Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.[NH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][N:29]([CH3:35])[CH2:30]2>CN(C=O)C>[CH3:35][N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][CH:33]=[CH:34][C:25]=2[NH:24][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([CH3:13])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:30]1
Reactant: COc1cc(C)c(Cl)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(C)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2
Temperature: 25 °C
Yield: 43.2 %

Procedure:
5-Chloro-2-methoxy-4-methylbenzoic acid (0.202 g, 1 mmol), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (0.200 g, 1 mmol) and 1-hydroxy-benzotriazole (0.155 g, 25 mmol) were dissolved in dry DMF (10 ml) and stirred at room temperature under argon for 25 mins before 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.163 g, 1 mmol) was added. The mixture was then stirred for 24 under argon at room temperature. The DMF was removed in vacuo and the residue suspended in ethyl acethate and washed with water. The insoluble white precipithate was filtered off, washed with water then dried to afford the title compound (149 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:10]([Cl:22])[CH:9]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24].FC(F)(F)C(O)=[O:29].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:29])=[C:10]([Cl:22])[CH:9]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)c1nnn(Cc2ccc(Sc3ccc(Cl)cc3)c(Cl)c2)c1N
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1nnn(Cc2ccc(S(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 83.3 %

Procedure:
A stirred suspension of 5-amino-1-(3-chloro4-[4-chlorophenylthio]benzyl)-1,2,3-triazole-4-carboxamide (475 mg, 1.20 mmol) in methanol (160 ml) was treated with trifluoroacetic acid (278 μl, 411 mg, 3.61 mmol), warmed until homogeneous, and cooled to ambient temperature. To this solution was added m-chloroperbenzoic acid (244 mg of 85% technical grade, 1.20 mmol), the mixture was stirred 75 minutes, an additional portion of m-chloroperbenzoic acid (33.1 mg of 85% technical grade, 0.163 mmol) was added, and the mixture was stirred an additional 45 minutes. The mixture was treated with 2.5N aqueous sodium hydroxide (2.5 ml), stirred until crystallization commenced, concentrated to approximately 40 ml under vacuum at 30° C., and chilled to 0° C. The precipitate was filtered, washed with methanol, and dried to afford 410 mg (83%) of 5-amino-1-(3-chloro-4-[4-chlorophenylsulfinyl]benzyl)-1,2,3-triazole- 4-carboxamide, m.p. 237°-238° C.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].O[N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.CN(C1C=CN=CC=1)C.Cl>[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][N:22]1[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]2[C:26]1=[O:27])=[O:19])([OH:18])=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(O)CCCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCCCCC(=O)ON1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
In 15 ml of anhydrous tetrahydrufuran 1,16-hexadecanedioic acid (500 mg, 1.75 mmoles) was dissolved. To the obtained solution, were added a solution of N-hydroxyphthalimide (285 mg, 1.75 mmoles) in 10 ml of anhydrous tetrahydrofuran and N,N-dimethylaminopyridine hydrochloride (1.4 mg) and the mixture was stirred for 30 minutes. To the mixture was added a solution of DCC (361 mg, 1.75 mmoles) in 3 ml of anhydrous tetrahydrofuran and the resulting mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography, to give N-(15-carboxypentadecanoyloxy)phthalimide (310 mg, 41%) having the following properties.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][NH2:15].[C:16](O)(=[O:23])[CH2:17][C:18]([C:20]([OH:22])=[O:21])=O>O>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:16]([OH:23])=[CH:17][C:18]([C:20]([OH:22])=[O:21])=[N:15]1
Reactant: NNc1ccccc1F
Reactant: O=C(O)CC(=O)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(O)n(-c2ccccc2F)n1
Temperature: 5 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Sulfuric acid (400 ml) was added slowly to water (400 ml). After cooling to 5° C., 2-fluoro-phenylhydrazine hydrochloride (123 g, 757 mmol) was added resulting in a brown suspension. Then a solution of oxalacetic acid (100 g, 757 mmol) in water (400 ml) was added slowly during a period of 25 min. After 2 h the conversion was complete and the solid was filtered. After washing with water the solid was dried. The product was obtained as light brown solid (151 g, 90%).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+].[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]2[C:37]([O:38][C:39]3[CH:53]=[CH:52][C:42]([O:43][CH2:44][CH2:45][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[CH:41][CH:40]=3)=[C:36]([C:54]3C=CC(S(C)(=O)=O)=C(F)[CH:55]=3)S[C:34]=2[CH:65]=1)C1C=CC=CC=1.B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.Br[C:83]1[CH:88]=[CH:87][C:86]([S:89]([CH3:92])(=[O:91])=[O:90])=[C:85]([S:93][CH3:94])[CH:84]=1>C(#N)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:92][S:89]([C:86]1[CH:87]=[CH:88][C:83]([C:36]2[CH:54]=[CH:55][C:32]3[C:33](=[CH:34][CH:65]=[C:30]([O:29][CH3:22])[CH:31]=3)[C:37]=2[O:38][C:39]2[CH:53]=[CH:52][C:42]([O:43][CH2:44][CH2:45][N:46]3[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]3)=[CH:41][CH:40]=2)=[CH:84][C:85]=1[S:93][CH3:94])(=[O:91])=[O:90]
Reactant: CS(=O)(=O)c1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1F
Reactant: CSc1cc(Br)ccc1S(C)(=O)=O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)c(SC)c3)ccc2c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 68.3 %

