Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11]N1C(=O)CCC1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:11][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(F)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
To a −78° C. solution of 3-fluoronitrobenzene (2 g, 14.2 mmol) in THF (30 mL) was added N-chlorosuccinimide (5.69 g, 42.6 mmol) in THF (20 mL), NaHMDS (1 M in THF, 28.4 mL, 28.4 mmol) was then added dropwise to maintain an internal temperature below −75° C. The resulting mixture was stirred for 30 min at −78° C. Then it was partitioned between 5% of HCl and ethyl acetate. The combined organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (20% Ethyl acetate Hexane) gave the desired product(231 mg, 9.2%). EI-MS m/z 176.5 (M+).
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=O)[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9]([Cl:16])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c2cccc(Br)c21
Solvent: O
Product: Cn1c(Cl)nc2cccc(Br)c21
Temperature: 110 °C
Reaction time: 1 h

Procedure:
7-Bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (2.20 g, 9.69 mmol) was dissolved in 30 mL of phosphorous oxychloride and the mixture was heated at 110° C. for 2 days. The reaction allowed to cool to room temperature, poured into water with an ice, and stirred for 1 h. The aqueous solution was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give 2.32 g of the title compound, which was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:42]([C:43]([O:45]C)=[O:44])=[C:11]3[CH:12]=[C:13]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([CH3:34])[CH3:33])[CH:25]=4)[C:14]([N:16]([CH2:21][CH2:22][OH:23])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[Li+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:42]([C:43]([OH:45])=[O:44])=[C:11]3[CH:12]=[C:13]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)([CH3:34])[CH3:33])[CH:25]=4)[C:14]([N:16]([CH2:21][CH2:22][OH:23])[S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CCO)S(C)(=O)=O)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1cccc(-c2cc3c(C(=O)O)c(-c4ccc(F)cc4)nn3cc2N(CCO)S(C)(=O)=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing methyl 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.021 g, 0.33 mmol), THF (0.20 mL) and methanol (0.13 mL) was added aqueous lithium hydroxide (0.081 mL, 2.0 M). The solution was maintained at room temperature for 20 h, then at 45° C. for 8 h. The solution was adjusted to below pH 4 with aqueous HCl (0.21 mL, 1.0 N) and extracted with ethyl acetate (2×0.50 mL). The combined organic portions were washed with brine (0.50 mL) and concentrated to afford 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid as a light yellow residue which was used without further purification. LCMS: retention time: 1.778 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol/90% H2O/10 mM TFA and solvent B was 10% H2O/90% methanol/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 631 (MH+).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[CH:11]1([CH2:14]Br)[CH2:13][CH2:12]1>>[Cl:1][C:2]1[N:7]([CH2:14][CH:11]2[CH2:13][CH2:12]2)[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: BrCC1CC1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Product: Cn1c(=O)cc(Cl)n(CC2CC2)c1=O

Procedure:
The sub-title compound was prepared by the method of example 9, part a) using 6-chloro-3-methyl uracil and cyclopropylmethyl bromide.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:29](=[O:30])[C:28]([CH3:31])=[C:21]2[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19]1=[O:32].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:29](=[O:30])[C:28]([CH3:31])=[C:21]4[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]4[C:19]3=[O:32])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: Sc1cccc2nccn12
Reactant: Cc1c2n(c(=O)n(CCCCCl)c1=O)CCCS2(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2n(c(=O)n(CCCCSc3cccc4nccn34)c1=O)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.26 g (6.5 mmol) of 60% oily sodium hydride in 30 ml of N,N-dimethylformamide, 0.98 g (6.5 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 1.92 g (6 mmol) of 7-(4-chlorobutyl)-1,1-dioxo-9-methyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.97 g (6.5 mmol) of sodium iodide were added, followed by stirring at 100° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=25/1) to yield 1.61 g (61.8%, white powder) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][C:27]#[N:28])=[CH:31][CH:32]=2)=[CH:20][CH:19]=1)[CH3:9]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: Cc1noc(-c2ccc(-c3ccc(CC#N)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl

