Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[N:6]1.C=O.[CH3:18][NH2:19].Cl.[CH3:21]O>>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH2:18][NH:19][CH3:21])[C:7]([CH3:11])=[N:6]1
Reactant: Cc1cc(C)n(Cc2ccccc2Cl)n1
Reactant: CN
Reactant: CO
Agent: C=O
Agent: Cl
Product: CNCc1c(C)nn(Cc2ccccc2Cl)c1C
Temperature: 60 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
A solution of 1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazole (1.00 g, 4.53 mmol), paraformaldehyde (0.82 g, 27.20 mmol) and methylamine.HCl (0.92 g, 13.59 mmol) dissolved in methanol (9.06 ml) was stirred at 60° C. for 24 hrs. The mixture was cooled to room temperature and quenched with aqueous NaHCO3 (15 mL). The aqueous layer was extracted 3 times with ether (15 mL) and the combined organic layers washed with brine (30 mL). The organic layer was dried with MgSO4 and concentrated under reduced pressure. The resulting yellow oil was purified using flash column chromatography with 1:4:0.01 ethyl acetate:hexanes:triethylamine as eluting solvent yielding 0.73 g (62%) of 1-(1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.40-7.31 (m, 1H), 7.23-7.08 (m, 2H), 6.54-6.43 (m, 1H), 5.32 (s, 2H), 3.31 (s, 2H), 2.91 (s, 1H), 2.25 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 148.12, 138.48, 135.57, 131.94, 129.42, 128.72, 127.61, 127.41, 114.38, 50.24, 49.08, 40.68, 12.36, 9.75. HRMS (m/z): [MH]+ calc for C14H18ClN3, 264.13. found 264.1253.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[CH3:12])=[CH:4][CH:3]=1.[I:13][CH3:14]>CC(C)=O>[I-:13].[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N+:8]([CH3:14])=[C:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC1=NCCc2ccc(N)cc21
Solvent: CC(C)=O
Product: CC1=[N+](C)CCc2ccc(N)cc21
Product: [I-]

Procedure:
(±) 7-Amino-1-methyl-3,4-dihydroisoquinoline (0.90 g, 5.6 mmol) in acetone (125 ml) and iodomethane (1.0 ml, 16 mmol) was stirrd at room temperature for 18 h. The resultant precipitate was collected by filtration and dried in vacuo at ambient temperature. The title compound was isolated as an orange powder (1.44 g, 85%). m/z (API): 175 (M)+
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][C:3]=1[CH:4]=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1.C1(OP(Cl)(Cl)=O)C=CC=CC=1.C(N(CC)CC)C>ClCCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:26])[O:1][C:2]3[C:3]([CH:4]=2)=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([O:12][CH3:13])[C:9]=3[O:10][CH3:11])=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: COc1c([N+](=O)[O-])cc(C=O)c(O)c1OC
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1c([N+](=O)[O-])cc2cc(-c3ccc(Cl)cc3)c(=O)oc2c1OC

Procedure:
2-Hydroxy-3,4-dimethoxy-5-nitro-benzaldehyde (2.44 g), 4-chlorophenyl acetic acid (1.82 g), PhOPOCl2 (1.6 ml) and triethylamine (4.5 ml) in 1,2-dichloroethane (125 ml) were refluxed for 5 hours as described in example 1(a). Yield: 2.40 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][CH:12]=[N:11][C:10]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[Br:24][C:12]1[S:13][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[C:10]([C:14]([OH:16])=[O:15])[N:11]=1
Reactant: CC(C)(C)OC(=O)Nc1scnc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution of 5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (1.72 g, 10 mmol) in DCM (50 mL) was added in three portions NBS (1.95 g, 11 mmol); the reaction mixture was stirred at ambient temperature for 1 h. Reaction was concentrated in vacuo; resulted residue was purified by silica gel column chromatography (6:1 Pet-ether-EtOAc) to afford 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (1.75 g, 70%) as white solid: 1H-NMR (CDCl3, 500 MHz) δ (ppm): 13.65 (s, 1H), 10.03 (s, 1H), 1.49 (s, 9H). MS (ESI) m/z: 324 [M+H+]
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][C:21]([O-:23])=[O:22])=[CH:15][CH:14]=2)(C(C)(C)C)(C)C.[F-].[CH2:25]([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[OH:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][C:21]([O:23][CH3:25])=[O:22])=[CH:15][CH:14]=2
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc2cc(CC(=O)[O-])ccc2[nH]1
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-(2-(t-butyldimethylsilyl-oxyethyl)-indole-5-acetate (400 mg; 1.15 mmol) in ca. 4 ml of THF was added a 1 M tetrabutylammonium fluoride in THF (1.2 mL; 1.05 eq) at 0° C. After 15 minutes, the reaction was allowed to warm to room temperature and stirred for an additional 3 hours. It was con-centrated, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4), concentrated and chromatographed (silica gel, hexane:ethyl acetate 4:1) to yield 241 mg of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.[C-:34]#[N:35].[Na+].[I-].[K+]>CC(N(C)C)=O.O>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([C:34]#[N:35])=[N:3][C:4]=3[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN1CCN(CCCOc2ccccc2Nc2nc(Cl)nc3c2ncn3C2CCCC2)CC1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCCOc2ccccc2Nc2nc(C#N)nc3c2ncn3C2CCCC2)CC1
Temperature: 160 °C
Reaction time: 24 h