Procedure:
Combine palladium (II) acetate (13 mg, 0.06 mmol), tricyclohexylphosphine (27 mg, 0.10 mmol), cesium fluoride (518 mg, 3.4 mmol) and acetonitrile (10 mL). Stir for 5 minutes. Add the compound of Preparation 1 (200 mg, 0.38 mmol) and bis(neopentylglycolato)diboron (129 mg, 0.57 mmol). Heat to 90° C. for 1 minute and add 4-bromo-1-methanesulfonyl-2-methylsulfanyl-benzene (118 mg, 0.42 mmol) in acetonitrile (4 mL). Stir at 90° C. for 10 minutes. Cool to room temperature and dilute the solution with EtOAc (20 mL) and wash with saturated aqueous NaHCO3 (10 mL). Separate the layers, wash the organic layer with brine (10 mL), dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol (4%) in dichloromethane to give 150 mg (64%) of the title compound. Mass spectrum (ion spray): m/z=578.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22](N(OC)C)=[O:23])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22]([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)=[O:23])=[CH:18][CH:19]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: Brc1cnccn1
Agent: [Li]CCCC
Product: Cc1ccccc1C(CC(=O)c1cnccn1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 1, 2-bromopyrazine was reacted first with n-butyllithium and later with 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) to give the title compound as a colorless solid, MS (ESI+): m/z=381.2 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:42])[CH:17]([N:24]2[C:28]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:27]=3[N:26]=[C:25]2[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:11]([F:43])[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:25]2[N:24]([CH:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:44])=[O:5])=[CH:10][C:11]=3[F:43])=[O:42])[C:28]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:27]=3[N:26]=2)=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of (4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-phenoxy)-acetic acid tert-butyl ester (120 mg, 0.19 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (1.5 ml). After 2 h, the solvent was removed under reduced pressure. The resulting oil (78 mg, 71%) solidified upon standing in the refrigerator.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH:5]=[N:6][CH:7]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2N(C3C=CC=CC=3)C3C=CC=CC=3N=2)=[CH:26][CH:25]=1>>[CH:29]1[C:28]2[C:27](=[CH:30][CH:11]=[CH:10][CH:22]=2)[CH:26]=[CH:25][C:24]=1[C:26]1[C:25]2[C:24](=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:29]([C:2]2[CH:3]=[C:4]([C:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]4[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=4[N:9]=3)[CH:5]=[N:6][CH:7]=2)=[C:28]2[C:27]=1[CH:30]=[CH:14][CH:13]=[CH:18]2
Reactant: Brc1cncc(-c2nc3ccccc3n2-c2ccccc2)c1
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Product: c1ccc(-n2c(-c3cncc(-c4c5ccccc5c(-c5ccc6ccccc6c5)c5ccccc45)c3)nc3ccccc32)cc1

