Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([C:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=2)=[CH:6][N:7]=1.C(Cl)Cl>CO>[NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CC(=O)CC3)cnc2N)cc1F
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(=O)C3)cnc2N)cc1F
Yield: 58.1 %

Procedure:
To tert-butyl 4-(3-amino-6-(3-oxocyclopent-1-en-1-yl)pyrazin-2-yl)-2-fluorobenzoate (650 mg, 1.760 mmol) in MeOH (15 ml) was added 15 ml of DCM under stirring until a clear solution was obtained. The solution was purged by nitrogen for 5 min, then Pd/C (300 mg, 10%, Degussa type) was added, and the resultant mixture was degassed by N2 stream for 15 min. After equipped with hydrogen gas balloon, the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrated solution was concentrated, and the crude material was purified by ISCO. (24 g silica gel, 20 to 80% EtOAc in heptane) to afford 380 mg of the desired product as a light yellow solid. 58.1% yield. LC-MS (m/z): (MH+) 372.1, 0.829 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=2)=[CH:5][N:4]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35]Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:35][CH2:34][CH2:33][S:30]([C:27]3[CH:28]=[CH:29][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:25][CH:26]=3)(=[O:31])=[O:32])[CH:12]=2)=[CH:5][N:4]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)CCCCl)cc1
Reactant: COc1ccc(Cc2cnc(N)nc2N)cc1O
Agent: Cl
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OCCCS(=O)(=O)c1ccc(NC(C)=O)cc1
Yield: 80 %

Procedure:
Following substantially the procedure of Example 1, Step B, 2,4-diamino-5-(3'-hydroxy-4'-methoxybenzyl)pyrimidine hydrochloride is treated with 3-(p-acetamidophenylsulfonyl)propyl chloride to afford 2,4-diamino-5-{3'-[3"-(p-acetamidophenylsulfonyl)propoxy]-4-methoxybenzyl}pyrimidine in 80% yield.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]1([C:7]2[O:8][CH2:9][C:10](=[O:13])[N:11]([CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1COC(c2ccccc2)=NN1
Reactant: OC1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1COC(c2ccccc2)=NN1C1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
2-Phenyl-4H-1,3,4-oxadiazine-5(6H)-one (0.30 g) synthesized according to Receuil des Travaux chimiques des Pays Bas, 1929, 48, 417, 3-hydroxy tetrahydrofuran (0.30 g) and triphenyl phosphine (0.89 g) were dissolved in tetrahydrofuran (10 ml). Under ice-cooling, 40% diethyl azodicarboxylate/toluene solution (0.59 g) diluted with tetrahydrofuran (3 ml) was added thereto, followed by stirring overnight at room temperature. The reaction solution was evaporated and purified by Cromatorex NH silica gel chromatography (hexane/ethyl acetate system), to give the title compound (0.15 g, 36%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][C:5]=1[C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.[NH2:28][NH2:29]>C(O)C>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:2])[NH:29][N:28]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: COC(=O)c1ccc(OCc2ccccc2)nc1C(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)c2nc(OCc3ccccc3)ccc12

Procedure:
2-Benzoyl-6-benzyloxynicotinic acid methyl ester (1.14 g) and hydrazine monohydrate (0.40 ml) were stirred together in ethanol (50 ml) at reflux overnight. The reaction was cooled (ice bath) precipitating a solid, which was separated by filtration and washed with diethyl ether. This was 2-benzyloxy-8-phenyl-6H-pyrido[2,3-d]pridazin-5-one (0.845 g). 1H NMR (400 MHz, DMSO) δ5.42 (2H, s), 7.33 (6H, m), 7.50 (3H, m), 7.86 (2H, m), 8.51 (1H, d, J=9.7 Hz), 13.04 (1H, s); MS (ES+) m/e 330 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.3 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 105 mg, 0.33 mmol) in pyridine (5 mL) was treated with dimethylsulfamoyl chloride (0.04 mL, 0.38 mmol). The reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in methylene chloride, and the organic phase was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 60/40 heptane/ethyl acetate) afforded the N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-dimethylsulfamide (21.3%) as a white solid: mp 110-112° C.; FAB-HRMS m/e calcd for C19H26N4O3S2 (M+H)+ 423.1524, found 423.1524.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:6].C1(C)C(C)=CC=CC=1.Cl[CH2:32][C:33]([OH:35])=[O:34]>C(N(CC)CC)C>[ClH:22].[C:33]([CH2:32][N:3]([CH3:2])[CH2:4][C:5]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:6])([OH:35])=[O:34]
Reactant: CNCC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(O)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CN(CC(=O)O)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 104 %

