Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]([CH3:14])[C:11]([NH2:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>COCCOC.C(OCC)(=O)C>[C:1]([O:9][CH:10]([CH3:14])[C:11]([NH2:13])=[S:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OC(=O)c1ccccc1)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(OC(=O)c1ccccc1)C(N)=S
Temperature: 25 °C
Reaction time: 24 h
Yield: 148.4 %

Procedure:
To a solution of 2-amino-1-methyl-2-oxoethyl benzoate (10.0 g, 52.0 mmol) in 1,2-dimethoxyethane (90 mL) was added Lawesson's reagent (11.2 g, 27.7 mmol) at 0° C. and the reaction mixture was allowed to warm up to room temperature. The resulting mixture was stirred at room temperature for 24 hours and the precipitate was removed by filtration. The resulting solution was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate and the solution was washed with brine. The organic solution was dried, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) to obtain a crude crystal. The crude crystal was recrystallized from ethyl acetate-hexane to give a title compound (8.60 g, yield 79%).
Reaction SMILES: C[Mg]Br.N#N.[O:6]=[C:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9]([CH:10]=[CH:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[O:27])=[CH:8]1.[CH2:39]1COCC1>CCOCC.Cl[Cu]>[CH3:39][CH:11]1[CH:10]=[C:9]2[C@:22]([CH3:25])([CH2:23][CH2:24][C:7](=[O:6])[CH2:8]2)[C@@H:21]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][CH2:20]2)([CH3:18])[C@@H:16]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:36])([F:37])[F:38])=[O:27])[CH2:15][CH2:14]1
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1ccccc1C(F)(F)F
Reactant: C1CCOC1
Agent: Cl[Cu]
Agent: C[Mg]Br
Agent: N#N
Solvent: CCOCC
Product: CC1C=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(=O)Nc4ccccc4C(F)(F)F)CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3.0 M methylmagnesium bromide (2.35 mmol) in ether under a stream of N2 was added 6.0 mL degassed THF. The solution was cooled to 0° C., then CuCl (0.03 g, 0.300 mmol) was added. The mixture was stirred for 5 min. A solution of the compound from Step A (5-2) (0.25 g, 0.55 mmol) in 6.0 mL degassed THF was added. The reaction was warmed to room temperature overnight. It was quenched by slow addition of 2.0 mL degassed water, then diluted with 10% KHSO4 solution and EtOAc. The organic phase was washed with 10% KHSO4 solution, saturated NaHCO3 solution, and brine. After removal of the solvent, the residue was purified by preparative HPLC (C18; 70% MeOH with 5 to 30% MeCN-water) to provide 5-5.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:20])[CH2:11][N:12]1[CH2:17][CH2:16][N:15](C=[O:19])[CH2:14][CH2:13]1.[ClH:21]>CO>[OH2:19].[ClH:21].[ClH:21].[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:20])[CH2:11][N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(C=O)CC1
Agent: Cl
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Product: O
Yield: 98 %

Procedure:
N-(2,6-dimethylphenyl)-4-formyl-1-piperazineacetamide (17.70 g, 64.0 mmol) was dissolved in a mixture of methanol (500 mL) and 1N HCl (130 mL) under nitrogen. The mixture was refluxed for 7 h before it was cooled, concentrated and partitioned between ethyl acetate and water. The aqueous phase was then separated away from the organic phase and evaporated down to dryness. There was isolated 21.00 g (98%) of the title compound as a white solid, m.p. 185°-195° C. (sealed tube); 1H NMR (300 MHz, D2O) δ 7.11-7.01 (m, 3H), 4.31 (s, 2H), 3.65-3.62 (m, 4H), 3.56-3.50 (m, 4H), 2.04 (s, 6H); 13C NMR (75 MHz, D2O) ppm 168.55, 140.74, 136.95, 133.37, 133.19, 61.89, 54.16, 45.56, 22.24; IR (KBr) 3440, 2958, 1690, 1532, 1472, 1442, 1386, 1308, 1240, 964, 770 cm-1 ; MS m/z calc'd for C14H22N3O 248.1763, found 248.1763.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.[C:28]([O:32][C:33](=[O:37])[CH:34](Br)[CH3:35])([CH3:31])([CH3:30])[CH3:29].[H-].[Na+]>>[C:28]([O:32][C:33](=[O:37])[CH:34]([N:13]1[C:14]2[C:10](=[C:9]([O:8][CH2:7][C:6]3[S:5][C:4]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=4)=[N:3][C:2]=3[CH3:1])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1)[CH3:35])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2[nH]ccc12