Procedure:
Almost the same procedure as step (2) in Synthesis Example 1 was carried out except that corresponding 2-(5-bromopyridine-3-yl)-1-phenyl-1H-benzimidazole was used instead of 2-(4-bromophenyl-phenyl-1H-benzimidazole, resultantly obtaining an aimed compound (Compound (4-6) (yield: 36%). As a result of MS analysis, it was recognized that m/e=573 for aimed substance's molecular weight of 573.22.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:38])[C:11]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)=[CH:29][CH:28]=1)([OH:26])[CH2:12][C:13]1[NH:14][CH:15]=[C:16]([CH2:18][C:19]2([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20]2)[N:17]=1>C(#N)C>[Br:1][C:15]1[NH:14][C:13]([CH2:12][C:11]([C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH:37]=[CH:36][CH:35]=[N:34]3)=[CH:31][CH:32]=2)([OH:26])[CH:10]([F:9])[F:38])=[N:17][C:16]=1[CH2:18][C:19]1([C:22]([F:25])([F:24])[F:23])[CH2:20][CH2:21]1
Reactant: OC(Cc1nc(CC2(C(F)(F)F)CC2)c[nH]1)(c1ccc(-n2cccn2)cc1)C(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: OC(Cc1nc(CC2(C(F)(F)F)CC2)c(Br)[nH]1)(c1ccc(-n2cccn2)cc1)C(F)F
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (95 mg, 0.53 mmol) was added to a solution of 1,1-difluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol (200 mg, 0.53 mmol) in acetonitrile (5 mL) at ambient temperature. After stirring for 1 hr, the reaction mixture was concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 3-(5-bromo-4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)-1,1-difluoro-2-[4-(1H-pyrazol-1-yl)phenyl]propan-2-ol as an orange solid.
Reaction SMILES: [CH2:1]([C:8]1[NH:13][C:12](=[O:14])[C:11](Br)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[F:33])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[CH2:1]([C:8]1[NH:13][C:12](=[O:14])[C:11]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:25]([F:33])[CH:26]=2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(Cc2ccccc2)ncc1Br
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)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: [Cl-]
Solvent: C1COCCO1
Product: O=c1[nH]c(Cc2ccccc2)ncc1-c1ccc(OCc2ccccc2)c(F)c1
Yield: 65 %

Procedure:
A solution of 2-benzyl-5-bromopyrimidin-4(3H)-one (0.300 g, 1.13 mmol), 4-(benzyloxy)-3-fluorophenylboronic acid (0.334 g, 1.36 mmol), Pd(PPh3)4 (0.065 g, 0.057 mmol) and lithium chloride (0.240 g, 5.66 mmol) in dioxane (3 mL) and 2 M aq Na2CO3 (0.3 mL) was stirred at 100° C. for 18 hours. The reaction mixture was partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude dark yellow solid. Purification of the crude product was achieved by trituration with dichloromethane. The resulting solid was filtered, washed with dichloromethane, collected and dried under vacuum. The filtrate was concentrated and the trituration procedure was repeated (2×) with EtOAc. The solids were combined to yield the desired product (0.284 g, 65%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.93 (br s, 1H), 8.13 (s, 1H), 7.66 (dd, J=2.3, 13.3 Hz, 1H), 7.53-7.22 (s, 12H), 5.21 (s, 2H), 3.90 (s, 2H). LRMS (APCI pos) m/e 387 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[O:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[OH-:19].[Na+]>[N+]([O-])([O-])=O.[Ag+].Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[O:13][C:12]([C:14]([OH:19])=[O:15])=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1cc(-c2ccc(C=O)o2)c([N+](=O)[O-])cc1C
Reactant: [OH-]
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Product: Cc1cc(-c2ccc(C(=O)O)o2)c([N+](=O)[O-])cc1C
Temperature: 60 °C