Procedure:
Prepared as described in Example 36, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and 4-cyanomethylphenylboronic acid.
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH2:12][OH:13])=[N:4]1)[CH3:2].C[N+]1([O-])CCOCC1.C(#N)C>CC(O)C>[CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]=[O:13])=[N:4]1)[CH3:2]
Reactant: CCn1cc2c(CO)cccc2n1
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)O
Solvent: CC#N
Product: CCn1cc2c(C=O)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
(2-Ethyl-2H-indazol-4-yl)methanol (1.14 g, 6.47 mmol), 4 Å molecular sieves (550 mg), 4-methylmorpholine N-oxide (1.89 g, 16.2 mmol) and tetra-n-propylammonium perruthenate(VII) (114 mg, 0.323 mmol) were added to acetonitrile (70 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. 2-Propanol was added, and the mixture was stirred for 30 min. The mixture was filtered by silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→50/50) to give the title compound (820 mg, yield 73%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].Cl.[O-:15][C:16]#[N:17].[Na+].C(Cl)(Cl)Cl>O>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:9][CH2:10][N:11]([NH:17][CH:16]=[O:15])[CH2:12][CH2:13]1)=[O:7]
Reactant: N#C[O-]
Reactant: O=C(C1CCCO1)N1CCNCC1
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=CNN1CCN(C(=O)C2CCCO2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
4-(2-Tetrahydrofuroyl)piperazine (33.25 g, 180.7 mmol) (III) is dissolved in 165 mL water. 5N Hydrochloric acid (34.5 mL) is added and the suspension is heated to 70° C. with stirring. Sodium cyanate (13.1 g, 201.15 mmol) is added in small portion to the stirring solution and heating is continued for an additional 2 hours. The reaction mixture is concentrated under reduced pressure to yield a thick oil. Chloroform (100 mL) is added to the oil and the solution is heated to reflux. The hot solution is filtered and the filtrate is dried over Na2SO4. The dried solution is concentrated under reduced pressure to a thick yellow oil. Ether (50 mL) is added to the oil and white crystals precipitated out. The product is filtered, washed with ether (25 mL) and dried. The product is used without further purification (33.8 g, 82.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCCC=O
Product: CCCCNCc1ccc(Cl)cc1
Yield: 40.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, (4-chlorophenyl)methanamine (750 mg, 5.30 mmol) and butyraldehyde (480 μL, 5.30 mmol) were converted to the title compound (421 mg, 40%). 1H NMR (CDCl3) δ 7.55 (d, J=8.4 Hz, 2H), 7.41-7.34 (m, 2H), 3.98 (s, 2H), 2.78-2.70 (m, 2H), 1.79 (td, J=7.7, 15.6 Hz, 2H), 1.36 (qd, J=7.4, 15.1 Hz, 2H), 0.95-0.88 (m, 4H); MS(ESI+) m/z 198.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]O)=[CH:24][CH:23]=1)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:19]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCOc1ccc(CO)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 62 %

Procedure:
To a solution of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (300 mg), 4-ethoxybenzyl alcohol (0.36 g) and triphenylphosphine (0.62 g) in THF (10 ml) was added at 0° C. diisopropyl azodicarboxylate (0.47 ml), and the resulting mixture was stirred at room temperature for 3.5 days. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:1) to obtain methyl 7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (279 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C@H:10]2[CH3:16])[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>O1CCOCC1>[CH3:16][C@@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][N:9]1[C:6]1[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=1
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@H]2C)n1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(NN)c(F)c(N2CCN(C)C[C@H]2C)n1
Temperature: 85 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
To a solution of 4-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (9.6 g, assumed 31.4 mmol) in 1,4-dioxane (126 mL) was added hydrazine monohydrate (8.5 mL, 175 mmol). The mixture was heated at 85° C. and stirred for 24 h. The mixture was cooled to room temperature and then concentrated in vacuo. The residue was partitioned between DCM (200 mL) and sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with a fresh portion of DCM (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude 4-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine (8.04 g, >100% crude yield) as a dark orange oil. LCMS: (M+H)+: 254.9.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]([O:32]CC4C=CC=CC=4)=[O:31])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]([OH:32])=[O:31])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)OCc5ccccc5)c34)n(-c3ccccc3)c(=O)c12
Agent: [Pd]
Solvent: CO
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Yield: 81.1 %

