Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5](=[O:43])[CH:6](NC(OC(C)(C)C)=O)[CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl.[CH3:45][OH:46]>O1CCCC1.O>[C:10]([O:1][C:45]([C@H:6]([CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([OH:4])=[O:43])=[O:46])([CH3:15])([CH3:11])[CH3:9]
Reactant: CO
Reactant: COC(=O)C(CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
2 N Sodium hydroxide solution (1.32 mL, 2.64 mmol) was added dropwise to a stirred solution of methyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)propionate (500 mg, 0.88 mmol) in tetrahydrofuran (15 mL) and methanol (3 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (10 mL), and acidified to pH 3 with 2 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water, sat'd aq NaCl, dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (5-10% methanol in methylene chloride) afforded the title compound has a white solid (420 mg), mp 205-206° C.
Reaction SMILES: C(O)C.[CH2:4]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=O)[C:14]=2[CH:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1CCCCC1.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34]>C(OCC)C>[CH2:4]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=[C:32]3[S:28][C:29](=[O:34])[NH:30][C:31]3=[O:33])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc2c1ccn2Cc1ccccc1
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cccc3c2ccn3Cc2ccccc2)S1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To 60 ml of ethanol, there were dissolved 3.00 g of 1-benzylindole-4-carbaldehyde prepared in Example 1 and 0.22 g of piperidine, followed by addition of 2.99 g of 2,4-thiazolidinedione to the resulting solution and heating the mixture under reflux for 24 hours. To the reaction solution, there was added 120 ml of diethyl ether and the mixture was stirred at 0° C. for one hour. The crystals precipitated were filtered off and washed with a diethyl ether/ethanol (2:1) mixed solvent. The crystals were dried under reduced pressure to give 3.24 g of 5-(1-benzylindol-4-yl)methylene-2,4-thiazolidinedione as yellow crystals. The yield thereof was found to be 76%.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:22][C:23]1[CH:40]=[CH:39][C:26]2[N:27]=[C:28]([S:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[NH:29][C:25]=2[CH:24]=1.Br[CH2:42][C:43]([NH:45][C:46]1[C:47]([O:59][CH2:60][C:61]([F:64])([F:63])[F:62])=[N:48][C:49]([CH3:58])=[CH:50][C:51]=1[O:52][CH2:53][C:54]([F:57])([F:56])[F:55])=[O:44].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:22][C:23]1[CH:40]=[CH:39][C:26]2[N:27]=[C:28]([S:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH2:42][C:43]([NH:45][C:46]4[C:47]([O:59][CH2:60][C:61]([F:64])([F:62])[F:63])=[N:48][C:49]([CH3:58])=[CH:50][C:51]=4[O:52][CH2:53][C:54]([F:56])([F:57])[F:55])=[O:44])[CH2:35][CH2:34]3)[NH:29][C:25]=2[CH:24]=1
Reactant: Fc1ccc2nc(SCCN3CCNCC3)[nH]c2c1
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCSc3nc4ccc(F)cc4[nH]3)CC2)c(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.4 %

Procedure:
1-[2-(5-Fluorobenzimidazol-2-ylthio)ethyl]piperazine tris(trifluoroacetic acid) salt (6.92 g, 11.12 mmol) and 2-bromo-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (4.50 g, 10.59 mmol) were suspended in acetonitrile (90 mL), and potassium carbonate (5.85 g, 42.33 mmol) was gradually added to the suspension. The mixture was stirred for five hours at room temperature, and water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform:methanol=50:1). The thus-obtained crystals were recrystallized from acetone-ether, to thereby yield 2-[4-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (4.72 g, yield 71%) as pale brown prisms.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[H][H]>[Pd]>[CH3:1][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][CH2:3][OH:2]
Reactant: [H][H]
Reactant: c1ccc2c(c1)CCOC2
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: Cc1ccccc1CCO
Temperature: 150 °C
Reaction time: 5 h