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2c1ccn2C(C)C(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 1 b], 4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole (example 1 a]) was reacted with 2-bromo-propionic acid tert-butyl ester in the presence of sodium hydride to obtain [rac]-2-{4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-propionic acid tert-butyl ester as yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.COCCOC.[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.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.CCOCC.O>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[C:24]=2[F:25])=[CH:3][CH:4]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: C[Si](C)(C)c1ccc(Br)cc1
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: COCCOC
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)c1ccc(-c2cccc(F)c2F)cc1
Temperature: 100 °C
Yield: 91 %

Procedure:
First, 7.9 g of 1-bromo-4-trimethylsilylbenzene was dissolved into 86 ml of DME, and 6.5 g of 2,3-difluorophenylboronic acid, 1.2 g of tetrakis(triphenylphosphine)palladium (0) and 86 ml of 2.0M Na2CO3 was added thereto. Next, the reaction mixture was heated to 100° C. to perform a reaction for about 10 hours. After being cooled to room temperature, the reaction mixture was worked up with water and ether, and then purified by silica gel column chromatography to obtain the 4′-trimethylsilyl-2,3-difluorobiphenyl compound with a yield of 91%. Then, 3.0 g of the biphenyl compound was dissolved into 20 ml of dry THF under nitrogen atmosphere, and 5.0 ml of 2.5M n-BuLi was added thereto at −78° C. to form an anion over about 3 hours. Then, 2.0 ml of 4-n-propylcyclohexanone was added to the anion, and the reaction mixture was warmed gradually to room temperature. After stirring at room temperature for 2 hours, the reaction mixture was worked up with water and ether, and evaporated under reduced pressure, and then dissolved into CH2Cl2 solvent. Next, 1.0 g of TsOH was added thereto, and the reaction mixture was allowed to react at 60° C. for 10 hours. After the completion of the reaction, the reaction mixture was purified by silica gel column chromatography to obtain the silicon-containing compound (yield: 80%). 400 MHz 1H-NMR, CDCl3, δ (ppm): 0.38 (s, 9H), 0.97 (m, 3H), 1.34˜1.46 (m, 5H), 1.63˜1.76 (br, 1H), 1.84˜1.98 (m, 2H), 2.33˜2.59 (m, 3H), 6.06 (br, 1H), 7.05˜7.12 (m, 1H), 7.12˜7.18 (m, 1H), 7.56 (d, 2H), 7.63 (d, 2H).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:16])[CH:14]=O)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC=CC=1.Cl>C(O)=O.O>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:16])[CH2:14][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCC(C)(C)c1ccc(CC(C)C=O)cc1
Agent: Cl
Solvent: O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1ccc(CC(C)CN2CCCCC2)cc1
Temperature: 75 °C

Procedure:
21.8 G. of 3-(p-tert.-amyl-phenyl)-2-methyl-propionaldehyde and 11.3 g. of piperidine are heated at reflux in 15 ml. of toluene in a water-separator under nitrogen gasification until the water-cleavage has been completed (6 hours). Subsequently, there are added dropwise at room temperature with stirring 6.9 g. of formic acid, the temperature rising to 36°-40° C. Then, the mixture is heated to 75° C. for 2 hours, 50 Ml. of 2 N hydrochloric acid are added to the cooled solution. The toluene solution is separated. The aqueous-hydrochloric acid solution is made alkaline with 40 ml. of 6 N sodium hydroxide and the product is extracted with ether. The combined ether extracts are washed with water, dried over sodium sulfate and evaporated. By distillation, there is obtained pure 1-[3-(p-tert.-amyl-phenyl)-2-methyl-propyl]-piperidine having a boiling point of 160° C./0.15 Torr.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([S:8][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Clc1cc(Cl)c2cccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1cc(SCc2ccccc2)c2cccnc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl mercaptan (6 mL, 50.5 mmol) was added dropwise to a mixture of 5,7-dichloroquinoline (10 g, 50.5 mmol), cesium carbonate (20 g, 60 mmol) and DMF (50 mL) at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 2 hours and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried with sodium sulfate and concentrated. Purification by column chromatography gave the 5-(benzylthio)-7-chloroquinoline (rf=0.5 in 2:1 hexanes/ethyl acetate) as a crystalline yellow solid. The undesired regioisomer elutes afterwards (rf=0.4 in 2:1 hexanes/ethyl acetate). The reaction is mildly selective for the desired isomer.
