Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[CH2:15][OH:16]>CC#N.O=[Mn]=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:11][CH2:12]2)=[O:9])=[CH:4][C:3]=1[CH:15]=[O:16]
Reactant: O=C(NCc1ccc(Cl)c(CO)c1)C1CC1
Agent: O=[Mn]=O
Solvent: CC#N
Product: O=Cc1cc(CNC(=O)C2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
MnO2 (6.29 g, 72.0 mmol) was added to a sol. of cyclopropanecarboxylic acid 4-chloro-3-hydroxymethyl-benzylamide (3.47 g, 14.0 mmol) in CH3CN (300 mL) at rt. The mixture was stirred for 3 h at rt, and MnO2 (2.52 g, 29.0 mmol) was added again. The mixture was stirred for 1 h at rt, and MnO2 (1.26 g, 14.0 mmol) was added again. The mixture was stirred for 1.5 h, and was filtered through celite. The filtrate was evaporated under reduced pressure, and the residue was dried under high vacuum to yield the crude title compound (3.13 g, 91%) that was used further without purification. LC-MS: tR=0.80 min; ES+: 279.31.
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:3]3[C:2]([NH:65][C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: Nc1ccccc1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCn1c(-c2nonc2N)nc2cncc(Nc3ccccc3)c21
Temperature: 175 °C
Yield: 0 %

Procedure:
Under Ar, a solution of the product from Example 100 (24 mg, 77.6 mol) in 1,4-dioxane (0.8 ml) and toluene (1.2 ml) was treated with Tris(dibenzylidene-acetone)dipalladium (7.2 mg, 7.8 mol), racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (9.7 mg, 15.6 mol), aniline (8.5 l, 93.1 mol), and sodium tert-butoxide (10.5 mg, 108.6 mol). This mixture was then heated to 175° C. by microwave for 45 min. After cooled to ambient temperture, the reaction mixture was diluted with ethyl acetate (30 ml), filtered though a celite pad and then the filtrate was concentrated in vacuo. The residue was purified with reverse phase HPLC (10% MeCN/H2O→80% MeCN/H2O), to afford the title compound, (6.3 mg, 24%); MS (ES+) m/e 322 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:24][CH2:25][C:26]([NH2:28])=[S:27]>C(#N)C.C(O)C.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:28]=[C:26]([CH2:25][O:24][C:23]3[CH:29]=[C:30]([Cl:32])[CH:31]=[C:21]([Cl:20])[CH:22]=3)[S:27][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)COc1cc(Cl)cc(Cl)c1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: CC#N
Solvent: CO
Product: CSc1ccc(-c2sc(COc3cc(Cl)cc(Cl)c3)nc2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Yield: 74 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromoethanone, (Example 1, Step 3) (4.01 g, 11.8 mmol) and 3,5-dichlorophenoxy thioacetamide (2.80 g, 11.9 mmol) in 20 mL of acetonitrile and 10 mL of ethanol was heated to reflux for 1.2 hours. The solution was diluted with methanol, cooled to 0° C. in an ice bath and a precipitate formed that was removed by filtration to provide pure 4-(4-fluorophenyl)-5-(4-methylthiophenyl)-2-((3,5-dichlorophenoxy)methyl)thiazole (4.19 g; 74%) which was used directly in the next step: mp 104.5°-105.0° C.; Mass spectrum M+H=476.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]3[NH:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:16][N:12]3[C:13](=[O:15])[CH:14]=1)[CH2:2]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]3[N:19]([CH2:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C@H:18]([C:20]([F:22])([F:21])[F:23])[CH2:17][CH2:16][N:12]3[C:13](=[O:15])[CH:14]=1)[CH2:2]2
Reactant: BrCCCc1ccccc1
Reactant: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2CCCc1ccccc1
Reaction time: 2 h
Yield: 36.6 %

Procedure:
A solution of 200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 790 mg (2.42 mmol) of cesium carbonate in 10 mL of DMF is heated at 90° C. for 10 minutes. After addition of 600 μl (1.21 mmol) of (3-bromopropyl)benzene, the reaction is continued for 2 hours at 90° C. The solvent is evaporated off. The residue is purified by RP18 reverse-phase chromatography (eluent: H2O 100% to CH3CN 100%) to give 100 mg of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:16][CH2:17][C:18]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=1)=[O:19]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc(F)c(Cl)c1
Temperature: 0 °C
Yield: 89 %

