Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.[I:21]I.S(=O)(O)[O-].[Na+]>O1CCCC1.O>[F:13][C:14]1[CH:19]=[C:18]([I:21])[C:17]([F:20])=[CH:16][N:15]=1
Reactant: Fc1ccc(F)nc1
Reactant: II
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: Fc1cc(I)c(F)cn1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
n-BuLi 2.5M in hexanes (4.9 mL, 12.25 mmol) was added to a solution of diisopropylamine (1.7 mL, 12.20 mmol) in tetrahydrofuran (22 mL) at −20° C., under nitrogen atmosphere, over a period of 10 minutes. The solution was stirred at −20° C. for 30 min and then it was cooled to −78° C. A solution of 2,5-difluoropyridine (1.33 g, 11.5 mmol) in tetrahydrofuran (3 mL) was added over a period of 30 min and the mixture was stirred at −78° C. for 4 hours. After this time, a solution of iodine (3.20 g, 12.6 mmol) in tetrahydrofuran (10 mL) was added dropwise and the mixture was stirred at −78° C. for 1 hour. Water (1 mL) and tetrahydrofuran (3 mL) were added and the temperature was allowed to raise until room temperature, then water (25 mL) and aqueous sodium bisulphite 40% p/v (3 mL) were added. The organic layer was separated and the aqueous layer was extracted with diethyl ether (3×50 mL), the combined organic layers were washed with brine, dried over anhydrous magnesium sulphate and the solvent removed under reduced pressure. The residue was purified by silica flash chromatography (5% diethyl ether in hexanes) to yield the title compound (1.35 g, 48%) as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[C:18]3[SH:26])[CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:35])(=O)=O>O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[C:18]3[S:26][CH3:35])[CH2:15][CH2:16]2)=[O:7])=[CH:27][CH:28]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(CCCN1CCC(n2c(S)nc3ccccc32)CC1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1nc2ccccc2n1C1CCN(CCCC(=O)c2ccc(F)cc2)CC1
Reaction time: 0.33 h

Procedure:
15.9 g of 1-[1-(3-(4-fluorobenzoyl)propyl)-4-piperidyl]-2-mercaptobenzimidazole and 3.2 g of sodium hydroxide were dissolved in a mixture of 24 ml of water and 200 ml of methanol. To the solution, 7.06 g of dimethyl sulfate was added through 4 hours at room temperature (i.e., about 20°-30°C) and then the solution was stirred for an additional 20 minutes. After the reaction, the solution was concentrated and a diluted sodium hydroxide solution was added thereto, followed by extracting with chloroform. The chloroform solution was washed with water, dried and concentrated. The residue was recrystallized from ethanol to give colorless crystals of 1-[1-(3-(4-fluorobenzoyl)-propyl)-4-piperidyl]-2-methylmercaptobenzimidazole having a melting point of 98° to 98.5°C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:3][CH2:2]1.NN.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][NH:8][S:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=2)(=[O:31])=[O:30])[CH2:5][CH2:6]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCOCC1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
2-(tetrahydro-2H-pyran-4-yloxy)-1H-isoindole-1,3(2H)-dione (6.8 mmol, 1.69 g) was combined with hydrazine (6.8 mmol, 0.22 mL) in anhydrous THF (20 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 1 hour. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (6.5 mmol, 1.34 g) and diisopropylethylamine (20.5 mmol, 3.6 mL) was added. After stirring at room temperature for 15 hours, the reaction was refluxed for 4 hours, then stirred at room temperature for 12 days and concentrated to a yellow solid. The resulting solid was partitioned between ethyl acetate and 1N HCl, and the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a white solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) and crystallization (hexanes/ethyl acetate) providing 0.554 g (30%) of a white solid. Rf=0.4 (1:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.83(2H,d), 7.00 (2H,d), 6.72 (1H,s), 4.23-4.11 (1H,m), 3.91-3.81 (2H,m), 3.87 (3H,s), 3.46-3.38 (2H,m), 2.03-1.94 (2H,m), 1.63-1.51 (2H,m).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.O.[NH2:14][NH2:15]>C(O)C>[N:6]1([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)CN1CCCCC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CN1CCCCC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
3.86 g of piperidin-1-yl-acetic acid ethyl ester was dissolved in 40 mL of ethanol, added with 3.39 mL of hydrazine monohydrate, and stirred at 70° C. for 5 hours. After allowing the solution to cool to room temperature, the solvent was evaporated, to afford 3.8 g of the title compound as pale yellow crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:14][CH2:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[CH:19]=1.[CH3:20][N:21]([CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:14][CH2:13][C:12]([C:16]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([CH2:28][N:21]([CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH3:20])=[CH:30][CH:31]=3)=[O:18])=[CH:11][C:10]=2[CH:19]=1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccco3)ccc2OCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccco4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a solution of 7-(2-furyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.15g) and triethylamine (0.25ml) in dimethylformamide (10ml) was added diethyl cyanophosphate (0.13ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(2-furyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 148) (0.1g) as brown crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[C:13]([Cl:19])=[CH:12][C:11]=2[C:20](=O)[CH3:21])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[C:13]([Cl:19])=[CH:12][C:11]=2[CH:20]([NH2:29])[CH3:21])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(C)=O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(=O)N1CCN(c2c(C(C)N)cc(Cl)c3cncn23)CC1
Temperature: 65 °C
Yield: 87 %