Procedure:
4.6 g of 2-(methylamino-acetamido)-5-chlorobenzophenone hydrochloride were heated in 100 mls. of dry xylene with 3 g of triethylamine and 1.9 g of chloracetic acid for 8 hours under reflux whilst stirring. After cooling, the precipitated triethylamine hydrochloride was filtered off and the filtrate was shaken 3 times with 100 mls. of water each time. After drying over potassium carbonate and filtering, it was concentrated in vacuo, the oily crude base obtained being dissolved in 100 mls. of dry ether and filtered again. By passing in dry hydrogen chloride gas, filtering under suction and drying in a vacuum desiccator, 2.8 g (71% of theory) of 2-(4-carboxy-3-methyl-3-aza-butyramido)-5-chlorobenzophenone hydrochloride were obtained with a melting point of 162°-164°.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:19][NH:20][CH3:21].O>C1COCC1>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:20]([CH3:21])[CH3:19])=[N:7][CH:6]=3)[S:9][C:10]=2[CH:16]=1
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3ccc(N(C)C)nc3)sc2c1

Procedure:
2-(6-Fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (0.201 g) and 2 M dimethylamine in THF (5 mL) were heated in a microwave oven at 100° C. for 5 min. Water was added and the precipitated product was filtered off, washed with water and dried in a desicator over P2O5 to yield 0.193 g of the product as a pale beige solid. 1H NMR δ ppm 8.71 (d, 1H) 8.07 (dd, 1H) 7.84 (d, 1H) 7.65 (d, 1H) 7.08 (dd, 1H) 6.77 (d, 1H) 3.84 (s, 3H) 3.12 (s, 6H); MS m/z (M+H) 286.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:16]([O:15][C:11]([CH2:12][CH2:13][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: N#CCc1ccc(Br)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(CC#N)cc1
Reaction time: 72 h

