Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC([N:36]1[CH2:41][CH2:40][CH:39]([O:42][C:43]2[CH:48]=[CH:47][C:46]([CH:49]=O)=[CH:45][C:44]=2[F:51])[CH2:38][CH2:37]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:49][C:46]1[CH:47]=[CH:48][C:43]([O:42][CH:39]2[CH2:40][CH2:41][NH:36][CH2:37][CH2:38]2)=[C:44]([F:51])[CH:45]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2F)CC1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OC2CCNCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 19.3 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-fluoro-4-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (75 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (5.1 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1(N)[NH2:9].[CH3:12]COCC.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>O>[CH3:1][N:2]([CH3:11])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH:9][CH3:12]
Reactant: CCOCC
Reactant: CN(C)C1CCCCC1(N)N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CNC1CCCCC1N(C)C
Yield: 82 %

Procedure:
A solution of the N-formyl-N-[2-(dimethylamino)cyclohexanediamine (4 g.; 0.0235 mole) in 50 ml. of ether was added during 5 minutes to a solution of LAH (4 g.) in 250 ml. of ether and refluxed 17 hours. It was cooled in ice, and decomposed in succession with 4 ml. of H2O, 4 ml. of 15% NaOH, 12 ml. of H2O, stirred 1 hour at room temperature and filtered. The cake was washed with ether, and the ether was distilled. The titled amine (B) residue was distilled at 14 mm, b.p. 86°-87°, 3 g. (82% yield). ir NH 3680 v.w., 3320; CH 2940, 2820; N-alkyl 2780; CH 1475, 1450; C-N/other 1270, 1155, 1145, 1125, 1060, 1045, 1005, 870, 805, 775. nmr in CDCl3 (60 MHz) was in accord. Mass spectrum M+ 156.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:17])=[C:11]([N:34]([C:38](=[O:41])[CH2:39]Cl)[CH:35]([CH3:37])[CH3:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([N:15]([C:16]([C:18]3[C:19]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=4)=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH2:39][C:38](=[O:41])[N:34]2[CH:35]([CH3:36])[CH3:37])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(C(=O)CCl)c1cc(OCc2ccccc2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)CN(C(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c2ccc(OCc3ccccc3)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid {4-benzyloxy-2-[(2-chloroacetyl)isopropylamino]phenyl}amide (134 mg) in DMF (2 mL) were added potassium carbonate (48 mg) and sodium iodide (one spatula), and he mixture was stirred at 80° C. for 2 hours. The reaction solution was allowed to stand for cooling to room temperature, and diluted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 7-benzyloxy-1-isopropyl-4-(4′-trifluoromethylbiphenyl-2-carbonyl)-3,4-dihydro-1H-quinoxalin-2-one (118 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[Cl:25][C:26]1[C:27]([NH2:41])=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[NH2:41][C:27]1[N:28]=[CH:29][C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)=[CH:31][C:26]=1[Cl:25]
Reactant: CC1(C)OB(c2cnc(N)c(Cl)c2)OC1(C)C
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N)c(Cl)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 0.075 mmol) and 3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (stage 148.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.53 min (Method A); M+H=485 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.94 (s, 1H), 8.51-8.49 (m, 1H), 8.08-8.04 (m, 1H), 7.96-7.92 (m, 1H), 7.72-7.69 (m, 1H), 7.39-7.36 (m, 1H), 6.74 (s, br, 2H), 3.80 (s, 3H), 3.58 (s, 3H), 2.08 (s, 3H), 1.89 (s, 3H))
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[N:33][CH:34]=1.[O-2].[Mg+2]>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH3:17][S:18]([C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[N:38][S:35]([C:32]1[CH:31]=[CH:30][C:29]([CH3:28])=[CH:34][N:33]=1)(=[O:37])=[O:36]
Reactant: Cc1ccc(S(N)(=O)=O)nc1
Reactant: CSc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: O=Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N=S(C)c2ccc([N+](=O)[O-])cc2)nc1
Reaction time: 24 h
Yield: 54 %

