Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.Cl.[Sn].Br[C:7]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[OH:18]>C1C=CC=CC=1.C(OCC)(=O)C>[Br:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH:7]=[C:8]([OH:18])[CH:9]=[CH:10]2
Reactant: Oc1ccc2cc(Br)ccc2c1Br
Agent: Cl
Agent: [Sn]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc2cc(Br)ccc2c1
Yield: 103.1 %

Procedure:
To a solution of 225 mL of ethanol and 90 mL of conc. HCl in a 500 mL round bottom flask were added of tin metal (32.6 g, 274 mmol) and 1,6-dibromo-2-naphthol (41.5 g, 137 mmol). The reaction mixture was refluxed on a steam bath for 9 hours. TLC (SiO2, 15:1 benzene/ethyl acetate) indicated consumption of starting material. The cooled solution was decanted from unreacted tin, concentrated to 150-200 mL on vacuo and poured into 600 mL of ice and water. The white precipitate was collected on a Buchner funnel and dried in the air to afford 31.5 g of an off-white solid. Recrystallization from benzene produced 23.8 g of pure product (78%): mp 127°-127.5° C.; lit. mp 127°-129° C.; reference: C. R. Koelsch, Org. Syn. Coll. Vol. 3, 132 (1955). ##STR25##
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].I[C:10]1[CH:18]=[CH:17][C:13]([C:14]([O-:16])=[O:15])=[C:12](C)[CH:11]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[O-]S(C(F)(F)F)(=O)=O.[Cu+]>[CH3:20][O:16][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]2)=[CH:11][CH:12]=1
Reactant: Cc1cc(I)ccc1C(=O)[O-]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: O=C([O-])[O-]
Agent: [Cu+]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc([N+](=O)[O-])c2)cc1
Temperature: 100 °C

Procedure:
4-nitroimidazole (1 equiv) was combined with 4-iodo-methylbenzoate (1.2 equiv), cesium carbonate (1.0 equiv), copper (I) triflate (0.05 equiv), in DMF and heated overnight at 100° C. The solid was filtered and washed with methylene chloride, the resultant solvent was concentrated, and residue purified by silica gel chromatography to provide the title compound: MS m/z 248.2 (M+1).
Reaction SMILES: [BH4-].[Na+].[N+:3]([CH:6]=[CH:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([O-:5])=[O:4].C(O)(=O)C>C(Cl)(Cl)Cl.C(O)(C)C>[N+:3]([CH2:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])C=Cc1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])CCc1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.7 g of silica 60 (230-400 mesh) and then 2.95 g of NaBH4 are added to a solution of 32.2 mmol of 2-(2-nitrovinyl)thiophene in 210 ml of chloroform and 70 ml of isopropanol. After stirring the mixture for one hour at ambient temperature, 5 ml of acetic acid are added dropwise and then, after 15 minutes, the resulting suspension is filtered and subsequently rinsed with dichloromethane. Concentration of the filtrate under reduced pressure enables the expected product to be isolated.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([OH:10])[C:6]([F:11])=[C:5]([F:12])[C:3]=1[OH:4].[C:13](O)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>O1CCCC1>[C:13]([O:4][C:3]1[C:2]([F:1])=[C:8]([F:9])[C:7]([OH:10])=[C:6]([F:11])[C:5]=1[F:12])(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCC(=O)O
Reactant: Oc1c(F)c(F)c(O)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: C1CCOC1
Product: CCCCCCCCC(=O)Oc1c(F)c(F)c(O)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
2.0 g (11.0 mM) of 2,3,5,6-tetrafluorohydroquinone, 0.87 g (5.5 mM) of nonanoic acid, 1.13 g (5.5 mM) of dicyclohexylcarbodiimide and a catalytic amount of 4-pyrrolidinopyridine were added to 20 ml of tetrahydrofuran, followed by stirring for 3 hours at room temperature. After the reaction, the insoluble residue was filtered off, followed by distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: toluene) to obtain 0.57 g of an objective product (Yield: 32.2%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15](CO)=[CH:14][CH:13]=1.[CH3:20]N(C)CCCO>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)CCCO
Reactant: OCc1ccncc1
Product: COC(=O)c1ccc(OCc2ccccn2)cc1

