Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:33])[NH:12][CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[N:18]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:17]2=[O:32])(C)(C)C.CC#N>C(O)=O>[O:31]=[C:25]1[CH:24]([N:18]2[C:17](=[O:32])[C:16]3[C:20](=[CH:21][CH:22]=[C:14]([CH2:13][NH:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:34])=[O:5])=[O:33])[CH:15]=3)[C:19]2=[O:23])[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1
Reactant: CC(C)(C)OC(=O)CCCCC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: O=CO
Solvent: CC#N
Product: O=C(O)CCCCC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 88 %

Procedure:
A solution of 5-{[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-carbamoyl}-pentanoic acid tert-butyl ester (0.85 g, 1.8 mmol) in formic acid (25 mL) was stirred at room temperature for 90 minutes. The mixture was evaporated under vacuum, and the residue was triturated in ether/ethyl acetate and filtered, providing 0.66 g, in 88% yield; mp 144-146° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 4.15 (95.81%); 1H NMR (DMSO-d6) δ 1.44-1.59 (m, 4H), 2.02-2.09 (m, 1H), 2.16-2.24 (m, 4H), 2.46-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4.43 (d, J=6.0 Hz, 2H), 5.14 (dd, J=12.9 Hz, J=5.4 Hz, 1H), 7.72-7.77 (m, 2H), 7.87 (d, J=7.8 Hz, 1H), 8.51 (t, J=6.0 Hz, 1H), 11.12 (s, 1H), 12.00 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 24.1, 24.7, 30.9, 33.3, 34.9, 41.9, 48.9, 121.9, 123.5, 129.7, 131.6, 133.3, 147.8, 167.0, 167.1, 169.8, 172.2, 172.7, 174.3; Anal. Calcd for C20H21N3O7+0.2H2O: C, 57.33; H, 5.13; N, 10.03. Found: C, 57.33; H, 4.89; N, 9.81.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]([NH2:8])[CH:5]([CH3:7])[CH3:6].[F:10][C:11]([F:17])([F:16])[CH:12](OC)O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]([N:8]=[CH:12][C:11]([F:17])([F:16])[F:10])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(O)C(F)(F)F
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@@H](N=CC(F)(F)F)C(C)C
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A solution of (S)-2-amino-3-methyl-butyric acid methyl ester hydrochloride (6.72 g, 40 mmol) in water (50 mL) was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford (S)-2-amino-3-methyl-butyric acid methyl ester (40 mmol). A solution of (S)-2-amino-3-methyl-butyric acid methyl ester (40 mmol), 2,2,2-trifluoro-1-methoxy-ethanol (5.2 g, 3.8 mL, 40 mmol) and 4-toluenesulfonic acid hydrate (100 mg) in toluene (125 mL) was heated at reflux using a Dean-Stark apparatus for 3 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 10:1 to 5:1 to afford the title compound (4.79 g, 56%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.94 (d, J=7.1 Hz, 3H), 0.97 (d, J=7.1 Hz, 3H), 2.32-2.44 (m, 1H), 3.73-3.77 (m, 4H), 7.67 (q, J=3.3 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.[CH:13]1([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[CH:18]=[CH:17][C:16]([CH:13]4[CH2:15][CH2:14]4)=[CH:21][N:20]=3)[CH2:23][CH2:24]2)=[O:8])=[C:9]([F:11])[CH:10]=1
Reactant: c1cc(N2CCNCC2)ncc1C1CC1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Product: O=C(c1c(F)cc(Br)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Yield: 88.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2,6-difluorobenzoic acid (1.20 g) and 1-(5-cyclopropylpyridin-2-yl)piperazine (1.15 g) described in Preparation Example 187, the title compound (1.90 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:13]1([C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C@H:16]2[CH2:17][CH2:18][C@H:13]([C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[CH2:14][CH2:15]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: NCCCc1cc(F)cc(F)c1
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4cc(F)cc(F)c4)CC3)cc2o1

