Azzindani/Open_Reaction_Data huggingface dataset:
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])[CH:16]([CH2:19][C:20]([OH:22])=O)[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:22])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)O)C2=O)cn1
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)Nc3ccccc3)C2=O)cn1
Temperature: 65 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
3-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)acetic acid (example 10-44) (100 mg, 0.3 mmol), aniline (33 mg, 0.36 mmol), Pybop (187 mg, 0.36 mmol) and triethyl amine (0.05 mL, 0.36 mmol) were mixed in DMF (1 mL). The reaction stirred at 65° C. for 4 hours. The reaction was allowed to cool to room temperature and then diluted with ethyl acetate (2 mL). The organic phase was washed with saturated sodium bicarbonate solution (2×, 2 mL) and then with saturated NaCl solution (1 ml). The organic phase was extracted, dried over anhydrous Na2SO4, and filtered. The crude product was re-suspended in MeOH (1 mL) and purified by reversed phase HPLC (5-95% acetonitrile in H2O; 16 minute gradient). The pure fractions were combined and solvent was removed on the rotovap to afford 2-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)-N-phenylacetamide as a white solid (50%). 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H), 2.40 (s, 3H), 2.72 (m, 1H), 3.14-3.13 (d, 1H, J=4 Hz), 4.54-4.51 (d, J=8 Hz 1H), 5.04 (s, 2H), 6.53 (bs, 1H), 7.15-7.13 (m, 1H), 7.33-7.22 (m, 2H), 7.47-7.45 (d, J=8 Hz, 2H), 7.78 (bs, 1H), 7.09 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.75 μM.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([O:12]C)=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:14][O:15][CH2:16][O:17][CH3:18])[N:3]=1.[OH-].[Na+]>O>[NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([OH:12])=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:14][O:15][CH2:16][O:17][CH3:18])[N:3]=1
Reactant: COCOCc1nc(N)c2ncc(OC)nc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCOCc1nc(N)c2ncc(O)nc2n1
Temperature: 80 °C

Procedure:
8.1 g (0.0322 mole) of 4-amino-7-methoxy-2-(methoxymethoxymethyl)pteridine are added to a solution of 3.2 g (0.080 mole) of sodium hydroxide in 130 ml of water. The suspension obtained is heated at 80° C. for 2 hours. After filtration while hot, the solution is allowed to return to room temperature and is then acidified with acetic acid. The precipitate formed is isolated by filtration. It is purified by washing with water and then with acetone and is recrystallized from a mixture of methanol and N,N-dimethylformamide. Yld. 4.4 g (58%), m.p. 210°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11](SC)[N:12]=2)=[CH:4][CH:3]=1.[CH:20]1([NH2:24])[CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11]([NH:24][CH:20]3[CH2:23][CH2:22][CH2:21]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CSc1nc(Cc2ccc(Cl)cc2)[nH]c(=O)c1C#N
Reactant: NC1CCC1
Product: N#Cc1c(NC2CCC2)nc(Cc2ccc(Cl)cc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(4-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 244 mg (3.43 mmol) of cyclobutylamine to give 15 mg (14% of theory) of the title compound.
Reaction SMILES: [I:1]I.C([Sn](CCCC)(CCCC)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1)=[CH:12][C:11]2=[O:26])CCC.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[I:1][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1)=[CH:12][C:11]2=[O:26]
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2oc(-c3ccc(NC)cc3)cc(=O)c2c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CNc1ccc(-c2cc(=O)c3cc(I)ccc3o2)cc1

Procedure:
A chloroform solution of iodine (1.5 ml, 1 M) was added to a chloroform solution (20 ml) that contained compound 8 (100 mg, 0.185 mmol) at room temperature. The obtained mixture was reacted at room temperature for 10 minutes, and a saturated sodium bisulfite aqueous solution (15 ml) was then added thereto, so as to terminate the reaction. The chloroform layer was separated, and it was then dried over sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure, and the residue was then subjected to silica gel column chromatography using ethyl acetate/hexane (1/2) as an elution solvent, so as to obtain a product of interest, 6-iodo-4′-methylaminoflavone (compound 10). Yield: 20 mg (yield constant: 28.7%) 1H NMR (300 MHz, CDCl3) δ8.53 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.28 (d, J=10.8 Hz, 1H), 6.64-6.69 (m, 3H), 4.15 (s, 1H), 2.93 (s, 3H). MS m/z 377 (M+).
