Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].CN1C(C)=CC(=O)C(O)=C1COC.Cl.[CH2:16]([N:18]1[C:23]([CH3:24])=[CH:22][C:21](=[O:25])[C:20]([O:26]CC2C=CC=CC=2)=[C:19]1[CH2:34][O:35][CH3:36])[CH3:17]>[Pd]>[ClH:1].[CH2:16]([N:18]1[C:23]([CH3:24])=[CH:22][C:21](=[O:25])[C:20]([OH:26])=[C:19]1[CH2:34][O:35][CH3:36])[CH3:17]
Reactant: CCn1c(C)cc(=O)c(OCc2ccccc2)c1COC
Agent: [Pd]
Agent: COCc1c(O)c(=O)cc(C)n1C
Agent: Cl
Product: CCn1c(C)cc(=O)c(O)c1COC
Yield: 83 %

Procedure:
In an analogous hydrogenation procedure in the preparation of 1,6-dimethyl-2-methoxymethyl-3-hydroxy-pyridin-4(1H)-one hydrochloride using 1-ethyl-2-methoxymethyl-3-benzyloxy-6-methyl-pyridin-4(1H)-one hydrochloride (1.3 g, 4 mmol) and 5% Pd/C catalyst (0.3 g) yield the title compound 0.78 g (83%) after recrystallisation from methanol/diethyl ether, as a white crystalline solid. m.p. 174-176° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:6][C@H:5]2O.C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O>[N:32]([C@@H:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[O:8][C:7]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:6]1)=[N+:33]=[N-:34]
Reactant: CC1(C(F)(F)F)C[C@@H](O)c2cc(Br)ccc2O1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C(F)(F)F)C[C@H](N=[N+]=[N-])c2cc(Br)ccc2O1
Reaction time: 0.33 h

Procedure:
To a cooled (ice bath) solution of (4R)-6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-ol (277 mg, 890 μmol) was added drop wise diphenylphosphoryl azide (249 μl, 1158 μmol). After stirring 20 min, 1,8-diazabicyclo(5.4.0)undec-7-ene (173 μl, 1158 μmol) was added drop wise. The reaction was stirred at the same temperature for 2 h, then stirred 15 h at ambient temperature. Water was added to quench the reaction. The resulted mixture was extracted with EtOAc. The organics were washed with brine, dried over Na2 SO4, filtered and concentrated. The residue was purified on a silica gel column (5-20% EtOAc/hexane) to afford the title compound. MS m/z: 308 (M−N2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[C:12]([CH2:17][N:18]([CH2:25][C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=3)[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:13][CH:14]=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:43]1[CH:47]=[CH:46][N:45]=[C:44]1[NH:48][C:49](N1C=CN=C1)=[O:50]>CN(C=O)C>[NH:43]1[CH:47]=[CH:46][N:45]=[C:44]1[NH:48][C:49]([N:22]1[CH2:21][CH2:20][CH:19]([N:18]([CH2:17][C:12]2[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:9])[CH3:10])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:25][C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=2)[CH2:24][CH2:23]1)=[O:50]
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccc(Cl)cc2)C2CCNCC2)c(C)c1
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccc(Cl)cc2)C2CCN(C(=O)Nc3ncc[nH]3)CC2)c(C)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a warm (70° C.), stirred, solution of {3-[1-(4-Chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-(3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (0.141 g, 0.30 mmol) and DIPEA (0.32 mL, 1.84 mmol) in DMF (3 mL) was added imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equivs). After 1.5 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (30 mL) and washed with water (5×10 mL). The organic phase was dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 157 mg (85%) of COMPOUND 275 as a white solid. 1H NMR (CDCl3) δ 1.28-1.39 (m, 2H), 1.58 (s, 6H), 1.65-1.71 (m, 2H), 2.24 (s, 3H), 2.29 (s, 3H), 2.56-2.65 (m, 3H), 3.36 (s, 2H), 3.68 (s, 2H), 4.10-4.14 (m, 2H), 6.68 (s, 2H), 6.83-6.85 (m, 2H), 7.07-7.10 (m, 2H), 7.17-7.21 (m, 2H), 7.81 (d, 1H, J=6.9 Hz), 8.09 (s, 1H), 8.50 (d, 1H, J=3.3 Hz); 13C NMR (CDCl3) δ 18.78, 19.21, 28.81, 31.76, 43.11, 45.08, 55.15, 55.65, 58.55, 122.21, 127.81, 129.21, 132.10, 132.30, 133.51, 134.67, 139.48, 143.61, 145.93, 147.15, 147.46, 149.05, 155.28, 156.16, 158.91; ES-MS m/z 572 (M+1) & 574 (M+1). Anal. Calcd. For C32H38N7OCl.0.4CH2Cl2: C, 64.20; H, 6.45; N, 16.18; Cl, 10.53. Found: C, 63.83; H, 6.43; N, 15.88; Cl, 10.92.
Reaction SMILES: [CH2:1]([Zn]CC)[CH3:2].FC(F)(F)C(O)=O.ICI.[F:16][C:17]([F:35])([F:34])[C:18]([N:20]1[CH2:26][C:25](=[CH2:27])[C:24]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:23]=2[CH2:22][CH2:21]1)=[O:19]>ClCCl>[F:35][C:17]([F:16])([F:34])[C:18]([N:20]1[CH2:26][CH:25]([CH:27]2[CH2:2][CH2:1]2)[C:24]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:23]=2[CH2:22][CH2:21]1)=[O:19]
Reactant: C=C1CN(C(=O)C(F)(F)F)CCc2cc(OC)ccc21
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Product: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C1CC1
Reaction time: 0.25 h