Procedure:
(S)-Benzyl 4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (560 mg, 1.08 mmol) was dissolved in methanol (200 ml) and hydrogenated in a Parr apparatus at 25 psi in the presence of Pd/C 10%. Once the reaction was completed, the mixture was filtered and the solvent evaporated under reduced pressure to yield 376 mg (79% yield) of the final compound, which was used in the next synthetic step without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][C:40]=1[CH2:41][CH2:42]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:42][CH2:41][C:40]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[NH2:34])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Reactant: Nc1cnccc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cnccc1CCOc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 4-nitronaphthol (2) (0.95 g, 5.00 mmol), PPh3 (1.97 g, 7.50 mmol) and 2-(3-aminopyridin-4-yl)ethanol (25) (1.04 g, 7.50 mmol) in THF (20 mL) was added dropwise DIAD (590 μL, 3.75 mmol) at −15° C. The mixture was stirred for 1 hr at RT and the volatiles removed in vacuo. The residues was absorbed on silica (20 g) and purified by column chromatography (SiO2, 80 g, 50-100% EtOAc in isohexane, gradient elution and then 5% MeOH in EtOAc, isocratic elution) to give the title compound (26) (1.36 g, 88%): m/z 310 (M+H)+ (ES+).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:10]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(Cc2ccccc2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
A mixture of thymine (7.68 g, 61 mmol), benzyl bromide (10.55 g, 61 mmol), potassium carbonate (17.05 g, 123 mmol) and DMF (90 mL) was stirred 12 hours at 25° C. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined extract was washed with water (5×100 mL), dried (Na2SO4) and concentrated in vacuo. The residue was crystallized from hexane/ethyl acetate to give 1-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione (9.4 g, 43.9 mmol), m.p. 170°-173° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([CH3:20])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Br:37])C(=O)C1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([Br:37])[CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([CH3:20])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)c2c1[nH]c1ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)c2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
To a stirred solution of 3-(4-fluorobenzoyl)-1-methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (compound in Example 32F) (110 mg, 0.28 mmol) in 6 mL of DCM was added NBS (48 mg, 0.27 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature under N2 for 1.5 hours and samples monitored by LC-MS. The solution was concentrated and purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (124 mg) as a yellow solid; 1H-NMR (CDCl3): δ 10.54 (1H, s), 7.98 (1H, d), 7.63 (2H, m), 7.50 (1H, d), 7.39 (1H, m), 7.16 (3H, m), 5.26 (1H, dd), 4.22 (2H, m), 3.78 (1H, m), 3.12 (1H, m), 1.28 (3H, d), 1.18 (3H, t). MS (ESI): 471, 473 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][S:13]([OH:16])(=[O:15])=[O:14].C(OCC)(=[O:19])C>>[CH3:12][S:13]([OH:16])(=[O:15])=[O:14].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][OH:19])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CCOC(C)=O
Agent: CS(=O)(=O)O
Product: Nc1ccc(CC(=O)OO)cc1
Yield: 98.5 %

