Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCNCC
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A stirred solution of 2.5 g of diethylamine and 3.5 g of triethylamine in 30 ml of methylene chloride was cooled in an ice bath while 4.9 g of benzoyl chloride was added dropwise. The cooling bath was removed and the mixture stirred at ambient temperature for 18 hours. The insolubles were removed by filtration followed by methylene chloride washing. The combined filtrates were washed with water and brine, dried and evaporated to a yellow oil which was distilled in a Kugelrohr still to give 5.91 g of the desired product as a colorless oil, 70°/300 mm.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]#[N:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C(C)N2Cc3c(ccnc3C#N)C2=O)cnc1OCC(F)(F)F
Temperature: 150 °C
Yield: 80 %

Procedure:
A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (200 mg, 0.52 mmol, Intermediate-2, single enantiomer), zinc cyanide (300 mg, 1.56 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (42 mg, 0.052 mmol) in DMF (5 mL) is heated at 150° C. for 30 min by microwave irradiation. The mixture is filtered through a pad of Celite™. The Celite™ pad is washed with water, and EtOAc. The filtrate is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (3:1) to give 160 mg (80% yield) of the title compound as colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[F:11].C1([O:18][C:19](=O)[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)C=CC=CC=1.C(#N)C>C(N(CC)CC)C>[NH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:19]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)=[O:18])=[CH:5][C:4]=1[F:11]
Reactant: NCc1ccc(N)c(F)c1
Reactant: CC(C)(C)c1ccc(CNC(=O)Oc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccc(CNC(=O)NCc2ccc(N)c(F)c2)cc1

Procedure:
To the 50 ml of round bottom flask were put 4-amino-3-fluorobenzylamine hydrochloride (0.46 g, 3.28 mmol) and 4-t-butylbenzylcarbamic acid phenyl ester (1.1 eq, 1.02 g). And to this mixture was poured 20 ml acetonitrile and added triethylamine (excess, 0.5 ml) and refluxed 12 hours. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, washed with 1N HCl solution. And the combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (n-hexane/ethyl acetate=1/1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][OH:22]>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:20][CH2:21][OH:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cc(O)c2ccccc2n1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(OCCO)c2ccccc2n1
Temperature: 150 °C
Reaction time: 7 h

Procedure:
To a mixture of 2-amino-4-hydroxyquinoline (0.505 g, 3.15 mmol) and K2CO3 (0.87 g, 6.3 mmol) in DMF (10 mL) was added of 2-bromoethanol (0.470 g, 3.78 mmol). The mixture was stirred at 150° C. for 7 h. The reaction mixture was concentrated and the residue purified by column chromatography on silica using MeOH/CHCl3 (1:9) as eluent. The resulting brown oil (0.30 g, 30%), which was used directly in the next step, contained 75% of the desired product and 25% of unreacted starting material. MS m/z 205 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13]CC)=O)[CH:5]=[CH:6][N:7]=1.[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[Li]>>[C:23]([O:22][C:19](=[O:21])[CH2:20][C:11]([C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:3]2[S:2][CH3:1])[CH:9]=1)=[O:13])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cccc(-n2ccnc2SC)c1
Agent: [Li]
Product: CSc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
Prepared from ethyl 3-(2-methylsulfanyl-imidazol-1-yl)-benzoate [prepared by esterification of 3-(2-methoxymethylsulfanyl-imidazol-1-yl)-benzoic acid [CAS-No. 108035-46-7] with conc. H2SO4 in EtOH, followed by treatment methyl iodide and NaH in THF/DMF] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a light brown oil (4.41 g).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6].C([BH3-])#N.[Na+]>CO>[C:5]([N:10]1[CH2:15][CH2:14][C:13]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: NC1CC1
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NC2CC2)(C(=O)OCC)C(C)C1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Cyclopropylamine (10 g, 169.5 mmol) was added to the stirred solution of 1-carbethoxy-3-methyl-4-piperidone (7.0 g, 37.83 mmol) obtained as described in Preparation 1, in methanol (50 ml) and stirring was continued for 12 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (3.0 g, 46.0 mmol) was added to it. Cooling was removed after 10 min. and stirring was continued for 12 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to afford 1-carbethoxy-4-carbethoxy-4-cyclopropylamino-3-methylpiperidine. Yield 6.0 g (70%), C12H22N2O2, m/z 227 (M+1), PMR (CDCl3): 0.38 (m, 4H), 0.88 (dd, 3H), 1.28 (t, 3H), 1.54 (m, 1H), 2.06 (m, 2H) 2.32 (m, 1H), 2.48 (m, 1H), 2.84 (m, 1H), 3.06 (m, 1H), 3.72 (m, 1H), 3.88-4.24 (m, 2H).
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[CH2:19][CH3:20])=[N:10][CH:9]=1
Reactant: CCC(Br)C(=O)Nc1ncc(Cc2ccccc2Cl)s1
Reactant: CCNCC
Product: CCC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)N(CC)CC