Procedure:
Following the procedure of Example 76(a) except substituting methyl 3-hydroxybenzoate for methyl 4-hydroxybenzoate and 4-pyridylcarbinol for 3-dimethylamino-1-propanol, the title compound was prepared as a yellow solid (0.599 g, 2.5 mmol). MS(ESI): 244.1 (+H)+.
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C([Li])CCC.[CH3:19][CH:20]1[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(OCC)(=O)C.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]2([OH:26])[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH:20]([CH3:19])[CH2:25]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CC(O)(c2ccc(F)cc2)CCN1C(=O)OC(C)(C)C
Yield: 100.7 %

Procedure:
To a tetrahydrofuran solution (10 mL) of 1-bromo-4-fluorobenzene (492 mg, 2.81 mmol), n-butyl lithium (1.62 M, hexane solution) (1.73 mL, 2.81 mmol) was added at −78° C. and the resultant mixture was stirred for 40 minutes. To the reaction solution, a tetrahydrofuran solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (500 mg, 2.34 mmol) was added and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product (729 mg) of the title compound.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:52])[OH:51])=[O:46])[CH2:40][CH2:41][C:42](=[O:44])[OH:43])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N1CCCCC1.C(O)(=O)C>CS(C)=O>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:51])[OH:52])=[O:46])[CH2:40][CH2:41][C:42](=[O:43])[OH:44])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: C1CCNCC1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
Fmoc-L-Trp-L-Leu-Gly-L-Arg-D-Glu-L-Asp-OH (50 mg), was dissolved in 0.5 ml of dimethylsulfoxide and 0.5 ml of piperidine was added to the solution. After reacting for an hour, the reaction mixture was neutralized with acetic acid under cooling.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([CH:26]=O)=[CH:20][NH:21]2.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:19]3[C:18]4[C:22](=[CH:23][CH:24]=[CH:25][C:17]=4[CH3:16])[NH:21][CH:20]=3)[C:34]([C:30]3[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: Cc1cccc2[nH]cc(C=O)c12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: Cn1ccnc1C=O
Product: Cc1cccc2[nH]cc(Cn3nc4c(c3-c3nccn3C)c(=O)n(C)c(=O)n4CC(C)C)c12

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 4-methyl-1H-indole-3-carbaldehyde, followed by 1-methyl-1H-imidazole-2-carbaldehyde. Mass: 446.45 (M+H).
Reaction SMILES: [Cl-].[Li+].C(OP(C[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)[CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[CH:31](N(C(C)C)CC)(C)C.[CH:40](=O)[CH:41]([CH3:43])[CH3:42].[Cl-].[NH4+]>C(#N)C.ClCCl.O>[CH3:42][CH:41]([CH3:43])/[CH:40]=[CH:31]/[C:12]([CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)[CH2:18][CH2:19]1)=[O:13]
Reactant: CCOP(=O)(CC(=O)C1CCN(c2cc(C)nc3ccccc23)CC1)OCC
Reactant: CC(C)C=O
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: Cc1cc(N2CCC(C(=O)/C=C/C(C)C)CC2)c2ccccc2n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 29.5 %

