Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][C:8]=2[CH3:11])[C:3]1=O.Cl.[CH2:15](OCC)C>>[CH3:1][C:2]1[CH2:3][C:4]2[C:9]([C:10]=1[CH3:15])=[C:8]([CH3:11])[CH:7]=[C:6]([CH3:12])[CH:5]=2
Reactant: CCOCC
Reactant: Cc1cc(C)c2c(c1)C(=O)C(C)C2
Agent: Cl
Product: CC1=C(C)c2c(C)cc(C)cc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
2,4,6-Trimethylindanone (30.0 g, 0.17 moles) was stirred in diethylether (300 mL) at 0° C. as MeMgl (0.24 moles, 80.00 mL of 3.0 M solution in diethylether) was added dropwise. This mixture was stirred for another 30 minutes at 0° C. and then at 20° C. for an additional 3 hours. After the reaction period the mixture was poured on crushed ice, acidified with HCl, and extracted with 1 M HCl (2×100 mL), 1 M NaHCO3 (1×100 mL), and then H2O (1×100 mL). Drying over MgSO4 followed by filtration and solvent removal resulted in the isolation of a light brown oil. Vacuum distillation resulted in the isolation of the desired product as a pale yellow oil (28.0 g, 94.3 percent yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4](=[O:18])[CH:3]=1.[Cl:19]N1C(=O)CCC1=O>C(#N)C>[Cl:19][C:3]1[C:4](=[O:18])[N:5]([CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCC(CC)Cn1c(=O)cc(Cl)n(C)c1=O
Solvent: CC#N
Product: CCCCC(CC)Cn1c(=O)c(Cl)c(Cl)n(C)c1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 111.2 %

Procedure:
To a solution containing 20 g of 6-chloro-3-(2-ethylhexyl)-1-methyluracil thus-obtained in 50 ml of acetonitrile was added 8.6 g of N-chlorosuccinimide, the mixture was heated to 40° C. and stirred for 2 hours. After allowing the mixture to cool, the acetonitrile was distilled off under reduced pressure, to the residue was added water and it was extracted with 100 ml of chloroform. The organic phase was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 22 g of 5,6-dichloro-3-(2-ethylhexyl)-1-methyluracil as an oily product.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:13][CH2:14][O:15][C:16]([CH:18]([C:22]([CH3:24])=O)[C:19]([CH3:21])=O)=[O:17]>CC(O)=O.O>[CH2:14]([O:15][C:16]([C:18]1[C:19]([CH3:21])=[N:12][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:22]=1[CH3:24])=[O:17])[CH3:13]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(C)nn(-c2cccc([N+](=O)[O-])c2)c1C
Reaction time: 20 h

Procedure:
Following the procedure described in Helvetica Chimica Acta (1952), 35, 478-85, 5.00 g (26.37 mmmol) of 3-nitrophenylhydrazine hydrochloride suspended in 46 ml of 55% aqueous AcOH were dissolved by careful heating and treated (without further heating) with 4.13 ml (26.37 mmol) of ethyl diacetoacetate. The reaction was immediately cooled and kept 20 h at 0° C. The precipitate was diluted with 28 ml of water and after 6 h filtered and washed with 2×5 ml of water to give after drying under reduced pressure 4.66 g (61%) of the title compound as a light yellow solid. MS: 289.9 (MH+).
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:19](=[O:21])[CH3:20])[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCSc2ccccc2C1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (5 g, 30.3 mmol) in dry dichloromethane (100 mL) was added triethylamine (5.06 mL, 36.3 mmol) at room temperature, followed by the dropwise addition of acetic anhydride (3.43 mL, 36.3 mmol) at 0° C. under nitrogen. The resulting solution was stirred for 1 hour whilst allowing the temperature to rise slowly to room temperature. The mixture was washed with brine (50 mL×2), dried over sodium sulfate, filtered and concentrated in vacuo to afford 6.28 g of product as yellow oil, which was used for next step without further purification.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C>[C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][C@@H:11]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
A 1 L 3-neck round bottom flask equipped with a mechanical stirrer and addition funnel was charged with 252B (14.7 g, 39 mmol) and acetonitrile (200 mL) and acetic acid (100 mL). The solution was cooled to 0° C. and Na(OAc)3BH (33.3 g, 157 mmol) was added in three portions over 2 hours. The reaction was stirred for two hours at this temperature after the final addition. The mixture was then cooled to −10° C. and slowly quenched by addition of 1 N NaOH (100 mL), 4 N NaOH (100 mL), 6 N NaOH (100 mL) followed by 50% NaOH (50 mL). The reaction was warmed to room temperature and the layers were separated. The aqueous layer was extracted with CH2Cl22 (2×250 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (10% to 30% EtOAc/hexane gradient) on silica gel afforded 6.0 g (yield: 41%) of Compound 252C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:19][CH:18]=1>CN(C)C=O>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:30][CH:29]=1
Reactant: ClCc1ccc(COc2ccccn2)cc1
Reactant: Nc1ncccc1-c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cnn(Cc2ccc(COc3ccccn3)cc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91.4 %