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-methylformamide containing diethylamine (146 mg, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (14 mg, 0.038, 38%). ESI-MS m/z calc. 365.1, found 366.2 (M+1)+ Retention time 2.18 minutes.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH2:10](Br)[C:11]#[CH:12]>CN(C)C=O>[CH2:12]([N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9])[C:11]#[CH:10]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: C#CCBr
Agent: [K]
Solvent: CN(C)C=O
Product: C#CCn1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A mixture of the potassium salt of 5-chloropyrimid-2-one (0.009 mol) and propargyl bromide (0.013 mol) in dimethylformamide (40 ml) was stirred at room temperature for 18 h. The solvent was then removed at reduced pressure (1 mm Hg) and the residue was extracted with chloroform (150 ml). The chloroform solution was passed through a column of Al2O3 (Woelm; 30 g, activity III). Evaporation of the chloroform eluates left a solid which was triturated with a little ether before recrystallization from EtOAc; yield 56%, m.p. 130° C. (Found: C, 50.11; H, 2.95. Calc. for C7H5ClN2O: C, 49.87; H, 2.99).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)[C:5]([F:17])=[CH:4][CH:3]=1.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>>[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]2[N:7]=[C:2]([NH:1][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])[CH2:9][CH2:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCN(c2nc(N)ccc2F)CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(F)c(N2CCN(C(C)=O)CC2)n1)C(=O)OCC
Yield: 86.7 %

Procedure:
A mixture of 6-amino-2-(4-acetyl-1-piperazinyl)-3-fluoropyridine (23.9 g) and diethyl ethoxymethylenemalonate (22.7 g) is heated for 5 hours with stirring. After cooling, the precipitate is collected by filtration, and recrystallized from ethanol to give 35.5 g of diethyl N-[6-(4-acetyl-1-piperazinyl)-5-fluoro-2-pyridyl)aminomethylenemalonate (m.p. 164°-165° C.).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[C:5](=[NH:8])[O:6][CH3:7])[CH3:2].C(N(CC)CC)C.[CH3:19][N:20]1[C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=[N:21]1>C1COCC1>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])/[C:5](=[N:8]/[C:25]([C:24]1[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=1)=[O:26])/[O:6][CH3:7])[CH3:11]
Reactant: Cn1nccc1C(=O)Cl
Reactant: CCOC(OCC)C(=N)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(OCC)/C(=N/C(=O)c1ccnn1C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.1 %