Procedure:
Condensation of 3-(3,5-difluorophenyl)-1-propylamine (1.5 g, 6.5 mmol) and ketone 5 (1.5 g, 6.5 mmol), following the procedure described in Example 1, gave 6-(trans-4-[3-(3,5-difluorophenyl)propylamino]cyclohexyl}-3H-benzoxazol-2-one (640 mg, 26%), as a white solid: 1H NMR (500 MHz, DMSO-d6): δ 7.13 (s, 1H), 7.01-6.92 (m, 5H), 2.66 (t, J=8 Hz, 2H), 2.57 (t, J=8 Hz, 2H), 2.49-2.40 (m, 2H), 1.95 (br d, J=10 Hz, 2H), 1.78 (br d, J=10 Hz, 2H), 1.74-1.68 (m, 2H), 1.45 (dddd, J=13, 13, 13, 3 Hz, 2H), 1.14 (dddd, J=13, 13, 13, 3 Hz, 2H).
Reaction SMILES: C1(C(=[N:14][CH:15]([CH:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][CH2:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)[C:16]([O:18]CC)=[O:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:36]>>[ClH:36].[NH2:14][CH:15]([CH:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24][C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]1=2)[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)C1c2ccccc2CCc2ccccc21
Agent: Cl
Product: NC(C(=O)O)C1c2ccccc2CCc2ccccc21
Temperature: 25 °C

Procedure:
The crude ethyl α-[(diphenylmethylene)amino]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetate is mixed with 250 mL of 6N hydrochloric acid solution and heated at reflux for 2 hours. After cooling to room temperature a solid is collected by filtration, washed with water and diethyl ether, air dried, then dried at 50° C./2 mm Hg. This provides 6.43 g of the title compound; mp >280° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20](O)=[O:21])=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[Si:43]([O:50][CH2:51][C:52]([CH3:55])([NH2:54])[CH3:53])([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Si:43]([O:50][CH2:51][C:52]([NH:54][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:12]=2)[NH:17][CH:18]=1)=[O:21])([CH3:55])[CH3:53])([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Reactant: CC(C)(N)CO[Si](C)(C)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 46.1 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), EDCI (130 mg, 0.68 mmol), DMAP (83 mg, 0.68 mmol) and DIEA (88 mg, 0.68 mmol) in 6 mL of DMF was added 1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-amine (138 mg, 0.68 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was washed with petroleum ether to give crude N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (75 mg, 46.0%) as a pale yellow solid. MS: (M+H)+=479.2.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13].Cl>O>[O:13]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][OH:12])[C:4]=2[CH2:3][CH2:2]1
Reactant: OCCc1cccc(O)c1CCO
Agent: Cl
Solvent: O
Product: OCCc1cccc2c1CCO2
Yield: 111 %

Procedure:
A mixture of 2,3-bis(2-hydroxyethyl)-phenol (1.2 g) and 36% aqueous hydrochloric acid (24 ml) was heated at reflux for 2 h. The mixture was cooled, diluted with water (24 ml) and extracted with ethyl acetate (2×24 ml). The combined extracts were dried (Na2SO4) and the solvent evaporated to give the title compound (1.2 g) as a brown oil.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1>CN(C=O)C.O>[CH3:18][S:17][C:13]1[N:14]=[C:15]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:16]=[CH:11][N:12]=1
Reactant: CSc1nccc(Cl)n1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc(Oc2ccccc2)n1