Procedure:
Lithiumchloride (4.2 mg, 0.1 mmol) which had been dried before in vacuum at 125° C. was placed in anhydrous acetonitrile (4 ml), the mixture was cooled to −78° C. and diethoxyphosphoryl-1-[1-(2-methyl-4-quinolyl)-4-piperidyl]ethanone from step B (40 mg, 0.1 mmol) dissolved in 1 ml anhydrous acetonitrile was added dropwise with stirring. The mixture was allowed to reach room temperature, stirring was continued for 10 minutes and diisopropylethylamine (10.1 mg, 0.1 mmol) and isobutyraldehyde (7.2 mg, 0.1 mmol) were added. Stirring was continued overnight. Water and dichloromethane (10 ml each) were added and the mixture poured into saturated ammoniumchloride solution (20 ml). The phases were separated, the aqueous phase extracted with dichloromethane (3×) and the combined organic phases washed with brine, dried over sodium sulfate and the solvent removed under reduced pressure. The raw product was purified with preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile). 9.5 mg of an amber-coloured solid were obtained (0.029 mmol, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1.P(Br)(Br)[Br:20]>C1COCC1.CCOC(C)=O>[Br:20][CH2:14][C:13]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:10][O:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: BrP(Br)Br
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CBr

Procedure:
To a solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-yl]-methanol (1.14 g, 4 mmol) in THF (20 mL) is added PBr3 (0.76 mL, 8 mmol). The reaction mixture is stirred at reflux for 30 minutes. The reaction mixture is diluted with EtOAc and washed with 0.2 N HCl. The organic layer is separated, dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound as an oil.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:24]2[C:32]3[C:31]([O:33][CH3:34])=[N:30][CH:29]=[N:28][C:27]=3[N:26]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:25]=2)O)=[C:18]([F:44])[N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>ClCCCl>[C:38]1([S:35]([N:26]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([O:33][CH3:34])[C:32]=3[C:24]([CH2:22][C:19]3[CH:20]=[CH:21][C:16]([NH:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[Cl:15])=[N:17][C:18]=3[F:44])=[CH:25]2)(=[O:37])=[O:36])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ncnc2c1c(C(O)c1ccc(N(Cc3ccccc3Cl)C(=O)OC(C)(C)C)nc1F)cn2S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ncnc2c1c(Cc1ccc(NCc3ccccc3Cl)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 91.1 %

Procedure:
To {5-[(7-Benzenesulfonyl-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(2-chloro-benzyl)-carbamic acid tert-butyl ester (44, 0.400 g, 0.612 mmol) in 15.0 mL of 1,2-dichloroethane, triethylsilane (2.0 mL, 12 mmol) and trifluoroacetic acid (1.0 mL, 13 mmol) were added. The reaction was heated at 80° C. for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (45, 0.30 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14](SC)[N:9]3[CH:8]=[CH:7][C:6]=2[CH:17]=1.[S:18](=[O:22])(=O)(O)[OH:19].OO.S([O-])([O-])=O.[Na+].[Na+].[C:31](O)(=O)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14]([S:18]([CH3:31])(=[O:22])=[O:19])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: O=S(=O)(O)O
Reactant: CSc1nnc2n1C=Cc1cc(C)ccc1C2
Reactant: CC(=O)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: Cc1ccc2c(c1)C=Cn1c(nnc1S(C)(=O)=O)C2

Procedure:
To a solution of 6.1 g of 8-methyl-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine in 75 ml of acetic acid was added 5.0 ml of concentrated sulfuric acid and under ice-cooling and stirring, 12.5 ml of 30% H2O2 was added dropwise. After stirring the mixture for 10 minutes at room temperature, it was heated on a water bath at 60°-65° C. for 2 hours. After ice-cooling, an aqueous solution of sodium sulfite was added to decompose the excess hydrogen peroxide. The solvent was evaporated off and, following addition of water, the residue was neutralized with concentrated aqueous ammonia, again under ice-cooling, and extracted with chloroform. The chloroform layer was washed with water and dried over Na2SO4. The solvent was evaporated off and the residue was treated with ether. By the above procedure was obtained 8-methyl-3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from ethanol yielded colorless needles melting at 152°-153° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[C:4](Cl)[N:3]=1.Br.Br.[CH3:13][N:14]1[CH2:19][C@@H:18]2[CH2:20][C@H:15]1[CH2:16][NH:17]2.CCN(C(C)C)C(C)C.[NH2:30][NH2:31]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:17]2[CH2:16][C@@H:15]3[CH2:20][C@H:18]2[CH2:19][N:14]3[CH3:13])[C:5]([F:9])=[C:4]([NH:30][NH2:31])[N:3]=1
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Reactant: NN
Reactant: CN1C[C@@H]2C[C@H]1CN2
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN1C[C@@H]2C[C@H]1CN2c1nc(Cl)nc(NN)c1F
Temperature: 25 °C

