Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]>CC(N(C)C)=O>[CH3:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH3:21])=[CH:9][N:8]=1
Reactant: Cc1ccc(O)cn1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Sodium hydride (25.6 g, 60% dispersion in oil, 0.64 mol) was added portion-wise to a solution of 5-hydroxy-2-methylpyridine (70 g, 0.64 mol) in DMA (700 ml) while keeping the temperature below 40° C. At the end of the addition, the mixture was stirred at room temperature for 1 hour and 2-fluoro-5-nitrotoluene (91.3 g, 0.59 mol) in DMA (100 ml) was added slowly. The mixture was stirred at 80° C. for 3 hours and then cooled. The solvents were evaporated under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 30% ethyl acetate in petroleum ether) to give 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine as an oil (141 g, 98%); NMR spectrum (CDCl3): 2.43 (s, 3H), 2.59 (s, 3H), 6.74 (d, 1H), 7.21 (d, 1H), 7.27 (d, 1H), 8.00 (d, 1H), 8.17 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([OH:5])=[O:4].C([OH:24])C.O.[OH-].[K+]>O>[O:24]=[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:2][C:3]([OH:5])=[O:4]
Reactant: CCCCCCCCCCCCCCCCC(=O)C(=O)O
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCC(=O)CCCCCCCCCCC(=O)O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
12-Hydroxystearic acid (2 g) dissolved in a 10% methanolic hydrochloric acid solution was stirred at room temperature for 2 hours. The mixture was then concentrated and distributed into chloroform and water, and the chloroform layer was washed with a 1% aqueous sodium hydrogen carbonate solution and water, dried with anhydrous sodium sulfate and concentrated to give the methyl ester of 12-hydroxystearic acid (2.0 g). To the methyl ester of 2-hydroxystearic acid (2.0 g) dissolved in methylene chloride (50 ml) were added Celite (4 g) and pyridinium chlorochromate (6 g), and the mixture was stirred at room temperature for 24 hours. Precipitates produced were removed by filtration. The filtrate mixed with silica gel (10 g) was concentrated and eluted with n-hexane-ethyl acetate (5:1) to give the methyl ester of 12-oxo-stearic acid (1.8 g). Then, the methyl ester of -oxo-stearic acid (1.8 g) was suspended into the mixed solvent of ethanol-water (1:1), and the potassium hydroxide (1.7 g) was dissolved in the suspension. The reaction mixture was heated to a temperature of 70° C. and stirred for 30 minutes. The reaction mixture was then cooled, adjusted to acidic range of pH by adding water and an excessive amount of citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 12-oxostearic acid (1.6 g). After the 12-oxostearic acid (500 mg) was dissolved in N,N-dimethylformamide (DMF), para-nitrophenol (231 mg) and N,N'-dicyclohexylcarbodiimide (343 mg) were added, and the mixture was stirred for 12 hours. The-reaction mixture was filtered, and the solvent was removed by distillation to give the active ester of 12-oxostearic acid. The active ester (438 mg) was dissolved in DMF, 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (400 mg) and triethylamine (2.0 ml) were added to the solution. The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK102 in the yield of 143 mg.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[I-:11].[Na+]>CC(C)=O>[I:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: [I-]
Reactant: OCCCCCCCCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: OCCCCCCCCI
Yield: 89.5 %