Procedure:
To a suspension of sodium hydride (0.3 g,6.85 mmol, 50% dispersion in oil pre-washed with n-hexane) in dry DMF (4 ml) was added dropwise a solution of phenol (0.59 g, 6.23 mmol) in dry DMF (1 ml). The resulting mixture was stirred under an atmosphere of nitrogen until effervescence had ceased. The resulting mixture was diluted with dry DMF (3 ml) and then added dropwise to a stirred solution of 4-chloro-2-methylthiopyrimidine (1.00 g, 6.23 mmol) in dry DMF (3 ml) at 0° C. An exothermic reaction took place and the temperature of the reaction mixture rose to 5° C. After stirring under nitrogen for 30 minutes at 10° C., GC analysis indicated the formation of a single product (98.8%). The reaction mixture was diluted with water (15 ml) and extracted with ether (2×20 ml). The combined ether extracts were washed with 5% sodium hydroxide solution (2×15 ml) and brine (15 ml) and then dried. Evaporation of the solvent gave 2-methylthio-4-phenoxypyrimidine as a pale yellow oil (1.40 g, 94% pure by GC) which was used directly in the next stage. 1H NMR delta: 2.37(3H, s)ppm.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:36]=[CH:35][C:7]2[O:8][C:9]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:10][O:11][C:6]=2[CH:5]=1.[CH3:37]I>CN(C)C=O>[CH3:37][O:3][C:4]1[CH:36]=[CH:35][C:7]2[O:8][C:9]([C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH:20]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[CH2:18][CH2:19]3)=[O:13])=[CH:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC=C(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
Add 0.98 mmol of 60% sodium hydride suspended in oil to a solution of 0.82 mmol of 6-hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin in 10 cm3 of N,N-dimethylformamide under a nitrogen atmosphere. Stir for 15 minutes at room temperature, then add dropwise 0.98 mmol of methyl iodide. Stir for 2 hours at room temperature and then concentrate to dryness under reduced pressure and purify the resulting crude product by chromatography on a silica column (eluant:petroleum ether/ethyl acetate, 50:50). 6-Methoxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin is thereby obtained in a yield of 83%.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C:13]([S:16][C:17](=O)[CH3:18])([CH3:15])[CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].BrC[CH:22]1[CH2:27][CH2:26][CH2:25]C[O:23]1.C[O-].[Na+]>C(O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:12])[C:13]([CH3:15])([S:16][CH2:17][CH:18]2[CH2:25][CH2:26][CH2:27][CH2:22][O:23]2)[CH3:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)SC(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: BrCC1CCCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(SCC1CCCCO1)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 130 °C
Yield: 99.3 %

Procedure:
To a solution of 100 mg (0.352 mmol) of thioacetic acid S-[1-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-1-methyl-ethyl]ester (synthesized according to Method F, step 1) in ethanol (2 mL) were added 126 mg (0.704 mmol) of 2-(bromomethyl)tetrahydropyran and 76 mg (1.41 mmol) of sodium methoxide at room temperature. The reaction was heated to 130° C. for 0.5 h within a microwave (CEM Discover). The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 ml) and washed with saturated aqueous NaHCO3 solution (5 ml). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to yield 119 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(tetrahydro-pyran-2-ylmethylsulfanyl)-propionamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:16][C:9]2[N:10]=[C:11]([NH2:15])[N:12]=[C:13](Cl)[C:8]=2[CH:7]=1)=[O:5])[CH3:2].C[C:18]([N:20](C)C)=O>[C-]#N.[C-]#N.[Zn+2].[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[S:16][C:9]2[N:10]=[C:11]([NH2:15])[N:12]=[C:13]([C:18]#[N:20])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Cl)nc(N)nc2s1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1cc2c(C#N)nc(N)nc2s1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
2-Amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (1 equiv.), Zn(CN)2 (0.6 equiv.), Zn dust (0.12 equiv.), Pd2(dba)3 (0.02 mole eq.) and 1,1′-bis(diphenylphosphino)ferrocene (0.04 equiv.) were mixed in DMA and the mixture was stirred under argon at 120° C. for 24 hours. The resulting suspension was filtered through a short Celite column, the filtrate was diluted with brine and extracted with ethyl acetate. The organic layer was then washed with brine, water and dried over sodium sulphate. After evaporation of the solvent, the crude oil was purified by preparative TLC.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C([BH3-])#N.[Na+]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:21])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCN2C(=O)COc3ccc(Cl)cc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(Cl)cc54)CC3)nc2N1
Yield: 20.7 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 56) (0.8 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (150 mg, 0.84 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21 to give 78 mg (21%) product as a solid.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:6]=1)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:12]([S:11][C:7]1[N:6]=[C:5]([CH:4]=[O:3])[CH:10]=[CH:9][N:8]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCSc1nccc(C(OCC)OCC)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCSc1nccc(C=O)n1

