2:24][S:23]3)[CH2:8][N:7]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(C(O)C2(c3ccccn3)SCCCS2)CCC1c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(C(OC(=O)c2ccccc2)C2(c3ccccn3)SCCCS2)CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 5-{hydroxy[2-(pyridin-2-yl)-1,3-dithian-2-yl]methyl}-2-phenylpiperidine-1-carboxylate (0.71 g, 1.459 mmol), benzoyl chloride (0.41 g, 2.92 mmol), triethyl amine (0.51 mL, 3.65 mmol) and DMAP (8.91 mg, 0.073 mmol) in DCM (15 ml) was stirred at room temperature overnight. The mixture was diluted with DCM. The organic layer was washed with saturated KHSO4 and brine, and dried over MgSO4. The drying agent was filtered off and the filtrate was concentrated in vacuo to give the title compound. LC-MS m/e 591.13 [M+1]+.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=O)[C:3](=[C:4]23)[CH:2]=1)=[O:22].[CH:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.N1C=CN=C1>>[CH:26]1([N:33]2[C:21](=[O:22])[C:5]3[C:4]4[C:19]5[C:8](=[CH:7][CH:6]=3)[C:9]3[C:20]6[C:13]([CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=[CH:16][C:17]=6[C:18]=5[CH:1]=[CH:2][C:3]=4[C:24]2=[O:23])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCCCCC1
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Agent: c1c[nH]cn1
Product: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1C1CCCCCC1)c54
Temperature: 150 °C

Procedure:
0.30 g (0.93 mmol) of perylene-3,4-dicarboxylic anhydride is mixed with 0.32 g (2.83 mmol) of cycloheptylamine and 3 g of imidazole, and the mixture is heated under argon at 150° C. for 4 h. The reaction product is removed from the flask by washing with ethanol, treated with 200 ml of 10% hydrochloric acid and filtered off with suction. The residue is boiled in potassium carbonate solution, filtered off with suction and washed with hot dist. water until the filtrate run-off is colourless. The product thus obtained is dried in a drying cabinet at 120° C. and then recrystallized by extraction with methanol. Yield 0.24 g (62%) of orange crystals showing a red solid fluorescence, m.p. 354°-355° C., Rf (CHCl3 /silica gel)=0.79. UV (CHCl3): λmax (ε)=505 (30370), 483 (30967), 353 (3170), 336 (3170), 295 (3460), 264 (29047). Fluorescence (CHCl3): λmax (Irel)=529 (1), 568 (0.48).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][C@H:13]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@@H:12]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@@H:9]1[CH2:14][C@H:13]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([S:23]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:24])=[O:25])=[C:18]([F:44])[CH:17]=2)[C@@H:12]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](OCc4ccccc4)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC[C@H](OCc2ccccc2)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 75.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*,5S*)-5-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (94.3 mg, 0.134 mmol) prepared in Example 113a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (56.0 mg, 75%) as a colorless solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][C:25]=1[CH3:38]>CN(C=O)C.CCOC(C)=O.[Cu]I>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:24]3[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:26][C:25]=3[CH3:38])=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: Cc1cc(OCCN2CCCC2)ccc1Br
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(OCCN2CCCC2)ccc1C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
0.13 mL (1.00 mmol) triethylamine, 22 mg (0.02 mmol) tetrakis-triphenylphosphane-palladium and 3.7 mg (0.02 mmol) CuI are added successively to a solution of 80 mg (0.37 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 106 mg (0.37 mmol) 1-[2-(4-bromo-3-methyl-phenoxy)-ethyl]-pyrrolidine in 3.0 mL DMF in an argon atmosphere. The mixture is stirred for 15 min at 100° C. and at 200 Watt in the microwave. The reaction solution is diluted with 30 mL EtOAc, washed with semisaturated NaHCO3 solution and the organic phase is dried over MgSO4. The solvent is eliminated i.vac. and the residue is triturated with tert-butylmethylether. The solvent is eliminated i.vac. and further purified by HPLC-MS.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[O:6]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[CH:16]=[C:15]([C:36]([OH:38])=O)[CH2:14][CH2:13]2)=[CH:7]1.S(Cl)(Cl)=O>O1CCCC1>[O:6]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[CH:16]=[C:15]([C:36]([NH:12][C:18]3[CH:19]=[CH:20][C:21]([CH2:4][N:2]([CH3:1])[CH:3]4[CH2:9][CH2:10][O:6][CH2:7][CH2:8]4)=[CH:22][CH:17]=3)=[O:38])[CH2:14][CH2:13]2)=[CH:7]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccoc2)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccoc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(3-furylmethyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (159 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (118 mg) and triethylamine (546 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 4.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1 8), which was recrystallized from hexane-ethyl acetate to give 1-(3-furylmethyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 61) (153 mg) as yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12](O)=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:3]1.CN(C(O[N:33]1N=N[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=CC=CN=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.O>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([NH:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:39]=3)=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)=[CH:3]1
Reactant: O=C(O)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)[nH]c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccn1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccccn1)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)[nH]c12
Temperature: 75 °C
Yield: 33.2 %