Procedure:
To a solution of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (150 mg, 0.94 mmol) described in Manufacturing Example 32-1-4 in N,N-dimethylformamide (10 mL) was added sodium hydride (48.7 mg, 1.22 mmol, 60% in oil) on an ice bath (0° C.) under nitrogen atmosphere. Following 40 minutes of stirring at room temperature, 2-(4-chloromethyl-benzyloxy)-pyridine (228 mg, 0.98 mmol) described in Manufacturing Example 30-1-1 was added and stirred for 30 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate) to obtain the title compound (307 mg, 92%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3S[CH2:22][CH2:21][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][C:18]=3[CH:29]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].OO.[S:32]([O-:35])([O-])=[O:33].[Na+].[Na+].O>C(O)(=O)C>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[S:32](=[O:35])(=[O:33])[CH2:22][CH2:21][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][C:18]=3[CH:29]=2)=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3)cc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3(=O)=O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
Ethyl 7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (45 g, 109.1 mmol) was suspended in 405 ml of acetic acid and was heated to 60° C. to dissolve. A solution of 30% hydrogen peroxide (25.35 g, 223.6 mmol) in 45 ml of acetic acid was dropped slowly at 60-70° C. After the dropping, the mixture was stirred at 65-70° C. for 3 hours. At that temperature, 40 ml of an aqueous sodium sulfite solution was dropped and disappearance of the peroxide was checked with iodo-starch paper. After dropping 275 ml of water at that temperature, the mixture was cooled and stirred for 2 hours and then was stirred at 0-10° C. for 30 minutes. After filtration, the residue was washed with an ice-cooled, mixed solution of acetic acid/water (45 ml/31.5 ml) and subsequently with 225 ml of water. After vacuum drying (40° C.), 45.9 g (Yield 94.6%) of ethyl 7-(4-propoxyethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate was obtained as white crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[Cl-].[Mg+2].[Cl-].[CH2:14]=[O:15].Cl>ClC(Cl)C.C(N(CC)CC)C>[F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:14]=[O:15]
Reactant: C=O
Reactant: COc1cccc(O)c1F
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1ccc(C=O)c(O)c1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of 2-fluoro-3-methoxyphenol (22.0 g) and triethylamine (93.9 g) in dichloroethane (250 mL) was added magnesium chloride (71.7 g), and the mixture was stirred at 40° C. for 1 hr. To this mixture was added paraformaldehyde (46.5 g), and the mixture was stirred for 16 hr. The reaction solution was allowed to be cooled to room temperature, 1N hydrochloric acid was added thereto, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by combi flash (petroleum ether/ethyl acetate) to give the title compound (26.0 g).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].[OH-].[K+].[CH2:16](Cl)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O.O>[CH2:16]([N:4]1[CH2:3][CH2:2][N:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]1=[O:6])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCC=Cc1ccccc1
Reactant: O=C(NCCCl)Nc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.5 %

Procedure:
To a solution of 20 g of N-(2-chloroethyl)-N'-(3-pyridyl) urea dissolved in 200 ml of dimethyl sulfoxide, 13 g of KOH powder was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Further, 3.4 g of KOH powder was added and then 16.8 g of cinnamyl chloride (trans-form) was added under ice-cooling and the mixture was stirred for 20 minutes, followed by stirring at room temperature for 30 minutes. The mixture was diluted with 300 ml of water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, saturated saline water ad dried, and ethyl acetate was distilled off. To the residue was added 100 ml of 70% acetic acid, and the mixture was heated at 90° C. for 10 minutes and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed twice with saturated saline water and twice with water, and dried. After distilling the ethyl acetate off, the residue was recrystallized from ethanol to give 21.96 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][CH:21]=3)[N:15]=2)[CH2:6]1)=[O:4].B.O1CCCC1.Cl.C(O)C>O1CCCC1>[F:29][C:2]([F:1])([F:28])[CH:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][CH:21]=3)[N:15]=2)[CH2:6]1)[OH:4]
Reactant: O=C(N1CCCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)C1)C(F)(F)F
Agent: B
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: OC(N1CCCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)C1)C(F)(F)F
Temperature: 65 °C

