Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([CH3:11])[C:6]([CH2:9][OH:10])=[CH:7][N:8]=1)[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([S:3][C:4]1[N:5]([CH3:11])[C:6]([CH:9]=[O:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCSc1ncc(CO)n1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCSc1ncc(C=O)n1C
Temperature: 25 °C
Yield: 94.4 %

Procedure:
5.50 g of (2-ethylthio-1-methylimidazol-5-yl)methanol was dissolved in 100 ml of 1,4-dioxane, and 24.34 g of manganese dioxide was then added. The mixture was stirred and heated under reflux for 7 hours. The reaction mixture was cooled to room temperature and then filtered through Celite®. The filtrate was concentrated under reduced pressure to obtain 5.13 g of 2-ethylthio-1-methylimidazole-5-carbaldehyde.
Reaction SMILES: CN1CCOCC1.[C:8]([NH:11][CH:12]([CH:16]=[CH2:17])[C:13]([OH:15])=O)(=[O:10])[CH3:9].C(OC(Cl)=O)C(C)C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:8]([NH:11][CH:12]([CH:16]=[CH2:17])[C:13]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15])(=[O:10])[CH3:9]
Reactant: NCc1ccccc1
Reactant: C=CC(NC(C)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=CC(NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
4-Methylmorpholine (0.71 g, 6.99 mmol) was added to a suspension of 2-acetamido-2-vinylacetic acid (1.00 g, 6.99 mmol) in THF (325 mL), and the mixture was stirred at room temperature (30 min). The reaction was cooled to -10° to -15° C. and then isobutylchloroformate (1.24 g, 9.08 mmol) was then added dropwise. After stirring (10 min), a solution of benzylamine (0.75 g, 6.99 mmol) in THF (25 mL) was added (15 min). The reaction mixture was allowed to warm to 0° C. The insoluble material was filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on SiO2 gel using 3% MeOH/CHCl3 as the eluant to give 1.00 g (62%) of the desired product: mp 136°-138° C. (recrystallized from EtOAc); Rf 0.24 (3% MeOH/CHCl3); 1H NMR (DMSO-d6) δ 1.88 (s, C(O)CH3), 4.27 (d, J=5.6 Hz, CH2), 4.89-4.94 (dd, J=6.4, 7.8 Hz, α-CH), 5.13-5.30 (m, --CH=CH2), 5.81-5.93 (m, --CH=CH2), 7.20-7.33 (m, 5 PhH), 8.27 (c, J=7.8 Hz, NH), 8.58 (t, J=5.6 Hz, NH); 13C NMR (DMSO-d6) 22.47 (C(O)CH3), 42.05 (CH2), 55.24 (α-CH), 116.44 (CH=CH2), 126.74 (C4'), 127.05 (2C2' or 2C3'), 128.24 (2C2' or 2C3'), 134.76 (CH=CH2), 139.25 (C1'), 168.78 (C(O)CH3), 168.99 (C(O)NH) ppm.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]2[C:9](=O)[CH:8]=[C:7]([CH3:11])[N:6]=[C:5]2[CH:12]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:26])=O.OP([O-])([O-])=O.[K+].[K+]>O.COC(C)(C)C.O1CCOCC1>[Cl:26][C:9]1[N:4]2[N:3]=[C:2]([CH3:1])[CH:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)n2[nH]c(C)cc2n1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CCN(CC)c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Cl)n2nc(C)cc2n1
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
Add 2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-one (20 g, 122 mmol) to 1,4-dioxane (60 mL). Stir the mixture at 22° C. for 10 min and then add N,N-diethylaniline (20.8 mL, 128 mmol). Stir for an additional 5 min and then add phosphorus oxychloride (11.7 mL, 126 mmol) over 15 min. Stir the mixture at 22° C. for 15 min, then heat to 80-85° C. over 35 min and hold the reaction at this temperature for 1.5 h. Add the cooled reaction mixture slowly to a solution of potassium phosphate dibasic (106.7 g, 612.82 mmol) in water (325 mL) cooled to 0-5° C., keeping the temperature below 5° C. during the addition. Stir the mixture at 22° C. and then add methyl-t-butyl ether (150 mL). Separate the organic layer and extract the aqueous layer with methyl-t-butyl ether (2×100 mL). Combine the organic portions, dry over sodium sulfate, filter, and evaporate the solvent. Purify by silica gel chromatography, eluting with hexanes/ethyl acetate (2/1) to provide the title compound as a yellow solid (20.7 g, 88%). ES/MS m/z (35Cl) 182 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CC#N>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCBr)nc3C)n2)cc1
