Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3].C(=O)(O)[O-].[Na+].I[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33].O>CN(C)C=O>[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH2:28][CH2:29][CH2:30][CH2:31][C:32](=[O:33])[NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:21]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2c(N3CCNCC3)cccc2s1
Reactant: O=C(CCCCI)Nc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(N3CCN(CCCCC(=O)Nc4ccccc4)CC3)cccc2s1
Temperature: 80 °C
Yield: 6.2 %

Procedure:
To a solution of ethyl-4-(1-piperazinyl)-benzo[b]thiophene-2-carboxylate monohydrochloride prepared in Example 5 (2.00 g, 6.12 mmol) in dry N,N-dimethylformamide (31 mL) was added sodium bicarbonate (1.03 g, 12.2 mmol) and 5-iodo-N-phenylpentanamide (1.86 g, 6.12 mmol). The mixture was heated at 80° C. under nitrogen for 24 h, cooled to 20° C., treated with saturated aqueous sodium bicarbonate (50 mL) and water (100 mL), and extracted with 2:1 ether:dichloromethane (4×75 mL). The combined extracts were diluted with ethanol (50 mL) washed with water (50 mL), brine (50 mL) dried over magnesium sulfate/sodium sulfate, filtered, and concentrated in vacuo. The crude product was chromatographed using 20:80 ethanol:ethyl acetate isolating the component with an Rf of ca. 0.5 (2.20 g). A solution of the product (0.20 g) in 5:2 ethanol:dichloromethane was treated with an equivalent of 1.0M hydrochloric acid and concentrated in vacuo. Recrystallization from 3:2 methanol:acetonitrile (10 mL) gave the title compound as a white solid (0.19 g).
Reaction SMILES: Cl.[C:2]1([C:8](=[O:19])[CH2:9][C:10]2[NH:14][C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>CO>[C:8]([C:9]1[CH:25]=[CH:24][C:23](=[O:26])[N:11]2[C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]=3[NH:14][C:10]=12)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccccc1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccccc1)c1ccc(=O)n2c3c([nH]c12)CCCC3
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
250 mg (0.9 mmol) of the compound of Example IX are dissolved in 2 ml Methanol. 50 mg (0.925 mmol) sodium methylate are added at room temperature and the mixture is stirred for 30 min. 75.9 mg (0.9 mmol) methyl propiolate are added and the reaction mixture is stirred for 20 h at room temperature. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP18-Column, Eluent: Acetonitrile-Water Gradient) to yield 113 mg (43% of th.) 4-benzoyl-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazol-1(5H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:24][CH:21]1[CH2:23][CH2:22]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: BrCC1CC1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CC1CC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(cyclopropylmethyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
Methyl 2-hydroxyphenylacetate (21.0 g) was dissolved in dry DMF (200 ml), and dry potassium carbonate (19.35 g) was added in one portion. Benzyl bromide (23.94 g) in dry DMF (50 ml) was added dropwise to this mixture, with stirring, at room temperature. After eighteen hours the mixture was poured into water (500 ml) and extracted with ether (2×400 ml). The extracts were washed with water (3×150 ml) and brine (100 ml), dried and filtered through silica gel (50 g; Merck 60), then concentrated under reduced pressure to afford a yellow oil. Distillation at 160° C. and 0.05 mmHg afforded methyl 2-benzyloxyphenylacetate as a clear, colourless oil (26.99 g; 83% yield), infrared maximum (film): 1730 cm-1 ; 1H nmr (CDCl3, 90 MHz): delta 3.60 (3H,s), 3.75 (2H,s), 4.10 (2H,s), 6.80-7.40 (9H,m).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4](=[O:17])[NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C=O)C.O>[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27][N:3]1[C@@H:2]([CH3:1])[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4]1=[O:17]
Reactant: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1Cc1ccc(F)cc1Cl
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a solution of Example 77 (40 mg, 0.17 mmol) in DMF (1.7 mL) was added cesium carbonate (226 mg, 0.70 mmol) and 2-chloro-4-fluorobenzyl bromide (58 mg, 0.26 mmol) and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried with Na2SO4, filtered, concentrated and purified by flash column chromatography (0-20% iPrOH in EtOAc) to provide the desired compound (41 mg, 65%). MS (ESI): mass calcd. for C17H14ClFN6O, 372.8; m/z found, 373.1 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.47 (d, J=1.3 Hz, 1H), 8.84-8.80 (m, 2H), 7.61-7.55 (m, 1H), 7.55-7.50 (m, 1H), 7.26-7.19 (m, 1H), 5.10 (d, J=15.9 Hz, 1H), 5.01-4.89 (m, 1H), 4.70 (dd, J=13.9, 4.6 Hz, 1H), 4.48 (d, J=16.0 Hz, 1H), 4.13-4.03 (m, 1H), 1.18 (d, J=6.7 Hz, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])[N:14]=1)=O>C1(C)C=CC=CC=1>[CH3:19][O:18][C:16]([NH:15][C:13]1[N:14]2[CH:6]=[N:8][CH:9]=[C:10]2[S:11][CH:12]=1)=[O:17]
Reactant: COC(=O)Nc1csc(CNC=O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)Nc1csc2cncn12
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 81.4 %