Reaction SMILES: O.NN.[CH2:4]([O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH2:9]1)[CH2:5][CH3:6]>CCO>[CH2:4]([O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1)[CH2:5][CH3:6]
Reactant: CCCO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCO[C@H]1CC[C@H](N)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Hydrazine hydrate (1.76 g, 55 mmol) was added to a solution of trans-2-(4-propyloxycyclohexyl)-isoindole-1,3-dione (7.90 g, 27.5 mmol) in absolute EtOH (100 mL). The reaction was stirred at 50° C. for 3 h before the reaction mixture was filtered. The solvent was removed in vacuo and Et2O (250 mL) was added after stirring for 30 min the solid was filtered off and the filtrate was added 150 mL 1 N HCl, the phases were separated and the aqueous phase was washed with Et2O (150 mL) before 10 N NaOH was added (until pH=11-12). The aqueous phase was extracted with EtOAc (200 mL+2×100 mL) and the organic fractions were collected and dried (MgSO4) to give 3.11 g (72%) of trans-4-propoxy-cyclohexylamine.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([CH2:12][CH:13]=O)[CH2:9]1)=O)(C)(C)C.[CH3:15][C:16]1N(CC2C=CC(NN)=CC=2)C=CN=1.C([O-])([O-])=O.[K+].[K+]>OS(O)(=O)=O>[NH:8]1[C:11]2[C:10](=[CH:12][CH:13]=[CH:15][CH:16]=2)[CH:9]=[CH:6]1
Reactant: CC(C)(C)OC(=O)N1CC(CC=O)C1
Reactant: Cc1nccn1Cc1ccc(NN)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 105.1 %

Procedure:
N-tert-Butyloxycarbonyl-3-formylmethylazetidine (0.3 g, 1.51 mmol) was added to a solution of 4-(2-methylimidazol-1-ylmethyl)phenylhydrazine (0.36 g, 1.51 mmol) in 4% H2SO4 (25 ml) and the resulting solution refluxed for 3h. The mixture was then cooled to room temperature, basified with K2CO3 and extracted with n-butanol (2×100 ml). The combined extracts were dried (MgSO4), evaporated, and the residue chromatographed through silica-gel eluting with CH2Cl2 /MeOH/NH3 (20:8:1) to give the title-indole (0.186 g, 46%), mp 88°-90° C.; δ (250 MHz, CD3OD) 2.02 (3H, s, CH3), 3.76-3.86 (4H, m, 2 of CH2), 4.04-4.20 (1H, m, CH of azetidine), 5.06 (2H, s, CH2), 6.70 (1H, d, J=1.4 Hz, Ar--H), 6.82 (1H, dd, J=1.5 and 8.4 Hz, Ar--H), 6.90 (1H, d, J=1.4 Hz, Ar--H), 7.12 (1H, s, Ar--H), 7.23 (1H, d, J =8.4Hz, At-H), 7.26 (1H, d, J =1.5Hz, Ar--H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:8][CH:9]=1.Br[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH2:25])=[O:24].O>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7](=[N:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:8]([CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([NH2:25])=[O:24])[CH:9]=1
Reactant: NC(=O)C(Br)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(F)cn2C(C(N)=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (0.040 g, 0.0017 mol) was suspended in N,N-dimethylformamide (15 mL) and was cooled at 0° C. N-(5-fluoropyridin-2-yl)-4-methylbenzenesulfonamide (compound a, 0.37 g, 0.0014 mol) was added and was stirred for 15 minutes. 2-Bromo-2-phenylacetamide h (0.3 g, 0.001 mol) was added then the reaction was warmed to room temperature and was stirred for 24 hours. The reaction was poured into water and extracted with ethyl acetate (3×50 mL) then dried then chromatographed on silica (50% ethyl acetate/hexanes) to give 2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)-2-phenylacetamide (compound j) Rf 0.42, 50% ethyl acetate/hexanes; MS m/z 400 (M+H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1>CN(C=O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCC(F)(F)F