Procedure:
To 5-(4,5-dimethyl-2-nitrophenyl)furan-2-aldehyde (5a) (0.69 g, 2.81 mmol) was added solid NaOH (0.12 g, 3.09 mmol) and 10% NaOH solution (6.2 ml). Silver nitrate (0.47 g, 2.81 mmol) was added, and the reaction mixture heated to 60° C. for 3 h. After cooling to room temperature the resulting mixture was poured into 2N HCl (50 ml) during which the product precipitated out of solution and was collected by filtration. The crude solid was purified by column chromatography using 0-2% MeOH/DCM as eluent. (5i) was obtained yellow solid (41%). mp 231-233° C. 1H NMR (400 MHz, DMSO-d6): δ 2.34 and 2.35 (6H, 2s), 6.93 and 6.94 (dd, J=1.6 and 3.6 Hz, 1H), 7.31 and 7.32 (dd, J=1.2 and 3.2 Hz, 1H) 7.63 (s, 1H), 7.80 (s, 1H) 13.20 (brs, 1H); 13C NMR (100 MHz, DMSO-d6): δ 19.63, 19.84, 111.67, 120.01, 120.63, 125.62, 131.19, 140.48, 143.26, 145.82, 145.91, 152.59, 159.71; HRMS (m/z): [M+H]+ calcd for C13H12NO5, 262.0710; found, 262.0714.
Reaction SMILES: CN(C)C=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[N:12].[O:14]=O>CN(C=O)C.Cl[Cu]>[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:4]=[O:14])#[N:12]
Reactant: CN(C)C=Cc1ccccc1C#N
Reactant: O=O
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C=O
Reaction time: 4 h

Procedure:
8.6 g of β-dimethylamino-2-cyanostyrene were dissolved in 100 ml of DMF. 0.25 g of CuCl was added and the mixture was aerated for 4 h at 35°-40° C. using oxygen. After the customary aqueous work-up, o-cyanobenzaldehyde was obtained as the product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH2:28][C:29]#[N:30])[CH2:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH:12]=2)[C:5]([O:31][CH3:32])=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:28][C:29]#[N:30])[CH:12]=2)[C:5]([O:31][CH3:32])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1-c1cnn(C(CC#N)CC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(Cl)nc1-c1cnn(C(CC#N)CC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-{2-[4-(2-chloro-5-methoxypyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyanopropyl}piperidine-1-carboxylate (0.030 g, 0.000065 mol) and 0.5 mL of TFA was stirred at room temperature for 1 h. After being evaporated to dryness, the residue was used directly in next step.
Reaction SMILES: C([Li])CCC.CC(C)([O-])C.[Li+].[C:12]([Li])([CH3:15])([CH3:14])[CH3:13].[CH:17]1([CH2:23][CH2:24][C:25](Cl)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.C(O)CCC>[CH3:13][C:12]([CH3:15])([C:25]([CH2:24][CH2:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:26])[CH3:14]
Reactant: [Li]C(C)(C)C
Reactant: O=C(Cl)CCC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCO
Product: CC(C)(C)C(=O)CCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Stage 1 of the preparation was carried out under an argon atmosphere. To a stirred solution of t butyl alcohol (4.92 g) in tetrahydrofuran (20 ml) at -30° C. was added dropwise n-butyl lithium (41.8 ml of 1.6 molar solution). The resultant lithium t-butoxide solution was allowed to warm to 0° C. and was added to a stirred solution of cuprous iodide (12.65 g) in tetrahydrofuran (50 ml). After about 15 minutes, the grey cuprous iodide was replaced by a beige solid, and the reaction mixture turned brown. The reaction mixture was then cooled to -70° C. and t-butyl lithium (34.0 ml of 1.9 molar solution) was added dropwise. A cooled (-40° C.) solution of 3-cyclohexyl propionic acid chloride (10 .0 g) in tetrahydrofuran (20 ml) was added rapidly. After 11/2 hours, the reaction was quenched by the addition of methanol (30 ml) and the reaction mixture was allowed to stand overnight at room temperature. The mixture was then poured into saturated ammonium chloride (200 ml) and insolubles were filtered off. The aqueous layer was extracted with ether (300 ml) and the extract was washed with 1% sodium thiosulphate solution (200 ml) and then dried over magnesium sulphate in the presence of charcoal. Concentration yielded an amber oil which was distilled to give a colourless liquid (5.56 g) which turned yellow on standing.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:44])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][O:36]C3CCCCO3)[CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:36][CH2:35][C:31]1[CH:30]=[C:29]([C:25]2[CH:24]=[C:23]([C:22]3[CH2:21][C:20](=[O:44])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-methyl-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M260) (6.20 g, 98.8 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (2.74 g, 65%).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[C:11]([NH:13][C:14]2[S:18][N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:19][O:20][Si](C(C)(C)C)(C)C)(=O)=O.Cl.[C:29]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([N:37]1[CH2:42][CH2:41][N:40]([CH2:6][C:7]2[C:8]([CH2:19][OH:20])=[CH:9][CH:10]=[C:11]([NH:13][C:14]3[S:18][N:17]=[CH:16][N:15]=3)[N:12]=2)[CH2:39][CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Nc2ncns2)nc1COS(C)(=O)=O
Agent: Cl
Product: O=C(c1ccccc1)N1CCN(Cc2nc(Nc3ncns3)ccc2CO)CC1

