Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[C:4]([CH3:18])[CH:3]=1.C(N(CC)CC)C.[Cl:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31].Cl>ClCCl.O>[Cl:26][CH2:27][CH2:28][CH2:29][C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[C:4]([CH3:18])[CH:3]=1)=[O:31]
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2C)cc1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccc(NC(=O)CCCCl)cc2C)cc1
Reaction time: 1 h
Yield: 41.1 %

Procedure:
Methyl 4'-amino-2'-methylbiphenyl-4-carboxylate (D27) (1.84 g, 7.6 mmol) and triethylamine (2.6 ml, 19 mmol) were stirred in dichloromethane (100 ml) as 4-chlorobutyryl chloride (0.94 ml, 8.4 mmol) was added dropwise. The mixture was stirred for 1 h, vigorously stirred with water for 15 min, acidified (5M HCl), and separated. The organic phase was washed with water and K2CO3 /brine solution, dried (Na2SO4) and evaporated to give a light yellow solid. Chromatography on silica gel, eluting with 0-40% ether/dichloromethane, gave the title compound (1.08 g, 41%) as a light yellow solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:28][N:27]=[N:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].[NH3:30]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:30])=[O:16])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:28][N:27]=[N:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:6][CH:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(-c3cnns3)cc2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(N)=O)cc2C(Nc2ccc(-c3cnns3)cc2)CC1C

Procedure:
Reactions and treatments were carried out in the same manner as in Example 118, using 61.2 mg of (2S,4R)-1-acetyl-2-methyl-4-{[4-(1,2,3-thiadiazol-5-yl)phen yl]amino}-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 44.9 mg (73.5%, cis:trans=20:1) of the title compound was obtained as a pale yellow amorphous substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.C(=O)([O-])[O-:39].[K+].[K+].O1CCOCC1>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:6]3[NH:7][C:2](=[O:39])[N:3]=[CH:4][CH:5]=3)=[CH:17][C:14]=2[C:15]#[N:16])=[CH:20][C:21]=1[C:26]([F:29])([F:28])[F:27]
Reactant: N#Cc1cc(COc2ccnc(Cl)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: C1CN2CCN1CC2
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(COc2ccnc(=O)[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 70 °C
Yield: 90.8 %

Procedure:
A mixture of 5-{[(2-chloro-4-pyrimidinyl)oxy]methyl}-2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzo-nitrile (2.30 g, 2.61 mmol), DABCO (0.147 g, 1.31 mmol) and potassium carbonate (1.08 g, 7.84 mmol) in a mixed solvents of 1,4-Dioxane (10 mL) and water (10 mL) was heated at 70° C. for 3 h, then concentrated and diluted with ethyl acetate (100 mL) and water (100 mL). Separated organic part was washed with water and brine, dried over sodium sulfate, concentrated. Purification via mass-directed autopreparation afforded the title product (1.0 g). LC-MS (ESI): m/z 420 [M−H]+; 3.89 min (ret time).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)=[O:4].[H-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C.O>[F:25][C:2]([F:1])([F:24])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:21][CH:22]=1)=[O:4]
Reactant: ClCCN1CCCC1
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A solution of 2,2,2-trifluoro-1-[1-(4-hydroxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (18.98 g, 54.0 mmol) in anhydrous DMF (200 ml) was added to a suspension of NaH (2.592 g, 108.0 mmol) in anhydrous DMF (400 ml) at rt under N2. After stirring at rt for 1 hr, a solution of 1-(2-chloroethyl)pyrrolidine hydrochloride (9.184 g, 54.0 mmol) in anhydrous DMF (200 ml) was added and the reaction mixture was heated to 100° C. for 4 hr. The reaction mixture was cooled to rt, diluted with H2O (2000 ml), and extracted with EtOAc (4×250 ml). The combined extracts were washed with H2O (3×250 ml), dried over MgSO4, and concentrated in vacuo to give 21.15 g of yellow oil. Purification by flash chromatography, eluting with EtOAc:MeOH (8:2) gave 10.503 g (43% yield) of yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(c2ccc(N)cn2)CC1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
1-Ethyl-4-(5-nitropyridin-2-yl)piperazine (3.09 g, 13.8 mmol) was dissolved in methanol (69 mL) and 10% Pd/C (300 mg) was added. The reaction mixture was stirred at room temperature for a day under a pressure of a balloon filled with hydrogen gas. The reaction mixture solution was concentrated by filtering with celite. The resultant target compound (2.4 g, 89% yield) was used in the following reaction without purification.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn](C)(C)C)[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[C:27]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:28]([O:31][CH3:32])=[N:29][CH:30]=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.CN(C=O)C>[NH2:23][C:14]1[CH:15]=[C:16]([C:25]2[CH:26]=[C:27]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[C:28]([O:31][CH3:32])=[N:29][CH:30]=2)[CH:17]=[C:18]2[C:13]=1[CH:12]=[N:11][N:10]2[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: COc1ncc(Br)cc1NS(C)(=O)=O
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ncc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Temperature: 120 °C
Yield: 52.4 %