Procedure:
2,4,6-Trichloro-5-fluoropyrimidine (2.01 g, 10 mmol) was dissolved in 30 mL of DMSO and stirred at room temperature. Commercially-available (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane, dihydrobromide (2.74 g, 10 mmol) was added, followed by DIPEA (5.51 mL, 32 mmol). The resulting reaction mixture was stirred for 2.5 h, and then hydrazine was added (3.0 mL) and the contents were stirred at room temperature overnight. The reaction mixture was then purified by RP-HPLC to provide the assumed (1S,4S)-2-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (first eluent), as well as the assumed 4-chloro-5-fluoro-6-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-2(1H)-pyrimidinone hydrazone (second eluent).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.CS(O[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])(=O)=O>>[ClH:37].[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][CH2:29][N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:5][CH2:6]1
Reactant: CS(=O)(=O)OCCc1ccccc1Cl
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Product: Cl
Product: O=C(CCC1CCN(CCc2ccccc2Cl)CC1)c1cc2c3c(c1)CCN3C(=O)CC2

Procedure:
Using 8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (600 mg and 2-(2-chlorophenyl)ethyl methanesulfonate (475 mg) according to the same method as that of Example 81, the title compound (303 mg) was obtained as colorless crystals having a melting point of 207 to 210° C.
Reaction SMILES: [C:1]([C@@:18]1(C(O)=O)[CH2:22][C@@H:21]([NH2:23])[CH2:20][N:19]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([O:3]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:2]>C(#N)C.N1CCCC1>[NH2:23][CH:21]1[CH2:20][N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:18]([C:1]([OH:3])=[O:2])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@]1(C(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(N)CC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of (2S,4R) Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (400 mg, 0.884 mmol) in acetonitrile (15 mL), five drops of pyrrolidine was added. The reaction mixture was stirred at rt for 3 hr. Then it was concentrated and put on high vacuum to give crude 4-amino-1-boc-pyrrolidine-2-carboxylic acid. In another round-bottomed flask, a solution of Pd2 dba3 (40 mg, 5% mol) and racemic-BINAP (56 mg, 10% mol) was stirred under nitrogen in degassed toluene (8 mL) at rt for 1 h. Then 1-chloroisoquinoline (216 mg, 1.326 mmol) and sodium t-butoxide (340 mg, 3.536 mmol) were added and the reaction mixture was stirred for 30 min. Then 4-amino-1-boc-pyrrolidine-2-carboxylic acid was added and the reaction mixture was heated under reflux for 1 h. Water was added to quench the reaction and the aqueous layer was separated and filtered through filter paper. It was then concentrated and purified by Prep. HPLC to give coupled product as TFA salt. (165 mg, 40% yield)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[CH:39]=[C:38]([S:40](Cl)(=[O:42])=[O:41])[S:37][C:36]=2[CH:44]=1>C(Cl)Cl.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:40]([C:38]3[S:37][C:36]4[CH:44]=[C:32]([Cl:31])[CH:33]=[CH:34][C:35]=4[CH:39]=3)(=[O:42])=[O:41])[CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)CC1
Reaction time: 16 h

