Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].OO.[CH2:5]([NH:7][C:8]1[CH:15]=[C:14]([C:16]2[N:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[C:21]3[N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[N:28]=[CH:27]2)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11])[CH3:6].O>CS(C)=O>[CH2:5]([NH:7][C:8]1[CH:15]=[C:14]([C:16]2[N:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[C:21]3[N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[N:28]=[CH:27]2)[CH:13]=[CH:12][C:9]=1[C:10]([NH2:11])=[O:1])[CH3:6]
Reactant: [OH-]
Reactant: CCNc1cc(-c2nccc3c(-n4cnc(-c5cnn(C)c5)c4)ccnc23)ccc1C#N
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCNc1cc(-c2nccc3c(-n4cnc(-c5cnn(C)c5)c4)ccnc23)ccc1C(N)=O
Reaction time: 0.5 h
Yield: 4 %

Procedure:
A suspension of 3-amino-2-chloropyridine (17.6 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.5 g) in isopropanol (274 ml) was heated to reflux for 5 minutes. After cooling, the deposit was filtrated to obtain 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.8 g). The obtained 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-di one (8.2 g) was gradually added to Dowtherm heated to 220° C., and the mixture was heated at 220° C. for 30 minutes. After cooling, hexane (300 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-chloro-1,7-naphthyridin-4(1H)-one (2.02 g). 4-(4-Chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.107 g) was obtained according to Example 5(1) using the obtained 8-chloro-1,7-naphthyridin-4(1H)-one (0.295 g) instead of compound (3a) and 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester instead of 3-quinolineboronic acid. A suspension of the obtained 4-(4-chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.0491 g), 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole hydrochloride (0.035 g), copper(II) oxide nanoparticles (0.06 g), and potassium carbonate (0.0883 g) in DMF (1.5 ml) was stirred overnight at 125° C. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile. An aqueous sodium hydroxide solution (4 M, 0.093 mL) and a 30% aqueous hydrogen peroxide solution (0.045 mL) were added to a solution of the obtained 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile in DMSO (3 mL) at room temperature, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, and the deposit was collected by filtration, then washed with water and ether by sprinkling, and then dried under reduced pressure to obtain compound (72) (0.040 g, yield based on 6 steps: 4%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([CH3:17])[CH:5]=1)(=[O:3])[NH2:2].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]([S:34]Cl)=[O:33]>O1CCOCC1>[CH3:17][C:6]1[CH:5]=[C:4]([C:1]2[O:3][C:32](=[O:33])[S:34][N:2]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: Cc1cc(C(N)=O)ccc1C(=O)OC(C)(C)C
Reactant: O=C(Cl)SCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nsc(=O)o2)ccc1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a stirring solution of tert-butyl 4-carbamoyl-2-methyl-benzoate (10 g) in mixture of Toluene and Dioxane (3:1, 240 mL) was added potassium carbonate (5.88 g) then chlorocarbonylsulfenyl chloride (5.5 mL). The mixture was heated at 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give tert-butyl 2-methyl-4-(2-oxo-1,3,4-oxathiazol-5-yl)benzoate (11.12 g) as a solid. 1H-NMR (CDCl3, 400 MHz): δ=7.87-7.96 (m, 1 H), 7.79-7.87 (m, 2 H), 2.63 (s, 3 H), 1.56-1.64 ppm (m, 9 H).