Solvent: CC#N
Product: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCN4CCN(C)CC4)nc3C)n2)cc1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-methoxyphenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with 1-methyl-piperazine. Anal. RP-HPLC: tR=13.0 min (0-60% MeCN, purity>94%). 1H-NMR (DMSO-D6) δ: 1.17 (m, 2H, CH2), 2.11 (m, 2H, CH2), 2.48 (m, 4H, CH2), 2.57 (s, 3H, CH3), 3.28 (s, 3H, CH3), 3.30 (m, 4H, CH2), 3.72 (s, 3H, CH3), 6.85 (m, 2H, Ph-H), 6.97 (m, 1H, pyrimidinyl-H), 7.63 (m, 2H, Ph-H), 8.38 (d, 1H, J=5.1 Hz, pyrimidinyl-H). MS (ESI+) m/z 468.57 [M+H]+ (C23H26N7SO2 requires 467.59).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:29][C:30]#[N:31])[CH2:21][N:20]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH2:19]4)[CH:17]=3)[N:10]3[CH:32]=[CH:33][N:34]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[B-](F)(F)(F)[F:36].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(O)(=O)C>CC#N>[F:36][C:32]1[N:10]2[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:29][C:30]#[N:31])[CH2:21][N:20]([S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])[CH2:19]4)[CH:17]=3)=[N:12][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][C:9]2=[N:34][CH:33]=1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C(F)(F)F)C4)c3)n2)cn1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)O
Solvent: CC#N
Product: Cn1cc(-c2cc3ncc(F)n3c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C(F)(F)F)C4)c3)n2)cn1
Temperature: 80 °C
Yield: 20.6 %

Procedure:
2-(3-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(trifluoromethylsulfonyl)azetidin-3-yl)acetonitrile (Example 96; 0.200 g, 0.407 mmol), Selectfluor (0.288 g, 0.814 mmol) and acetic acid (0.233 mL, 4.07 mmol) were suspended in MeCN (20 mL) and heated to 80° C. overnight. The reaction mixture was cooled to ambient temperature and the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The combined organic extracts were washed with brine, dried, magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 1-2% (9:1 MeOH:NH4OH)/dichloromethane to provide 2-(3-(4-(3-fluoro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(trifluoromethylsulfonyl)azetidin-3-yl)acetonitrile (0.043 g, 0.084 mmol, 21% yield). MS (apci) m/z=510.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].[Cl-].[Na+]>ClCCl.O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (60 g) and imidazole (12.9 g) in dichloromethane (300 ml) was added dropwise a solution of tert-butyldimethylsilyl chloride (31.4 g) in dichloromethane at 0° C. over a 30-minute period. After one hour, the reaction mixture was poured into a mixture of ethyl acetate (1 l), water (400 ml) and saturated aqueous sodium chloride (200 ml). The organic layer was separated, washed in turn with water and brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (1.2 l) eluting with a mixture of hexane and ethyl acetate (1:1 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-(tert-butyldimethylsilyloxy)methyl-4-methanesulfonyloxypyrrolidine (71 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:38]1[CH2:47][CH2:46][CH2:45][C:40]2([CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39]1)=O)(C)(C)C>>[CH2:44]1[C:40]2([CH2:45][CH2:46][CH2:47][NH:38][CH2:39]2)[CH2:41][CH2:42][N:43]1[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCNC2)C1
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCC5(CCCNC5)C4)c3)nc12

Procedure:
1-{2-[3-(2,7-Diaza-spiro[4.5]dec-2-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester following general procedures as described in these Examples. M+H=418.