Procedure:
1-(Phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (4.2 g, 9.63 mmol), N-[5-bromo-2-(methyloxy)-3-pyridinyl]methanesulfonamide (3.25 g, 11.56 mmol) and Pd(PPh3)4 (1.113 g, 0.963 mmol) were weighed into a round-bottomed flask. DMF (30 ml) was added and the reaction was heated at 120° C. for 20 mins. The solvent was removed in vacuo and the crude material (9.8 g) was dissolved in DCM and loaded onto the top of a 750 g RediSep silica cartridge that was then eluted with 0-100% EtOAc/cyclohexane over 10 column volumes using the Companion XL. The product-containing fractions were combined and the solvent removed in vacuo to afford the title compound as a pale yellow solid (2.39 g).
Reaction SMILES: [C:1]([N:8]([CH3:20])[C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:22][O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH2:26].OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH3:22][O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH:26][C:17](=[O:19])[C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:20]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-BOC-N-methyl-(D)-phenylalanine (2.1 g, 7.5 mmol) [BOC=tert-butyloxycarbonyl] in dry DMF [N,N-dimethylformamide] (15 ml) are added (L)-tryptophan methyl ester hydrochloride (2 g, 7.8 mmol) and hydroxybenztriazole (1.2 g, 8.8 mmol). The mixture is cooled to 0° and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.7 ml, 9.2 mmol) is added dropwise. The reaction mixture is slowly warmed to r.t. (room temperature) and stirring continued for 2 hours. The homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to give N-BOC-N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester as a white foam. [a]D =+42° (c=1.0, ethanol).
Reaction SMILES: CCN=C=NCCCN(C)C.[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=1[CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[CH3:29][NH:30][O:31][CH3:32].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:30]([O:31][CH3:32])[CH3:29])=[O:19])=[CH:15][C:14]=1[CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CNOC
Reactant: O=C(O)c1ccc(O)c(CN2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(O)c(CN2CCOCC2)c1
Reaction time: 48 h

Procedure:
EDCI (4.44 g, 23.18 mmol) was added portionwise to a solution of 4-hydroxy-3-(morpholinomethyl)benzoic acid (5 g, 21.07 mmol), N,O-dimethylhydroxylamine (2.67 g, 27.40 mmol), DIPEA (4.05 mL, 23.18 mmol) and HOBt (3.55 g, 23.18 mmol) in DMF (25 mL) whilst maintaining the temperature below 10° C. The mixture was stirred for 48 h, diluted with EtOAc (200 mL), washed with saturated NaHCO3 (200 mL), water (2×100 mL) & brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography on silica with EtOAc as eluent to give the sub-title compound as a colourless oil. Yield: 3.20 g
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][CH2:26][F:27])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:36](=[O:38])[CH3:37].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:36](=[O:38])[CH3:37])[N:23]([CH:25]=[CH2:26])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:36](=[O:38])[CH3:37])[N:23]([CH2:25][CH2:26][F:27])[CH:24]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1cn(CCF)cn1)(c1ccccc1)c1ccccc1
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=Cn1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1C(C)=O
Product: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cn1CCF
Temperature: -78 °C
Reaction time: 4 h