Procedure:
(2-Chloro-9-cyclopentyl-purin-6-yl)-{2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-amine (0.1 mmol), sodium cyanide (50 mg), potassium iodide (5 mg) are suspended in DMA (2 ml) and heated up to 160° C. and the mixture is stirred at this temperature for 24 hours. The mixture is diluted with water and extracted 3 times with ethyl acetate. The combined organic phases are washed with brine and the extract is dried over sodium sulfate and evaporated. The residue is dissolved in diethylether, filtered over powdered charcoal and cooled to 4° C. The solid material formed is filtered of and dried (vacuum). A white powder with mp. 136-138PC is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:15](=[O:34])[C@H:16]([CH2:28][C:29]2[N:33]=[CH:32][NH:31][CH:30]=2)[NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.C1C=C2N=NN(O)C2=CC=1.O.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH2:62](OC(=O)CN)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.CCN(CC)CC>CN(C=O)C>[C:63]1([CH2:62][O:13][C:12](=[O:14])[CH2:11][N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:15](=[O:34])[C@H:16]([CH2:28][C:29]2[N:33]=[CH:32][NH:31][CH:30]=2)[NH:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: COc1ccc(CN(CC(=O)O)C(=O)[C@H](Cc2c[nH]cn2)NC(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CN(CC(=O)OCc2ccccc2)C(=O)[C@H](Cc2c[nH]cn2)NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of the acid from Step 3 (0.41 g, 0.88 mmol) in DMF (5 mL) was added HOBT hydrate (0.16 g, 1.05 mmol) and DCC (0.22 g, 1.05 mmol) followed by glycine benzyl ester hydrochloride (0.18 g, 0.88 mmol). Et3N (0.12 mL, 0.88 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was filtered, the filtrate was diluted with CHCl3, washed twice with saturated NaHCO3, brine, dried over MgSO4, and concentrated. Flash chromatography (2-5% MeOH/CHCl3) gave 0.29 g (54%) of the title compound as a white foam; ES-MS 614 (m+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:10]=[C:9]([C:19]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[OH:20])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:29][S:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C(O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[CH:7]([C:5]2[S:6][C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:30][CH3:29])[CH:36]=3)=[CH:3][CH:4]=2)[CH2:8][C:9]([C:19]([C:21]([F:22])([F:24])[F:23])([C:25]([F:27])([F:26])[F:28])[OH:20])=[N:10]1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CSc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CSc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)s2)c1
Temperature: 88 °C
Reaction time: 4 h
Yield: 8.3 %