Procedure:
To 130 ml of toluene was added, with stirring, 24.0 g (0.165 mole) of 3-chloro-4-fluoroaniline and 13.5 ml (0.166 mole) of pyridine. The resulting solution was cooled to ca. 0° C. and 13.2 ml (0.166 mole) of 2-chloroacetyl chloride was added. The reaction mixture was stirred at room temperature for 5 hours and then it was extracted twice with 100 ml of 1N hydrochloric acid, followed by 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried using magnesium sulfate, and then it was concentrated in vacuo to give 32.6 g (88% yield) of N-(2-chloroacetyl)-3-chloro-4-fluoroaniline.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Cl.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cu][C:23]#[N:24].[C-]#N.[Na+]>O.C(OCC)(=O)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:23]#[N:24])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: N#C[Cu]
Reactant: Nc1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]ncc2c1
Temperature: 35 °C
Reaction time: 3.5 h
Yield: 91.3 %

Procedure:
To a 1-L beaker was added 20.0 g (150 mmol) of 5-aminoindazole, and 150 g of ice. The mixture was stirred with a magnetic stir bar and cooled on an ice-water bath. To this mixture was added 37.5 mL of concentrated aqueous hydrochloric acid, followed by a solution of 10.5 g (152 mmol, 1.01 equiv.) of sodium nitrite in 30 mL of H2O, dropwise over 15 min. The mixture was vigorously stirred for 30 min. and then carefully neutralized to pH ca. 7.0 with 9.5 g of solid sodium carbonate (Na2CO3). This mixture was transferred to a 1-L separatory funnel, kept cold by the addition of ice, and added dropwise to an ice cooled, magnetically stirred mixture of 16.8 g (188 mmol, 1.24 equiv.) of copper (I) cyanide (CuCN), 24.4 g (498 mmol, 3.32 equiv.) of sodium cyanide (NaCN), 112 mL H2O, and 250 mL of ethyl acetate (EtOAc) in a 2-L erlenmeyer flask over 20 min. Nitrogen gas was evolved from the reaction. The mixture turned dark quickly, and was stirred on ice for 30 min. and then the ice was removed. Stirring was continued for 3.5 h. The mixture was then heated on a hot plate until the internal temperature was 50° C. The reaction was removed from the hot plate and allowed to cool to 35° C., and filtered through filter paper. The layers were separated, and the organic layer was washed with saturated aqueous NaCl, and dried (Na2SO4). The organic layer was poured directly onto a 65 mm column containing 200 g of silica gel and eluted with EtOAc. Fractions of 500 mL were collected, and all product containing fractions were combined and concentrated to give the title compound (19.60 g, 91% yield): ES-MS (m/z) 144 [M+1]+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1>C(O)(C)C>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:5]([CH2:4][CH:2]([OH:1])[CH2:3][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]2)=[CH:6]1
Reactant: c1ccc2c(CC3CO3)coc2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCN(CC(O)Cc2coc3ccccc23)CC1

Procedure:
A solution of 2.9 g of 3-(2-oxiranylmethyl)benzofuran, 4 g of tert-butyl 4-piperidyl-carbamate and 35 ml of isopropanol is heated at 80° C. for 5 hours. After evaporation to dryness, chromatography over silica gel enables the expected product to be isolated.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].CC1(C)C(C)(C)OB([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[C:22]#[N:23])O1.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[OH-].[Na+]>O1CCCC1>[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:20]2[C:21]([C:22]#[N:23])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Reactant: CC(=O)c1ccc(F)c(Cl)c1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(F)c(-c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
1-(3-Chloro-4-fluorophenyl)ethanone (0.86 g, 5.0 mmol), 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzonitrile (1.37 g, 6.0 mmol) (prepared according to the procedure described in WO 02/74773) and potassium fluoride (0.96 g, 16.5 mmol) were suspended in tetrahydrofuran (20 ml) and the mixture degassed with nitrogen for 30 min. Tris(dibenzylidineacetone)dipalladium(0) (0.14 g, 0.15 mmol) and tri-tert-butylphosphine (0.3M in 1,4-dioxane, 1.0 ml) were added and the mixture stirred at room temperature for 1 h then heated at 50° C. for 18 h. The mixture was allowed to cool to room temperature and then poured into 0.5N sodium hydroxide solution (300 ml) and stirred for 30 min. The solid was filtered, washed with water (50 ml) and isohexane (50 ml) and the brown solid left to air-dry. The solid was purified by flash column chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10-30%). Collecting the appropriate fractions gave 5′-acetyl-2′-fluorobiphenyl-2-carbonitrile (0.31 g, 26%) as a yellow solid: δH(400 MHz, CDCl3) 2.64 (3H, s), 7.31 (1H, t, J 8.8 Hz), 7.52-7.56 (2H, m), 7.68-7.72 (1H, m), 7.81 (1H, dd, J 0.8, 7.4 Hz), 8.04-8.09 (2H, m).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][CH:4]2[NH:3][O:2][CH3:1])=[CH:9][CH:10]=1
Reactant: CON=C1CCCc2ccc(Cl)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC1CCCc2ccc(Cl)cc21
Temperature: 23 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
To a stirred solution of crude 7-chloro-3,4-dihydro-2H-naphthalen-1-one-O-methyl-oxime (5.9 g; 28.14 mmol) prepared as described in example P1a in acetic acid (100 ml) was added portion wise sodium cyanoborohydride 95% (3.54 g; 56.3 mmol) at 15° C. The mixture was stirred for 6 hours at 23° C. Most of acetic acid was removed under reduced pressure. The residue was poured in 2N NaOH (100 ml) and was extracted with ethylacetate (3×80 ml). Combined organics were dried over sodium sulfate and solvent was removed in vacuo. The crude (8.2 g) was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10) to afford 2.70 g (45% of theory) of N-(7-chloro-1,2,3,4-tetrahydro-naphthalen-1-yl)-O-methyl-hydroxylamine as a yellow oil.
Reaction SMILES: O[CH2:2][C@H:3]([NH:8][C:9]([C:11]1[N:12]=[CH:13][N:14]2[C:20]3[CH:21]=[CH:22][S:23][C:19]=3[C:18](=[O:24])[N:17]([CH3:25])[CH2:16][C:15]=12)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[CH3:25][N:17]1[C:18](=[O:24])[C:19]2[S:23][CH:22]=[CH:21][C:20]=2[N:14]2[CH:13]=[N:12][C:11]([C:9]3[O:10][CH2:2][C@@H:3]([C:4]([O:6][CH3:7])=[O:5])[N:8]=3)=[C:15]2[CH2:16]1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1COC(c2ncn3c2CN(C)C(=O)c2sccc2-3)=N1
Yield: 22.5 %