Procedure:
A mixture of 5 g of p-bromophenylacetonitrile, 4.6 ml of t-butyl acrylate, 57 mg of palladium diacetate, 310 mg of tri-o-tolylphosphine and 12 ml of triethylamine is refluxed for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with 10% HCl and saturated sodium bicarbonate solution. After drying over magnesium sulfate the solvent is removed in vacuo. This material is dissolved in ethanol and hydrogenated over 1.1 g of 10% palladium on carbon catalyst for 3 days at 3 atmospheres pressure of hydrogen. After filtration the solvent is removed in vacuo and the residue is chromatographed on silica gel with ether/hexane (1:1) as the eluent to afford p-(2-t-butoxycarbonyl-ethyl)-phenylacetonitrile; 2.8 g of this product is dissolved in 90 ml of tetrahydrofuran and 50 ml of methanol and to this is added 6.2 g of cobalt chloride in 90 ml of water followed by 2.1 g of sodium borohydride in small portions. After filtration and removal of solvent, the residue is chromatographed on silica gel with 7.5% methanol saturated with ammonia in methylene chloride as the eluent to afford p-(2-t-butoxycarbonyl-ethyl)-2-phenethylamine as an oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11][CH2:12][CH:13]([OH:36])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH:21]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:13]([OH:36])[CH2:12][NH:11][C:7]34[N:6]=[CH:5][N:4]=[C:3]3[CH:2]=[N:10][CH:9]=[N:8]4)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1
Reactant: NCC(O)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CO
Solvent: CCN(CC)CC
Product: OC(CNC12N=CN=CC1=NC=N2)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 6-chloropurine (0.728 g, 4.7 mmol), 1-amino-3-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-propanol (1.73 g, 4.77 mmol) and triethylamine (1.36 mL, 9.5 mmol) in MeOH (20 mL) was heated to reflux for 7 days and the solvent was removed in vacuo. The residue was dissolved in CHCl3 and the extracted with aqueous sodium bicarbonate (2×100 mL); the organic phase was dried over sodium sulfate and evaporated to give a solid which was purified by flash chromatography on silica gel with 5% MeOH in CHCl3. The product was a colorless solid which was triturated with ether, 1.5 g (70%), mp 140°-170° C.; IR (KBr) 3000 cm-1 ; 300 MHz 1H NMR (CDCl3); δ: 8.17 (s, 1H), 8.11 (s, 1H), 7.5-7.0 (m, 8H), 4.90 (br s, 1H), 4.34 (s, 1H), 3.87 (br s, 1H), 3.7-2.0 (m, 12H); MS 480 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[CH:16]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH:29]2[CH2:31][CH2:30]2)O)=[C:23]([F:32])[CH:22]=1>ClCCl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH:29]2[CH2:31][CH2:30]2)[C:16]2[C:15]3[C:19](=[C:11]([CH2:10][S:9][CH3:8])[CH:12]=[CH:13][CH:14]=3)[NH:18][CH:17]=2)=[C:23]([F:32])[CH:22]=1
Reactant: OC(c1ccc(Cl)cc1F)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.13 ml (1.73 mmol) of trifluoroacetic acid was added to 256 mg (1.45 mmol) of the compound from Example 8A and 290 mg (1.45 mmol) of the compound from Example 151A in 20 ml of dichloromethane, and the mixture was stirred at RT for 2 h. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 273 mg (51% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:24])([CH3:23])[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.O.[CH3:26][N:27](C)C=O>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.[C-]#N.[Zn+2].[C-]#N>[C:19]([SiH2:18][O:17][C:16]([CH3:24])([CH3:23])[C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=2)[C:26]#[N:27])=[O:9])=[CH:11][CH:12]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)c2cncc(Br)c2)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)c2cncc(C#N)c2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
Add tetrakis(triphenylphosphine)palladium (284 mg, 0.246 mmol) to a solution of (5-bromo-pyridin-3-yl)-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanone (1.0 g, 2.46 mmol) and zinc cyanide (578 mg, 4.92 mmol) in dimethylformamide (25 mL) and stir. Purge solution with nitrogen and heat to 80° C. After 18 hours, add water (100 mL) and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue with flash chromatography eluting with 12.5% ethyl acetate:hexanes to yield the title product as a white solid (550 mg, 63%): 1H NMR (DMSO-d6) δ 0.11 (s, 6H), 0.93 (s, 9H), 4.84 (bs, 2H), 7.53 (d, 2H), 7.83 (d, 2H), 8.61 (t, 1H), 9.09 (d, 1H), 9.26 (d, 1H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1>C(Cl)(Cl)Cl>[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:5](=[O:7])[CH3:6])=[C:11]([CH3:16])[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(F)ccc1N
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(F)cc1C
Yield: 99.8 %

Procedure:
Acetic anhydride (17.7 ml, 0.19 mol) was dropwise added to 4-fluoro-2-methylaniline (234 g, 0.19 mol). The solidified reaction mixture was dissolved in chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the residue was dried with a vacuum pump to obtain the entitled compound (31.7 g, 99%) as a pale red solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 81 %

Procedure:
To a 50 mL flask was added 5 (220 mg, 1 mmol) and 5 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 300 mg of silica gel. The solvent was evaporated to afford a plug Column chromatography of the plug with hexane:acetyl acetate=20:1 as eluent afford 192 g (81%) of 6 as a yellow solid: 1H NMR (DMSO-d6) δ 1.82 (m, 4H), 2.63 (s, 3H), 2.84 (m, 2H), 2.96 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH:22]=O)=[O:19])=[O:12].Cl.[NH2:28][OH:29].N1C=CC=CC=1>CN(C)C=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH:22]=[N:28][OH:29])=[O:19])=[O:12]
Reactant: NO
Reactant: O=C[C@@H]1CCCN1C(=O)[C@H]1NCSC1C(=O)CC1Cc2ccccc2C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCC[C@H]1C=NO
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-L-prolinal (372 mg), hydroxylamine hydrochloride salt (76 mg) and pyridine (89 μl) were dissolved in 5 ml of dimethylformamide, and stirred at 70° C. for 1.5 hours. After concentrating the reaction solution under reduced pressure, the resulting residue was dissolved in 30 ml of methylene chloride, washed by saturated aqueous sodium chloride solution, and dried over magnesium sulfate, followed by distillation of the solvent under reduced pressure. The resulting residue was purified by column chromatography to obtain 120 mg of (2S)-1-[3-(indan-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine aldoxime. Yield; 31%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]1.C(N(CC)CC)C>C(#N)C>[NH2:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:3]=2)[CH2:24]1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: N[C@@H]1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 100 °C
Yield: 53.6 %