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH2:16][CH2:17][CH3:18])[C:12]=2[Cl:14])[NH:7][CH:6]=1)C.[C-:19]#[N:20].[K+].CI>CN(C=O)C>[C:19]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH2:16][CH2:17][CH3:18])[C:12]=2[Cl:14])[NH:7][CH:6]=1)#[N:20]
Reactant: [C-]#N
Reactant: CCCOc1ccc2[nH]cc(CN(C)C)c2c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCOc1ccc2[nH]cc(CC#N)c2c1Cl

Procedure:
Reaction of 3-dimethylaminomethyl-4-chloro-5-n-propyloxyindole (3.50 g, 13.1 mmol) with potassium cyanide (3.28 g, 50.4 mmol) and methyl iodide (7.44 g, 52.4 mmol) in DMF by the method described in 1 (d) gave 3-cyanomethyl-4-chloro-5-n-propyloxyindole as an oil which crystallised on standing (2.53 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][N:25]4[C:28](=[O:32])[CH2:29][NH:30][CH3:31])=[CH:21][C:20]=3[O:33][CH3:34])[NH:15][C:14]3=[N:35][CH:36]=[CH:37][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5].CN[O:40][CH3:41]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][N:25]4[C:28](=[O:32])[CH2:29][N:30]([CH3:31])[O:40][CH3:41])=[CH:21][C:20]=3[O:33][CH3:34])[NH:15][C:14]3=[N:35][CH:36]=[CH:37][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CNCC(=O)N1CCc2cc(OC)c(Nc3nc(Nc4cccc(F)c4C(N)=O)c4ccnc-4[nH]3)cc21
Reactant: CNOC
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)OC)CC2

Procedure:
One third of the reaction mixture from the preparation of 2-fluoro-6-[(2-{[1-(N-methylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide was treated with N,O-dimethylhydroxylamine (145 mg, 2.37 mmol) and KI (90 mg, 0.54 mmol). After 1 h the resulting mixture was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-fluoro-6-[(2-{[1-[N-methyl-N-(methyloxy)glycyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide as a yellow solid (43 mg 42%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 (s, 3H), 3.08-3.20 (m, 2H), 3.43 (s, 3H), 3.60 (s, 2H), 3.78 (s, 3H), 4.22 (t, J=8.26 Hz, 2H), 6.23 (s, 1H), 6.81-6.92 (m, 1H), 6.95 (s, 1H), 6.97 (s, 1H), 7.28-7.40 (m, 1H), 7.61 (s, 1H), 8.02 (s, 1H), 8.10 (s, 1H), 8.51 (d, J=8.42 Hz, 1H), 8.63 (s, 1H), 10.54 (s, 1H), 11.31 (s, 1H); ESIMS (M+H)+=535.18.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[C:20]([Mg]Br)#[C:21][CH3:22]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:18][CH2:19]1)([C:20]#[C:21][CH3:22])[OH:16]
Reactant: CC#C[Mg]Br
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C(=O)C1CC1
Product: CC#CC(O)(c1cc(-c2cccc(Cl)c2)ccc1N)C1CC1

Procedure:
1-(4-Amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-1-propynyl-methanol was prepared from (4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone and propynylmagnesium bromide according to Example 41.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:23])[C:8]2[N:9]=[CH:10][N:11]([C:21]=2[N:22]=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)(=[O:3])[CH3:2].[C:24]([O:32][C@@H:33]1[C@H:37]([F:38])[C@@H:36]([CH2:39][CH:40]([P:48]([O:53][CH2:54][CH3:55])([O:50][CH2:51][CH3:52])=[O:49])[S:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:35][C@H:34]1OC(=O)C)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl.ClCCCl>[C:24]([O:32][C@@H:33]1[C@H:37]([F:38])[C@@H:36]([CH2:39][CH:40]([P:48]([O:53][CH2:54][CH3:55])([O:50][CH2:51][CH3:52])=[O:49])[S:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:35][C@H:34]1[N:11]1[CH:10]=[N:9][C:8]2[C:7](=[O:23])[NH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:22][C:21]1=2)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOP(=O)(OCC)C(C[C@H]1O[C@@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1F)Sc1ccccc1
Reactant: CC(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(C[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(C)=O)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1F)Sc1ccccc1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
