Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)CC(C)C)cc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (19.72 g, 88.78 mmol) in dichloromethane (300 mL) is added pyridinium chlorochromate (22.03 g, 97.65 mmol). The mixture is allowed to stir at room temperature, and the solution turns black over time. The reaction is monitored by HPLC. Upon complete conversion, the reaction is diluted with dichloromethane and silica gel (2% by wt) is added to the mixture. The mixture is purified by flash column chromatography using dichloromethane as mobile phase, producing 15.79 g (72%) of product. MS (ES): 221.3 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:22](N(OC)C)=[O:23])[CH3:21])=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[CH3:21][C@H:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])[C:22](=[O:23])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 4 h

Procedure:
To a stirred mixture of isopropylmagnesium chloride-lithium chloride complex (14% wt 1 M solution, 726 mg, 5 mmol, 5 ml) and THF (5 ml) was added 1-bromo-4-(trifluoromethyl)benzene (1.125 g, 5 mmol) under argon. The stirring was continued at r.t. for 4 h. A solution of N2-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-alaninamide (232 mg, 1 mmol) in THF (10 ml) was added dropwise, and the stirring was continued overnight at r.t. Then the reaction mixture was quenched with sat. aq. NH4Cl (20 ml), and stirring was continued for 30 min. The layers were separated, the aqueous layer extracted with ethyl acetate (20 ml). The combined organic extracts were dried over Na2SO4, and the solvent was evaporated to give yellow partly crystalline product. Purification by flash chromatography on silica gel with n-heptane/ethyl acetate afforded colourless solid, 260 mg (82%).
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[S:35][C:32]1[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=1)(=[O:27])[CH3:26]
Reactant: Cc1ccc(S)cc1
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Sc2ccc(C)cc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a mixture of D-mannose pentaacetate (16.0 g, 0.041 mol) and p-thiocresol (7.6 g, 0.0615 mol) in CH2Cl2 (200 mL), boron trifluoride diethyl etherate (6.8 mL, 0.0533 mol) was added. The mixture was stirred overnight. The reaction mixture was then diluted with CH2Cl2 (200 mL), washed with sat. NaHCO3 (2×120 mL) and water (100 mL). The organic layer was dried over Na2SO4. The solvent was removed, and the residue was purified by column chromotography on silia gel (hexanes/EtOAc 3:1) to give product (16.2 g, 87%) as a syrup: 1HNMR (500 MHz, CDCl3), δ 7.38 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 5.49 (dd, 1H, J=2.5, 1.5 Hz), 5.42 (d, 1H, J=1.0 Hz), 5.30–5.35 (m, 2H), 4.54–4.58 (m, 1H), 4.30 (dd, 1H, J=12.5, 6.0 Hz), 4.11 (dd, 1H, J=12.0, 2.5 Hz), 2.33 (s, 3H), 2.15 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H); HRMS (M+Cs) calcd for C21H26O9SCs 587.0352. found 587.0331.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[C:9]([OH:12])[CH:10]=[CH:11][N:5]2[N:4]=1.[H-].[Na+].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[C:9]([O:12][CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH:10]=[CH:11][N:5]2[N:4]=1
Reactant: CSc1ncc2c(O)ccn2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2c(OCOCC[Si](C)(C)C)ccn2n1
Reaction time: 0.5 h