Procedure:
The amination reaction was performed in the same manner as in Example 16-(3) using 6-(methanesulfonyloxymethyl)-5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-(1,2,4-thiadiazol-5-yl)pyridin-2-amine and 1-benzoylpiperazine hydrochloride obtained in the same manner as in Reference Example 1. Then, the deprotection reaction was performed in the same manner as in Example 5-(3) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)#[N:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][CH:9]([C:7](=[O:8])[C:6]2[CH:14]=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)CC(=O)c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(C#N)cc1)C(=O)c1ccc(C#N)cc1
Reaction time: 1.5 h

Procedure:
Methyl p-cyanobenzoylacetate 17.77 g, 0.087 mole) and p-cyanobenzyl bromide (17.16 g, 0.087 mole) were combined in 525 ml DMF under N2 . K2CO3 (12.1 g, 0.087 mole) was added, the slurry stirred 1.5 hours and finally poured into a mixture of 2.5 liters H2O and 0.5 liter ethyl acetate. The organic layer was separated, washed with fresh H2O and then brine, stripped to dryness, and the residue slurried in ether to yield title product: 14.83 g (53.6%); m.p. 154°-157°; tlc (4:1 toluene:ethyl acetate) Rf 0.44.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[NH:13]1[C:23]2[C:24]3[C:15]([CH2:16][NH:17][C:18](=[O:25])[C:19]=3[CH:20]=[CH:21][CH:22]=2)=[CH:14]1>C(Cl)Cl>[C:1]1([S:7]([N:13]2[C:23]3[C:24]4[C:15]([CH2:16][NH:17][C:18](=[O:25])[C:19]=4[CH:20]=[CH:21][CH:22]=3)=[CH:14]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1NCc2c[nH]c3cccc1c23
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NCc2cn(S(=O)(=O)c3ccccc3)c3cccc1c23
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzenesulfonyl chloride (140 mg, 0.79 mmol), NBu4HSO4 (24 mg, 0.07 mmol) and 4M aq. NaOH (2 mL) were, in that order, added to 3,4-Dihydropyrrolo[4,3,2-de]isoquinolin-5(1H)-one, Intermediate 1 (124 mg, 0.72 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 2 h and then extracted with water and DCM (×2). The product seems to be only partially soluble in DCM and some solid material in the water layer was filtered off and added to the DCM layer, which was concentrated and dried to give 227 mg of the title compound, as a light brown solid. MS m/z 313 [M+H]+.
Reaction SMILES: [NH2:1][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]([CH3:17])[CH2:15][CH:16]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH: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]([CH3:17])[CH2:15][CH:16]=1)=[O:24]
Reactant: O=C(Cl)c1cccs1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4cccs4)cc23)CC1
Yield: 32.9 %

Procedure:
Beginning with 1.0 gm (4.4 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.494 mL (4.6 mMol) 2-thiophenecarbonyl chloride, 0.489 gm (33.0%) of the title compound were recovered as a bright yellow solid.