Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:13][C:14]([N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:13][C:14]([N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1)=[O:33]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CN(C(=O)CN(C(=O)CN)c1ccccc1Cl)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc2Cl)c1
Yield: 46.2 %

Procedure:
Using a procedure similar to that described in Example 11, but starting with 2-[2-amino-N-(2-chlorophenyl)acetamido]-N-methyl-N-phenylacetamide (3.4 g) and 3-methylphenyl isocyanate (1.4 g), and after recrystallisation in acetonitrile, 2-{N-(2-chlorophenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-N-methyl-N-phenylacetamide (2.2 g), m.p. 180° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][S:14][C:15](SC)=[N:16][C:17]#[N:18].[OH-].[Na+].Cl>C(O)C.O>[C:17]([N:16]=[C:15]([S:14][CH3:13])[NH:12][S:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:11])#[N:18]
Reactant: CSC(=NC#N)SC
Reactant: NS(=O)(=O)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC(=NC#N)NS(=O)(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A solution of 10.6 g (43.2 mmol) of 2,5-dichloro-benzenesulfonamide, 7.15 g (44.0 mmol) of 90 percent dimethyl N-cyanodithioiminocarbonate and 1.8 g (44 mmol) of NaOH in 60 ml of ethanol and 10 ml of H2O was heated at reflux for 6 hours. After cooling to room temperature the reaction mixture was poured into 600 ml of ice water. The resulting solution was acidified with 6N HCl to separate 2.2 g of the desired product as a white solid. Concentration of the filtrate gave an additional 8.5 g of the desired product. The total yield of material was 10.7 g (76 percent) of white solid, mp 145° C. IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.N1C=CC=CC=1.[F:39][C:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>C1COCC1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:43]([C:40]3([F:39])[CH2:42][CH2:41]3)=[O:44])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1(F)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3(F)CC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, 1-fluorocyclopropanecarbonyl chloride (20 mg, 165 μmol, 2.5 eq.) in abs. THF (1 ml) was added in two portions, and the mixture was stirred for 12 h. The reaction mixture was then concentrated under reduced pressure and directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (29.5 mg, 89% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([NH2:44])(=[S:43])[CH3:42].C(N(C(C)C)CC)(C)C>ClCCl>[C:41]([NH:44][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16])(=[S:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(N)=S
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=S)NC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (2.213 g, 9.65 mmol), HATU (4.050 g, 10.65 mmol) and thioacetamide (1.597 g, 21.26 mmol) were mixed in anhydrous dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 30 min. N,N-diisopropyl-N-ethylamine (5.3 mL, 30.3 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The solution was concentrated and the crude residue was purified on SiO2 (10 to 60% ethyl acetate, hexanes) to afford the title compound, which was used without further purification. HPLC/MS: 112.1 (M−174), Rt=3.00 (LC4).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30]Br>>[CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[N:9]1[CH2:28][O:29][CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCBr
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Product: COCn1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1Cc1ccccc1
Yield: 18 %

Procedure:
Prepared as in example 10-91 from 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (example 10-91a) and bromomethyl methyl ether. Yield: 18%. MS M+H calculated 411.17; found 411.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 μM.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[CH:9]=[C:10]1[NH:14][C:13](=[O:15])[CH:12]=[C:11]1[OH:16]>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[CH:9]=[C:10]1[NH:14][C:13](=[O:15])[C:12](=[N:1][OH:3])[C:11]1=[O:16]
Reactant: O=N[O-]
Reactant: O=C1C=C(O)C(=Cc2cccc(Cl)c2)N1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2cccc(Cl)c2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(3-chlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(3-chlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 50%, with a melting point of 185° C.
Reaction SMILES: C1(O[C:8](=[S:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([Cl:29])[CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:24]=[C:23]([Cl:22])[CH:28]=[C:27]([Cl:29])[CH:26]=3)[CH2:35][CH2:34]2)=[S:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=S)Oc2ccccc2)c(OC)nc1C
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: CCc1cc(NC(=S)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)c(OC)nc1C
Yield: 84 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>CO.[Zn]>[NH2:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:15]
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Yield: 75.3 %