Procedure:
A 1.17 ml portion of phosphorus oxychloride was added to a suspension formed by adding 2.8 ml of dry toluene to 560 mg of 2-(formylamino)methyl-4-methoxycarbonylaminothiazole, and the mixture was then stirred at an oil temperature of 100° C. for 45 minutes. Then, the solvent was evaporated under reduced pressure, and 30 ml of dichloromethane and 10 ml of a 15% aqueous potassium carbonate solution were then added to the resulting residue to adjust the solution to pH 9.5. The organic layer was separated, and the aqueous layer was then salted out with sodium chloride. Afterward, extraction was carried out three times with 30 ml of dichloromethane, and the extract was then combined with the above organic layer. The solution was dried (magnesium sulfate), and then filtered. Further, the solvent was evaporated under reduced pressure to obtain a milky white powder, and this powder was then purified by a silica gel column chromatograph to obtain 417.5 mg of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH:23](O)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15](=[O:25])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2C(O)C1C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=c1[nH]c2ccccc2cc1C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 63 %

Procedure:
3-(1-Benzylpiperidin-4-yl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one (550 mg, 1.6 mmol) was suspended in benzene (10 mL). p-Toluenesulfonic acid monohydrate (370 mg, 1.9 mmol) was added to the mixture. The reaction was heated to reflux and held there for 1 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in 10% ethanol/dichloromethane (50 mL) and washed with aqueous sodium bicarbonate (2×). The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was triturated with diethyl ether to give a solid which was filtered, washed with diethyl ether, and dried in vacuo. The title compound was obtained as off-white solid in 63% yield. 1H NMR (300 MHz, DMSO-d6): δ 11.72 (s, 1H), 7.72 (s, 1H), 7.62 (d, J=6.95, 1H), 7.47-7.38 (m, 1H), 7.35-7.30 (m, 4H), 7.29-7.20 (m, 2H), 7.14 (t, J=7.50, 1H), 3.49 (s, 3H), 2.92 (d, J=11.34, 2H), 2.83-2.69 (m, 1H), 2.04 (t, J=10.61, 2H), 1.78 (d, J=12.08, 2H), 1.71-1.47 (m, 2H). Mass spec.: 319.3 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([S:14]([C:17]3[CH:18]=[C:19]([C:24]#[N:25])[S:20][C:21]=3[S:22][CH3:23])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH3:26][O-:27].[Na+]>O.CO>[CH3:26][O:27][C:24]([C:19]1[S:20][C:21]([S:22][CH3:23])=[C:17]([S:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:9]=2)(=[O:16])=[O:15])[CH:18]=1)=[NH:25]
Reactant: CSc1sc(C#N)cc1S(=O)(=O)c1cccc(N2CCN(C)CC2)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=N)c1cc(S(=O)(=O)c2cccc(N3CCN(C)CC3)c2)c(SC)s1
Temperature: 50 °C
Yield: 74 %

Procedure:
To a flask containing 15 mg (0.03 mmol) of 4-[3-(4-methyl-piperazin-1-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-2-carbonitrile (Example 292: step a) was added 1 mL of MeOH and the resultant solution was treated with 1 mL 2M NaOMe in MeOH (2 mmol) at room temperature. The reaction was heated to 50° C. for 2 h. At this time it was cooled to room temperature and 2 drops of H2O was added. Concentration of the mixture in vacuo 5 followed by purification by preparative TLC (5% MeOH-CHCl3) yielded 12 mg (74%) of 4-[3-(4-methyl-piperazin-1-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-2-carboximidic acid methyl ester as a yellow solid.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1>C1COCC1>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]1=[O:8]
Reactant: O=C1CCCCCC1
Reactant: Fc1cccc(CBr)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CCCCCC1Cc1cccc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Cycloheptanone Compound 1a (3.0 g, 26.8 mmol) in THF (5 mL) was added dropwise to a solution of LDA (17.6 mL, 31.7 mmol) in anhydrous THF (50 mL) at −78° C. under a N2 atmosphere. The mixture was stirred at −78° C. for 60 mins, then 1-bromomethyl-3-fluoro-benzene Compound 1b (5.0 g, 26.5 mmol) in anhydrous THF (10 mL) was added dropwise. The mixture was stirred for 5 hrs, while warming to r.t. The reaction was quenched with water (5 mL) and the organic layer was diluted with EtOAc (100 mL), then washed with water and brine. The organic layer was separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield a crude oil which was purified by flash chromatography using 3% EtOAc in hexane to afford 2-(3-fluoro-benzyl)-cycloheptanone Compound 1c (4.72 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.[Pt](=O)=O>[C:1]([O:5][C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=Cc1cccc(Br)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1cccc(Br)c1
Reaction time: 10 h
Yield: 58.6 %