Procedure:
1250 Grams of isochroman having the structure: ##STR63## 25 grams of 5% palladium-on-carbon and 12.5 grams of citric acid are placed in a 4-liter autoclave. The autoclave is sealed, heated to 150° C. and pressurized with hydrogen at 200 psig. After five hours, 12.5 grams of additional citric acid is added to the autoclave and the autoclave is resealed. The autoclave is then heated at a pressure of 200 psig and 150° C. for an additional three hours. At the end of this additional three hour period, the autoclave is opened, the contents filtered and the filtrate is distilled over 2 grams of calcium carbonate through a 24" Goodloe column yielding the following fractions:
Reaction SMILES: [ClH:1].N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:26]=1[NH2:27].C(O)C>>[OH2:24].[ClH:1].[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:26]=1[NH:27][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1.[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:26]=1[NH:27][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1.[ClH:1]
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: COc1ccc(OC)c(N)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc(OC)c(Nc2cc(C)nc3ccc4nc[nH]c4c23)c1
Product: O
Reaction time: 8 h

Procedure:
A mixture of 40 g. (0.184 m.) of the compound of Example I, C., 282 g. (0.184 m.) of 2,5-dimethoxyaniline and 500 ml. of ethanol was heated at reflux with stirring overnight. The reaction was concentrated to dryness in vacuo. The product was recrystallized from 800 ml. of MeOH, to give 28 m.p. 258°-293°C. A second recrystallization from 1000 ml. of MeOH gave m.p. 257°-260°C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=[CH:11]1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl.O>[Si:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH3:11])=[CH:4][CH:3]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: c1c[nH]cn1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (20.0 g, 0.16 mol) in 200 mL of CH2Cl2 at 0° C., imidazole (24.5 g, 0.36 mol) and tBuSiMe2Cl (27.2 g, 0.18 mol) were added. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The organic phase was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes:ethyl acetate=50:1 (v/v)) to give colorless oil (35.63 g, 86.9%). 1H NMR (300 MHz, CDCl3, δ): 9.86 (s, 2H), 7.77 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 0.97 (s, 9H), 0.23 (s, 6H). 13C{1H} NMR (75 MHz, CDCl3, δ): 190.76, 161.49, 131.87, 130.50, 120.47, 25.55, 18.25, −4.37. HRMS-FAB (m/z): [M+H]+ calcd for C14H23O2Si, 251.1467; found, 251.1469.
Reaction SMILES: BrC1C2N(C(=O)NN=2)C(C)=CC=1C1C=CC(Cl)=CC=1.ClCC1C=CC(C(F)(F)F)=NC=1.[Br:32][C:33]1[C:34]2[N:35]([C:47](=[O:62])[N:48]([CH2:50][C:51]3[C:52](C)=[N:53][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:55][CH:56]=3)[N:49]=2)[C:36]([CH3:46])=[CH:37][C:38]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1>>[Br:32][C:33]1[C:34]2[N:35]([C:47](=[O:62])[N:48]([CH2:50][C:51]3[CH:52]=[N:53][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:55][CH:56]=3)[N:49]=2)[C:36]([CH3:46])=[CH:37][C:38]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Agent: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2n[nH]c(=O)n12
Agent: FC(F)(F)c1ccc(CCl)cn1
Product: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Yield: 74 %

Procedure:
The title compound (27 mg, 74%) was prepared from 8-bromo-7-(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (25 mg, 0.074 mmol) and 5-(chloromethyl)-2-(trifluoromethyl)pyridine (21.7 mg, 0.11 mmol) by procedures analogous to those used for the preparation of 8-bromo-7-(4-chlorophenyl)-5-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. HPLC/MS: retention time=4.03 min, [M+H]+=498.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH3:24])[CH2:9][CH2:8][CH2:7][N:6]([CH2:10][C@@H:11]([C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[C:14]=2[CH3:23])[OH:12])[CH2:5]1.[CH3:25][C:26]1[C:34]2[CH2:33][O:32][C:31](=[O:35])[C:30]=2[CH:29]=[CH:28][C:27]=1[C@@H:36]1[CH2:38][O:37]1>>[OH:12][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:10][N:6]1[CH2:7][CH2:8][CH2:9][C:4]([CH2:3][NH:2][CH2:38][C@H:36]([OH:37])[C:27]2[CH:28]=[CH:29][C:30]3[C:31](=[O:35])[O:32][CH2:33][C:34]=3[C:26]=2[CH3:25])([CH3:24])[CH2:5]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c([C@@H](O)CN2CCCC(C)(CN)C2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CNCC2(C)CCCN(C[C@H](O)c3ccc4c(c3C)COC4=O)C2)ccc2c1COC2=O