Procedure:
4-(4-chlorophenyl)-1-ethyl-2-nitrobenzene (22.6 g, 86 mmol) is suspended in methanol (250 ml) and the reaction mixture is stirred at room temperature. Water (100 ml) is added, followed by zinc dust (39.0 g, 0.60 mol) and ammonium chloride (13.8 g, 0.26 mol) and the mixture is heated to reflux for 1 hour. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure to remove most of the methanol. The residue is partitioned between ethyl acetate and water and the aqueous phase is re-extracted with ethyl acetate. The organic extracts are combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 3-amino-4′-chloro-4-ethylbiphenyl (15.0 g) as a colourless solid. The product is used directly without further purification in Step 5.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][C@@H:14]([CH3:28])[C@@H:15]([CH3:27])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].C[O-].[Na+].[N+:32]([C:35]1[NH:36][CH:37]=[CH:38][N:39]=1)([O-:34])=[O:33]>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([CH2:16][C@H:15]([CH3:27])[C@H:14]([CH3:28])[CH2:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH2:3][CH2:2][N:36]3[CH:37]=[CH:38][N:39]=[C:35]3[N+:32]([O-:34])=[O:33])[CH:6]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCBr)c2)cc1OC
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCn3ccnc3[N+](=O)[O-])c2)cc1OC
Yield: 52.9 %

Procedure:
The Standard Procedure 2 was followed by use of 5a (57.9 mg, 0.129 mmol, 1.0 equiv), sodium methoxide (15.4 mg, 0.285 mmol, 2.2 equiv), and 2-nitroimidazole (6b, 29.3 mg, 0.259 mmol, 2.0 equiv). After workup and purification with column chromatography (80% EtOAc in hexanes as eluant), 7b (32.9 mg, 0.0682 mmol) was obtained in 53% yield as a yellow gummy oil: 1H NMR (CDCl3, 400 MHz) δ 0.79 (d, J=6.8 Hz, 3H, CH3), 0.82 (d, J=6.8 Hz, 3H, CH3), 1.70-1.72 (m, 2H, 2×CH), 2.21-2.31 (m, 2H, 2×ArCH), 2.67-2.73 (m, 2H, 2×ArCH), 3.75 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.30 (t, J=3.8 Hz, 2H, CH2N), 4.81 (t, J=4.6 Hz, 2H, CH2O), 6.56 (m, 1H, ArH), 6.63-6.68 (m, 2H, 2×ArH), 6.71-6.78 (m, 2H, 3×ArH), 7.13 (s, 1H, nitroimidazole C5-H), 7.35 (s, 1H, nitroimidazole C4-H); 13C NMR (CDCl3, 100 MHz) δ 15.95, 15.99, 38.27, 38.68, 38.94, 39.02, 49.41, 55.59, 55.62, 55.69, 67.78, 110.86, 111.68, 112.12, 115.69, 120.73, 122.78, 127.46, 127.87, 134.18, 134.46, 144.51, 146.72, 146.82, 147.68, 148.43; IR (neat) 2924 (s), 2851 (s), 1588 (w), 1537 (w), 1515 (s), 1488 (w), 1361 (s), 1260 (s), 1235 (s), 1028 (s) cm−1; HRMS (FAB) m/z calcd for C26H34N3O6 (M+H)+: 484.2448. found: 484.2433.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C:6](=O)/[C:5]/2=[CH:14]\[O:15][CH3:16].S(=O)(=O)(O)[OH:18]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[C:5]2[C:14]([O:15][CH3:16])=[O:18]
Reactant: O=S(=O)(O)O
Reactant: CO/C=C1\C(=O)OC(=O)c2ccc(F)cc21
Solvent: CO
Product: COC(=O)c1coc(=O)c2ccc(F)cc12
Temperature: 45 °C

Procedure:
To a suspension of (4Z)-6-fluoro-4-(methoxymethylene)-1H-isochromene-1,3(4H)-dione (1.30 g) in methanol (20 ml) was slowly added sulfuric acid (1.5 ml). The mixture was heated at 40-50° C. for 3 h. As the reaction proceeded the sub-title compound crystallized out. The reaction was cooled to room temperature and a white solid was collected by filtration and washed with cold methanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][C@@H:16]1[C@@H:20](/[CH:21]=[CH:22]/[C@@H:23]([OH:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[C@H:19]([OH:32])[CH2:18][C@@H:17]1[OH:33].[I:35]I>C(Cl)Cl.C(OCC)C>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH:13]([I:35])[CH:14]1[O:33][C@H:17]2[CH2:18][C@@H:19]([OH:32])[C@H:20](/[CH:21]=[CH:22]/[C@@H:23]([OH:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[C@H:16]2[CH2:15]1
Reactant: II
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)C(C)CCCCCl)[C@H](O)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCCC(I)C1C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CCCCCl)[C@H](O)C[C@@H]2O1
Temperature: 0 °C
Yield: 74.1 %