Procedure:
Platinum(IV) oxide (0.002 g, 0.032 mmol) was added to a solution of 3-(3-bromophenyl)acrylic acid tert-butyl ester (2.24 g, 7.90 mmol) in methanol (7 mL) and tetrahydrofuran (1 mL) at room temperature under a nitrogen atmosphere. The mixture was hydrogenated under a balloon pressure for 10 hours. The mixture was filtered and the filtrate was concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate, gave 3-(3-bromophenyl)propionic acid tert-butyl ester as a clear oil (1.32 g, 58%).
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:19][C:20]([CH3:26])([CH3:25])[C:21]([NH:23][NH2:24])=[O:22]>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:24]/[NH:23][C:21](=[O:22])[C:20]([CH3:26])([CH3:25])[CH3:19])/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(=O)NN
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCN1C(=O)/C(=N\NC(=O)C(C)(C)C)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 2,2-Dimethylpropionic acid hydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.36 to 1.39 (m, 13H), 1.69-1.75 (m, 2H), 3.70 (t, 2H), 3.87 (s, 3H), 6.42 (d, 1H), 6.62 (dd, 1H), 7.74 (d, 2H), 13.34 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: COc1cc(CCl)ccc1F
Product: COc1cc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)ccc1F

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 4-(chloromethyl)-1-fluoro-2-methoxybenzene. MS 442 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.18 μM.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13]C(C)(C)C)(=[O:12])=[O:11].FC(F)(F)C(O)=O>>[Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:11])=[O:12]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1CCCl
Yield: 86.6 %

Procedure:
The product from Example 14 (15.8 g) was added to 96 ml of trifluoroacetic acid at room temperature. After being stirred for 30 inutes, the reaction mixture yielded white crystals which were collected by filtration, washed well with diethyl ether, and dried to afford 10.9 g of the title compound, m.p. 168°-171° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[N:5]([CH2:12][CH2:13][N:14]=3)[CH:6]=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.O>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]2[C:4]3[N:5]([CH:12]=[CH:13][N:14]=3)[CH:6]=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Brc1cccc2c1C1=NCCN1C=N2
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: c1ccccc1
Product: Brc1cccc2ncn3ccnc3c12
Yield: 53.6 %

Procedure:
4. 242 g of manganese dioxide are added to a warm solution of 22 g of 10-bromo-2,3-dihydroimidazo[1,2-c]quinazoline in 2 l of benzene in a reaction vessel which is provided with a water separator. The mixture is heated at reflux temperature for 15 h. Then, a further 8 g of maganese dioxide are added thereto and the mixture is heated at reflux temperature for a further 1 h. The hot reaction mixture is filtered over Dicalite. The filter cake is rinsed with 1 l of hot benzene, then again boiled up in 1.5 l of dichloromethane/ethanol 199:1 and again filtered. The filtered solutions are concentrated to about 1.51 in a vacuum. A byproduct crystallizes and is filtered off (1.65 g). The filtrate is chromatographed over a column of 2 kg of silica gel. A total of 12.0 g of the desired product is eluted with dichloromethane/ethanol 99:1. 11.7 g of 10-bromoimidazo[1,2-c]quinazoline of m.p. 215°-216° C. are obtained after crystallization from ethyl acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[C:15]([N:17]=[C:18](SC)[NH:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[O:25][C:26]([CH2:29][N:30]([CH3:32])[CH3:31])=[CH:27][CH:28]=1)#[N:16]>>[C:15]([N:17]=[C:18]([NH:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[O:25][C:26]([CH2:29][N:30]([CH3:32])[CH3:31])=[CH:27][CH:28]=1)[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)#[N:16]
Reactant: CSC(=NC#N)NCCSCc1ccc(CN(C)C)o1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: CN(C)Cc1ccc(CSCCNC(=NC#N)NCCSCc2ccc(CN(C)C)o2)o1
Yield: 57.1 %