Procedure:
879 mg (2.73 mmol) of iodosobenzene diacetate are added to a suspension of 300 mg (1.77 mmol) of 1-methylsulphanyl-4-nitrobenzene, 610 mg (3.55 mmol) of 5-methyl-2-pyridinesulphonamide, 285 mg (7.10 mmol) of magnesium oxide and 78 mg (0.18 mmol) of rhodium(II) acetate dimer in 12 ml of dichloromethane at room temperature. The mixture is stirred for 24 h and then concentrated. The resulting residue is purified by chromatography (dichloromethane/ethanol 95:5). 326 mg (0.96 mmol; yield: 54%) of the product are obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].Cl[CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21]>CN(C)C=O>[O:22]=[C:20]([CH2:19][CH2:18][CH2:17][N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH3:21]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(=O)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Yield: 11.2 %

Procedure:
A suspension of 80% sodium hydride in mineral oil (3 g; 0.1 moles) was added in small portions during 10 minutes, to a suspension of 18 g (0.1 moles) of theobromine in 400 ml of anhydrous dimethylformamide. The reaction mixture was heated to 95°-100° C. for 3 hours. Then 13.26 g (0.11 moles) of 5-chloro-2-pentanone were added, and the reaction mixture was maintained at 95°-100° C. for 20 hours more. After filtration, the filtrate was evaporated under reduced pressure, the residue was treated with 150 ml of water and the pH was adjusted to 13-14 with a 10% NaOH aqueous solution. The mixture was extracted with 3×80 ml of methylene chloride, the combined organic extracts were washed with 3×50 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. 2.95 Grams (11.2%) of the title compound were obtained, melting at 109°-111° C., which was directly used in the next step. The 1H-NMR spectrum was consistent with the formula.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]=[C:10]=[O:11])[CH:3]=1.[CH3:12][C:13]1[N:14]=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([NH2:23])[C:21]=2[CH:22]=1.BrC1C=CC(CN=C=O)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:9][C:10]([NH:23][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[CH:22]=[C:13]([CH3:12])[N:14]=[CH:15]2)=[O:11]
Reactant: O=C=NCc1cccc(F)c1
Reactant: Cc1cc2c(N)cccc2cn1
Agent: O=C=NCc1ccc(Br)cc1
Product: Cc1cc2c(NC(=O)NCc3cccc(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 60F using 1-fluoro-3-(isocyanatomethyl)benzene and 3-methyl-5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.69 (bs, 1H), 8.87 (bs, 1H), 8.20 (d, 1H, J=6.9 Hz), 7.76 (s, 1H), 7.70 (d, 1H, J=7.8 Hz), 7.50 (t, 1H, J=7.8 Hz), 7.41 (m, 1H), 7.23-7.05 (m, 3H), 4.39 (d, 2H, J=6 Hz), 2.65 (s, 3H). MS (ESI) 310 (M+H)+. Anal. Calcd for C18H16FN3O: C, 69.89; H, 5.21; N, 13.58. Found: C, 69.86; H, 5.24; N, 13.56.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25].O>N1C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][S:24]([N:23]([CH3:28])[CH3:22])(=[O:26])=[O:25])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,6-diamine (0.05 g, 0.18 mmol) was dissolved in pyridine (1 mL). Dimethylsulfamoyl chloride (0.02 mL) was added and stirred for 72 h at ambient temperature. Then water was added and the mixture extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography (silica gel, heptane, ethyl acetate 4:1/1:1) to yield the title compound as a brown oil (30 mg, 43%); MS: m/e=383.6 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10](=[O:14])[C:11]#[C:12][CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1>CO>[CH3:1][C:2]1[CH:3]([C:10](=[O:14])/[CH:11]=[CH:12]\[CH3:13])[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=1
Reactant: CC#CC(=O)C1C(C)=CCCC1(C)C
Solvent: CO
Product: C/C=C\C(=O)C1C(C)=CCCC1(C)C

Procedure:
The acetylenic carbinol which was obtained as described above under paragraph b) was oxidised as described for its isomer in Example 18, paragraph c). Thus, 1.38 g. of carbinol gave 0.9 g. (66 %) of 2,6,6-trimethyl-1-tetrolyl-2-cyclohexene, b.p. 100°-105°/0.7 Torr. NMR spectrum (CCl4): 0.96 (6 H, d badly resolved), 1.52 (3 H, m), 2.0 (3 H, s), 5.57 (1 H, m), 2.66 (1 H, m) ppm (δ).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.[OH-].[K+].Cl>C(O)C.O>[C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][CH:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)[C:3]([OH:32])=[O:2])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)C(Oc1cccc(C(C)(C)C)c1)c1ccc(OCOc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cccc(OC(C(=O)O)c2ccc(OCOc3ccc(Cl)cc3)cc2)c1
Yield: 91.2 %