Procedure:
A solution of 13.7 g (0.0377 mol) of methyl (S)-3-hydroxy-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-ylcarbonylamino)-propionate in 270 ml of tetrahydrofuran was treated while gassing with argon with 9.87 g (0.0414 mol) of methoxycarbonylsulphamoyltriethylammonium hydroxide internal salt (Burgess reagent) according to the method described in Tetr. Letters 1992, 33, 907. The mixture was boiled at reflux for 2 hrs. and completely freed from the solvents. The residue was partitioned between water and dichloromethane, extracted, chromatographed over silica gel with ethyl acetate as the eluent and recrystallized from acetonitrile. There were obtained 2.94 g (22%) of methyl (S)-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-yl)-4,5-dihydro-oxazole-4-carboxylate as white crystals; m.p. 215°-217°. [α]D20 =+41.2° (CHCl3, c=1%). A further 3.25 g (25%) of yellowish crystals were recovered from the mother liquor.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[C:14](=[O:15])[N:13]([CH2:16][C:17]3[CH:22]=[CH:21]C(C(F)(F)F)=CC=3)[N:12]=[CH:11]2)[S:5][C:6]=1[C:7]([OH:9])=O.C1(CN2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)CC1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][NH2:53])[CH:47]=1>>[CH:17]1([CH2:16][N:13]2[C:14](=[O:15])[N:10]([C:4]3[S:5][C:6]([C:7]([NH:53][CH2:52][C:48]4[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=4)=[O:9])=[C:2]([CH3:1])[N:3]=3)[CH:11]=[N:12]2)[CH2:22][CH2:21]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 49 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 49% yield: mp 116-117° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.57 (br s, 1H), 8.47 (br s, 1H), 8.24 (s, 1H), 7.79-7.71 (m, 1H), 7.44-7.27 (m, 1H), 6.38 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H), 3.70 (d, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.34-1.14 (m, 1H), 0.63-0.52 (m, 2H), 0.46-0.31 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 161.8, 153.4, 151.2, 149.9, 149.2, 148.9, 135.8, 130.5, 123.8, 121.4, 117.9, 50.6, 41.6, 17.2, 10.2, 3.7; MS (ES+) m/z 371.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH3:37][O-].[Na+]>C(Cl)Cl.CO>[CH3:37][O:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:28]([F:30])([F:31])[F:29])[C:25]([CH3:27])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COCc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 283) (213 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with sodium methanolate (5.4M, 1 ml) in MeOH (5 ml)/CH2Cl2 (5 ml) according to the general procedure of example 288. Obtained as an off-white solid (101 mg, 46%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:14]#[N:15])[C:11]([NH2:13])=[NH:12].[F:16][C:17]([F:28])([F:27])[C:18](=O)[CH2:19][C:20](=O)[C:21]([CH3:24])([CH3:23])[CH3:22].[O-]CC.[Na+]>CS(C)=O.CC(=O)OCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:11]1[N:13]=[C:20]([C:21]([CH3:22])([CH3:23])[CH3:24])[CH:19]=[C:18]([C:17]([F:16])([F:27])[F:28])[N:12]=1)[C:14]#[N:15]
Reactant: CC(C)(C)C(=O)CC(=O)C(F)(F)F
Reactant: N#CC(C(=N)N)=C1Nc2ccccc2S1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(C(F)(F)F)nc(C(C#N)=C2Nc3ccccc3S2)n1
Temperature: 180 °C