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]N,N-dimethyl-2-furanmethanamine (1.39 g) and N'-cyano-N-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]carbamimidothioic acid, methyl ester (2.0 g) was heated at 120° for 2 days. The oily product was subjected to column chromatography (silica-methanol) giving the title compound as a yellow oil (1.75 g).
Reaction SMILES: CN(C)C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:15]=[CH:14][C:13]1=[O:24].[Br:25]N1C(=O)CCC1=O>O>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:15]=[C:14]([Br:25])[C:13]1=[O:24]
Reactant: O=c1ccc(-c2ccccn2)cn1-c1ccccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccn1
Yield: 54.3 %

Procedure:
2 ml of a dimethylformamide solution containing 0.07 g of 1-(2-pyridyl)-5-(2-pyridyl)-1,2-dihydropyridin-2-one was incorporated with 0.07 g of N-bromosuccinic acid imide, under stirring and ice-cooling. After stirring the mixture at room temperature for 2 hours, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=3:1), to give 0.05 g of the title compound as a pale brown powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:17])=[CH:5][C:6]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH:12]=1)[C:8](OC)=[O:9])#[N:2].[NH2:18][NH2:19]>CCO>[C:1]([C:3]1[C:4]([CH3:17])=[CH:5][C:6]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH:12]=1)[C:8]([NH:18][NH2:19])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)c(C)cc1C1CCC1
Reactant: NN
Solvent: CCO
Product: Cc1cc(C2CCC2)c(C(=O)NN)cc1C#N
Temperature: 90 °C

Procedure:
To a solution of methyl 5-cyano-2-cyclobutyl-4-methylbenzoate (219.4, 2.0 g, 8.73 mmol) in EtOH (10 ml) was added anhydrous hydrazine (2 ml, excess) at room temperature. The mixture was heated at 90° C. overnight. After cooling to ambient temperature, the mixture was partitioned between water (60 ml) and EtOAc (200 ml). The EtOAc layer was washed with water (×2), brine, dried with Na2SO4, and concentrated to give the product as a white solid. Yield: 1.9 g, 95%. m/z (ES+) 230 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 7.52 (s, 1H), 7.32 (s, 1H), 6.91 (br, 1H), 4.08 (br, 2H), 3.89 (m, 1H), 2.61-2.52 (m, 3H), 2.42-2.28 (m, 2H), 2.18-1.98 (m, 3H), 1.91-1.78 (m, 1H).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:6][CH:7]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: CC(C)(O)c1nc(C(=O)O)co1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1coc(C(C)(C)O)n1
Yield: 79 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylic acid (184 mg, 1.076 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (250 mg, 0.897 mmol). The product was purified by flash chromatography. Yield 79%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 1.52 (s, 6H), 4.31 (dd, 1H), 4.41 (dd, 1H), 4.44-4.52 (m, 1H), 5.64 (s, 1H), 7.02 (d, 1H), 7.84-7.88 (m, 2H), 7.97-7.98 (m, 1H), 8.10 (d, 1H), 8.48 (s, 1H).
Reaction SMILES: [C:1](C(C)(CCCC)C(O)=O)(OCC)=O.ClCCl.F.[F:19][C:20]([F:32])([F:31])[CH:21]([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCCCC>[F:19][C:20]([F:31])([F:32])[C:21]([CH3:1])([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCCCC(C(=O)OCC)C(F)(F)F
Reactant: CCCCC(C)(C(=O)O)C(=O)OCC
Agent: F
Solvent: CCCCC
Solvent: ClCCl
Product: CCCCC(C)(C(=O)OCC)C(F)(F)F
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a 90 ml. stainless steel bomb was added 6.6 g. of 2-carboethoxy-2-methylhexanoic acid, 5 ml. of dichloromethane, and 0.4 ml. of 48% hydrofluoric acid. The bomb was sealed with an assembly consisting of a rupture disk (2400-3600 psig) and a needle valve. The bomb was then cooled in a dry ice-acetone bath and evacuated to less than 10 mmHg pressure. Sulfur tetrafluoride (15 g.) was condensed into the bomb from an attached lecture bottle. The needle valve was closed and the bomb was stored in a hood at room temperature for 3 days. After this time, the bomb was immersed to 1/3 of its length in a 60° C. bath. After warming at 60° C. for 3 days, the bomb was cooled and vented. The residual materials were taken up in pentane (250 ml.). The pentane solution was dried (NaF/MgSO4), filtered and distilled to give 3.14 g. (42%) of ethyl 2-trifluoromethylhexanoate, b.p. 79°-81° /20 mmHg.