Procedure:
To a room temperature solution of (±)-2,2,2-trifluoro-1-(3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)ethanone (18 mg, 0.04 mmol) in tetrahydrofuran (1 mL) was added borane-tetrahydrofuran (1M, 0.13 mL, 0.13 mmol). The reaction mixture was heated at 65° C. for four hours, cooled, treated carefully with 6 mL of 6N HCl and 2 mL of ethanol and heated at 65° C. for one hour. The cooled reaction mixture was extracted four times with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered, and rotovapped. The residue was chromatographed on silica (4 g) and eluted with 1:20:80 to 5:30:70 triethylamine-isopropanol-hexanes to give the title compound as a bright yellow solid white solid; Rf 0.15 with 1:20:80 v/v triethylamine-isopropanol-hexanes; MS (ESI+) m/z 404 (M+1); H-PGDS FPBA IC50: 10 μM.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[O:24][C:23]([CH:25]=O)=[CH:22][CH:21]=5)[CH:18]=[CH:19][C:14]4=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[O:24][C:23]([CH2:25][N:27]6[CH2:32][CH2:31][O:30][CH2:29][CH2:28]6)=[CH:22][CH:21]=5)[CH:18]=[CH:19][C:14]4=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(-c2ccc3nnc(Cc4ccc5c(c4)CCO5)n3n2)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1cc2c(cc1Cc1nnc3ccc(-c4ccc(CN5CCOCC5)o4)nn13)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
5-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-furan-2-carbaldehyde (21.6 mg, 0.06 mmol), morpholine (6.5 μL, 0.07 mmol) and AcOH (2 drops) were combined in DCM (1 mL). To this was added sodium triacetoxyborohydride (19 mg, 0.09 mmol) and the reaction was stirred at rt for 2 hours. The reaction was concentrated in vacuo followed by purification by HPLC (5-65% CH3CN over 35 min) resulting in the title compound (5.9 mg, 27%) as a solid. 1H-NMR (CD3OD/CDCl3): δ 8.23-8.21 (1H, d, J=9.6 Hz), 7.81-7.78 (1H, d, J=9.8 Hz), 7.42-7.41 (1H, d, J=3.5 Hz), 7.22 (1H, s), 7.17-7.15 (1H, d, J=9.6 Hz), 6.99-6.98 (1H, d, J=3.5 Hz), 6.67-6.65 (1H, d, J=8.3 Hz), 4.57 (2H, s), 4.45-4.38 (4H, m), 3.94 (4H, br s), 3.40-3.33 (4H, m), 3.17-3.13 (2H, t, J=8.8 Hz). ESI-MS (m/z): Calcd. For C23H23N5O3: 417.18; found: 418.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH:12]=[CH:13][CH2:14][CH3:15].C(NC(C)C)(C)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:10][C:4]1[CH:3]=[C:2]([CH:13]([CH2:14][CH3:15])[CH2:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:6]([OH:8])[C:5]=1[F:9]
Reactant: Oc1cc(Br)cc(F)c1F
Reactant: CCC=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(C)NC(C)C
Solvent: CCC#N
Product: CCOC(=O)CC(CC)c1cc(O)c(F)c(F)c1
Temperature: 120 °C
Yield: 87 %