Procedure:
A solution of diethyl zinc (1 mL, 1 M in hexanes) in dichloromethane (1 mL) at 0 C was treated with trifluoroacetic acid in dichloromethane (0.5 mL) and the mixture stirred for 15 min. Diiodomethane (0.280 g, 1.0 mmol) in dichloromethane (0.5 mL) was then added and stirred for 15 minutes. N-Trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (0.075 g, 0.26 mmol) in dichloromethane (1 mL) was added and the mixture stirred for 30 minutes at 0 C and then for 2 hours at 20 C. The product mixture was quenched with aqueous saturated NH4Cl (5 mL), extracted twice with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 (10 mL), washed with H2O (10 mL), and concentrated. Flash chromatography (7% EtOAc in hexanes, silica) resulted in 0.050 g of a white solid. MS calculated for C15H16F3NO2+H: 300, observed: 300.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[S-:12][C:13]#[N:14].[NH4+]>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:14]=[C:13]=[S:12])=[O:10])=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [NH4+]
Solvent: CC#N
Product: O=C(Cc1ccc(F)cc1)N=C=S
Temperature: 50 °C

Procedure:
To a solution of crude 1a (27.4 g, 159 mmol) from the previous step in MeCN (159 mL) was added ammonium thiocyanate (12.69 g, 167 mmol, 1.05 eq.). The fine yellow slurry was heated at 50° C. for 1 h. After cooling down to 0° C., the reaction mixture was filtered through a Celite pad and the cake was washed with MeCN (10 mL). The filtrate and washings were combined and concentrated to a volume of 30-40 mL, cooled again to 0° C. and filtered through a Celite pad. The cake was washed with MeCN (10 mL). The filtrate and washings were combined and concentrated to the same volume of 30-40 mL. The resultant solution contained 2-(4-fluorophenyl)acetyl isothiocyanate (2, assumed quantitative yield, Method B). Half of this solution was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([S:11][CH3:12])[S:8][C:6]=2[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([S:11]([CH3:12])=[O:38])[S:8][C:6]=2[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Solvent: ClCCl
Product: CS(=O)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To an ice cooled suspension of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-methylthio-thiazolo[5,4-d]pyrimidine (90 mg, 0.2 mmol) in dichloromethane (5 ml) was added mCPBA (125 mg, 0.5 mmol). The resulting mixture was stirred at 0° C. for 2 h. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (65 mg, 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]#[N:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]([NH:24][OH:25])=[NH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1ccc2nc(C#N)c(OCc3ccccc3)c(=O)n2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(C(=N)NO)c(OCc3ccccc3)c(=O)n2c1
Temperature: 70 °C
Yield: 80 %

Procedure:
The product from Example 11.2 (530 mg, 1.82 mmol) and hydroxylamine hydrochloride (0.549 g, 7.9 mmol) were mixed with ethanol (50 mL). To this stirred solution was added sodium bicarbonate (663 mg, 7.9 mmol) and the mixture was heated at 70° C. for 3 h. The solvent was removed in vacuo and the residue dissolved in a mixed solvent (dichloromethane/ethanol 200 mL: 10 mL), washed with water, dried (Na2SO4) and concentrated in vacuo to give the desired compound (472 mg, 80%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:24])[O:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:10]=2)=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>COC(O)C>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:13]=2)[O:8][C:7](=[O:24])[C:6]=1[C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5]
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2ccc(Oc3ccccc3)cc2oc1=O
Agent: COC(C)O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2ccc(Oc3ccccc3)cc2oc1=O
Yield: 105.5 %