Reaction SMILES: C([NH:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([NH2:19])=[C:13]3[C:20]#[N:21])=[CH:7][CH:6]=1)(=O)C.O.Cl.C([O-])(O)=O.[Na+]>CO>[NH2:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([NH2:19])=[C:13]3[C:20]#[N:21])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Oc2ccc3[nH]c(N)c(C#N)c3c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1c(N)[nH]c2ccc(Oc3ccc(N)cc3)cc12
Yield: 95 %

Procedure:
A suspension of 5-(4-acetylaminophenoxy)-2-amino-1H-indole-3-carbonitrile (Example 14)(306 mg; 1 mmol) in MeOH (10 ml) was treated with water (2 ml) and conc. HCl (1 ml) and the mixture heated under reflux for 30 hours. After cooling the mixture was poured into sat. aqueous NaHCO3 and extracted with EtOAc. The organic phase was washed with brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/hexanes (80 to 100% EtOAc) to give 5-(4-aminophenoxy)-2-amino-1H-indole-3-carbonitrile as a pale beige solid (251 mg).
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:16][CH:17]=[N:18][N:19]=3)=[CH:11][CH:10]=2)[O:3]1.I([O-])(=O)(=O)=O.[Na+].C(O)(=O)C>C1COCC1.O>[O:16]1[CH:17]=[N:18][N:19]=[C:15]1[C:12]1[CH:11]=[CH:10][C:9]([B:4]([OH:5])[OH:3])=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2ccc(-c3nnco3)cc2)OC1(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: OB(O)c1ccc(-c2nnco2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
A solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-oxadiazole (0.504 g, 1.85 mmol) in THF (10 mL) and water (5 mL) was treated with sodium periodate (1.19 g, 5.56 mmol). The resultant slurry was stirred at RT for 5 h. Glacial acetic acid (0.21 mL, 3.7 mmol) was added and the mixture was stirred for 1 h and filtered. The filtered solid was washed with ethyl acetate (75 mL) and THF-methanol (1:1, 100 mL) and the filtrates were concentrated in vacuo to a white solid. The solid was suspended in THF (75 mL) and 10 mL of 0.1 M aq HCl and was sonicated to promote dissolution. The trace of insolubles were filtered and the organic layer was diluted with ethyl acetate (25 mL), washed with 0.1 M Na2S2O3 (2×20 mL), water (2×20 mL) and brine (20 mL), dried (Na2SO4) and concentrated in vacuo to provide 4-(1,3,4-oxadiazol-2-yl)phenylboronic acid (304 mg, 86% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1 H), 8.32 (s, 2 H), 7.99 (s, 4 H).