Procedure:
Into a 1-Neck round-bottom flask, 2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-5-ol (0.810 g, 4.47 mmol) and N,N-Dimethylformamide (35.00 mL, 452.0 mmol) were added. Sodium Hydride (60% dispersion mineral oil)(6:4, Sodium hydride:Mineral Oil, 0.214 g, 5.36 mmol) was added portion wise at room temperature and stirred for 30 minutes. [β-(Trimethylsilyl)ethoxy]methyl chloride (0.745 g, 4.47 mmol) in DMF (5 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 1 hour. The reaction was partitioned with water and Et2O. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with Hexane and EtOAc as eluant (0 to 40% EtOAc). The collected fractions afforded 2-Methylsulfanyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (1.05, 75%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:25][CH2:26][CH3:27])=[C:7]([CH:13]([NH:15][C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[CH3:11])[CH2:2]1.[CH3:28]CN(C(C)C)C(C)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C1COCC1.C(#N)C>[Cl:12][C:9]1[C:10]([CH3:11])=[C:5]([CH:3]2[CH2:4][N:1]([CH3:28])[CH2:2]2)[C:6]([O:25][CH2:26][CH3:27])=[C:7]([CH:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)[CH3:14])[CH:8]=1
Reactant: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl 3-{3-chloro-6-ethoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate (83 mg, 0.16 mmol) and 5% palladium (74 mg) was combined in methanol (5 mL), to which was added 0.25 M HCl in water (1.6 mL, 0.40 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature overnight. The suspension was filtered and concentrated to give N-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-9H-purin-6-amine. LCMS calculated for C19H24ClN6O (M+H)+: m/z=387.2. found: 387.1. The azetidine made above was combined with DIPEA (0.1 mL, 0.6 mmol) in methanol (0.5 mL)/acetonitrile (0.5 mL)/THF (0.5 mL), followed by the addition of 37% formaldehyde (0.1 mL, 2 mmol). The mixture was stirred at room temperature for 10 min before the addition of sodium triacetoxyborohydride (0.17 g, 0.80 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with MeOH and purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H26ClN6O (M+H)+: m/z=401.2. found: 401.1.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1)=[O:4].[CH2:19]([C:21]([O-:23])=[O:22])[CH3:20].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O>[N:24]1([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)=[O:4])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[CH2:19]([C:21]([O-:23])=[O:22])[CH3:20]
Reactant: O=C(CCl)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: C1COCCN1
Agent: CCC(=O)[O-]
Solvent: O
Product: O=C(CN1CCOCC1)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 26 %

Procedure:
A solution of 80 mg (0.24 mmol) of 8-(2-chloro-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 420 μL (4.8 mmol) of morpholine is heated at 60° C. for 4 hours. Water is added and the solid is filtered and then purified by chromatography on silica (eluent dichloromethane/methanol 95/5) to give 24 mg (26%) of 8-(2-morpholin-4-yl-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a brown solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccccc3)c12

Procedure:
The title compound, grey solid (52 mg, 74%), MS (ISP) m/z=281.3 [(M+H)+], mp 236.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[OH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C.C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][OH:12])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 90 °C

Procedure:
1-Bromo-4-trifluoromethyl-benzene (814 mg, 3.62 mmol), 4-hydroxymethylphenylboronic acid (600 mg, 3.98 mmol), cesium carbonate (2.36 g, 7.24 mmol), and PdCl2(dppf) (132 mg, 0.181 mmol) were added to 10 ml of a 1:1 solution of DMF/THF. The reaction was flushed with nitrogen and heated to 90° C. for 1 h. The reaction was cooled, poured into diethyl ether and washed with water (2×50 ml), brine (1×50 ml) and dried over anhydrous sodium sulfate. The crude product was filtered through silica gel, eluted with diethyl ether, and concentrated to provide the title compound. MS m/z 251 (M−1).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH:12]=O)=[C:8]([N:14](C)C)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:17]N>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[N:17][NH:14][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cnn(C(C)(C)C)c(=O)c1C=O
Reactant: NN
Solvent: CCO
Product: CC(C)(C)n1ncc2[nH]ncc2c1=O