Procedure:
A mixture of 4-hydroxy-2-oxo-7-phenoxy-2H-chromene-3-carboxylic acid ethyl ester (84 mg, 0.248 mmol) and sodium glycinate (121 mg, 1.24 mmol) in methoxyethanol (5 mL) was refluxed for 15 h; then cooled, the solvent was removed, the residue was redissolved in water, acidified with 2 M HCl, the precipitates were collected and freeze dried to give the desired title product (93 mg). ESI (m/z): 356 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12]1([CH2:18][CH2:19][CH2:20][C:21](OC)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC[O-].[Na+].CC(O)=O.O>C(O)C>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:21]([CH2:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=[C:4]2[OH:5]
Reactant: COC(=O)CCCc1ccccc1
Reactant: NC(=O)c1cc(Cl)ccc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1nc(CCCc2ccccc2)nc2ccc(Cl)cc12
Temperature: 25 °C
Yield: 22.8 %

Procedure:
Preparation D8, Step 1: 2-Amino-5-chlorobenzamide (Avocado) (0.50 g, 2.93 mmol, 1 eq.), methyl 4-phenylbutyrate (3.14 g, 17.6 mmol, 6 eq.), NaOEt in ethanol (3.09 M, 5.69 mL, 17.6 mmol, 6 eq.) and ethanol (20 mL) were refluxed overnight. Cooled to 25° C. Added 10 mL of 10% HOAc/H2O. Solids formed which were filtered, the solids rinsed with 5 mL H2O, then dissolved in 20 mL of EtOAc/THF. Dried and stripped in vacuo followed by purification over silica gel in 3:1 to 1:1 Hexanes/EtOAc to give 6-chloro-2-(3-phenyl-propyl)-quinazolin-4-ol as a tan solid (200 mg). MS found: (M+H)+=299.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:4])=[O:3].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)[N:19]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.O>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:26]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:3])=[O:4])=[O:27])[N:19]=1
Reactant: COc1cc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: CON=C(Cl)c1ccccc1S(N)(=O)=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CON=C(Cl)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.4 g of the product of Example 4 and 0.46 of phenyl (4-methoxy-6-methylpyrimidin-2-yl)carbamate in 10 ml of dry acetonitrile was added 0.25 g of DBU. The suspension was stirred for about two hours at room temperature, then diluted with excess water and filtered. The filtrate was acidified with concentrated hydrochloric acid to yield a precipitate. After filtration, the residue was washed with excess water and suction-dried to yield 0.35 g of the subject compound, m.p. 178° to 179° C.;
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1.[F:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1.CC#N.O>C(O)=O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:4]([CH2:5][C:6]3[NH:7][C:8](=[O:16])[C:9]4[CH2:15][O:14][CH2:13][CH2:12][C:10]=4[N:11]=3)[CH2:3][C:2]([F:1])([F:17])[F:18])=[O:34])[CH2:30][CH2:31]2)=[O:25])=[CH:36][CH:37]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c(CNCC(F)(F)F)nc2c1COCC2
Solvent: O=CO
Solvent: CC#N
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC(F)(F)F)CC1

Procedure:
Following the general procedure of Example 1, the title compound was prepared (0.015 g) from 2-((2,2,2-trifluoroethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. 1H NMR (400 MHz, MeOD) δ ppm 8.04-8.18 (m, 2H), 7.21-7.33 (m, 2H), 4.62-4.70 (m, 2H), 4.36-4.53 (m, 5H), 4.17-4.30 (m, 1H), 3.87-4.00 (m, 2H), 3.66-3.80 (m, 2H), 3.38-3.59 (m, 1H), 3.08-3.26 (m, 2H), 2.54-2.69 (m, 2H), 1.93-2.27 (m, 4H). HRMS calculated for C24H27F4N4O4 511.1968. found (ESI, [M+H]+) 511.1963. MS (ESI) m/z 511.2. (M+H)+. Retention time: 3.02 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: [CH2:1]([O:7]C1C=CC(N)=CC=1)[CH2:2]CCCC.[CH2:15]([C:19]1[CH:23]=[C:22]([C:24]2[CH:40]=[CH:39][C:27]([C:28](NCC3CCCC3(C)C)=[O:29])=[CH:26][CH:25]=2)O[N:20]=1)[CH2:16][CH2:17][CH3:18].[NH2:41]N>>[CH2:1]([O:7][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([C:22]2[NH:41][N:20]=[C:19]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:23]=2)=[CH:40][CH:39]=1)[CH3:2]
Reactant: CCCCCCOc1ccc(N)cc1
Reactant: CCCCc1cc(-c2ccc(C(=O)NCC3CCCC3(C)C)cc2)on1
Reactant: NN
Product: CCCCc1cc(-c2ccc(C(=O)OCC)cc2)[nH]n1