Procedure:
The compound (5.35 g) obtained in (2) was dissolved in THF (200 mL), and cooled to −78° C. while stirring under nitrogen stream. To the present solution was added dropwise n-butyl lithium (2.76 M hexane solution, 7.60 mL), followed by stirring at the same temperature for 30 minutes. Then, N-methoxy-N-methylacetamide (2.91 mL) was added, and stirring was continued for 4 hours while the temperature was gradually brought back to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=4%→40%) using silica gel column (product name: Hi-Flash Column 3 L, manufactured by Yamazen Corporation) to afford the title compound (1.48 g) and 1-[4-(tert-butyldiphenylsilyloxymethyl)-1-(2-fluoroethyl)-1H-imidazol-2-yl)ethanone (3.91 g).
Reaction SMILES: CCN=C=NCCCN(C)C.[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]1[O:26][C:25](=[O:27])[C:24]([CH3:28])=[C:23](O)[C:22]=1[CH3:30].N1C=CC=CC=1[C:37]([OH:39])=[O:38].[CH:40]1[CH:41]=[CH:42]C2N(O)N=[N:46][C:44]=2[CH:45]=1>CN(C=O)C>[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]1[O:26][C:25](=[O:27])[C:24]([CH3:28])=[C:23]([C:37]([O:39][C:44]2[CH:45]=[CH:40][CH:41]=[CH:42][N:46]=2)=[O:38])[C:22]=1[CH3:30]
Reactant: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1O
Reactant: O=C(O)c1ccccn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1C(=O)Oc1ccccn1
Temperature: 25 °C
Reaction time: 21.5 h

Procedure:
WSC (43 mg) was added to a solution of 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg), picolinic acid (23 mg) and HOBt (21 mg) in DMF (3 ml), and the mixture was stirred at room temperature for 21.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=2/1→3/2) to obtain 6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-pyridylcarboxy)-2H-pyran-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-chloro-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (82) and benzyl bromide according to General Procedure B. Yield 319 mg (59%), MP 197° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.15 (m, 4H), 3.95 (m, 4H), 4.32 (q, J=7.2 Hz, 2H), 5.52 (s, 2H), 7.15-7.28 (m, 6H), 7.46 (d, J=3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.29 (d, J=2.8 Hz, 1H), 8.73 (d, J=2.8 Hz, 1H); EIMS: 537 (M+1). Anal. (C27H25ClN4O4S) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:17][CH2:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=2)=[N:14][CH:15]=1.C(O)(=O)C.FC(F)(F)C(O)=O>C(OCC)(=O)C.[Pt]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[NH:20][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[N:14][CH:15]=1
Reactant: COC(=O)[C@@H]1CCC(c2ccc(OCc3ccccc3F)cn2)=N1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cn2)N1
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a solution of methyl (2S)-5-(5-{[(2-fluorophenyl)methyl]oxy}-2-pyridinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (D85, 300 mg, 0.91 mmol) in ethyl acetate was added platinum on activated carbon (70 mg, 5 wt. % dry basis Degussa type F101 RAW) and the mixture was stirred under hydrogen atmosphere (P=1 atm) for 4 hours. After a further addiction of acetic acid (0.4 ml) and stirring for 12 hours the reaction wasn't complete. A further addiction of catalyst (70 mg) and trifluoroacetic acid was required before the reaction was complete. The catalyst was filtered off, the solvent removed under reduced pressure and the residue filtered on scx cartridge. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (7:3 to 6:4) to afford the title compound as a colourless oil (180 mg, 60%). Rt (HPLC): 3.69 min; MS: (ES/+) m/z: 331 [MH]+ C18H19FN2O3 requires 330; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.27-8.43 (m, 1H); 7.45-7.56 (m, 1H); 7.38-7.44 (m, 1H); 7.31-7.38 (m, 1H); 7.24-7.31 (m, 1H); 7.15-7.23 (m, 1H); 7.08-7.15 (m, 1H); 5.18 (s, 2H); 4.32-4.41 (m, 1H); 3.98-4.05 (m, 1H); 3.79 (s, 3H); 2.19-2.31 (m, 2H); 2.04-2.13 (m, 1H); 1.77-1.90 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[CH3:11][I:12]>ClC(Cl)C>[I-:12].[CH3:1][N+:2]([CH3:11])([CH3:10])[C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(N(C)C)c1
Reactant: CI
Solvent: CC(Cl)Cl
Product: Cc1cccc([N+](C)(C)C)c1
Product: [I-]
Temperature: 25 °C
Yield: 70.9 %

Procedure:
Dimethyl-m-tolyl-amine (556 mg, 4.12 mmol) was dissolved in dry dichloroethane (2 mL) and methyl iodide (880 mg, 6.2 mmol) was added dropwise. The reaction was refluxed for 1 h during which time sedimentation occurred. The reaction was cooled to room temperature, the solid filtered out, washed with dichloromethane, and dried overnight in a desiccator to give a white powder (809 mg, 72% yield). 1H NMR (DMSO-d6): δ7.82 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.51 (t, J=8 Hz, 1H), 7.93 J=7.5 Hz, 1H), 3.59 (s, 9H), 2.42 (s, 3H); MS (ESI, m/z): 150 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:3]1=[O:34].C([N:37](CC)CC)C.ClC(OCC)=O>O1CCCC1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]([NH2:37])=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:3]1=[O:34]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(=O)O)n(Cc3cccc4ccccc34)cc21
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(N)=O)n(Cc3cccc4ccccc34)cc21
Reaction time: 0.25 h