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12]([O:14]C)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:3]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.O=C1C2C(C(OCC)=O)=CC=CC=2NC(C2C=CN=CC=2)C1C1C=CN=CC=1.O.[NH2:57][NH2:58]>>[N:19]1[CH:20]=[CH:21][C:16]([CH:4]2[NH:5][C:6]3[C:11]4[C:2](=[N:57][NH:58][C:12](=[O:14])[C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH:3]2[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:17][CH:18]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccncc1)C(c1ccncc1)N2
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1ccncc1)C(c1ccncc1)N2
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccncc1)C2c1ccncc1
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of methyl 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (60 mg, 0.17 mmol) in hydrazine monohydrate (7 mL) was heated to reflux for 4 hr. Then the mixture was cooled to room temperature and solvent was removed in vacuum to give crude product. The crude product was purified by pre-HPLC to give 8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (15 mg, yield 68%) as a light yellow solid. 1H-NMR (400 MHz, DMSO) δ 4.46-4.48 (d, J=8.4 Hz, 1H), 4.90-4.92 (d, J=8.4 Hz, 1H), 7.16-7.20 (m, 3H), 7.32-7.34 (d, J=5.2 Hz, 2H), 7.40-7.42 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.59-7.63 (t, J=8.0 Hz, 1H), 8.40-8.40 (d, J=5.2 Hz, 2H), 8.44-8.45 (d, J=5.2 Hz, 2H). LC-MS (ESI) m/z: 342(M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:34]1[CH2:37][CH2:36][CH2:35]1>C(Cl)(Cl)Cl>[N:34]1([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([CH:17]4[CH2:22][O:21][CH2:20][CH2:19][O:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:37][CH2:36][CH2:35]1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CCC4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and azetidine. [α]D20=+25.5° (c=0.26, CHCl3), ES-MS m/e (%): 427 (M+H+, 100).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=2[C:10]1=O)([O:3][CH2:4][CH3:5])=[O:2]>C(O)(=O)C.[Pd]>[C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=2[CH2:10]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCC1C(=O)c2ccccc2N(CCCN(C)C)c2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CCCC1Cc2ccccc2N(CCCN(C)C)c2ccccc21
Reaction time: 96 h
Yield: 0.1 %

Procedure:
In a 150 ml glass hydrogenation vessel were placed 1 g (2.45 mole) of the 10-carboethoxypropyl-5-(3'-dimethylaminopropyl)-5H-dibenz[b,f]azepine-11-one prepared in Example 6 dissolved in 35 ml of glacial acetic acid and 1 g of 10% palladium on carbon. The vessel was placed on a Parr-pressure apparatus, flushed with nitrogen, evacuated, pressurized to 60 psi hydrogen and shaken for 4 days with daily pressure adjustment. The vessel was then flushed with nitrogen, evacuated, filtered through a Celite pad, washed with absolute methanol and concentrated on a rotary evaporator under reduced pressure. The residue was dissolved in chloroform and extracted with 10% NaHCO3 to remove excess acid. The organic phase was dried with magnesium sulfate, filtered and concentrated. The reaction was repeated on another 1 g lot of 10-carboethoxypropyl-5-(3'-dimethylaminopropyl)-5H-dibenz[b,f]azepine-11-one prepared in Example 6. The products were combined yielding 1.6 g crude material. The 1.6 g was applied to chromatographic plates (20-20 cm 2.5 mm prep tlc plates silica gel PF-254) and eluted with diethyl ether saturated with ammonia gas. The plates were air dried and developed four times until separation was maximized by UV inspection. The two bands were isolated, extracted with methanol, concentrated, redissolved in chloroform, filtered and concentrated on a rotary evaporator yielding 0.600 g of 10-carboethoxypropyl-5-(3'-dimethylaminopropyl)-10,11-dihydro-5H-dibenz[b,f]azepine and 0.805 g of starting material. The product (0.600 g) containing trace amounts of starting material was rechromatographed (using silica gel PF-254 20×20 cm 2.5 mm prep plates) and eluted with methanol:chloroform 1:9. The isolation procedure was the same as above.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].I[CH3:16]>O1CCCC1>[NH:2]=[C:1]([S:3][CH3:16])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CI
Reactant: COC(=O)c1ccc(C)c(C(N)=S)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(C(=N)SC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a stirred solution of methyl 3-carbamothioyl-4-methylbenzoate (compound 38.3, 2.10 g, 9.85 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) was added iodomethane (2.8 g, 19.73 mmol, 2.00 equiv) dropwise. The resulting mixture was stirred at room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure and the residue was dried under vacuum to yield 1.6 g (73%) of the title compound as a light yellow solid.