Procedure:
Under an atmosphere of nitrogen, 194 mg of anhydrous potassium carbonate was added to a solution of 140 mg of (5Z,13E)-(9α,11α,15S,16RS)-9,11,15-trihydroxy-16-methyl-20-chloroprosta-5,13-dienoic acid methyl ester [prepared as described in Example 8 of British Patent Application No. 22090/75 and e.g. the equivalent Belgian Specification No. 842,113] in 5 ml of methylene chloride. To the reaction mixture was added 200 mg of iodine in portions during 2 hours with stirring at 0° C. The reaction mixture was diluted with diethyl ether, washed with an aqueous solution of sodium thiosulphate, water and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 135 mg of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[C:20](=[O:21])[CH2:19][NH:18][C:17]1=[O:22].C([O-])([O-])=O.[K+].[K+].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1>CN(C=O)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:18]2[CH2:19][C:20](=[O:21])[N:16]([CH2:15][C:5]3[N:4]([CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:8]4[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=4[CH:6]=3)[C:17]2=[O:22])=[CH:34][CH:33]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)Cn1c(CN2C(=O)CNC2=O)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2C(=O)CN(Cc3ccc(Cl)cc3)C2=O)cc2cnc(C#N)nc21
Reaction time: 18 h
Yield: 73.8 %

Procedure:
To a solution of 200 mg (0.61 mmoles) of 7-(2,2-dimethyl-propyl)-6-(2,5-dioxo-imidazolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 10 ml of DMF, 136 mg (0.98 mmoles) of K2CO3, 138 mg (0.86 mmoles) of p-chlorobenzylchloride in 2 ml of DMF and 142 mg (0.86 mmoles) of KI are added successively at ambient temperature. After being stirred for 18 hours, the reaction mixture is quenched with ice water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: CH2C2:AcOEt=8:1) give 203 mg of desired 6-[3-(4-chloro-benzyl)-2,5-dioxo-imidazolidin-1-ylmethyl]-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 73% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([O:7][C:8]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCOc1ccc(C=O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCOc1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Oven-dried potassium carbonate (0.272 g, 2 mmol) was added to a solution of 2-hydroxy-4-methoxymethyloxy-benzaldehyde (0.182 g, 1 mmol) in 10 mL of acetonitrile and the mixture was stirred for one hour at RT. Benzylbromide (0.24 mL, 2 mmol) was added and the mixture was refluxed for 10 hours. After disappearance of 2-hydroxy-4-methoxymethy-benzaldehyde (TLC), the solvent was evaporated. The residue was chromatographed over silica using hexanes:EtOAC (5:1). The organic fractions were evaporated to obtain 0.218 g (80%) of yellow oil; TLC Rf0.27 hexanes:EtOAc (5:1), 1H NMR (400 MHz, CDCl3) δ 10.4 (s, 1H, CHO); 7.81-7.83 (d, 1H, J=8.4 Hz, Ar—H6); 7.46-7.39 (m, 5H, C6H5); 6.7-6.69 (m, 2H, Ar—H3/Ar—H5); 5.21 (s, 2H, O—CH2—O); 5.16 (s, 2H, PhCH2); 3.48 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ 188.6, 163.9, 162.9, 136.1, 130.5, 128.9, 128.5, 127.6, 120.2, 108.8, 101, 94.4, 70.7; analysis calc'd. for C16H16O4: C, 70.57; H, 5.92; O, 23.5. found: C, 70.35; H, 5.95; O, 23.72.
Reaction SMILES: [Na].[CH3:2][N:3]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:14]([C:15]([O-])=[O:16])=[CH:13][C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][N:10]=2)[CH2:4]1.S(Cl)([Cl:26])=O>>[CH3:2][N:3]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:14]([C:15]([Cl:26])=[O:16])=[CH:13][C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][N:10]=2)[CH2:4]1
Reactant: CN1CCC(Oc2ncc(-c3ccccc3)cc2C(=O)[O-])C1
Reactant: O=S(Cl)Cl
Agent: [Na]
Product: CN1CCC(Oc2ncc(-c3ccccc3)cc2C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The crude salt: sodium-2-[(1-methyl-3-pyrrolidinyl)oxy]-5-phenyl-3-pyridinecarboxylate (96 g) prepared in Preparation 55 was mixed with about 400 ml of thionyl chloride and stirred at room temperature for 10 minutes. The unreacted thionyl chloride was evaporated off at 70° C. and the residue was azeotroped with toluene to give the title compound which was used to prepare 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-phenylpyrido[3,2-f]-1,4-oxazepin-5-(4H)-one midway in preparation of Intermediate 79.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][N:9]2[C:13](=[O:14])/[C:12](=[CH:15]/[C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[C:33]([F:36])([F:35])[F:34])[N:20]=[CH:19]4)/[S:11][C:10]2=[O:37])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl[C:39]([O:41][CH3:42])=[O:40]>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:21]2[C:22]3[C:18](=[CH:17][C:16](/[CH:15]=[C:12]4/[C:13](=[O:14])[N:9]([CH2:8][C:2]5([NH:1][C:39](=[O:40])[O:41][CH3:42])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]5)[C:10](=[O:37])[S:11]/4)=[CH:24][CH:23]=3)[CH:19]=[N:20]2)=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:28]=1
Reactant: COC(=O)Cl
Reactant: NC1(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CCOCC1
Product: COC(=O)NC1(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CCOCC1