Procedure:
This title compound was prepared from compound 1 (title A compound of Example 49) and hydrazine by a similar procedure as described for the title B compound of Example 49.
Reaction SMILES: C(OC([N:8]([CH2:22]/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[S:32][C:33]([NH:39][C:40](=[O:42])[NH2:41])=[C:34]([C:36](=[O:38])[NH2:37])[CH:35]=2)=[CH:27][CH:26]=1)[C@H:9]([C:14]([O:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.FC(F)(F)C(O)=O.CCCC(C)C>ClCCl>[C:36]([C:34]1[CH:35]=[C:31]([C:28]2[CH:27]=[CH:26][C:25](/[CH:24]=[CH:23]/[CH2:22][NH:8][C@H:9]([C:14]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:30][CH:29]=2)[S:32][C:33]=1[NH:39][C:40](=[O:42])[NH2:41])(=[O:38])[NH2:37]
Reactant: CC(C)C[C@@H](C(=O)OC1CCCC1)N(C/C=C/c1ccc(-c2cc(C(N)=O)c(NC(N)=O)s2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCC(C)C
Product: CC(C)C[C@H](NC/C=C/c1ccc(-c2cc(C(N)=O)c(NC(N)=O)s2)cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyclopentyl N-(tert-butoxycarbonyl)-N-[(2E)-3-{-4-[4-carbamoyl-5-(carbamoylamino)thiophen-2-yl]phenyl}prop-2-en-1-yl]-leucinate (Intermediate 9a) (39 mg, 0.065 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (0.5 ml). The reaction mixture was left to stir at RT for 2 hrs. The reaction mixture was worked up by removal of the solvents in vacuo. The residue was diluted with methanol and captured by SCX chromatography, eluting the product with ammonia in methanol. The ammonia fractions were concentrated in vacuo to afford an oily residue. This was taken up in dichloromethane and isohexane added. After removal of the solvent in vacuo a pale orange solid was obtained (24.3 mg, 0.049 mmol, 75%).
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)[C:4]([NH2:6])=[O:5])[CH3:2].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]=O>>[CH2:1]([N:3]1[C:7]2[C:12](=[CH:11][C:10]3[O:13][CH2:14][O:15][C:9]=3[CH:8]=2)[CH:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[NH:6][C:4]1=[O:5])[CH3:2]
Reactant: CCN(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2ccccc2c1
Product: CCN1C(=O)NC(c2ccc3ccccc3c2)c2cc3c(cc21)OCO3
Yield: 46 %

Procedure:
This compound was synthesized from N-ethyl-N-[3,4-(methylenedioxy)phenyl]urea (247 mg) and 2-naphthaldehyde (182 mg) by the procedure described in example 10 in 46% yield, mp: 193-195° C. 1H NMR (CDCl3): 7.86-7.82 (m, 2H), 7.74 (s, 1H), 7.52-7.42 (m, 4H), 6.57 (s, 1H), 6.30 (s,1H), 5.90 (s,1H), 5.87 (s, 1H), 5.61 (s, 1H), 5.18 (s, 1H), 3.97 (q, J=6.6, 2H), 1.32 (t, J=6.6, 3H). Anal. calcd. for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C, 72.53; H, 4.95; N, 7.54.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH2:7]>[Hg]>[C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: O
Reactant: C1=CCCCC1
Agent: [Hg]
Product: C1CCC2OC2C1
Product: O=C1C=CCCC1