N-Acetyl Guanosine (108 mg, 0.56 mmol) was suspended in 10 mL anhydrous CH2Cl2. With stirring under nitrogen, BSA (345 mg, 1.4 mmol) was added to the suspension. The mixture was stirred at 80° C. for 2 h and cooled to r.t. Compound 35.14 (200 mg, 0.37 mmol) in 5 mL anhydrous DCE was added to the mixture, followed by SnCl4 (64 mL, 0.55 mmol). The mixture was heated to 65° C. for 6 h and then cooled to r.t., diluted with 50 mL CH2Cl2 and poured onto a mixture of 50 g ice/50 mL saturated Rochelles Salt. The mixture was stirred for another 1 h. The organic layer was separated and the aqueous layer was extracted with 100 mL additional CH2Cl2. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 5% MeOH in CH2Cl2 to give compound 35.15 (73 mg, 30% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2].[CH2:26]([NH:28][CH2:29][CH2:30][OH:31])[CH3:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][OH:31])(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Reactant: CCNCCO
Product: CCOc1ccc(S(=O)(=O)N(CC)CCO)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 70 mg (0.784 mmol) of 2-(ethylamino)-ethanol, 23 mg (20.1% of theory) of 4-ethoxy-N-ethyl-N-(2-hydroxyethyl)-3-(5,7-dimethyl-4-oxo-3,4-dihydroimindazo-[5,1-f][1,2,4]triazin-2-yl)-benzene-sulphonamide are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([CH:10]2[O:14][CH:13]([CH2:15][O:16]C(C3C=CC(OC)=CC=3)(C3C=CC(OC)=CC=3)C3C=CC=CC=3)[CH:12]([OH:40])[CH2:11]2)[CH:3]=1.[Si:41](Cl)([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N1C=CN=C1>CN(C=O)C>[Si:41]([O:40][C@@H:12]1[C@@H:13]([CH2:15][OH:16])[O:14][C@@H:10]([N:4]2[CH:3]=[C:2]([CH3:1])[C:8](=[O:9])[NH:7][C:5]2=[O:6])[CH2:11]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(OCC2OC(n3cc(C)c(=O)[nH]c3=O)CC2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
5′-O-Dimethoxytritylthymidine is silylated with 1 equivalent of t-butyldiphenylsilyl chloride (TBDPSC1) and 2 equivalents of imidazole in DMF solvent at room temperature. The 5′-protecting group is removed by treating with 3% dichloracetic acid in CH2Cl2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N+:22]([O-:24])=O)[C:7]([NH:14][C:15]([C:17](OCC)=[O:18])=[O:16])=[C:8]2[C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9]2)(=[O:3])[CH3:2].CN(C)C=O>C(O)C.[Pt]>[C:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]2[NH:14][C:15](=[O:16])[C:17](=[O:18])[N:22]([OH:24])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(C(C)=O)c2c1CCCC2
Agent: [Pt]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)c1cc2c([nH]c(=O)c(=O)n2O)c2c1CCCC2
Yield: 72.9 %

Procedure:
A solution of 8-acetyl-5-ethoxalylamino-1,2,3,4-tetrahydro-6-nitronaphthalene (0.67 g, 2 mmol) in 100 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 50 mg of 5% platinum on carbon for 1 h. Then 50 ml of N,N-dimethylformamide was added to dissolve the precipitated solid, and the catalyst was removed by filtration. The filtrate was concentrated and the residue was washed with 50 ml of ethanol to give 0.40 g (73%) of the title compound. M.p. >200° C. decomp. (DSC); IR (KBr): 1709, 1677 cm1, 1H-NMR (DMSO-d6): 1.43-1.93 (m, 4H, 2CH2), 2.57 (s, 3H, COCH3), 2.53-3.07 (m, 4H, 2CH2), 7.57 (s, 1H, H-7), 11.4 (very broad s, 2H, OH and NH); MS (m/e: 274 (M+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][S:12]([CH3:11])(=[O:14])=[O:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](N)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(NS(C)(=O)=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.5 g, 2.49 mmol), in anhydrous CH2Cl2 (5 mL) under argon were added methane sulfonyl chloride (0.23 mL, 2.99 mmol) and pyridine (0.30 mL, 3.73 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.40 g, 58%) as a white solid. 1H NMR (CDCl3) δ: 1.52 (d, J=6.8 Hz, 3H), 2.67 (s, 3H), 4.61-4.72 (m, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H). ESIMS (MNa+): 279.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]([N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[O:23])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)N3CCSCC3)cc2)=C(C)C1=O
Yield: 24.3 %

Procedure:
4-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (50 mg, 0.14 mmol) obtained in Example 26 and thiomorpholine (0.016 ml, 0.15 mmol) were used, a method similar to that described in Example 24 was employed to obtain the title compound (15 mg, 0.034 mmol, yield 24%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([NH2:23])=[S:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(O)C>[CH2:35]([O:34][C:32]([C:31]1[N:23]=[C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:13]3[CH2:14][C:15](=[O:17])[NH:16][C:10]4[CH:9]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH:28]=[CH:27][C:11]=4[N:12]=3)[CH:19]=2)[S:22][CH:30]=1)=[O:33])[CH3:36]
Reactant: NC(=S)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo [b][1,4]diazepin-2-yl]-thiobenzamide (Example 149) (39 mg, 0.1 mmol) and ethyl bromopyruvate (29 mg,0.15 mmol) in ethanol (0.5 mL) was heated at reflux for 7 h. The solution was cooled to 0° C., stirred for 0.5 h, and the title compound was isolated by filtration as light yellow solid (29 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[S:10])[CH2:8][O:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14].CI.[C:19](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([S:10][CH3:19])[CH2:8][O:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(N)ccc2c1OCC(=S)N2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1c(N)ccc2c1OCC(SC)=N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of methyl 7-amino-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylate (Intermediate 29, 0.795 g), methyl iodide (0.710 g) and potassium carbonate (1.38 g) in acetone (20 mL) was stirred at room temperature for 2 hours. The resultant mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25% to give methyl 7-amino-3-methylsulfanyl-2H-benzo[1,4]oxazine-8-carboxylate (0.648 g) as a sandy coloured solid.
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:30])[CH:7]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[N:8]([C:10](=[O:21])[CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])[CH3:9])C.C(O)C.[H][H]>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH:7]2[N:8]([CH3:9])[C:10](=[O:21])[CH:11]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]2=[O:30])=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)N(C)C(=O)Cc1c(C)cc(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(C)c(C2C(=O)C(Cc3ccc(Cl)cc3)N(C)C2=O)c(C)c1
Yield: 68.3 %

Procedure:
To a boiling solution of 120 ml of absolute toluene and 7.5 g (0.25 mol) of sodium hydride there are added dropwise 79.9 g (0.199 mol) of 2-(4-chlorobenzyl)-N-(2,4,6-trimethylphenylacetyl)-sarcosine ethyl ester in 200 ml of absolute toluene, and the batch is refluxed while being monitored by thin-layer chromatography. When the reaction is complete, ethanol is added dropwise, while cooling in an ice-bath, until no more hydrogen escapes. After the mixture has been evaporated under reduced pressure, the residue is taken up in water and the mixture is acidified with concentrated hydrochloric acid at 0° C. to 20° C. The precipitate is filtered off with suction and recrystallised from chloroform/n-hexane. 48.4 g (68.4% of Theory) of 5-(4-chlorobenzyl)-1-methyl-3-(2,4,6-trimethylphenyl)-pyrrolidine-2,4-dione of melting point >230° C. are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][CH3:28])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C(O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:27]([CH3:28])[CH2:2][CH2:3][CH:4]2[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]=3[O:5]2)=[CH:21][CH:20]=1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Reactant: CNCCc1ccc(OC)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN(C)CCC2CN(C)C(=S)c3cccnc3O2)cc1
Reaction time: 8 h

Procedure:
To 40 ml of absolute ethanol was added 5.0 g (0.0195 mole) of 2-(2-chloroethyl-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione and 3.65 g (0.022 mole) of 4-methoxy-N-methylbenzene-ethanamine and 2.5 g (0.0195 mole) of diisopropylethylamine. After ~6 hr heating at reflux 3.15 g (0.022 mole) of 4-methoxy-N-methylbenzeneethanamine was added and heating was continued overnight. After removing the solvent by rotary evaporation, the residue was taken up in 100 ml of methylene chloride and the solution was washed with 2×50 ml of 1N sodium hydroxide and 50 ml of water, dried over sodium sulfate and filtered. The solution was then treated with 10 ml of acetic anhydride overnight. The methylene chlordide was extracted with 3×100 ml of hydrochloric acid. The combined aqueous extracts were washed with 2×100 ml of chloroform made basic with concentrated sodium hydroxide and extracted into 3×100 ml of chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give 2.8 g (37%) of yellow, analytically pure crystals, m.p. 75°-78° C.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([OH:15])=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:19])=O>CCCCCC>[CH2:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([Cl:19])=[O:15])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1ccc(C2CC2C(=O)O)s1
Solvent: CCCCCC
Product: CCCCc1ccc(C2CC2C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of 2-(5-n-butylthiophen-2-yl)-cyclopropanecarboxylic acid (9.0 g, 0.04 mol) and oxalyl chloride (6.35 g, 0.05 mol) in hexane (70 ml) was stirred at room temperature for 2 hours and then warmed at 60° C. for 3 hours. The hexane and excess oxalyl chloride were removed in vacuo to give 2-(5-n-butylthiophen-2-yl)-cyclopropanecarbonyl chloride (9.7 g, 100%) as a pale yellow liquid which was used in the next stage without further purification.
Reaction SMILES: O.[CH3:2][O:3][C:4](=[O:15])[C:5](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:6]([CH2:8]Cl)=O.[NH2:16][C:17]([NH2:19])=[S:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][O:3][C:4](=[O:15])/[C:5](/[C:6]1[N:16]=[C:17]([NH2:19])[S:18][CH:8]=1)=[N:10]\[O:11][CH2:12][CH2:13][CH3:14]
Reactant: NC(N)=S
Reactant: CCCON=C(C(=O)CCl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCO/N=C(\C(=O)OC)c1csc(N)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture solution of 20 ml of water and 25 ml of ethanol are added 7.0 g of 4-chloro-2-(n-propoxyimino)-acetoacetic acid methyl ester, 2.4 g of thiourea and 4.3 g of sodium acetate(trihydrate). The mixture is stirred for one hour at 40° C. The reaction mixture is, under cooling, adjusted to pH 6.5 with a saturated aqueous solution of potassium carbonate, followed by stirring for 30 minutes. The resulting crystals are collected by filtration, washed with water and isopropyl ether in this order, and dried to yield 2-(2-amino-4-thiazolyl)-(Z)-2-(n-propoxyimino)acetic acid methyl ester as crystals, m.p. 115°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:6][CH:5]=1.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[C:21](Cl)[N:20]=1>C(O)CC(C)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:21]3[N:20]=[C:19]([NH2:18])[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=3)[CH2:13][CH2:12]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(NC2CCNCC2)nc1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Product: COC(=O)c1ccc(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
Compound (40) (1.18 g, 5 mmol) was added to a solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (1.0 g, 4 mmol) in isoamyl alcohol (10 mL) at 25° C. The mixture was stirred at 120 C. for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 1.5 g (68%) of the title compound; 1H NMR (DMSO) δ 12.37 (s, 1H), 8.74 (d, 2H, J=6.3), 8.57 (d, 1H, J=2.2), 7.80 (m, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.60 (d, 1H, J=8.8), 6.56 (d, 1H, J=8.9), 4.57 (m, 2H), 4.20 (m, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.76 (s, 3H), 3.42 (m, 2H), 2.03 (m, 2H), 1.51 (m, 2H); 13C NMR (DMSO) δ 165.6, 161.3, 160.2, 155.1, 151.0, 150.6, 146.6, 136.8, 136.4, 113.1, 107.9, 105.2, 101.5, 99.3, 56.2, 55.9, 51.2, 46.6, 43.4, 30.9; HRMS (FAB) m/z 439.2083 (M+H)+ (C22H26N6O4 requires 439.2094); Anal. (C22H26N6O4 ·1HCl) C, H, N.