Procedure:
2-[Benzothiazol-2(3H)-ylidene]-2-cyanoacetamidine (0.2 g, 0.92 mmol) was dissolved in dimethylsulfoxide (1 mL), and 1,1,1-trifluoro-5,5,-dimethyl-2,4-hexanedione (320 μL, 1.84 mmol) and sodium ethoxide (0.6 mL of 21 wt % solution in ethanol, 1.84 mmol) were added. The solution was heated to 180° C. under microwave irradiation for 20 min, dissolved in EA, and washed with 1N hydrochloric acid and then water. Removal of the solvent gave 2-[benzothiazol-2(3H)-ylidene]-2-[4-tert-butyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile as a beige solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:15]C)[C:9]=2[O:13]C)[C:4]1=[O:17].[BrH:18]>>[BrH:18].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:15])[C:9]=2[OH:13])[C:4]1=[O:17]
Reactant: COc1ccc2c(c1OC)CCC(N)C2=O
Agent: Br
Agent: Cl
Product: NC1CCc2c(ccc(O)c2O)C1=O

Procedure:
30 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride is subjected to boiling reflux in 500 volume parts of a 47% aqueous solution of hydrogen bromide for 3 hours and, then, concentrated to dryness under reduced pressure. The residue is dissolved in methanol, followed by the addition of ethyl acetate, whereupon crystals separate. Filtrative recovery yields 31 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=2)=[CH:4][CH:3]=1.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28].O>O1CCCC1>[CH2:20]([NH:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[NH:30][CH:27]([CH3:29])[CH3:28])=[CH:7][CH:6]=2)[N:14]=[CH:13][C:12]=1[CH2:15][C:16]([NH2:18])=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)N=C=O
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NC(=O)Nc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 120.5 %

Procedure:
10 mg of 6-[(4-aminophenyl)amino]-4-(benzylamino) pyridine-3-carboxyamide (the compound of Example 65) was dissolved in 0.5 mL of tetrahydrofuran, and, under ice cooling, 7.6 mg of isopropyl isocyanate was added, and stirred at room temperature for 24 hours. To the reaction mixture, water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was washed with methanol-ether to obtain 15 mg (80%) of the title compound as a light pink crystalline powder.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([OH:27])[CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Ethyl acetate (5.8 ml) was dissolved in tetrahydrofuran (80 ml), to which was then added 1.5M lithium diisopropylamide/cyclohexane solution (43 ml) in nitrogen atmosphere at −70° C., and then the mixture was stirred for 15 min. 4-Bromobenzaldehyde (10.151 g)/tetrahydrofuran (10 ml) solution was added to the reaction mixture, which was then stirred for 30 min. A saturated aqueous solution of ammonium chloride was added thereto, and then it was extracted with in ethyl acetate. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by (NH) silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (11.906 g, yield; 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Br.[Br:48][CH2:49][CH2:50][NH2:51].C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:48][CH2:49][CH2:50][NH:51][C:19]([C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2cccc(C(=O)O)c2)CC1
Reactant: NCCBr
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCc2cccc(C(=O)NCCBr)c2)CC1
Reaction time: 8 h

Procedure:
A DMF (15 ml) solution of 3-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl]benzoic acid (1.25 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (863 mg) and 1-hydroxybenzotriazole (608 mg) was stirred at room temperature for 1 hour, and then a TEA (1.6 ml) solution of 2-bromoethylamine hydrobromide (2.30 g) was added thereto, followed by stirring overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, followed by extraction with EtOAc, then washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain a crude product of tert-butyl 4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidine-1-carboxylate.
Reaction SMILES: [N:1]([CH:4]([CH:6]1[O:21][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH:7]1[CH3:22])[NH:14][C:13](=[O:19])[C:12]([CH3:20])=[CH:11]3)[CH3:5])=[N+]=[N-].[H][H]>CO.O1CCCC1.CN(C)C=O.[Pd]>[NH2:1][CH:4]([CH:6]1[O:21][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH:7]1[CH3:22])[NH:14][C:13](=[O:19])[C:12]([CH3:20])=[CH:11]3)[CH3:5]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(C(C)N=[N+]=[N-])O3
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(C(C)N)O3
Yield: 65.6 %

Procedure:
The compound obtained in Example 290 (2.08 g, 7.0 mmol) was dissolved in a mixture of methanol (30 ml), tetrahydrofuran (30 ml) and dimethylformamide (30 ml). To the obtained solution, 10% palladium-on-carbon (0.70 g) was added, and allowed to react at ambient temperature for 4 hours in the stream of hydrogen gas. The insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (benzene:methanol=2:1) to obtain 1.25 g of the title compound as a colorless solid (66.0%, mp.: 195°-207° C.)