Procedure:
Methyl (4-{[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}tetrahydro-2H-pyran-4-yl)carbamate was prepared from (5Z)-3-[(4-aminotetrahydro-2H-pyran-4-yl)methyl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (Example 308) and methyl chloroformate following General Procedure R3.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([NH2:16])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:17][CH:18]([CH:22]([CH3:24])[CH3:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[CH3:7][C:8]([NH:16][C:19](=[O:20])[CH:18]([Br:17])[CH:22]([CH3:24])[CH3:23])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)C(Br)C(=O)Cl
Reactant: CC(C)(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)C(Br)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Into a 200 ml four necked flask, there were charged benzene (100 ml), α,α-dimethylbenzylamine (9 g) and triethylamine (7.4 g), and α-bromo-isovaleryl chloride (13.3 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. The reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 16.9 g of N-(α,α-dimethylbenzyl)-α-bromo-isovaleramide. M.P., 128°-129.5° C.
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1)[CH3:6])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Br:13][C:11]1[CH:12]=[C:7]([C@H:5]([OH:4])[CH3:6])[CH:8]=[N:9][CH:10]=1
Reactant: CC(=O)O[C@H](C)c1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@@H](O)c1cncc(Br)c1
Reaction time: 1 h

Procedure:
To a stirred solution of (R)-1-(5-bromopyridin-3-yl)ethyl acetate (1.21 g, 4.96 mmol, synthesis described herein) in MeOH (20 mL), was added K2CO3 (1.37 g, 9.92 mmol) and the reaction was stirred for 1 h. All the solvent was removed, the residue was dissolved in cold water and extracted with EtOAc (2×50 mL), to provide 1.0 g of crude (R)-1-(5-bromopyridin-3-yl)ethanol.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[N+:8]([CH2:11][CH2:12][CH3:13])([O-:10])=[O:9].Cl>C(#N)C.O>[CH3:4][CH:3]([CH:11]([N+:8]([O-:10])=[O:9])[CH2:12][CH3:13])[CH2:2][C:1]([O:6][CH3:7])=[O:5]
Reactant: CCC[N+](=O)[O-]
Reactant: C/C=C/C(=O)OC
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CCC(C(C)CC(=O)OC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 84.7 %

Procedure:
A solution of 4 g (40 mmol) of methyl crotonate and 4.72 g (53 mmol) of 1-nitropropane in 20 mL of acetonitrile was treated with 6 mL (40 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU). After stirring for 22 h at room temperature the reaction mixture was diluted with water and acidified with 2N HCl. The solution was extracted with Et2O and the Et2O layer was washed with brine, dried and concentrated. The residue was chromagraphed on a flash column using 10% Et2O-Hexane to isolate 6.41 g (85%) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:31](=[O:32])[CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)Cc3ccccc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.51 g, 1.5 mmol) in acetonitrile (10 mL), was added phenyl acetyl chloride (0.22 mL, 1.7 mmol) and N,N-diisopropyl ethylamine (0.57 mL, 3.5 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-phenyl-acetamide as a light yellow solid (254 mg, 40% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.70 min (98.5%); mp, 275-277° C.; 1HNMR (DMSO-d6)2.11-2.18 (m, 1H, CHH), 2.58-2.86 (m, 6H, CHCH2, CH3), 3.53 (s, 2H, CH2), 4.74-4.78 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.21-7.71 (m, 8H, Ar), 8.35 (t, J=6 Hz, 1H, CH2NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.27, 30.58, 41.69, 42.41, 56.48, 117.69, 124.70, 125.56, 126.34, 128.20, 129.03, 133.80, 136.30, 140.74, 148.44, 154.79, 160.91, 169.48, 170.23, 172.58. LCMS MH=419; Anal Calcd For C23H22N4O4+0.2H2O: C, 65.45; H, 5.35; N, 13.27. Found: C, 65.32; H, 5.04; N, 13.10.