Reaction SMILES: Br[C:2](=[C:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>N1CCCCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[C:3]1([C:2](=[C:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]3[C:26]4[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=4[O:27][CH3:28])[NH:20][CH:19]=3)=[O:17])[CH2:11][CH2:10]2)[C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(Br)c4ccccc4)CC3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: N#Cc1ccccc1
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(C#C[Si](C)(C)C)c4ccccc4)CC3)c[nH]c12
Temperature: 60 °C
Yield: 38.8 %

Procedure:
As shown in Scheme 31 to a solution of 1-[4-(1-bromo-1-phenyl-methylene)-piperidin-1-yl]-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione (0.094 g, 0.195 mmol), PdCl2(PhCN)2 (0.005 g, 0.0117 mmol), and CuI (0.005 g, 0.0252 mmol) in piperidine (1.5 mL) was added trimethylsilylacetylene (0.070 mL, 0.495 mmol). The mixture was heated at 60° C. for 2 h and the solvent removed in vacuo. The residue was diluted with EtOAc and H2O, the organic phase was separated and the aqueous phase was re-extracted with EtOAc (×2). The combined organic layers were washed, (H2O, brine), dried (Na2SO4) and evaporated, and the residue was purified by preparative HPLC to give the title compound as a colorless solid (0.038 g, 39%).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:7]=[N:6][CH:5]=[N:4]1.[OH-].[Na+].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[O:22])=[CH:19][CH:18]=1
Reactant: NCCCCCn1cncn1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCCCn1cncn1)c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
A mixture of about 2.30 g of 1H-1,2,4-triazole-1-pentanamine dihydrochloride, about 75 ml of methylene chloride, about 30 ml of approximately 1N sodium hydroxide and about 1.2 ml of 4-chloro benzoyl chloride was stirred for about 18 hours, then about 5 ml of approximately 1N sodium hydroxide and about 50 ml of methylene chloride were added and the layers were separated. The organic layer was washed with water dried and concentrated, giving the desired product, mp 68°-70° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]O.CN(C=O)C.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][Cl:20]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(CCl)ccc1[N+](=O)[O-]

Procedure:
3-methyl-4-nitrobenzylalcohol (2 g) and 0.2 ml of DMF were dissolved in 20 ml of toluene. The solution was added with 1 ml of thionyl chloride and stirred under heating with reflux for 3 hours. The reaction mixture was concentrated and thus 2.2 g of an oil, 3-methyl-4-nitrobenzyl chloride, was obtained. This compound was used for the following reaction without further purification.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:31]([CH2:45][CH3:46])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:48].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:48][C:26]1[C:25]2[N:30]=[C:31]([CH2:45][CH3:46])[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])[C:24]=2[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:29][C:28]=2[N:27]=1
Reactant: [NH4+]
Reactant: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
mCPBA (10.6 g, 33.7 mmol) was added in one portion to a solution of tert-butyl [4-(7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (16.0 g, 33.7 mmol) in chloroform (270 mL). After the reaction was stirred for 1.5 hours, ammonium hydroxide (270 mL) was added. The mixture was stirred for 15 minutes, and p-toluenesulfonyl chloride (6.42 g, 33.7 mmol) was added in three portions. The reaction was stirred for 18 hours. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic fractions were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to afford 9.73 g of tert-butyl [4-(4-amino-7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a gray powder.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[NH2:17][NH2:18]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH:17][NH2:18])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(-c2ccnc(Cl)c2Br)cc1