Reaction SMILES: [OH-].[K+].[C:3]([N:5]=[C:6]([NH2:8])[NH2:7])#[N:4].CC(C)=O.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>O.C(O)(=O)C>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:7][C:6]([NH:5][C:3]#[N:4])=[NH:8])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N#CN=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: N#CNC(=N)NC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Potassium hydroxide, 13.02 g (0.2 mole) is dissolved in 40 ml of water and 10.51 g (0.125 mole) of dicyanodiamide is added, followed by the addition of 50 ml of acetone. The mixture is cooled to 0° C. and the 4-fluorobenzoyl chloride from Step 1A, above, is added dropwise. The mixture is stirred at 0° C. for 1 hour and placed in the refrigerator overnight. The mixture is poured into 500 ml of water and the water is then acidified with an excess of acetic acid. The product forms a precipitate which is filtered, washed with water followed by ether and air dried to give 10.1 g of 1-(4'-fluorobenzoyl)-3-cyanoguanidine, m.p. 322° C. dec.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:22]=1.[CH2:29](Br)[C:30]#[CH:31].[Cl-].[NH4+]>O1CCCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([N:11]([CH2:31][C:30]#[CH:29])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][N:22]=1
Reactant: C#CCBr
Reactant: CCOC(=O)Nc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCN(C(=O)OCC)c1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
Then, a mixture of 20 mg of sodium hydride (60% in oil) and 1.3 ml of tetrahydrofuran was cooled to 0° C. To this was added dropwise a solution of 0.21 g of 3-(2,4-dichloro-5-ethoxycarbonylaminophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-346) in 1.3 ml of tetrahydrofuran. After stirring at 0° C. for 10 minutes, 42 μl of propargyl bromide was added, and the mixture was stirred at 0° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into saturated ammonium chloride solution, followed by extraction with diethyl ether. The organic layer was dried with anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, which afforded 36 mg (yield, 16%) of 3-{2,4-dichloro-5-[N-(ethoxycarbonyl)propargylamino]phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-351; m.p., 132.3° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[N:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:19])([F:20])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cncnc3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M78) (0.35 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (170 mg, 62%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][O:11]C(=O)C)(=[S:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl>CO>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][OH:11])(=[S:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=S)(CCOC(C)=O)OCC
Agent: Cl
Solvent: CO
Product: CCOP(=S)(CCO)OCC
Yield: 95.2 %

Procedure:
149 g of 2-acetoxyethane-thiophosphonic acid-O,O-diethyl ester (preparation according to German Offenlegungsschrift No. 2.127.821) are heated to 65°-70°C in 100 ml of methanol containing 3 wt.% of HCl, while removing simultaneously by distillation a mixture of methyl acetate/methanol. The reaction is terminated after approx. 5 hours. The residue is submitted to distillation under reduced pressure; 117 g of 2-hydroxyethanethiophosphonic acid-O,O-diethyl ester (b.p. 84°-88°C/0.1 torr) are obtained, corresponding to a yield of 95% of the theoretical.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.F[C:23]1[CH:24]=[CH:25][C:26]([N+:31]([O-:33])=[O:32])=[C:27]([CH:30]=1)[NH:28][CH3:29]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:8][C:23]1[CH:24]=[CH:25][C:26]([N+:31]([O-:33])=[O:32])=[C:27]([CH:30]=1)[NH:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CNc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Benzyl alcohol (49.6 mL, 0.48 mol), tetrabutyl ammonium chloride (6.66 g, 24.0 mmol) and potassium carbonate (40.0 g, 0.29 mol) were added to a toluene solution (200 mL) of 5-fluoro-N-methyl-2-nitroaniline (40.8 g, 0.24 mol), and the mixture was heated under reflux for 3.5 hours. The reaction solution was cooled, and 100 mL of water was added thereto. Thereafter, the mixture was stirred for 1 hour at 60 to 70° C. After the mixture was stirred under ice cooling for 30 minutes, precipitated crystals were collected by filtration. The resulting crystals were washed with water, and dried at 50° C., thereby obtaining 57.1 g of an orange, powdery target compound (yield: 92%).