Procedure:
The procedures of Example 8 were repeated, by substituting 3-amino-benzoic acid with 4-amino-phenyl-acetic acid (3 g: 0.0198 mole) and by using 19 g of CH3SO3H instead of 30 g, 2.2 g of H2O2 at 85% (0.055 mole) instead of 2.9 g, and ethyl acetate (300 moles) instead of THF. 5.2 g of crystalline and substantially pure 4-amino-phenyl-peracetic acid methanesulphonate were obtained. Yield: 98.5%.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:16](=[O:19])[CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
To a solution of benzyl alcohol (4.76 mL, 0.046 mol), 4-dimethylamino-pyridine (“DMAP,” 0.790 g, 0.0065 mol) and triethylamine (12.85 mL, 0.09297 mol) in dichloromethane (92 mL) was added a solution of acryloyl chloride (7.54 mL, 0.09297 mol) slowly at 0° C., and the mixture was stirred at 0° C. for 2.5 hours. The mixture was quenched with aqueous sodium bicarbonate, and the quenched mixture was extracted with dichloromethane (2×100 mL). The extracts were combined, dried (MgSO4), and rotary evaporated to give a yellow oil. The oil was purified by column chromatography, eluting with hexanes/ethyl acetate (95:5) to give 5.19 g (64%) of acrylic acid benzyl ester as a clear oil.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].[NH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.[Cl:59][C:60]1[CH:65]=[C:64]([Cl:66])[CH:63]=[CH:62][C:61]=1Br>C1COCC1>[Cl:59][C:60]1[CH:65]=[C:64]([Cl:66])[CH:63]=[CH:62][C:61]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1
Reactant: C1CNCCN1
Reactant: Clc1ccc(Br)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Product: Clc1ccc(N2CCNCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BINAP (219 mg), Pd(II) acetate (397 mg, 0.176 mmol), tBuONa (1.19 g, 12.3 mmol), piperazine (837 mg, 9.73 mmol) and THF (40 mL) were mixed together and stirred at room temperature for 30 min under nitrogen atmosphere. 2,4-dichlorobromobenzene (2 g, 8.84 mmol) in THF (10 mL) was added to the mixture drop wise and heated at 70° C. for 14 h. Excess THF was then evaporated and extracted with ethyl acetate. The crude product was obtained on concentration of the ethyl acetate layer after washing with brine and drying. Flash chromatography on silica gel eluting with 2% MeOH in CHCl3 gave 1-(2,4-Dichloro-phenyl)-piperazine.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][NH:5][C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH-].[Na+].Cl>O1CCCC1.O>[C:12]([O:11][C:9]([NH:8][CH2:7][C:6]([NH:5][CH2:4][C:3]([OH:17])=[O:2])=[O:16])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
Add, to a solution of t-butoxycarbonyl-glycyl-glycine methyl ester (3.9 g.) in tetrahydrofuran (30 ml.) and water (30 ml.), 16 ml. of 1 N sodium hydroxide dropwise. Stir the mixture until homogenous (1 1/2 hours), then acidify to pH 3 with dilute hydrochloric acid and evaporate to dryness. Suspend the residue in acetone, filter and evaporate the filtrate to dryness to afford the title product (m.p. 125°-128° C.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][CH:26]([CH3:28])[CH3:27]>>[CH2:25]([N:24]([CH3:23])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20])[CH:26]([CH3:28])[CH3:27]
Reactant: CNCC(C)C
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CC(C)CN(C)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and N,2-dimethylpropan-1-amine to give 254. MS: (ESI+)=369.1
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([NH2:12])[C:5]=2[CH:4]=1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25][C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1>CN1C(=O)CCC1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([N:12]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:25][CH2:24][CH2:23][O:22][CH3:21])[CH2:31]3)[C:5]=2[CH:4]=1
Reactant: NC1=Nc2ccccc2Nc2ccc(C(F)(F)F)cc21
Reactant: COCCC[C@H]1CNCCN1
Solvent: CN1CCCC1=O
Product: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Temperature: 200 °C
Reaction time: 2 h

Procedure:
Add 2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine-11-ylamine (0.438 g, 1.58 mmol), (S)-2-(3-methoxy-propyl)-piperazine (0.25 g, 1.58 mmol) in NMP (2.8 mL). Heat at 200° C. with stirring. After 2 hours, stop heating and allow the reaction mixture cool down to ambient temperature. Add brine and extract with ethyl acetate. Wash the organic solution with brine three times, dry over sodium sulfate, filter, and concentrate under reduced pressure to give crude residue. Purify the residue by flash chromatography, eluting with 2M ammonia in methanol:dichloromethane (5:95) to give the title compound: mass spectrum (m/e):419.05 (M+1).