Procedure:
To a 10 mL vial was added N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.166 g), (3R)-3-pyrrolidinamine (0.127 g), triethylamine (0.083 mL) and acetonitrile (5 mL). The vial was sealed and heated at 100° C. for 30 minutes within a microwave. The reaction was cooled to room temperature and the resulting solid removed by filtration. This solid was purified (Varian SCX cartridge, using methanol and 10% ammonia in methanol as eluant) to afford the title compound (0.102 g).
Reaction SMILES: [C:1]([CH:3]([CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH3:7])=[O:5])#[N:2].O1CCOCC1.[ClH:29]>>[Cl:29][C:1]1[NH:2][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cl
Reactant: COC(=O)C(C#N)CC(=O)c1ccc(C2CCCCC2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(C3CCCCC3)cc2)[nH]c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14% Hydrogen chloride-1,4-dioxane solution (50 mL) was added to methyl 2-cyano-4-(4-cyclohexylphenyl)-4-oxobutanoate (12.1 g) and the mixture was stirred at room temperature for 8 hr and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether and collected by filtration to give a nearly 1:1 mixture (3.41 g) of the title compound and methyl 2-amino-5-(4-cyclohexylphenyl)-3-furoate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:2) to give the title compound as crystals (yield 0.64 g, 5%).
Reaction SMILES: [CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH2:31][CH2:32][CH:33]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:11][CH2:12][N:13]([CH2:33][CH2:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2OC2(CCNCC2)CN1Cc1ccccc1
Reactant: O=CCCc1ccccc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2OC2(CCN(CCCc3ccccc3)CC2)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in Example 30 (0.01 mmol) in tetrahydrofuran (0.4 mL) were added 3-phenylpropanal (0.02 mmol) and MP-BH(OAc)3 (Argonaut, product number 800415, loading; 2.25 mmol/g) (13.3 mg). The mixture was stirred overnight at 25° C. To the reaction mixture were added tetrahydrofuran (0.4 mL) and PS-NHNH2 (Argonaut, product number 800272, loading; 3.65 mmol/g) (8.2 mg). After stirring overnight, the mixture was filtered and the filtrate was concentrated to give the compound of the present invention having the following physical data.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[CH:30][C:31]([F:40])=[C:32]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:33]=2)[CH2:24][CH2:23]1>>[F:40][C:31]1[CH:30]=[CH:29][C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:27][CH2:26]2)=[CH:33][C:32]=1[NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38]
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)ccc1F

Procedure:
Example 51 was prepared from 2,2-diphenylpropanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.27–8.13 (m, 1H), 8.04 (s, 1H), 7.62 (s, 1H), 7.50–7.39 (m, 1H), 7.39–7.16 (m, 7H), 7.12–6.90 (m, 2H), 6.79–6.60 (br, 1H), 4.94–4.61 (br, 1H), 3.60–3.22 (m, 4H), 2.89–2.76 (m, 2H), 2.76–2.55 (m, 4H), 2.55–2.34 (m, 3H), 2.14–1.82 (m, 3H), 2.00 (s, 3H), 1.26 (d, 6H, J=6.4 Hz); ESMS m/e: 530.4 (M+H)+; Anal. Calc. for (HCl salt) C33H41ClFN3O2.0.24CHCl3.0.96H2O: C, 65.23; H, 7.11; N, 6.86. Found: C, 64.96; H, 7.36; N. 6.87.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])[C:12]([CH:25]([CH3:27])[CH3:26])=[C:11]([O:28]CC2C=CC=CC=2)[N:10]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[CH:25]([C:12]1[C:11](=[O:28])[NH:10][C:9](=[O:8])[NH:14][C:13]=1[O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:19]#[N:20])([CH3:27])[CH3:26]
Reactant: Cc1cc(C#N)cc(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
3-(2,6-Bis-benzyloxy-5-isopropyl-pyrimidin-4-yloxy)-5-methyl-benzonitrile (372 mg, 65% pure, 0.52 mmol) was dissolved in 20 mL of EtOAc and 5 mL of EtOH. 10% Pd/C (75 mg) was added and a hydrogen balloon was applied. The reaction mixture was stirred at room temperature for 1 hour. The Pd/C was filtered through celite, and the filtrate was concentrated and purified using silica gel (EtOAc/hexane) to give a white solid (100 mg, 29%). LC-MS shows 286.0 (M+1).