Procedure:
To a stirred solution of diethoxyacetonitrile (60 g, 0.465 mol) in absolute methanol (150 mL) under an atmosphere of argon was added a solution of sodium methylate (2.5 g; 0.047 mol) in absolute methanol (20 mL), and the reaction mixture was stirred at room temperature until the nitrile disappeared completely (70–75 h). The reaction was monitored by 1H NMR. The reaction mixture was treated, while stirring, with CO2 until the precipitate of sodium carbonate ceased to form. The latter was filtered off and washed with methanol (50 mL). The filtrate was evaporated under on a rotary evaporator at a bath temperature less than 30° C. The resulting liquid was dissolved in ether (250 mL), filtered to remove the remaining inorganic salts, and evaporated again to give the crude methyl 2,2-diethoxyethanimidoate (71.0 g, 95%). It was distilled under vacuum through a 15-cm Vigreux column, affording 56.2 g (75%) of methyl 2,2-diethoxyethanimidoate (bp. 77–78° C. at 20–22 mm Hg) with a purity of more than 95% by 1H NMR. To a solution of the methyl 2,2-diethoxyethanimidoate (52.1 g, 0.321 mol) and triethylamine (49 mL, 0.353 mol) in absolute THF (300 mL) was added a solution of 1-methyl-1H-pyrazole-5-carbonyl Chloride (46.5 g, 0.321 mol, from Step 1) in absolute THF (150 mL) dropwise under an atmosphere of argon at 0–5° C. over a period of 2 h. The reaction mixture was stirred overnight at a room temperature. The residue the formed was filtered off, and the filtrate was evaporated on a rotary evaporator to give methyl (1Z)-2,2-Diethoxy-N-[(1-methyl-1H-pyrazol-5-yl)carbonyl]ethanimidoate (90 g) as a yellow viscous mass, which was used at the next stage without additional purification. The 90 g of the crude product N-acylated imidate ester obtained at the previous stage was dissolved in absolute dichloromethane (450 mL), and treated with methylhydrazine (17.1 mL, 0.321 mol) with stirring over a period of 10 min. The reaction mixture was stirred at room temperature for 3 h, washed with water (3×300 mL), and dried with anhydrous sodium sulfate. The solvent was removed under vacuum on a rotary evaporator, and the residue (56.5 g) was purified chromatographically on silica gel using hexane/ethyl acetate (1:2) as the eluent. The solvent was evaporated to give 40.1 g (47% based on 1-methyl-1H-pyrazole-5-carbonyl chloride) of the pure title product.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([Cl:22])=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2].S(OC)(O[CH3:30])(=O)=O>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([N:17]([CH3:30])[S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([Cl:22])=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCN1CCCC1CNC(=O)c1cc(NS(C)(=O)=O)c(Cl)cc1OC
Product: CCN1CCCC1CNC(=O)c1cc(N(C)S(C)(=O)=O)c(Cl)cc1OC

Procedure:
Using N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-methanesulfonamidobenzamide and dimethyl sulfate, the reaction is effected as in Example 5, whereby N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-chloro-5-(N-methylmethanesulfonamido)benzamide is obtained as crystals melting at 140.5° to 142° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH:18][CH3:19]>C(Cl)Cl.O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N:18]([CH3:19])[CH3:17])=[O:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: COc1cc(C(C)(C)C)ccc1CC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C(C)(C)C)ccc1CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Step B was dissolved in 20 mL CH2Cl2 and 5.0 mL of a 2 M solution of dimethylamine in tetrahydrofuran was added. The reaction mixture was stirred overnight at room temperature, and then concentrated in vacuo. The residue was partitioned between 50 mL EtOAc, 20 mL water and 10 mL of 5 N sodium hydroxide. The aqueous layer was separated and re extracted with EtOAc, then the organic layers were combined, dried Na2SO4), filtered and evaporated in vacuo to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([O:15]C)=[O:14].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)Cn1c(=O)ccc2cnccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)ccc2cnccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetate (1.51 g, 6.92 mmol) in THF (10 mL) was added sodium hydroxide (4 mL of a 3 N aqueous solution, 13.8 mmol) and the reaction mixture was stirred at room temperature for 18 h. The resulting solution was diluted with ethyl acetate and washed with water. The aqueous phase was separated, adjusted to pH 2 with aqueous HCl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum to give 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetic acid. Retention time (min)=0.368, method [3], MS(ESI) 205.0 (M+H).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]1[CH:15]2[N:6]([CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]2=O)[C:5](=[O:17])[CH2:4]1>Cl[Ti](Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][N:2]=[C:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7][N:6]2[C:5](=[O:17])[CH2:4][CH2:3][CH:15]12
Reactant: CN
Reactant: O=C1c2ccccc2CN2C(=O)CCC12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CN=C1c2ccccc2CN2C(=O)CCC12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methylamine (1 mL) was condensed at −78° C. into a flask containing 1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-3,10-dione (5.54 mmol, 1.113 g). CH2Cl2 (30 mL) was added, and TiCl4 (2.77 mmol, 2.77 mL of 1 M solution in toluene) was gradually added and the mixture was warmed up to room temperature and stirred for 20 hours. Petroleum ether (20 mL) was added and then the mixture was filtered through CELITE. The filtrate was concentrated in vacuo to give 10-methylimino-1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-3-one as a red oil (1.28 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21]O[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:29](OC(N1CCC(=C(Br)C2C=CC(C(N3CCCCC3)=O)=CC=2)CC1)=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH2:29][CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)N3CCCCC3)cc2)CC1
Reactant: O=C(c1ccc(C(c2cccc(F)c2)C2CCNCC2)cc1)N1CCOCC1
Product: O=C(c1ccc(C(c2cccc(F)c2)C2CCNCC2)cc1)N1CCCCC1