Procedure:
5-(5-Bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (100.0 mg, 0.20 mmol) prepared in Step 5 of Preparation 23, 3-methylthiophenylboronic acid (50.4 mg, 0.30 mmol), Pd(PPh3)4 (23.0 mg, 0.02 mmol), and a 2N sodium carbonate solution (1.0 mL) were added to a mixed solvent of 1,2-dimethoxyethane (2.0 mL) and ethanol (1.0 mL). The reaction mixture was stirred at 88° C. for 4 hours and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 9.2 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[OH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([N:11]([CH3:12])[C:20](=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:1]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C(O)c1ccccc1)N(C)C(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Into a dry 1 L round-bottomed flask equipped with a magnetic stirrer was added (+)-pseudoephedrine (22.34 g, 135.22 mmol, 1.0 equiv), triethylamine (21.5 mL, 154 mmol, 1.14 equiv), and tetrahydrofuran (300 mL). The solution was cooled to 0° C. and hydrocinnamoyl chloride (25.08 g, 148.74 mmol, 1.1 equiv) in tetrahydrofuran (100 mL) was added via cannula over a 20 minute interval. After 30 minutes, the reaction was quenched with water. The amide was extracted from water (1 L) with ethyl acetate (400 mL, 120 mL, 120 mL), and the combined organic extracts were dried over sodium sulfate. After removal of the solvent under reduced pressure, a white solid was obtained, which was recrystallized from 2:1:1 ether/dichloromethane/hexanes (500 mL) affording the hydrocinnamide as white crystals (30.24 g, 75% yield): mp 102°-104° C.; 1H NMR (300 MHz, C6D6) δ7.0-7.4 (m, 5H), 4.59 (br, 1H), 4.48 (t, 1H, J=7.1 Hz), 4.20 (m, 1H), 4.01 (dd, 1H, J=8.4 Hz, 2.4 Hz), 3.66 (m, 1H), 3.15 (m, 2H), 2.93 (t, 2H, J=7.7 Hz), 2.79 (s, 3H), 2.49 (m, 2H), 2.13 (m, 2H), 2.02 (s, 3H), 0.92 (d, 3H, J=7.0 Hz), 0.49 (d, 3H, J=6.8 Hz); 13C NMR (75.5 MHz, CDCl3) δ174.3, 173.2, 142.2, 141.5, 141.3, 141.1, 128.6, 128.39, 128.36, 128.31, 128.29, 128.2, 127.6, 126.8, 126.4, 126.1, 125.9, 76.3, 75.3, 58.0, 36.1, 35.4, 32.3, 31.5, 31.1, 26.9, 15.2, 14.3; FTIR (neat film) cm-1 3374 (br, m), 3027 (m), 1621 (s), 1495 (m), 1454 (m), 1406 (m), 1118(m), 1048 (m), 753 (m), 701 (m); HRMS (FAB) Calcd for C19H24NO2 (MH+): 298.1808; Found: 298.1806.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][C@H:8]1[CH2:32]O)=[O:6])[CH:2]=[CH2:3].CS(C)=O.C(OP([CH:46]1C[CH2:49][NH:48][C:47]1=[O:51])(OCC)=O)C.[C:52](Cl)(=O)C(Cl)=O.[H-].[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([SH:12])[CH2:9][C@H:8]1/[CH:32]=[CH:46]/[C:47]([N:48]([CH3:52])[CH3:49])=[O:51])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOP(=O)(OCC)C1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1/C=C/C(=O)N(C)C
Yield: 21.4 %