Procedure:
4-Diethoxymethyl-2-hexylsulfanyl-pyrimidine (250 mg, 0.8 mmol) was stirred in THF (5 mL) and 4 N HCl (5 mL) at 20° C. for 64 h. The reaction mixture was poured in cold 10% Na2CO3 and extracted twice with AcOEt and once with sat. NaCl solution.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:15])[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])[N:6]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[C:16]1([NH:22][C:23](=[O:24])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:15])[C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9])[N:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)COC(=O)C(=O)c1csc(N)n1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CC(C)COC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 1 g of isobutyl 2-aminothiazol-4-ylglyoxylate, 620 mg of phenyl isocyanate and 10 ml of tetrahydrofuran. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].[H-].[Na+].[CH3:43]I.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:43])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2]
Reactant: CI
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OC
Yield: 49.1 %

Procedure:
In 2.2 ml of DMF was dissolved 335 mg (0.61 mmol) of Compound 47 obtained in Example 47, 25 mg (0.61 mmol) of 60% sodium hydride was added at ice-cooling, and stirred at ice-cooling for 20 minutes. 0.042 ml (0.67 mmol) of methyl iodide was added to the above reaction mixture and stirred at room tempareture for 2 hours. Saturated ammonium chloride solution was added and resulting precipitate was collected by filtration, washed with water, dried at heating, purified by silica gel column chromatography (eluent: chloroform/methanol=100/1) and recrystallized from ethanol/ether to give 168 mg (yield: 49%) of Compound 48 as white crystals.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH2:28][CH2:27][CH2:26][C:25]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)=[O:23])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C([O-])(=O)C.[NH4+:41]>CO>[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH2:28][CH2:27][CH2:26][C:25]=2[C:29]2[CH:30]=[C:31]([C:35]([NH2:41])=[NH:36])[CH:32]=[CH:33][CH:34]=2)=[O:23])=[CH:19][CH:20]=1)(=[O:8])(=[O:7])[NH2:5]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2=C(c3cccc(C#N)c3)CCC2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: N=C(N)c1cccc(C2=C(C(=O)Nc3ccc(-c4ccccc4S(N)(=O)=O)cc3)CCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl][2-(3-cyanophenyl)cyclopent-1-enyl]carboxamide (70 mg, 0.137 mmol) in 5 ml anhydrous methanol cooled in an ice bath was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (77 mg, 1 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-(2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}cyclopent-1-enyl)benzenecarboxamidine (40 mg, 63%) as a fluffy white powder after lyophilization. ES-MS (M+H+): 461.15
Reaction SMILES: O[CH:2]1[C:6]2[C:7]3[C:12]([CH:13]=[CH:14][C:5]=2[C:4](=[O:18])[O:3]1)=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=[CH:9][CH:8]=3.CC1C=CC(S(O)(=O)=O)=CC=1.[CH:30](OC)([O:33]C)[O:31][CH3:32].CC(O)=O>CO.C([O-])(O)=O.[Na+]>[OH:17][C:15]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][C:5]1[C:4](=[O:18])[O:3][CH:2]([C:30]([O:31][CH3:32])=[O:33])[C:6]=12)=[O:16]
Reactant: COC(OC)OC
Reactant: O=C1OC(O)c2c1ccc1c(C(=O)O)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1OC(=O)c2ccc3c(C(=O)O)cccc3c21
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 1-hydroxy-6-hydroxycarbonylnaphtho[1,2-c]furan-3(1H)-one in dry MeOH (15 mL) was added TsOH (150 mg) and CH(OMe)3 (0.5 mL). The mixture was stirred at reflux for 2 h. The mixture was then cooled to rt, diluted with saturated aqueous NaHCO3, acidified with AcOH and extracted with EtOAc. The extract was dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed on silica gel (85:15:1 to 66:33:1 hexanes:EtOAc:AcOH) to give the title compound (120 mg, 79% from 1-hydroxy-6-hydroxycarbonylnaphtho[1,2-c]furan-3(1H)-one).
Reaction SMILES: C(C[C:4]([CH2:10]C)(Br)[P:5]([O-:8])(=[O:7])[O-:6])C.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>O>[OH2:6].[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:10][CH2:4][P:5]([OH:6])(=[O:7])[OH:8]
Reactant: CCCC(Br)(CC)P(=O)([O-])[O-]
Reactant: NCCCCCCCCN
Solvent: O
Product: NCCCCCCCCNCCP(=O)(O)O