Procedure:
A mixture of 5-bromo-2,3-difluorophenol (20 g 0.0957 mol), ethyl pentenoate (24.53 g, 0.191 mol), N,N-diisopropylamine (66.68 ml, 0.383 mol) and catalytic reagents [Pd(OAc)2=2.15 g, 9.57 mmol; P(O-tol)3=11.65 g, 0.0383 mol] in propionitrile (500 mL) in solution was degassed by bubbling nitrogen. The reactions were heated to 120° C. overnight. The reaction mixtures were filtered through a Celite and washed with CH2Cl2 and filtrates were combined and concentrated. The crude residue was purified by flash column chromatography eluting with 0-10% EtOAc in hexanes to afford the desired product (21.5 g). Subsequent hydrogenation in Parr shaker using Pd/C at 65 psi overnight, followed by filtration, concentration and column chromatography (0-10% ethyl acetate:hexane) afforded the desired product (17.6 g, 71%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH:42]([N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)([CH3:44])[CH3:43]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]5[CH2:49][CH2:50][N:45]([CH:42]([CH3:44])[CH3:43])[CH2:46][CH2:47]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a mixture of 0.050 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.08 mL (0.44 mmole) of ethyldiisopropyl amine and 0.018 g (0.12 mmole) of 1-isopropyl-piperidin-4-ylamine in 1.5 mL of dimethylformamide was added 0.053 g (0.12 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-85:15) gave 0.010 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-isopropyl-piperidin-4-yl)-3-methoxy-benzamide (I-64) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].[OH-].[Na+:38]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([O-:23])=[C:7]([C:24]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:25])[C:6]1=[O:29].[Na+:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: NCCCO
Agent: [Na+]
Agent: [OH-]
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCCO)c([O-])c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-1-propanol employing methods similar to those described in Example 245. The resulting material was triturated with water, covered with EtOH and treated with 1 equivalent of 1N NaOH solution. Concentration in vacuo afforded the product as a white solid: 1H NMR (d6-DMSO) δ 10.53 (1H, br), 8.14 (1H, s), 7.25 (3H, m), 7.10 (2H, t, J=9 Hz), 4.92 (2H, s), 4.49 (1H, br), 3.98 (2H, s), 3.43 (2H, m), 3.25 (2H, m), 3.07 (3H, s), 2.78 (3H, s), 1.58 (2H, m, J=6 Hz); AP+ MS: 457 (M+H+, 100).
Reaction SMILES: C(O)C.C(=S)(OCC)[S:5][C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1.[OH-].[Na+]>O>[F:15][C:12]([F:13])([F:14])[C:9]1[N:8]=[CH:7][C:6]([SH:5])=[CH:11][CH:10]=1
Reactant: CCOC(=S)Sc1ccc(C(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1ccc(S)cn1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To an ethanol (2 ml) solution of O-ethyl S-(6-trifluoromethylpyridin-3-yl) dithiocarbonate (160 mg, 0.60 mmol) was added a 1N aqueous sodium hydroxide solution (2 ml). The resulting mixture was stirred at 65° C. for 2 hours. After the reaction mixture was cooled to room temperature and then, water was added thereto. The resulting mixture was washed with dichloromethane. The water layer was acidified with 1N hydrochloric acid, and the product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to afford 6-trifluoromethylpyridine-3-thiol as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[O:15])[N:6]([CH2:8][C@H:9]([C@H:12]([OH:14])[CH3:13])[CH2:10][OH:11])[CH:7]=1.[C:17](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:26]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[CH:28][CH:27]=1)[C:18]1[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([C:17]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[CH:24][CH:25]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH2:10][C@H:9]([CH2:8][N:6]2[CH:7]=[C:2]([CH3:1])[C:3](=[O:16])[NH:4][C:5]2=[O:15])[C@H:12]([OH:14])[CH3:13])=[CH:33][CH:32]=1
Reactant: Cc1cn(C[C@@H](CO)[C@@H](C)O)c(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H](Cn2cc(C)c(=O)[nH]c2=O)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.9 %

Procedure:
To a stirred solution of 33 (0.6 g. 2.6 mmol) in 20 ml of anhydrous pyridine was added 0.9 g (2.66 mmol) of DMTCl. After being stirred at room temperature for 5 hrs the reaction was quenched with methanol (3 ml), concentrated and portioned between 10% citric acid and ethyl acetate. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to a solid foam. The crude product was chromatographed on silica eluting with ethyl acetate to afford 0.95 g (69%) of 34 as an amorphous white solid. 1H NMR (DMSO-d6): δ 11.16 (s, 1H), 7.28 (m, 6H), 7.21 (m, 4H), 6.85 (m, 4H), 4.59 (d, J=5 Hz, 1H), 3.76 (m, 2H), 3.74 (s, 6H), 3.57 (m, 1H), 3.10 (m, 1H), 2.95 (m, 1H), 2.11 (m, 1H), 1.67 (s, 3H), 1.02 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([CH:13]=O)=[CH:3]1.[CH3:15][NH:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:15][N:16]([CH3:17])[CH2:13][C:4]1[C:5]2[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=2[CH3:12])[N:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)c2c(C=O)cn(C)c2c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)c2c(CN(C)C)cn(C)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,4,6-trimethyl-1H-indole-3-carbaldehyde (875 mg, 4.7 mmol) in CH2Cl2 (30 mL) and dimethylamine (2.0 M solution in MeOH) (4.7 mL, 9.3 mmol) was added sodium triacetoxyborohydride (NaBH(OAc)3) (2.9 g, 14 mmol) at 0° C. Upon complete addition the cooling bath was removed and the reaction mixture was stirred at room temperature for 48 h. When the reaction was complete, the mixture was diluted with CH2Cl2 and washed with saturated NaHCO3. The layers were separated and the organic phase was dried over MgSO4, filtered and concentrated. The residue was used in the next step of the synthesis without purification.