Procedure:
A mixture of 8-chlorooctan-1-ol (25 g, 152 mmol) and sodium iodide (125 g, 834 mmol) in acetone (500 ml) was heated at reflux overnight. The mixture was filtered to remove precipitated sodium chloride, the filtrate was evaporated in vacuo, and the residue partitioned between water (200 ml) and ether (200 ml). The ether layer was separated, washed with 1M sodium thoisulfate solution (200 ml), and dried over anhydrous magnesium sulfate. Filtration, and solvent removal in vacuo, afforded 8-iodooctan-1-ol as a colorless oil (34.85 g, 90%).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[C:8]1([C:14]2[C:15]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)=[N:16][C:17]3[CH:18]=[CH:19][N:20]4[CH:26]=[N:25][N:24]=[C:21]4[C:22]=3[CH:23]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH3:1][C:2]([S:5](/[N:7]=[CH:31]/[C:30]1[CH:33]=[CH:34][C:27]([C:15]2[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:23][C:22]3[C:21]4=[N:24][N:25]=[CH:26][N:20]4[CH:19]=[CH:18][C:17]=3[N:16]=2)=[CH:28][CH:29]=1)=[O:6])([CH3:4])[CH3:3]
Reactant: O=Cc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Reactant: CC(C)(C)S(N)=O
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Racemic 2-methyl-2-propane-sulfinamide (7-1, 647 mg, 5.3 mmol), cupric sulfate (1.70 g, 7.30 mmol), and aldehyde 4-2 (511 mg, 1.45 mmol) were stirred in methylene chloride (10 mL) for 5 d at 50° C. After cooling to rt, the mixture was filtered through celite, concentrated to a minimum volume and purified via automated silica gel chromatography (0-10% MeOH in CH2Cl2 over 30 min) to give the title compound as a brown foam. LRMS m/z (M+1) Calcd: 454.2. Found 454.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C@H:6]([CH3:13])[CH2:5]2.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:16])[C@H:6]([CH3:13])[CH2:5]2
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1Cc2cc(Br)ccc2C(=O)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
426 mg (1.7 mmol) (R)-6-bromo-3-methyl-3,4-dihydro-2H-isoquinolin-1-one are dissolved in 3 ml DMF and at 0° C. combined with 80 mg (2 mmol) sodium hydride (60% in mineral oildispersion). After 10 minutes 122 μl (1.9 mmol) methyl iodide are added dropwise, and the mixture is stirred for 16 hours at RT. Then the reaction mixture is mixed with water and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The residue is purified by flash chromatography on silica gel (eluant DCM/MeOH 20:1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][S:10][C:3]2[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=2[OH:1])=[CH:15][CH:14]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: Cc1cc(O)c(S)c(=O)o1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccc(CSc3c(O)cc(C)oc3=O)cc2)c(=O)o1
Reaction time: 15 h

Procedure:
To a stirred solution of 15.8 g. (0.100 mole) of 4-hydroxy-3-mercapto-6-methyl-2-pyrone in 100 ml. of pyridine was added 8.75 g. (0.0500 mole) of α,α'-dichloro-p-xylene in one portion at room temperature. The reaction mixture was allowed to stand at room temperature for 15 hours and then was poured into a mixture of ice and 200 ml. of concentrated hydrochloric acid. The mixture was extracted with methylene chloride, leaving the methylene chloride-insoluble, white solid product behind. This was collected on a filter and found to weigh 5.3 g., m.p. 224°C. (dec.). The extract was dried over anhydrous sodium sulfate, and the methylene chloride was removed by evaporation in vacuo. The remaining 4.1 g. of light yellow solid residue was triturated with benzene containing a little ethanol, leaving 1.7 g. more product as an insoluble white solid, m.p. 228°-229°C. (dec.). Recrystallization of the combined product fractions from nitromethane gave the pure α,α'-bis(4-hydroxy-6-methyl-2-oxo-3-pyranylthio)-p-xylene as very pale yellow crystals, m.p. 234°C. (dec.).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1(C)C=CC(S(O[CH2:17][C@H:18]2[O:24][C@H:23]([CH2:25]OS(C3C=CC(C)=CC=3)(=O)=O)[C@@H:21]([OH:22])[C@@H:19]2[OH:20])(=O)=O)=CC=1.[H][H]>C1COCC1>[CH3:25][C@H:23]1[O:24][C@H:18]([CH3:17])[C@@H:19]([OH:20])[C@@H:21]1[OH:22]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@@H]2O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1O[C@H](C)[C@@H](O)[C@@H]1O