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
2,2,2-Trifluoro-ethanol (7.09 g, 70.09 mmol) and stirred for 30 min. A solution of 1-Fluoro-4-nitro-benzene (10 g, 70.09 mmol) in DMF (25 mL) was added at 5-15° C., allowed to rt, stirred for 2 h, quenched with ice-water, filtered, washed with water and dried under high vacuum to obtain 14 g (89%) 1-Nitro-4-(2,2,2-trifluoro-ethoxy)-benzene as yellow solid. Subsequently, a solution of 1-Nitro-4-(2,2,2-trifluoro-ethoxy)-benzene (50 g, 226.2 mmol) in methanol (400 mL) was purged with nitrogen and 10% Pd—C (4.6 g) was added under nitrogen. This was stirred at rt under hydrogen atmosphere (balloon pressure) for 24 h. The reaction mixture was filtered through a celite bed and washed with methanol and the filtrate was removed under reduced pressure and washed with hexane to get 37 g (87%) 4-(2,2,2-Trifluoro-ethoxy)-phenylamine as a brown liquid. LC-MS: 192.4 [M+1]+. To a solution of 4-(2,2,2-Trifluoro-ethoxy)-phenylamine (12 g, 62.82 mmol) in DCM (1000 mL) was added solid NaHCO3 (52.77 g, 628.2 mmol). After 10 min, triphosgene (27.96 g, 94.24 mmol) dissolved in toluene (30 mL) was added to the reaction mixture under cooling at 10° C. and stirred for 10 min. The reaction mixture was filtered and the filtrate was concentrated, azeotroped twice with dry toluene to give 10 g 1-Isocyanato-4-(2,2,2-trifluoro-ethoxy)-benzene as yellow oily liquid which was used in the next step without further purification.
Reaction SMILES: O1CCCC1.[H-].[Na+].[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[C:18]([O:36][CH2:37][CH2:38][OH:39])=[N:19][N:20]([CH3:35])[C:21]=3[NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=3)(=[O:25])=[O:24])=[CH:16][C:11]=2[O:10][CH2:9]1.[Cl:40][C:41]1[CH:42]=[N:43][C:44](S(C)(=O)=O)=[N:45][CH:46]=1>CC(N(C)C)=O>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[C:18]([O:36][CH2:37][CH2:38][O:39][C:44]4[N:45]=[CH:46][C:41]([Cl:40])=[CH:42][N:43]=4)=[N:19][N:20]([CH3:35])[C:21]=3[NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=3)(=[O:25])=[O:24])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2C)nc1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Reaction time: 0.08 h
Yield: 45 %

Procedure:
In an oven-dried flask a solution of tetrahydrofuran (50 ml) and dimethylacetamide (3 ml) was treated with sodium hydride as a 60% dispersion in oil (460 mg) under an atmosphere of nitrogen. The reaction was stirred for 5 min and then treated with N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (1.0 g) (Preparation 13). The reaction was stirred for 3 h and was then treated with 5-chloro-2(methylsulfonyl)pyrimidine (460 mg). After stirring for a further 3 h the reaction mixture was concentrated and the residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous was extracted with ethyl acetate (3×75 ml) and the combined organics were dried over sodium sulfate. The solvent was removed and the crude residue was purified on a silica (40 g) column eluting with 20% ether in dichloromethane rising to 45% ether in dichloromethane to yield the title compound as an off-white foam (560 mg).