Procedure:
2-Tert-butyl-5-dimethylamino-4-formyl-3(2H)-pyridazinone (3.5 g) was added to hydrazine (5.1 g)/ethanol (30 ml) and the mixture was refluxed for 40 hours. The solvent ethanol-hydrazine was then distilled off and the residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was washed with n-hexane-diethyl ether and dried. White powder, 1.9 g. 1H-NMR (CDCl3) δ: 1.71(9H,s), 8.19(1H,s), 8.32(1H,s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:16][CH2:17][CH3:18])[C:12]=1[O:13][CH2:14][CH3:15])C(O)=O)[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N+:19]([O-:21])=[O:20])[CH:10]=[C:11]([O:16][CH2:17][CH3:18])[C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1OCC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOc1cc([N+](=O)[O-])cc(OCC)c1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of 3,4,5-triethoxybenzoic acid (20.0 g, 78.7 mmol) in acetic acid (68 mL) was stirred at 15° C., and concentrated nitric acid (d 1.38)(34 mL, 750 mmol) was added. After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 3,4,5-triethoxy-1-nitrobenzene as a colorless oil (12.9 g, yield: 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=O)=[CH:20][CH:19]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:30].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:30])=[O:27])=[CH:20][CH:19]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 40 h
Yield: 70.9 %

Procedure:
A 20-mL vial was charged with methyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methyl)phenyl)acetate (98 mg, 0.25 mmol, 1.0 eq.) and ammonium chloride (40 mg, 0.75 mmol, 3.0 eq.). Methanol (3 mL) was added to the mixture followed by NH3 (7.1 mL, 7N in methanol, 50 mmol, 200 eq.). The vial was sealed and the resulting mixture was stirred at 100° C. for 40 hr. The crude reaction solution was adsorbed onto silica, then purified by chromatography on silica gel using dichloromethane/methanol (0 to 10%) as eluent, to give 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methyl)phenyl)acetamide (67 mg, 71% yield) as a white solid. MW=377.87. 1H NMR (DMSO-d6, 500 MHz) δ 8.36-8.31 (m, 2H), 7.57-7.51 (m, 2H), 7.40 (br s, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H), 4.08 (s, 2H), 3.31 (s, 2H), 2.97 (t, J=8.0 Hz, 2H), 2.90 (t, J=7.5 Hz, 3H), 2.07 (quintet, J=7.5 Hz, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=2)[CH:9]=1)=[O:4].[OH-].[Li+].O>O1CCCC1>[I:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=1[CH3:19]
Reactant: COC(=O)c1cc(COc2cccc(I)c2)c(C)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1COc1cccc(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
A mixture of 4-(3-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (106) (2.7 g, 7.25 mmoles) and lithium hydroxide (1.5 g, 36.25 mmoles) in tetrahydrofuran (25 ml) containing water (2 ml) was stirred at room temperature for 3 h. The tetrahydrofuran was evaporated, the residue was diluted with water and the mixture acidified to pH=1 with 1M aqueous hydrochloric acid. The precipitate was collected washed with water and dried at 70° C. in vacuo to give compound 107 (1.76 g) as a white solid. LC/MS System B; Rt=3.51 mins, m/z (ES−)=357 (M−H for C13H11IO4).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[Br:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>CN(C=O)C.C(OCC)(=O)C>[Br:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH:57][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:5]=2)=[O:9])=[CH:52][CH:51]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: NCc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Br)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of biphenyl-4-carboxylic acid 10-2 (0.89 g, 4.5 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (1.7 g, 4.5 mmol) and DIEA (2.34 mL, 13.5 mmol) in DMF (15.0 mL) was added (4-bromophenyl)methanamine 10-1 (1.0 g, 4.5 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the resulting precipitate was collected by vacuum filtration to give N-(4-bromobenzyl)biphenyl-4-carboxamide 10-3 as a white solid. MS m/z 366.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.[NH2:16][C:17]1[C:21]([C:22]#[N:23])=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[NH:19][N:18]=1>C(O)(=O)C>[C:31]1([CH2:30][N:27]2[CH2:28][CH2:29][N:24]([C:20]3[C:21]([C:22]#[N:23])=[C:17]4[N:16]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=[C:5]([C:7]5[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=5)[N:18]4[N:19]=3)[CH2:25][CH2:26]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: N#Cc1c(N)n[nH]c1N1CCN(Cc2ccccc2)CC1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccncc1
Solvent: CC(=O)O
Product: N#Cc1c(N2CCN(Cc3ccccc3)CC2)nn2c(-c3ccncc3)cc(C(F)(F)F)nc12