Procedure:
0.86 g (22.66 mmol) of LiAlH4 was added to a solution of 3.60 g (7.63 mmol) of B3 in 20 ml of anhydrous THF and stirred at reflux for 2 hours. After cooling, Arberlite® IR-120(plus) was added and stirring was continued until hydrogen evolution had ended. The mixture was filtered through Celite® and the solvent was subsequently removed under reduced pressure. The crude product was purified by means of column chromatography (CH2Cl2/MeOH=12:1). Yield: 0.84 g (84% of theory).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=O)#[N:2].C1(P(=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[CH:30]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH3:35]
Reactant: N#CCCCCCCC=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C=CCCCCCCC#N
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The mixture of 14 g of 7-cyanoheptanal, 38 g of ethyl triphenylphosphoranylidene-acetate and 100 ml of benzene is refluxed for 15 hours and evaporated. The residue is triturated with diethyl ether, filtered and the filtrate evaporated. The residue is allowed to stand overnight in the refrigerator, triturated with the minimum amount of diethyl ether, the suspension filtered, the filtrate evaporated, the residue distilled and the fraction boiling at 130°-138°/0.1 mm Hg collected, to yield the 9-cyano-2-nonenoic acid ethyl ester of the formula
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12]([CH2:11][N:1]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5][N:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1)=[O:13])[CH3:16]
Reactant: C1CNCCNCCN1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN1CCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), ethyl bromoacetate and base.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][C:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([CH3:40])[O:28][N:27]=1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([C:30]4[C:26]([CH3:25])=[N:27][O:28][C:29]=4[CH3:40])[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Product: Cc1noc(C)c1-c1ccc2c(c1)OCCc1sc(C(=O)N(CCO)C(C)C)nc1-2

Procedure:
Following Example 267, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxyethyl)-isopropylamide and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole to give 291. MS: (ESI+)=428.1
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[O:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:21]3[CH:20]=[N:19][O:18][CH:22]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1nc(N2CCOCC2)c2sc(-c3cnoc3)cc2n1
Yield: 67 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 84 mg of 4-isoxazoleboronic acid pinacol ester and 14 mg of bis(triphenylphosphine)palladium(II) dichloride in 0.7 mL of 1M Na2CO3 aqueous solution and 0.7 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 10 min. The reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 0-20% MeOH/DCM to yield 2-chloro-6-(isoxazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine (85 mg, 67%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([Br:16])[CH:11]=1)([CH2:8][OH:9])[CH2:6][OH:7])[CH3:2].[C@@:18]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:24]1)C[C:19]2=O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Br:16])[CH:11]=2)[CH2:8][O:9][C:18]([CH3:24])([CH3:19])[O:7][CH2:6]1)=[O:17])[CH3:2]
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Reactant: CCOC(=O)C(CO)(CO)c1ccnc(Br)c1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccnc(Br)c2)COC(C)(C)OC1
Temperature: 80 °C

Procedure:
A mixture of 2-(2-bromo-pyridin-4-yl)-3-hydroxy-2-hydroxymethyl-propionic acid ethyl ester (30.0 g, 98.6 mmol) 2,2-dimethoxy propane (51.11 g, [60.5 ml], 493.1 mmol) and (1R)-(−)-10-camphor sulphonic acid (5.72 g, 24.65 mmol) in DMF (100 ml) was heated at 80° C. for 10 h. Reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and worked up by washing with water, brine, followed by drying over anhy. Na2SO4. Organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography using 10% ethyl acetate in Hexane to obtain title compound as a yellow solid. Yield=18.15 g (53%). TLC (30% ethyl acetate in hexane) Rf=0.52; LCMS: RtH7=1.487; [M+1]+=344.0 and 346.0; HPLC RtH9=7.6 min (74%); 1H NMR (300 MHz, CDCl3): δ 8.41-8.34 (t, 1H), 7.54 (s, 1H), 7.32-7.28 (m, 1H), 4.51 (dd, 2H), 4.27-4.21 (q, 4H), 1.45 (s, 3H), 1.39 (s, 3H), 1.23 (t, 3H).
Reaction SMILES: [C:1]([CH:5]([N:7]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[CH2:15])[C:8]1=[O:16])[CH3:6])([O:3][CH3:4])=[O:2].C1(C)C=CC=CC=1.[C:24]([OH:27])(=[S:26])[CH3:25]>>[C:1]([CH:5]([N:7]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([CH2:15][S:26][C:24](=[O:27])[CH3:25])[C:8]1=[O:16])[CH3:6])([O:3][CH3:4])=[O:2]
Reactant: C=C1CCCCCN(C(C)C(=O)OC)C1=O
Reactant: CC(O)=S
Solvent: Cc1ccccc1
Product: COC(=O)C(C)N1CCCCCC(CSC(C)=O)C1=O