Procedure:
To a solution of 9.5 g of methyl(m-tert.-butylphenoxy){p-[(p-chlorophenoxy)methoxy]phenyl}acetate in 60 ml of ethanol is added a solution of 7 g of potassium hydroxide in 60 ml of water. The mixture is stirred and refluxed for 18 hours and while hot is acidified with 11.5 ml of concentrated HCl. The mixture is chilled immediately. The supernatant is decanted from the oil which separates. Water is added and decanted. The gummy material is dissolved in dichloromethane, dried (MgSO4) and the solvent removed under reduced pressure to give 8.4 g of a gum. The gum is triturated with hexane containing a small amount of dichloromethane to give 5.7 g of yellow crystals. The crystals are dissolved in 25 ml of dichloromethane and the solution diluted with 50 ml of hexane. Chilling gives 4.4 g of product as pale yellow crystals, mp 122°-124° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[N:6]=1.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:14][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH3:21])[O:3][C:4]=2[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)c(Cl)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-chloro-4-(3,4-dichlorophenyl)-5-oxazolepropionate (1.00 g), 2-methylimidazole (0.82 g), potassium carbonate (0.69 g) and N,N-dimethylformamide (20 mL) was stirred at 120° C. for 1 h. The reaction mixture was poured into iced water (100 mL) and the precipitated crystals were collected by filtration, washed with water and then with isopropyl ether and air-dried to give the title compound as crystals. Recrystallization from ethyl acetate-isopropyl ether gave pale-yellow prism crystals (0.82 g, 72%). melting point: 116-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30][CH3:31])[CH:24]=2)[CH2:19][CH2:18]1)=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:14][C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30][CH3:31])[CH:24]=4)[CH2:21][CH2:22]3)=[O:16])[C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: Cn1c(=O)[nH]c2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)n(C)c4cc(Cl)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-one (61) (75 mg, 0.41 mmol, 1 eq), 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (125 mg, 0.41 mmol, 1 eq), cesium carbonate (401 mg, 1.23 mmol, 3 eq) in DMF (2 ml) was stirred at rt overnight. The reaction solution was diluted with ethyl acetate, washed with water. The organic layer was evaporated to dryness and the crude residue was purified by flash chromatography to provide the desired product 5-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-1,3-dihydro-benzoimidazol-2-one (62): LCMS observed for (M+H)+: 449.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:28][CH:29]1[C:33]([CH3:35])([CH3:34])[CH2:32][S:31][C:30]1([CH3:37])[CH3:36]>C(OCC)(=O)C.O1CCCC1>[CH3:36][C:30]1([CH3:37])[CH:29]([NH:28][C:12](=[O:14])[C@@H:9]([CH2:10][OH:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:33]([CH3:35])([CH3:34])[CH2:32][S:31]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: CC1(C)CSC(C)(C)C1N
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CO)C(=O)NC1C(C)(C)CSC1(C)C
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.26 g. (11 mmole) of N-t-butoxycarbonyl-D-serine in 75 ml. of tetrahydrofuran is added 1.47 ml. (10 mmole) of triethylamine and the mixture cooled to -10° C. At this temperature is added 0.96 ml. (10 mmole) of ethyl chloroformate and stirring continued for 15 minutes. After cooling to -20° C., 1.6 g. (10 mmole) of dl-3-amino-2,2,4,4-tetramethyltetrahydrothiophene is added and the resulting mixture is allowed to warm to room temperature. Ethyl acetate is added and the mixture is washed twice with 50 ml. portions of 5% (by weight) aqueous citric acid, aqueous sodium bicarbonate (1 ×50 ml.) and saturated brine (1 ×50 ml.). The organic layer is dried (Na2SO4) and evaporated to dryness at reduced pressure to afford N(2,2,4,4-tetramethyltetrahydrothiophene-3-yl)-t-butoxycarbonyl-D-serine amide. This product is used without further purification in the next step. ##STR113##
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[NH:12]1[C:16]2[CH:17]=[C:18]([CH:21]=O)[CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1>>[NH:14]1[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[C:4]3/[C:3](=[O:11])[N:2]([CH3:1])[C:10]4[C:5]/3=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:17][C:16]=2[N:12]=[N:13]1
Reactant: CN1C(=O)Cc2ccccc21
Reactant: O=Cc1ccc2nn[nH]c2c1
Product: CN1C(=O)/C(=C/c2ccc3[nH]nnc3c2)c2ccccc21