Procedure:
A mixture of 3.9 g (0.014 moles) of 4,4,4-trifluoro-1-(4-pyridyl)-1,3-butanedione (U.S. Pat. No. 3,200,128), 3.9 g (0.014 moles) of 3-amino-5-(4-phenylmethyl-1-piperazinyl)-4-pyrazolecarbonitrile (prepared as described in Example 1) and 100 ml of glacial acetic acid was stirred at reflux for 16 hours.
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[CH:40]([N:43]=[C:44]=[S:45])([CH3:42])[CH3:41]>C(#N)C>[CH:40]([NH:43][C:44]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:3]2[N:4]=[C:5]3[N:11]([CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[CH:6]3[O:16][CH:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[C:2]=2[CH3:1])=[CH:25][CH:26]=1)=[S:45])([CH3:42])[CH3:41]
Reactant: Cc1c(-c2ccc(N)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Reactant: CC(C)N=C=S
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(NC(=S)NC(C)C)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 80 °C

Procedure:
To a solution of 4-[1-methyl-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 173) (50 mg, 0.124 mmole) in ACN (1 mL) are added DIEA (65 μL, 0.372 mmole) and isopropylisothiocyanate (18.8 mg, 0.182 mmole). The reaction mixture is heated overnight at 80° C. Solvent is removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH:NH4OH) from (98:2:02) to (96.5:3.5:0.35) to give 1-isopropyl-3-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diazabenzo[f]azulen-2-yl]-phenyl}-thiourea. [M+H]+=504.37.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([O:12]COC)=[C:6]([F:16])[CH:5]=1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([OH:12])=[C:6]([F:16])[CH:5]=1
Reactant: C=Cc1cc(C(=O)OC)cc(F)c1OCOC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cc(C(=O)OC)cc(F)c1O
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of 3-fluoro-4-methoxymethoxy-5-vinylbenzoic acid methyl ester (185 mg) in THF (2 mL)-3N hydrochloric acid (1 mL) was stirred at 60° C. for 3 hours under heating. The mixture was allowed to stand for cooling down to room temperature, diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1, v/v) to give the title compound (121 mg). (In the above, THF is tetrahydrofuran).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.Cl.[F:46][C:47]1([F:51])[CH2:50][NH:49][CH2:48]1.CN1CCOCC1>CN(C=O)C>[F:46][C:47]1([F:51])[CH2:50][N:49]([C:13](=[O:15])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:18])[CH3:17])[CH2:48]1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: FC1(F)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](C(=O)N1CC(F)(F)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). 3,3-Difluoroazetidine hydrochloride (10.0 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. Following reaction, the product was purified by preparative HPLC (10-60% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a white solid (10 mg, 53%). 1H NMR (500 MHz, DMSO-d6) δ 0.80 (d, J=6.0 Hz, 3H), 0.96 (d, J=6.0 Hz, 3H), 2.30-2.41 (m, 1H), 4.26-4.36 (m, 2H), 4.41-4.51 (m, 1H), 4.70-4.79 (m, 1H), 5.00 (AB q, J=104.5, 22.0 Hz, 2H), 5.07 (d, J=23.0 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 12.40 (s, 1H). [M+H] calc'd for C17H17F3N4O2, 367; found, 367.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Cl-].[NH4+]>ClCCl>[Br:8][C:4]1[N:3]=[C:2]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Br)n2)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-dibromopyridine (34 g) in dichloromethane (740 ml) is added dropwise, at −78° C. under argon, n-butyllithium (1.6 M in tetrahydrofuran, 100 ml). The reaction mixture is stirred at −78° C. for 20 minutes and then tert-butyl 4-oxopiperidine-1-carboxylate is added. The mixture is stirred at room temperature for 20 minutes. The reaction mixture is subsequently admixed with saturated ammonium chloride solution at −30° C. and the aqueous phase is removed. After the aqueous phase has been extracted with dichloromethane, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives tert-butyl 4-(6-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (60 g).