Procedure:
Diethylbromoethanephosphonate (15.3 g, 0.062 moles) and 1.8-diaminooctane (54.0 g, 0.375 moles) were heated under reflux in water (250 cm3) for 5 hours. The water and excess diamine were then distilled off. Concentrated hydrochloric acid (280 cm3) was added and the solution heated under reflux for 8 hours. The solution was then evaporated to dryness on a rotary evaporator and the residue was dissolved in methanol (75 cm3) and propylene oxide wad added to pH 6. The phosphonic acid was filtered off and dried. The crude yield was 10.2 g (60.5%). A sample was purified by recrystallization from water/ethanol to give N-(8-aminooctyl)-2-aminoethanephosphonic acid monohydrate as a fine white crystalline solid having a melting point of 210° C.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.C([O-])=O.[Na+].CCN(C(C)C)C(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:30]2[C:34](=[O:35])[C@:33]([CH2:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)([CH3:36])[N:32]3C(I)=[CH:47][N:48]=[C:31]23)[CH:25]=[C:26]([Cl:29])[C:27]=1[F:28].[Li+].[Cl-]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:42]([C:41]1[CH:40]=[CH:39][C:38]([CH2:37][C@@:33]2([CH3:36])[N:32]3[C:6]([C:5]([OH:4])=[O:7])=[CH:47][N:48]=[C:31]3[N:30]([C:24]3[CH:23]=[C:22]([Cl:21])[C:27]([F:28])=[C:26]([Cl:29])[CH:25]=3)[C:34]2=[O:35])=[CH:45][CH:44]=1)#[N:43]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(I)n21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)O)n21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.6 %

Procedure:
Acetic anhydride (14.0 mL, 148 mmol), sodium formate (15.1 g, 222 mmol) and Hunig's base (25.8 mL, 148 mmol) were suspended in anhydrous DMF (50 mL) in a 1000 mL screw-top glass pressure-vessel. This was sealed with the screw cap and allowed to stir for 45 min at room temperature. To this mixture was added a solution of 4-[(R)-1-(3,5-dichloro-4-fluoro-phenyl)-5-iodo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-3-ylmethyl]-benzonitrile (40.0 g, 73.9 mmol) in anhydrous DMF (200 mL) followed by Pd(OAc)2 (830 mg, 3.70 mmol) and anhydrous LiCl (9.40 g, 221 mmol). The vessel was capped tightly and allowed to stir at 80° C. for 20 h. In a well ventilated fume hood, the reaction was cooled to room temperature and the screw cap was slowly removed allowing for gas release. The reaction was transferred to a separatory funnel containing a solution of aqueous HCl (2N, 1 L) using EtOAc (1 L). The layers were separated and the organic phase was washed with aqueous 2N HCl (1 L). The combined aqueous phase was extracted with EtOAc (2×1 L). The combined organic phase was dried with MgSO4 and concentrated in vacuo. Toluene was added to the dark colored residue causing precipitation of a solid. The solid was filtered and washed with 1:1 toluene:hexanes followed by hexanes. The filtrate was concentrated and re-processed in a similar manner to give additional solids. A total of 29.4 g of the title compound was obtained as an off-white solid, m/z. 459.4 [M+H]+.