Procedure:
The title compound was synthesized according to the method described for Example A11B, except substituting 1-methylindolin-2-one (18 mg, 0.124 mmol) and 1H-benzo[d][1,2,3]triazole-6-carbaldehyde (20 mg, 0.136 mmol) and then purified by preparatory HPLC to obtain 3.4 mg, 10% of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.23 (bs, 1H), 8.00 (bs, 1H), 7.95 (s, 1H), 7.84-7.75 (m, 1H), 7.59 (d, J=7.58 Hz, 1H), 7.34 (t, J=8.00 Hz, 1H), 7.04 (d, J=7.83 Hz, 1H), 6.92 (d, J=7.58 Hz, 1H), 3.35 (s, 3H); MS ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.11.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[C:16]([NH:24][NH2:25])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.C(O)C>[C:16]([NH:24][NH:25][C@@H:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Solvent: CCCCCC
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NNC(=O)c2ccccc2)[C@@H]1O
Yield: 54.1 %

Procedure:
The procedure of Reference Example 2 was repeated except that 1.3 g of 6-cyano-3,4-epoxy-3,4 dihydro-2,2-dimethyl-2H-1-benzopyran and 1.0 g of benzoylhydrazine was used, and 1.18 g of trans-4-(2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol was obtained as white crystals, m.p. 197°-199° C. (recrystallized from hexane-ethanol).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[OH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21].C(N(C(C)C)CC)(C)C>ClCCl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cncc(O)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
4-Nitrophenyl chloroformate (7.0 g) was added to a dichloromethane (100 ml) solution of methyl 5-hydroxynicotinate (5.3 g) and diisopropylethylamine (6.1 ml), followed by stirring at room temperature for 1 hour. The reaction liquid was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting solid was washed with EtOAc/hexane and dried under reduced pressure to obtain methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (8.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[F:32])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:40](OC(=O)C)(=[O:42])[CH3:41]>>[C:40]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[F:32])[CH:5]=[CH:4][N:3]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (90 mg, 0.21 mmol) in acetic anhydride (6 mL) was added Et3N (0.3 mL). The reaction was stirred at rt for 8 hours, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the title compound as a white solid (53 mg, 49%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=C=O)=[CH:15][CH:14]=1.O>[O-]CC.[Na+].CC(N(C)C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: COc1ccc(N=C=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(NC(=O)c2ccc(O)cc2)cc1
Temperature: 30 °C
Reaction time: 0.42 h
Yield: 81.2 %

Procedure:
p-Hydroxybenzoic acid (69.06 grams, 0.50 mole), sodium ethoxide catalyst (0.155 gram, 0.225% wt. of the p-hydroxybenzoic acid used) and dimethylacetamide solvent (400 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at 80° C. p-Methoxyphenylisocyanate (78.30 grams, 0.525 mole) is added dropwise over a ten minute period with cooling of the reactor exterior to maintain the 80° C. reaction temperature. After an additional ten minutes at 80620 C., heating of the reactor commenced and a 160° C. temperature is achieved 25 minutes later. After three hours at the 160° C. reaction temperature, the reactor is cooled to 30° C. then the contents poured into two liters of deionized water. A precipitated white powder is recovered via filtration of the aqueous slurry then dissolved into one liter of boiling methanol. After cooling the methanol solution to 5° C., a first crop of white crystalline product is filtered off and dried at 90° C. under vacuum to a constant weight of 67.9 grams. The methanol solution is concentrated by rotary evaporation to a 300 milliliter volume then cooled to 5° C. until a second crop of white crystalline product appeared. After filtration, drying of the product to constant weight provided an additional 30.8 grams to give a total isolated yield of 81.2% of 4-hydroxy-4'-methoxybenzanilide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][C:26]([C:30]([NH2:32])=O)=[C:27]([CH3:29])[N:28]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][C:26]([C:30]#[N:32])=[C:27]([CH3:29])[N:28]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(N)=O)s3)cc12
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C#N)s3)cc12
Yield: 79.4 %

Procedure:
A solution of tert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.33 g, 0.6 mmol) and cyanuric chloride (0.33 g, 1.8 mmol) in N,N-dimethylformamide (10 mmol) was stirred for 1 h at 0° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-6-(5-cyano-4-methyl-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.25 g, 80.6%) as crystals.