Reactant: NN
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccnc(NN)c2Br)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(3-bromo-2-chloropyridin-4-yl)benzonitrile (0.59 g, 2.02 mmol) in dioxane (7 mL) at room temperature was added anhydrous hydrazine (1 mL). The resulting mixture was stirred at 80° C. for 2 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional anhydrous hydrazine (1 mL) was added, and the reaction mixture was stirred at 90° C. for 5 h more. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the resulting suspension was sonicated for 5 min. The resulting slurry was filtered, and the collected solid was washed with water (10 mL×2), then dried in a 45° C. vacuum oven for 16 h to afford 510 mg of the title compound as a beige solid. HPLC/MS: retention time=1.74 min, [M+H]+=289.
Reaction SMILES: NC1C=CC([C:6]([NH:8][CH2:9][CH2:10]C)=[O:7])=CC=1.Cl.[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([CH2:24][OH:25])=[CH:21][CH:22]=2)[CH2:17][NH:16]1.Cl.C1[C:35]2[C:30](=[CH:31][C:32]([C:36](OC)=O)=[CH:33][CH:34]=2)CN1>>[OH:25][CH2:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[CH2:15][N:16]([C:6]([NH:8][CH2:9][CH2:10][CH2:36][C:32]1[CH:31]=[CH:30][CH:35]=[CH:34][CH:33]=1)=[O:7])[CH2:17]2
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: CCCNC(=O)c1ccc(N)cc1
Reactant: OCc1ccc2c(c1)CNC2
Agent: Cl
Product: O=C(NCCCc1ccccc1)N1Cc2ccc(CO)cc2C1

Procedure:
The title compound was prepared as described in Example 272B, substituting 3-phenylpropan-1-amine for 4-amino-N-propylbenzamide and isoindolin-5-ylmethanol hydrochloride for methyl isoindoline-5-carboxylate hydrochloride. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.30-7.14 (m, 8H), 6.30 (t, J=5.5 Hz, 1H), 5.16 (t, J=5.5 Hz, 1H), 4.55 (bs, 4H), 4.49 (d, J=4.9 Hz, 2H), 3.16-3.05 (m, 2H), 2.64-2.56 (m, 2H), 1.76 (p, J=7.4 Hz, 2H); MS (ESI(+)) m/e 311 (M+H)+.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[CH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:37]1=[O:50]>>[OH:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[C:36]1([CH2:5][OH:16])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:37]1=[O:50]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2ccc(OC)cc2O)c2ccccc21
Product: CCCCCN1C(=O)C(CO)(c2ccc(OC)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(2-hydroxy-4-methoxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (41%): 1H NMR (300 MHz, CDCl3) δ 10.79 (s, 1H), 7.51-7.37 (m, 2H), 7.26 (td, 1H), 6.99 (d, 1H), 6.95 (d, 1H), 6.59 (d, 1H), 6.34 (dd, 1H), 4.67 (d, 1H), 4.14 (d, 1H), 3.76 (s, 3H), 3.78-3.69 (m, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 338 (M−17), 378 (M+23).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].C[O:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1>O1CCCC1>[C:1]([CH2:2][C:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:7])#[N:3]
Reactant: CC#N
Reactant: COC(=O)c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