Procedure:
5-{(1R)-1-Hydroxy-2-[3-({[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)-3-methylpiperidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(R)-2-[3-(aminomethyl)-3-methylpiperidin-1-yl]-1-hydroxyethyl]-4-methyl-2-benzofuran1(3H)-one hydrochloride [INTERMEDIATE 8] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one [INTERMEDIATE 2B].
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH3:13])[CH:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]2=[O:19].C([Sn]([C:35]#[C:36][Si:37]([CH3:40])([CH3:39])[CH3:38])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.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>[CH2:12]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([F:20])=[C:3]([F:21])[C:2]=2[C:35]#[C:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:7](=[O:19])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9]1)[CH3:13]
Reactant: CCOC(=O)c1cn(CC)c2c(Br)c(F)c(F)cc2c1=O
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Yield: 80 %

Procedure:
5.4 g of ethyl 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (Example Z22), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0.87 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 24 hours in 50 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is concentrated, the residue is stirred with 100 ml of hexane, and the resulting solid is filtered off with suction and dried. 4.53 g of ethyl 1-ethyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate are obtained (80% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[N:4]=[C:5]2[C:14]3[C:13]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:12][C:11]([O:20][CH3:21])=[CH:10][C:9]=3[NH:8][C:7](=[O:22])[C:6]=12.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[NH2:1][C:2]1[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[N:4]=[C:5]2[C:14]3[C:13]([O:15][CH2:16][C:17]([NH:34][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[O:19])=[CH:12][C:11]([O:20][CH3:21])=[CH:10][C:9]=3[NH:8][C:7](=[O:22])[C:6]=12
Reactant: COc1cc(OCC(=O)O)c2c(c1)[nH]c(=O)c1c(N)n(-c3ccccc3C)nc12
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)NCCN(C)C)c2c(c1)[nH]c(=O)c1c(N)n(-c3ccccc3C)nc12
Temperature: 25 °C