Procedure:
To a solution of 4-(2-oxo-piperazin-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.44 g, 4.8 mmol) in CH2Cl2 (75 mL) and MeCN (10 mL) is added diisopropylethylamine (1.3 mL, 4.8 mmol) followed by 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (1.29 g, 4.8 mmol), and the reaction is allowed to stir 16 h. The reaction is diluted with CH2Cl2 and washed with 1N HCl and NaHCO3, dried and concentrated. The residue is purified by column chromatography (silica, 40% EtOAc/CH2Cl2) to provide 4-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, CDCl3) δ 7.88-7.83 (m, 3H), 7.47 (dd, 1H), 4.1 (br, 2H), 3.86 (s, 2H), 3.46 (bs, 4H), 3.25 (br, 2H), 2.61 (t, 2H), 1.87-1.75 (m, 1H), 1.51 (d, 2H), 1.41 (s, 9H), 1.10 (ddd, 2H); MS (Ion spray) 528 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:12][C:13]([O:15]CC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO.C1COCC1.O>[CH2:1]([O:8][C:9]([N:11]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN(C(=O)OCc1ccccc1)c1ccnc2ccc(C(F)(F)F)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1ccnc2ccc(C(F)(F)F)cc12

Procedure:
A solution of ethyl 2-(((benzyloxy)carbonyl)(6-(trifluoromethyl)quinolin-4-yl)amino)acetate (404 mg, 0.934 mmol, prepared in step E) in MeOH (15 mL) and THF (5 mL) and treated with a solution of LiOH (112 mg, 4.67 mol) in water (5 mL). After stirring at room temperature for xx hours, the pH was adjusted to ˜5 by the addition of aqueous HCl. After extraction with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated in vacuo to yield the product.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCCn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
3-Nitro-1-butyl-1H-pyrazole (111 mg, 0.66 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The reaction was passed through a plug of celite and concentrated in vacuo to afford 1-butyl-1H-pyrazol-3-ylamine (82 mg, 90%) as a golden oil: ESI-LRMS m/e calcd for C7H13N3 [M+] 139.12, found 140.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:5][C@H:6]([C:19]([O:21]C)=[O:20])[N:7]2[NH:13][C:14]([CH2:16][O:17][CH3:18])=[O:15].[OH-].[Li+]>O1CCCC1.O>[C:19]([C@H:6]1[CH2:5][C@H:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]1[NH:13][C:14]([CH2:16][O:17][CH3:18])=[O:15])([OH:21])=[O:20]
Reactant: COCC(=O)NN1c2cc(Cl)cc(Cl)c2[C@@H](c2ccccc2)C[C@@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCC(=O)NN1c2cc(Cl)cc(Cl)c2[C@@H](c2ccccc2)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
To a solution of trans-5,7-dichloro-2-methoxycarbonyl-4-phenyl(methoxy)methylcarbonylamino-1,2,3,4-tetrahydroquinoline (Isomer A, 0.180 g, 0.426 mmol) in a mixture of tetrahydrofuran (10 ml) and water (5 ml) was added aqueous lithium hydroxide (0.904 ml of a 0.50M solution, 0.47 mmol), and the resulting mixture was stirred at room temperature for 3 h. The solvent was then removed under vacuum and the residue was diluted with sodium bicarbonate solution (50 ml) and washed with diethyl ether (1×30 ml). The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2×40 ml). The combined extracts were washed with saturated brine (1×40 ml), dried (MgSO4) and evaporated to give a solid which was recrystallised from hot ethyl acetate/petroleum ether (bp 60°-80°) to give the title compound as colourless crystals (0.102 g), m.p. 232°-233° C. δ (360 MHz, DMSO) 1.63 (1H, ddd, J=13.2, 12.6 and 4.1 Hz, CHACHBHCCHD), 2.11 (1H, dd, J=13.2 Hz, CHACHBHCCHD), 3.27 (3H, s, NHCOCH(OCH3)Ph), 3.90 (1H, dd, J=12.6 and 7.7 Hz, CHACHBHCCHD), 4.64 (1H, s, NHCOCH(OCH3)Ph), 5.00 (1H, m, CHACHBHCCHDNHCO), 6.63 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.78 (1H, s, ArNH), 6.88 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.27-7.41 (5H, m, ArH), 8.48 (1H, d, J=7.4 Hz, CHDNHCO); m/e (CI+) 409 (M+H), 166 (100%); Found C, 55.83; H, 4.46; N, 6.81; C19H18Cl2N2O4 requires C, 55.76; H, 4.43 ; N, 6.85%.