Procedure:
The compound of Example 5, 4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoic acid (100 mg), was dissolved in tetrahydrofuran (3 ml) and the solution was cooled in ice. Triethylamine (30 μl) was added followed by ethyl chloroformate (21 μl); the ice bath was removed and the solution was allowed to stir for 15 minutes and was then cooled in ice again. Aqueous ammonia (0.88 specific gravity, 1 ml) was added and the mixture was stirred for 3 days. The mixture was poured onto water and extracted thrice with dichloromethane. The organic extracts were combined, washed with brine, dried, flltered and evaporated to give an oil which was purified by chromatography, eluting first with ethyl acetate:isohexane:acetic acid (75:25:1) and then with ethyl acetate:acetic acid (199:1) to give the title compound (70 mg).
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]=1>C(O)(=O)C>[N:10]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]=2)[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: COC(=O)c1cccc(N)n1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-n2cccc2)n1

Procedure:
6.3 ml of 2,5-dimethoxy-tetrahydrofuran were added with stirring at room temperature to a solution of 7 g of the product of Step C in 17.5 ml of acetic acid and was refluxed for one hour. Acetic acid was evaporated under reduced pressure and the oil residue was chromatographed over silica gel. Elution with methylene chloride yielded 3.7 g of 2-(pyrrol-1-yl)-6-methoxy carbonyl-pyridine melting at 61° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13].[Na+].[I-].[CH3:18][CH2:19][SH:20].O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][S:20][CH2:19][CH3:18])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13]
Reactant: FC(F)(F)COc1ccc(CCl)cc1Br
Reactant: CCS
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCSCc1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 30 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
To a solution of the title compound from Step 3 (2.00 g, 6.59 mmol) in DCM (200 mL) was added TEA (1 g, 9.89 mmol), NaI (898 mg, 5.99 mmol) and EtSH (613 mg, 9.89 mmol). The mixture was stirred at 30° C. for 4 hrs. The reaction was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. Solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (PE:EA=1:0˜3:1) to give the title compound (2.1 g, 96.8%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.55 (d, J=2.0 Hz, 1 H), 7.24 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.42 (q, J=8.0 Hz, 2H), 3.66 (s, 2H), 2.47-2.41 (m, 2H), 1.26-1.22 (m, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Cl.[Mg].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:13]([C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([Cl:9])[CH:11]=1)[OH:14]
Reactant: ClCCCCCBr
Reactant: O=Cc1cccc(Cl)c1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC(CCCCCBr)c1cccc(Cl)c1

Procedure:
A solution (30 ml) of 1-bromo-5-chloropentane (7.0 g) in tetrahydrofuran was gently added dropwise under refluxing to a suspension (30 ml) of magnesium (0.92 g) in tetrahydrofuran. After confirmation of disappearance of magnesium, a solution (30 ml) of 3-chlorobenzaldehyde (5.3 g) in tetrahydrofuran was dropwise added. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 6-bromo-1-(3-chlorophenyl)-1-hexanol, which was dissolved in chloroform (50 ml). Thereto was added 15 equivalents of manganese dioxide, and the mixture was stirred at room temperature for 48 hr. The reaction mixture was filtered, and the residue was purified by silica gel column chromatography to give 6-bromo-1-(3-chlorophenyl)-1-hexanone.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>C(#N)C>[O:21]1[CH2:20][CH:19]1[CH2:17][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: BrCC1CO1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1ccc2c(c1)CCN(CC1CO1)C2
Yield: 43.9 %

Procedure:
1,2,3,4-tetrahydroisoquinoline (25.0 g) was dissolved in acetonitrile (100 ml), and sodium carbonate (40.0 g) and epibromohydrin (31.0 g) were added thereto. Then, the mixture was heated under reflux for 4 hours. After separating salts in the mixture by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Wako gel C-200, 500 g), and then was eluted with a mixed solvent of 99 parts of chloroform and 1 part of methanol to obtain 2-{1-(2,3-epoxy) propyl}-1,2,3,4-tetrahydroisoquinoline (15.6 g).