Procedure:
A mixture of {[3-amino-7-methoxy-2-(2-methylphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-9-yl]oxy}acetic acid (80 mg), N,N-dimethylethylenediamine (33 μl), (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (58 mg), 1-hydroxybenzotriazole (41 mg), triethylamine (43 μl) and N,N-dimethylformamide (2 ml) was stirred at room temperature for one night. The reaction mixture was concentrated under reduced pressure, and the residue was purified with column chromatography to obtain the target compound (61 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-])=[CH:4][CH:3]=1.[Si]([C:17]#[N:18])(C)(C)C.CN(C)C(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:17]#[N:18])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc2ccc[n+]([O-])c2c1
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc2ccc(C#N)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 7-methylquinoline N-oxide (1-2, 246 g, 1.54 mol, 1.0 equiv) in methylene chloride (5 L, 0.31 M) was added TMS-CN (414 ml, 3.1 mol., 2 equiv.) followed by dimethylcarbamoyl chloride (284 ml, 3.1 mol. 2 equiv), and the resulting mixture was stirred at room temperature overnight. The solution was quenched with saturated sodium bicarbonate, diluted with water, and extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and the solvent removed to give 260 g of crude material which was recrystallized from methanol to give 186 g of 7-methylquinoline-2-carbonitrile (1-3) in two crops. LRMS m/z (M+H)+ 169.1 found, 169.2 required.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][N:38]=[N+]=[N-])=[CH:6][CH:5]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(NCCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To 4-{2-[2-(2-azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoic acid methyl ester (400 mg, 0.709 mmol) in THF (4 mL) at 0 C was added Ph3P (223 mg, 0.851 mmol) in portions. The reaction mixture was stirred at rt for 11 h and 35° C. for 4 h before water (50 uL) was added and stirring continued overnight. The reaction mixture was diluted with EtOAc, dried with MgSO4 and purified by flash column chromatography (EtOAc to 20% MeOH/EtOAc with 1% Et3N) to give the desired 4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoic acid methyl ester (201 mg, 53%) as a solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][C@@H:39]([CH3:43])[CH2:38]1)(=[O:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:32][C:29]2[CH:30]=[N:31][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:9]=[CH:8][C:7]([S:4]([CH:1]5[CH2:3][CH2:2]5)(=[O:6])=[O:5])=[CH:12][CH:11]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[CH:22][CH:23]=3)=[CH:27][CH:28]=2)[C@@H:39]([CH3:43])[CH2:38]1)(=[O:36])[CH3:35]
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: CC(=O)N1CCN[C@@H](C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in 1,2-dichloroethane (3 mL) was added (3S)-1-acetyl-3-methylpiperazine (140 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (273 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (184 mg, yield 72%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 591 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([C:19]#[N:20])=[C:8]2[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.[H-].[Na+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O>CN(C)C=O>[C:19]([C:9]1[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:11][C:12]2[C:7]([C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[CH:6][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:14][CH:13]=2)#[N:20]
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(OCCO)cc23)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(OCCOCC(=O)OC(C)(C)C)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of 6-(2-hydroxyethoxy)-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (1.0 g, 2.8 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 0.14 g, 3.4 mmol), and the mixture was stirred at room temperature for 1 hr. tert-Butyl bromoacetate (1 ml, 6.8 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 17 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2-{[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}ethoxy)acetate (0.9 g, yield 69%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]2[C:22]([C:23]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:15]1[C:13]([O:12][CH3:11])=[O:14]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cc1c(C(=O)OC)[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1c(C(=O)OC)n(Cc2ccc(Cl)c(Cl)c2)c2ccccc12
Temperature: 80 °C
Yield: 65.1 %

Procedure:
3,4-Dichlorobenzyl chloride (8.2 g) was added to a stirred solution of methyl 2-methoxycarbonyl-3-indoleacetate (6.5 g) and potassium carbonate (8.36 g) in acetonitrile (200 ml) under an atmosphere of argon. The reaction was heated to 80° C. for 24 hours. The reaction was concentrated in vacuo and partitioned between ethyl acetate and water. Combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography using 25% ethyl acetate:iso-hexane as eluent to give the product as a white solid (6.95 g, 65%), NMR d (CD3SOCD3) 3.60 (s, 3H), 3.77 (s, 3H), 4.13 (s, 2H), 5.89 (s, 2H), 6.89 (dd, 1H), 7.16 (t, 1H), 7.27 (d, 1H), 7.34 (t, 1H), 7.52 (d, 1H), 7.57 (d, 1H), 7.78 (d, 1H); M/z (+) 406 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([CH3:29])([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][CH:26]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:28][CH:17]1[N:16]2[C:21]([CH2:22][O:23][C:24]3[C:15]2=[CH:14][C:13]([O:12][C:10]2([CH3:29])[CH2:9][NH:8][CH2:11]2)=[CH:26][CH:25]=3)=[N:20][NH:19][C:18]1=[O:27]
Reactant: CC1C(=O)NN=C2COc3ccc(OC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3ccc(OC4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 3-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.064 g, 0.159 mmol) in DCM (2 mL) was added TFA (0.5 mL) dropwise and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 4-methyl-6-(3-methyl-azetidin-3-yloxy)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as white solid (0.045 g, 68%). LC/MS (Table 1, Method 5) Rt=1.691 min; MS m/z: 303 [M+H]+.