Procedure:
The same operation as in Reference Example 4-1) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (the compound obtained in Reference Example 3-1); 11.12 g, 24.2 mmol), dimethyl sulfoxide (4.81 ml, 67.7 mmol), oxalyl chloride 3-(diethylphosphono)-2-oxopyrrolidine (5.35 g, 24.2 mmol) and 60% sodium hydride (870 mg, 21.8 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 100 ml, elution with hexane-ethyl acetate 1:1 - ethyl acetate) to give the title compounds ((Z)-form 2.72 g, 21.4% yield; (E)-form 5.15 g, 40.6 % yield).
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH2:64])[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1.[OH:65][C:66]1[CH:67]=[C:68]2[C:72](=[CH:73][CH:74]=1)[NH:71][CH:70]=[C:69]2[CH2:75][C:76](O)=[O:77]>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH:64][C:76](=[O:77])[CH2:75][C:69]2[C:68]3[C:72](=[CH:73][CH:74]=[C:66]([OH:65])[CH:67]=3)[NH:71][CH:70]=2)[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1
Reactant: NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: O=C(Cc1c[nH]c2ccc(O)cc12)NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 33G and 2-(5-hydroxy-1H-indol-3-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 8.63 (d, J=8.0 Hz, 1H), 8.45 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.6 Hz, 1H), 7.00-6.84 (m, 2H), 6.79 (d, J=8.4 Hz, 3H), 6.55 (d, J=8.7 Hz, 1H), 5.28 (q, J=7.8 Hz, 1H), 3.39 (s, 2H), 3.10 (m, 2H). MS (m/z) 508.1 [M+H]+.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[CH:8]2.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O.O>[C:4]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[CH:8]2)#[CH:3]
Reactant: C[Si](C)(C)C#Cc1ccc2cnccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C#Cc1ccc2cnccc2c1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 6-(2-(trimethylsilyl)ethynyl)isoquinoline (2.2 g, 9.8 mmol) in 45 mL of MeOH was added potassium carbonate (2.7 g, 20 mmol). After 1 hour, the reaction mixture was diluted with 100 mL of EtOAc and 50 mL of water. The mixture was partitioned and the aqueous portion was extracted three times with 50 mL of EtOAc. The combined organic layers were washed with 100 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 30% EtOAc/hexanes) afforded 6-ethynylisoquinoline (1.3 g, 87% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ pp 9.25 (s, 1H), 8.56 (d, J=5.7 Hz, 1H), 7.99 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.65 (dd, J=1.2 Hz, 8.6 Hz, 1H), 7.62 (d, J=5.8 Hz, 1H), 3.26 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[CH3:13][NH:14][C:15]([C:17]1[C:18]([Cl:24])=[C:19](F)[CH:20]=[CH:21][CH:22]=1)=[O:16]>>[ClH:24].[CH3:13][NH:14][C:15]([C:17]1[C:18]([Cl:24])=[C:19]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[O:12][CH:11]=[CH:10][C:5]2=3)[CH:20]=[CH:21][CH:22]=1)=[O:16]
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: CNC(=O)c1cccc(F)c1Cl
Product: CNC(=O)c1cccc(OC2CCN(C)Cc3occc32)c1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-methylcarbamoyl-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:32]([F:35])([F:34])[F:33])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH3:41][NH:42][CH3:43]>ClCCl.CN(C=O)C>[CH3:41][N:42]([CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:32]([F:33])([F:35])[F:34])[C:24]([N:26]([CH2:28][CH:29]([CH3:30])[CH3:31])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1)[CH3:43]
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: CNC
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN(C)C)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 117) (300 mg, 0.62 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in DMF according to the method described in Example 45. Obtained as a light brown solid (110 mg, 35%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>CCO.O>[F:15][C:12]([F:13])([F:14])[C:9]1[N:8]=[C:7]([C:16]([F:19])([F:18])[F:17])[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc(C(F)(F)F)nc1C(F)(F)F
Yield: 33.9 %

Procedure:
A solution of ethyl-2,4-bis(trifluoromethyl)pyrimidine-5-carboxylate (5.0 g, 17 mmol) and NaOH (0.72 g, 18 mmol) in EtOH (20 mL) and H2O (50 mL) was stirred at room temperature for 1 h. The solution was acidified (HCl) and the resulting solid was filtered and dried to give 2,4-bis (trifluoromethyl)-pyrimidine-5-carboxylic acid (1.5 g, 25%), m.p. 59° C., 1HNMR (DMSO-d6) δ 9.62 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c15) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].[CH:28]1([CH2:31]Cl)[CH2:30][CH2:29]1>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:31][CH:28]2[CH2:30][CH2:29]2)[CH2:15][CH:16]=1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2[nH]cc(C3=CCN(CC4CC4)CC3)c2c1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 12.5 g of 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 120 ml of anhydrous dimethylformamide, 11.5 g of sodium carbonate and 6.5 ml of cyclopropylmethyl chloride was stirred for 24 hours under an inert atmosphere at 70° C. and was then cooled to 30° C. after which 300 ml of distilled water were added thereto while cooling in an ice bath. Precipitation occured and the mixture was stirred for 45 minutes, stood for 15 minutes and was then filtered. The product was washed 3 times with distilled water and was empasted with 20 ml of 50% aqueous ethanol. The product was dried at 50° C. under reduced pressure in the presence of a dehydrating agent to obtain 13.54 g of raw product which was dissolved in 350 ml of refluxing ethanol. The solution was filtered and the filtrate was concentrated to 300 ml for crystallization. The solution was cooled to room temperature and was held in a refrigerator for 90 minutes. The mixture was vacuum filtered and the product was rinsed with ethanol and dried under reduced pressure to obtain 7.8 g of 5-chloro-3-(1-cyclopropylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 205° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22]([OH:24])=O)[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:43])([C:39]([F:42])([F:41])[F:40])[CH2:36][CH2:37][NH2:38]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22]([NH:38][CH2:37][CH2:36][C:35]([F:43])([F:34])[C:39]([F:42])([F:41])[F:40])=[O:24])[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCC(F)(F)C(F)(F)F
Reactant: O=C(O)CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: O=C(CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21)NCCC(F)(F)C(F)(F)F

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic acid and ,3,3,4,4,4-pentafluorobutylamine, the title compound was prepared in the same manner as described for example 1c. Colorless, waxy solid (98%). MS: m/e=590(M+H+).