Procedure:
Same procedure as described for the preparation of compound 85, but using compound 83 as starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14]([OH:16])=O.[C:17]1([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14]([N:25]1[CH2:26][CH2:27][CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24]1)=[O:16]
Reactant: c1ccc(C2CCNC2)cc1
Reactant: COc1ccccc1-c1oncc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1oncc1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-(2-methoxyphenyl)-isoxazole-4-carboxylic acid (50.6 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O3: 348.1474, found 348.1479.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH3:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH3:8])[C:17]1=[S:18])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: CSc1ccccc1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccccc2SC)C1=S
Yield: 48.6 %

Procedure:
A mixture of N-ethyl glycine (9.23 g), 2-(methylthio)-phenyl-isothiocyanate (9.1 g), triethylamine (10.1 g) and methylene chloride (150 mL) was heated at reflux for 3 hours. The mixture was evaporated to dryness. The residue was recrystallized from ethanol to give the title compound (6.5 g) as a creamy solid, m.p. 128°-131° C. Anal. Calcd. for. C12H14N2S2O: C, 52.11; H, 5.30; N, 10.52. Found: C, 52.28; H, 5.26; N, 10.54. Mass spectrum (EI, M.+) m/z 266.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1>CN(C)C=O>[C:20]1([C:17]2[S:18][CH:19]=[C:15]([CH2:14][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[CH:16]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCc1csc(-c2ccccc2)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1csc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
Prepare a solution of potassium phthalimide (457 mg, 2.47 mmol) in dimethylformamide (6 mL). Add a solution of 4-bromomethyl-2-phenyl-thiophene (523 mg, 2.06 mmol) in dimethylformamide (6 mL), dropwise. Stir the reaction mixture overnight at room temperature under nitrogen. Concentrate the solution, redissolve in ethyl acetate, wash with saturated aqueous sodium hydrogencarbonate (20 mL), then brine (20 mL). Dry (magnesium sulfate), filter aid concentrate. Preform flash chromatography of the resulting residue on silica gel eluting with 5:1 hexane/ethyl acetate to afford 565 mg of 2-(5-phenylthiophen-3-ylmethyl)isoindole-1,3-dione as a yellow solid. 1H NMR (CDCl3) δ 7.84-7.88 (m, 2H), 7.70-7.72 (m, 2H0, 7.54-7.57 (m, 2H), 7.25-7.34 (m, 5H), 4.83 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([C@H:29]4[C@H:33]([CH2:34][O:35][CH3:36])[O:32]C5(CCCCC5)[O:30]4)[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[ClH:42]>CCO>[ClH:42].[CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([C@H:29]([OH:30])[C@@H:33]([OH:32])[CH2:34][O:35][CH3:36])[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC3(CCCCC3)O[C@H]2COC)ns1
Agent: Cl
Solvent: CCO
Product: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)[C@@H](O)COC)ns1
Temperature: 50 °C
Yield: 64.6 %

Procedure:
N-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (1.6 g, 2.70 mmol) was dissolved in EtOH (30 mL) and 4N HCl (1 mL) added and heated to 50° C. overnight. Additional 4N HCl was added (1 mL) and heated for 4 hours. The reaction was cooled to ambient temperature, partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (10% methanol in EtOAc) to afford (1S,2S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-3-methoxypropane-1,2-diol hydrochloride (0.957 g, 1.74 mmol, 64.6% yield) as a tan solid after HCl salt formation. Mass Spectrum (apci) m/z=513.1 (M+H—HCl).
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[C:3](=[O:14])O1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC>[C:16]1([N:15]2[CH2:1][C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:6]=[CH:5][C:4]=3[C:3]2=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C1OCc2c1cnc1ccccc21
Solvent: CCCCCC
Product: O=C1c2cnc3ccccc3c2CN1c1ccccc1
Temperature: 25 °C

Procedure:
A mixture Furo[3,4-c]quinolin-3(1H)-one (100 mg) and aniline (2 mL) was heated at 180° C. for 5 min. After cooling to room temperature the mixture was slowly diluted with hexane and the resulting product was collected and washed with hexane to afford 2-Phenyl-pyrrolo[3,4-c]quinolin-3(1H)-one.