A solution of acetonitrile (9.22 mL, 176 mmol) in tetrahydrofuran (320 mL) was added to sodium hydride (60% dispersion in mineral oil) (11.80 g, 294 mmol). This mixture was stirred at room temperature for 15 minutes, and then 4-Cyano-benzoic acid methyl ester (23.70 g, 147 mmol) was added. The reaction mixture was stirred at 60° C. for 2 hours, And then quenched onto an aqueous solution of hydrochloric acid (2M, 500 mL), and extracted with ethyl acetate (3×500 mL). The combined organic extracts were washed with brine (500 mL), dried over magnesium sulphate, filtered and evaporated under reduced pressure. This residue was triturated with 20% ethyl acetate in heptane to give the title compound as a solid (23.17 g, 93%). ESCI MS m/z 169 [M−H]−
Reaction SMILES: ClCCCCC[C:7]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[CH:9][C:8]=1[CH:17]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:18]#[N:19].[CH3:28][C:29]([Si:32]([CH3:47])([CH3:46])[O:33][C:34]1[CH:43]=[C:42]2[C:37]([CH2:38][CH2:39][NH:40][CH2:41]2)=[CH:36][C:35]=1[O:44][CH3:45])([CH3:31])[CH3:30]>>[CH3:14][O:13][C:12]1[CH:7]=[C:8]([C:17]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:9][CH2:8][CH2:7][CH2:12][CH2:11][N:40]2[CH2:39][CH2:38][C:37]3[C:42](=[CH:43][C:34]([O:33][Si:32]([C:29]([CH3:28])([CH3:30])[CH3:31])([CH3:46])[CH3:47])=[C:35]([O:44][CH3:45])[CH:36]=3)[CH2:41]2)[C:18]#[N:19])[CH:9]=[CH:10][C:11]=1[O:15][CH3:16]
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)c(CCCCCCl)c1OC
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CNCC2
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(O[Si](C)(C)C(C)(C)C)cc3C2)Sc2ccc(C)cc2)cc1OC

Procedure:
The procedure of Example 3 is repeated using 2.5 g of α-(5-chloropentyl-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 2.54 g 7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1,2,3,4-tetrahydro-6-methoxyisoquinoline. This affords 1.2 g of the desired product as a light yellow oil.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=1>C1(C)C(C)=CC=CC=1>[CH2:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=2)[CH2:3][CH2:2]1)=[O:8])[CH3:11]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCOC(=O)N1CCNCC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A mixture of 10.1 g of ethyl 1-piperazine carboxylate, 5.0 g of 6-chloronicotinic acid and 15 ml of xylene was stirred at 140°-150° C. for 3 hours. After cooled crystals were filtered, to the crystals was added a solution of 2.6 g of sodium hydroxide in 30 ml of water followed by extraction with toluene. Concentrated hydrochloric acid was added to the aqueous layer, and crystals precipitated were filtered, washed with water and dried to afford 7.1 g of 6-(4-ethoxycarbonyl-1-piperazinyl)nicotinic acid (yield 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=O)[CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][OH:19].C(O)(=O)C.[BH4-].[Na+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:16][CH2:17][CH2:18][OH:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=CC1CCCC(c2ccc(Cl)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: OCCNCC1CCCC(c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
To a solution of C6 (338 mg, 1.52 mmol) in methanol (5 mL) was added 2-aminoethanol (139 mg, 2.28 mmol) followed by acetic acid (89 μL, 1.55 mmol). The reaction was stirred at reflux for 2 hours, then cooled to 0° C. Sodium borohydride (115 mg, 3.04 mmol) was added and the mixture was allowed to warm to room temperature. The reaction was diluted with ethyl acetate, quenched with water, and then extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide the crude title compound as a liquid. Yield: 362 mg, 1.35 mmol, 89%. This was presumed to be a mixture of stereoisomers. LCMS m/z 268.3 (M+1). 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 7.22-7.28 (m, 2H), 7.10-7.16 (m, 2H), 3.63 (dd, J=5.3, 5.1 Hz, 2H), 2.75 (dd, J=5.3, 5.1 Hz, 2H).