Procedure:
A mixture of 4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-8-carboxylic acid 44 (250 mg, 0.750 mmol), HATU (570 mg, 1.5 mmol), 2-aminopyridine 21 (141 mg, 1.5 mmol) and diisopropylethylamine (392 μl, 2.25 mmol) in DMAC (5 mL) was heated at 75° C. for 16 h. The reaction mixture was poured in H2O (25 mL) and the resulting precipitate was collected by filtration. The crude residue was purified by MPLC Compound 401 (102 mg, 33% yield). MS (ESI) calc. for C22H14F3N3O2: 409.10. found: 410 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([F:12])[C:5]=1[F:13].[Br:15][C:16]1[N:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH3:24])[NH:18][C:17]=1[CH:25]=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:18]2[C:17]([CH:25]=[O:26])=[C:16]([Br:15])[N:20]=[C:19]2[CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([F:12])[C:5]=1[F:13]
Reactant: COC(=O)c1ccc(CBr)c(F)c1F
Reactant: CCCCc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Br)c(C=O)n1Cc1ccc(C(=O)OC)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
4-bromomethyl-2,3-difluorobenzoic acid methyl ester (3.5 g, 13.2 mmol), 5-bromo-2-butyl-3H-imidazole-4-carbaldehyde (3.1 g, 13.2 mmol) and potassium carbonate (1.8 g, 13.2 mmol) were combined and dissolved in DMF (20 mL, 300 mmol). The mixture was stirred at room temperature overnight. The mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The crude reaction was purified by silica gel chromatography (0-50% EtOAc:hexanes) to obtain 4.16 g of intermediate (8a) as a yellow solid. MS m/z: [M+H+] calcd for C17H17BrF2N2O3, 416.23. found 417.1. 1H-NMR (CDCl3): 9.68 (1H, s), 7.64 (1H, t), 6.55 (1H, t), 5.64 (2H, s), 3.95 (3H, s), 2.63 (2H, t), 1.69 (2H, m), 1.36 (2H, m) 0.90 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=S)[CH3:15])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:17]([NH:20][NH2:21])(=O)C.[C:22](OCC)(=O)C.ClCCl.CO.ClCCl>C(O)CCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:14]([CH3:15])[CH2:17][N:20]([CH3:22])[NH:21]2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(NC(C)=S)ccc1OC
Reactant: CCOC(C)=O
Reactant: CC(=O)NN
Solvent: ClCCl
Solvent: CCCCO
Solvent: CO
Product: COC(=O)c1cc(N2NN(C)CC2C)ccc1OC
Reaction time: 18 h

Procedure:
According to the method of Heterocycles, 34, 771 (1992), combine methyl 2-methoxy-5-thioacetamidobenzoate (1.00 g, 4.2 mmol) and acetylhydrazine (0.35 g, 4.8 mmol) in n-butanol (8 mL). Heat to reflux. After 18 hours, cool and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 30% ethyl acetate/dichloromethane and then 5% methanol/dichloromethane to give a residue. Recrystallize the residue from ethyl acetate/hexane to give methyl 2-methoxy-5-(3,5-dimethyl-4H-triazol-1-yl)benzoate: mp; 180-182° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([CH3:11])[C:9]#N)=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.C(=O)(O)[O-:18].[Na+].[CH2:22]([OH:24])[CH3:23]>>[Cl:1][C:2]1[C:3]([CH:8]([CH3:11])[C:9]([O:24][CH2:22][CH3:23])=[O:18])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CCO
Reactant: CC(C#N)c1ncccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(C)c1ncccc1Cl
Temperature: 0 °C
Yield: 91 %

Procedure:
The product of Example 38A (1.15 g, 6.9 mmol) was dissolved in absolute ethanol (14 mL) and cooled to 0° C. Concentrated sulfuric acid (13.54 g, 7.36 mL, 138 mmol) was added, and the reaction mixture was allowed to warm to ambient temperature. The reaction was then heated at reflux for 2 hours, cooled, and poured onto ice. The mixture was neutralized with saturated aqueous sodium bicarbonate, and extracted with two portions of ethyl acetate. The organic layers were separated and concentrated to give the title compound (1.34 g, 91%) which was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.49 (dd, J=1.5, 4.7, 1H), 7.93 (dd, J=1.5, 8.1, 1H), 7.36 (dd, J=4.7, 8.1, 1H), 4.29 (q, J=7.1, 1H), 4.07 (q, J=7.1, 2H), 1.42 (d, J=7.1, 3H), 1.11 (t, J=7.1, 3H). MS (DCI) m/z 214 (M+H)+.