Procedure:
Cyclohexene oxidation was carried out in aqueous solvent media. A stirred suspension of 10 ml water, 100 mg of TiO2 semiconductor powder, and 0.2 ml cyclohexene was illuminated with a 500 watt mercury lamp for about 3 hours. This procedure resulted primarily in the formation of 2-cyclohexene-1-one (28 μmol) with a minor amount of cyclohexene oxide (0.3 μmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[Br:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[CH:19]=[C:18]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH2:3][CH2:2]2)[CH:17]=[CH:16][CH:15]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: OB(O)c1cccc(Br)c1
Product: Brc1cccc(N2CCC(N3CCOCC3)CC2)c1

Procedure:
4-[1-(3-Bromo-phenyl)-piperidin-4-yl]-morpholine was prepared from 4-piperidin-4-yl-morpholine (0.21 g, 1.2 mmol) and 3-bromophenylboronic acid (0.50 g, 2.5 mmol) in a manner analogous to Step 49a. The reaction product was isolated as a tan resin (0.238 g, 59%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.08 (t, J=7.1 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J=7.3 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 3.75-3.68 (m, 6H), 2.79-2.70 (m, 2H), 2.60-2.55 (m, 4H), 2.37-2.28 (m, 1H), 1.97-1.89 (m, 2H), 1.68-1.56 (m, 2H). MS=325, 327 (MH)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:30](=[O:31])[C:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:35][CH:34]=3)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]=[C:26]2[CH3:50])=[CH:21][CH:20]=1)[CH2:16][CH3:17])[CH3:14]>O.C(OCC)(=O)C>[CH2:13]([CH:15]([O:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:30](=[O:31])[C:29]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]4[NH:3][C:4](=[O:7])[O:5][N:46]=4)=[CH:37][CH:38]=3)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]=[C:26]2[CH3:50])=[CH:23][CH:24]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(OC(CC)CC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(CC)CC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.45 g), sodium hydrogen carbonate (2.10 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(1-ethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.98 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.41 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.77 g, 71%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>CCOCC>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:22])=[CH:16][CH:15]=1
Reactant: C1CCNCC1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(Cc1ccc(F)cc1)N1CCCCC1

Procedure:
A well stirred mixture of 111.8 g of piperidine, 103 g of pyridine and one liter of anhydrous ether was treated dropwise with 220 g of freshly distilled 4-fluorophenyl acetyl chloride. This mixture was stirred overnight, then filtered and the filtrate washed successively with water twice, 0.1N sodium hydroxide twice, 0.1N hydrochloric acid twice, water and saturated sodium chloride, then dried in vacuo. The residue was distilled giving a yellow liquid which crystallized on standing, giving 245 g of N-(4-fluorophenylacetyl)piperidine.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH2:10][OH:11])[CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:17]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:10][O:11][CH3:17])[CH2:8][OH:9])=[CH:12][CH:13]=1
Reactant: OCC(CO)Oc1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(CO)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Dissolve 2-(4-fluorophenoxy)propane-1,3-diol (186 mg, 0.99 mmol) in THF (5 mL), and add sodium hydride (60% dispersion in mineral oil, 24 mg, 1 mmol). Stir the mixture for 30 minutes at ambient temperature then add iodomethane (0.4 mL, 4.09 mmol). Stir the reaction at ambient temperature for 16 hours. Remove the solvents under reduced pressure and add water to the residue. Extract with EtOAc three times; collect the EtOAc extracts; dry; and remove the solvents under reduced pressure. Purify the residue via prep-TLC using 1:1 EtOAc:petroleum ether, to give the title compound (50 mg, 31.0%). 1H NMR (300 MHz, CDCl3) δ 7.0 (m, 4H), 4.2-4.5 (m, 2H), 3.8 (m, 2H), 3.55 (m, 1H), 3.35 (m, 2H), 2.35 (bs, 1H), 2.0 (s, 3H).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:20][CH2:21][CH2:22][CH:23]1[CH2:25][CH2:24]1.C(OCC)C>C(#N)C>[I-:20].[CH:23]1([CH2:22][CH2:21][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:24]1
Reactant: ICCC1CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: [I-]
Product: c1ccc([P+](CCC2CC2)(c2ccccc2)c2ccccc2)cc1

Procedure:
Triphenylphosphine (2.86 g, 10.9 mmol) was added to a solution of (2-iodoethyl)cyclopropane obtained (2.14 g, 10.9 mmol) in acetonitrile (5 mL), and the mixture was heated to reflux for 15 hr. After cooling, diethyl ether was added thereto and a precipitaed solid was collected by filtration to afford (2-cyclopropylethyl)(triphenyl)phosphonium iodide as a colorless powder (3.87 g).