Procedure:
A solution of 50 mg of 1-(1-carbomethoxyethyl)-3-methyleneperhydroazocin-2-one in thioacetic acid (0.5 ml) is kept at room temperature for 18 hours. Toluene (5 ml) is added and the mixture is concentrated to dryness under reduced pressure. The product is purified by preparative tlc on silica gel (system 5% acetone in chloroform) to yield the title compound (62 mg) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[CH:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>C1COCC1>[C:32]1([C:29]2[CH:28]=[CH:27][CH:26]=[CH:31][CH:30]=2)[CH:33]=[CH:34][C:35]([NH:38][C:39]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[O:40])=[CH:36][CH:37]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-biphenyl isocyanate: ESMS m/e: 541.3 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=O)[NH:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1.[CH:21]([N:24](C(C)C)CC)(C)C>C(Cl)Cl>[C:21]([C:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[N:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:6]=2[N:7]=1)#[N:24]
Reactant: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccnc2c1N=C(C#N)c1cccnc1N2C1CC1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
Trifluoromethanesulfonie anhydride (5.02 g, 17.8 mmole) was added dropwise to a cooled mixture of 3.00 g (11.3 mmole) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, 2.32 g (18.0 mmole) of diisopropylethylamine, and 45 mL of methylene chloride. After the addition was complete, the ice bath was removed and the mixture was stirred for one hour. Ethyl acetate (500 mL) was added and the resulting solution was washed with three 100 mL portions of water. The organic solution was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed over silica gel (eluted with 50% ethyl acetate/hexane) to provide 3.18 g (8.0 mmole) of the title compound as a yellow oil, suitable for the next reaction.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.C(=O)(O)[O-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([N:6]1[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1
Yield: 51.8 %

Procedure:
To a solution of (cis)-2,6-dimethylpiperazine (900 mg, 8.49 mmol) and sodium bicarbonate (0.2 ml of saturated solution) in THF (5 ml) was added benzyl bromide (1.02 ml, 8.49 mmol). The mixture was exposed to microwave irradiation at 80° C. for 15 minutes. The solvent was removed in vacuo and the residue was washed with sodium bicarbonate solution and extracted with dichloromethane. The residue was purified by flash chromatography eluting with 5-10% (v/v) methanol in dichloro-methane to afford 1-N-benzyl-(cis)-3,5-dimethylpiperazine as a clear oil (900 mg, 4.40 mmol).
Reaction SMILES: [C:1]([NH:5][CH2:6][C@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17]C(=O)OC(C)(C)C)[CH3:16])=[CH:11][CH:10]=1)[OH:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:17][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([C@H:7]([OH:8])[CH2:6][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:11]=1)[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc([C@H](O)CNC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C[C@H](N)c1ccc([C@H](O)CNC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
15.8 g of the compound [5-5] was dissolved in 50 mL of chloroform, 45 mL of trifluoroacetic acid was added thereto under an ice-cold condition, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0 to 90/10) to obtain 10.7 g of (1S)-1-{4-[(1S)-1-aminoethyl]phenyl}-2-(tert-butylamino)ethanol [67-3] (hereinafter, referred to as the compound [67-3]) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:30])=[C:16]([NH:22]C(=O)OC(C)(C)C)[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:16]1[C:15]([F:30])=[C:14]([C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([Cl:1])=[N:11]3)=[O:13])[C:19]([F:20])=[C:18]([F:21])[CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of tert-butyl (3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)carbamate (128 mg, 0.29 mmol, 1.0 eq.) in DCM (5 mL) was added TFA (5 mL). After the resulting mixture was stirred at rt for 0.5 h, the solvent was evaporated. The resulting residue was washed with saturated NaHCO3 and extracted with EA (20 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford (3-amino-2,5,6-trifluorophenyl)(3-chloroquinoxalin-6-yl)methanone (40 mg, 40.9%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:35](O)([CH3:37])[CH3:36]>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH:35]([CH3:37])[CH3:36])=[O:30])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)O
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Product: CC(C)OC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and isopropanol Rf value: 0.4 (aluminium oxide, methylene chloride/isopropanol=30:1) C31H33N3O3
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>O>[C:22]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:24])[CH3:23]
Reactant: O=C1CCC(CO)(c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC1(c2ccccc2)CCC(=O)CC1
Reaction time: 20 h
Yield: 35.8 %

Procedure:
6.6 g. of 4-hydroxymethyl-4-phenylcyclohexanone is dissolved in 40 ml. of pyridine and 20 ml. acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution, and brine, and then evaporated to dryness. The solid residue is recrystallized from Skellysolve B to give 6.74 g. (35.8% yield) of 4-acetoxymethyl-4-phenylcyclohexanone, having a melting point of 74° to 79°C.