Reaction SMILES: C(N(CC)CC)C.CS([Cl:12])(=O)=O.[C:13]([O:17][C:18]([N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[CH2:30]O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[CH2:30][Cl:12])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCc2c(CO)cccc2C1
Reactant: CS(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(CCl)cccc2C1
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
Triethylamine (160 μl, 1,16 mmol) and then methane sulphonyl chloride (72 μl, 0.92 mmol) were added to 5-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (202 mg, 0.77 mmol) (WO 02053558 p 59) in tetrahydrofuran (20 ml) and the mixture was stirred for 30 minutes. Tetrabutyl ammonium chloride (322 mg, 1.16 mmol) was added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate and the organic solution was washed with sodium hydrogen carbonate solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (2:98) to give the title compound (100 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[S:35](Cl)(=[O:37])=[O:36]>O1CCCC1.CS(C)=O>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@@H:2]([NH:1][S:35]([C:31]2[O:30][CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:10]3)[CH:16]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=S(=O)(N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
(R)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.08 mmol, 25 mg) was dissolved in tetrahydrofuran (1 mL) and triethylamine (0.25 mmol, 35 μL, 25 mg) followed by furan-2-sulfonyl chloride (0.084 mmol, 14.05 mg) and the solution stirred at room temperature overnight. The reaction was concentrated before partitioning between dichlormethane (3 mL) and 1N HCl. (3 mL). The organic layer was collected and dried using a hydrophobic frit and concentrated under a stream of nitrogen to give a brown residue which was dissolved in DMSO (1 mL) and purified on preparative basic HPLC to give (R)—N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)furan-2-sulfonamide (13.1 mg, 0.03 mmol, 37.1%) MS (ESI): m/z [M+H]+ 442.2
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>O=S(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([Br:18])[CH:20]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Reactant: Nc1cccc(Br)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) (1.0 g, 4.26 mmol) (from Example 15, Step A, supra) in SOCl2 (12.5 mL) (Aldrich) was added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (20 mL), then 3-bromoaniline (0.806 g, 4.69 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-4-(3-bromo-phenylamino)-7-methoxy-quinazoline as a gray solid. (Yield 1.65 g, 100%).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]1([C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[C:18]1([C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:25][CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 1B (6.27 g, 26.8 mmol) and 3,3-diphenylacrylaldehyde (7.26 g, 34.8 mmol) in dichloromethane/methanol (30 mL/30 mL) was added acetic acid (0.6 mL) followed by addition of sodium triacetoxyborohydride (8.52 g, 40.2 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The organic solvents were concentrated in vacuo and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was washed with water and with brine, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The remaining residue was crystallized from acetonitrile.
Reaction SMILES: [Mn:1].[Zn:2].[CH2:3]([NH:9][C:10](=[S:12])[S-:11])[CH2:4][NH:5][C:6](=[S:8])[S-:7].C1C2C(N(SC(Cl)(Cl)C(Cl)Cl)C(=O)C2CC=C1)=O>>[CH2:3]([NH:9][C:10]([S-:12])=[S:11])[CH2:4][NH:5][C:6]([S-:8])=[S:7].[CH2:3]([NH:9][C:10]([S-:12])=[S:11])[CH2:4][NH:5][C:6]([S-:8])=[S:7].[Mn+2:1].[Zn+2:2]
Reactant: [Mn]
Reactant: [Zn]
Agent: O=C1C2CC=CCC2C(=O)N1SC(Cl)(Cl)C(Cl)Cl
Agent: S=C([S-])NCCNC(=S)[S-]
Product: [Mn+2]
Product: [Zn+2]

Procedure:
manganese and zinc (2.5% w/w) ethylene-bisdithiocarbamate as a wettable powder containing 80% w/w of active ingredient captafol: N-(1,1,2,2-tetrachloroethylthio)-1,2,3,6-tetrahydrophthalimide as a suspension concentrate containing 480 g./l. of active material.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: C1CCN(CCCC2CCCNC2)CC1
Solvent: CC#N
Product: O=C1Nc2ccccc2N(C(=O)N2CCCC(CCCN3CCCCC3)C2)c2ncccc21
Yield: 58 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[3-(1-piperidinyl)propyl]piperidine in a yield of 58% of theory. Colourless crystals, m.p. 165.5°-167.0° C. (acetonitrile).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1([CH2:35][OH:36])[CH2:34][O:33][CH2:32]1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][C:31]2([CH2:35][OH:36])[CH2:34][O:33][CH2:32]2)[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCC2(CO)COC2)c1OC
Temperature: 80 °C
Yield: 28.2 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile (7 mL) was added potassium carbonate (110 mg, 0.798 mmol) and (3-Bromomethyl-oxetan-3-yl)-methanol (96 mg, 0.532 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (30 mg, 28%).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:28]#[N:29].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:29]=[C:28]([C:27]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:25]([Cl:24])[CH:26]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: Cc1ccc(C#N)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (7.50 g), 3-chloro-4-methylbenzonitrile (3.33 g), anhydrous aluminum chloride (3.00 g) and o-dichlorobenzene (20 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, it is washed with saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 3.70 g of desired compound.