Procedure:
A mixture of 1-[5-(4-acetylpiperazin-1-yl)-8-chloroimidazo[1,5-a]pyridin-6-yl]ethanone (12.6 mg, 0.0393 mmol) (10010-158P) and ammonium acetate (30.3 mg, 0.393 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. in a sealed vial for 1 hour. The mixture was cooled to room temperature and sodium cyanoborohydride (7.40 mg, 0.118 mmol) was added. The reaction was heated at 65° C. overnight. The mixture was diluted with methanol and purified on preparative LCMS using pH 10 buffer to give the desired compound (11 mg, 89%). LCMS calculated for C15H21ClN5O (M+H)+: m/z=322.1. found: 321.9.
Reaction SMILES: [I:1]I.[CH2:3]([N:7]([CH2:14][CH2:15][CH2:16][CH3:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH3:6].C([O-])(O)=O.[Na+].CCOCC>O>[I:1][C:11]1[CH:12]=[CH:13][C:8]([N:7]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=1
Reactant: II
Reactant: CCCCN(CCCC)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCCCN(CCCC)c1ccc(I)cc1
Temperature: 12.5 °C
Yield: 70.7 %

Procedure:
Iodine (7.88 g, 31 mmol) was added portionwise to a mixture of N,N-dibutylaniline (7 g, 34 mmol) and NaHCO3 (2.87 g, 34 mmol) in water (25 mL) with stirring at 10-15° C. After 1 h the mixture was poured into Et2O (200 mL), washed with water (100 mL), Na2S2O3 (2×100 mL), water (2×100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using hexane as eluent. The first fraction was collected and the solvent removed under reduced pressure to give the title compound (7.26 g, 71%) as a pale brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].C([O-])([O-])=O.[K+].[K+].[C:19](OC(=O)C)(=[O:21])[CH3:20].O>CN(C=O)C>[C:19]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1NCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1cccc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 47.8 %

Procedure:
A mixture of 2.0 g (12.3 mmol) of 3,4-dihydro-5-hydroxy-1(2H)-isoquinolinone, 2.0 g (52 mmol) of K2CO3 and 0.75 g of acetic anhydride in 20 ml of DMF was stirred at room temperature for 2.5 days. The mixture was then warmed to 70°-80° and an additional 1.5 g of acetic anhydride was added and stirring was continued for five hours. The reaction was poured into 250 ml of water and the resulting solid was collected, washed with water, and air dried. It was recrystallized from EtOH and then chromatographed (SiO2, 9:1 methylene chloride/MeOH) to give 0.72 g (29%) of product; mp 189°-193°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.Cl.[CH3:12][O:13][NH2:14]>C(O)C.N1C=CC=CC=1>[CH3:12][O:13][N:14]=[CH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=Cc1cc(Cl)cc(Cl)c1
Yield: 93.6 %

Procedure:
A solution of 3,5-dichlorobenzaldehyde (0.0571 mol) and methoxyamine hydrochloride (0.0629 mol) in ethanol (50 ml) and pyridine (50 ml) was stirred 18 hours at room temperature. The reaction was concentrated and partitioned between methylene chloride and water. The organic phase was washed with 3N aqueous hydrogen chloride, dried over sodium sulfate and was concentrated to yield 10.9 g (94%) white solid, mp 53°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([C:29](Cl)=[O:30])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:29]([C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:30]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCc1ccc(F)cc1F
Product: O=C(NCc1ccc(F)cc1F)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 2,4-difluorbenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:16](/[CH2:21][CH3:22])=[C:17](/[F:20])\[CH2:18][OH:19])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].C[N+]1([O-])CCOCC1>>[CH2:1]([O:3][C:4]1[C:5](/[C:16](/[CH2:21][CH3:22])=[C:17](/[F:20])\[CH:18]=[O:19])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:14])([CH3:15])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1/C(CC)=C(/F)CO)C=CCC2(C)C
Agent: C[N+]1([O-])CCOCC1
Product: CCOc1cc2c(cc1/C(CC)=C(/F)C=O)C=CCC2(C)C

Procedure:
Following General Procedure H-1, (2E)-3-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-pent-2-en-1-ol (Compound A-50, 35 mg, 0.12 mmol) and 4-methylmorpholine N-oxide (27 mg, 0.23 nmol) were reacted to give the title compound as a yellow solid after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: [N:1]1([C:6](=[C:9]2[S:13][CH:12]([CH2:14]Cl)[CH2:11][S:10]2)[C:7]#[N:8])[CH:5]=[CH:4][N:3]=[CH:2]1>O1CCCC1>[N:1]1([C:6](=[C:9]2[S:13][C:12](=[CH2:14])[CH2:11][S:10]2)[C:7]#[N:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#CC(=C1SCC(CCl)S1)n1ccnc1
Solvent: C1CCOC1
Product: C=C1CSC(=C(C#N)n2ccnc2)S1
Yield: 79.1 %

Procedure:
In 10 ml of tetrahydrofuran were dissolved 0.52 g (0.002 mole) of the 2-(1-imidazolyl)-2-(4-chloromethyl-1,3-dithiolan-2-ylidene)acetonitrile obtained in Example 2 and 0.31 g of 1,8-diazabicyclo-[5,4,0]-7-undecene, and the reaction was carried out with heating under reflux for 1 hour. After the reaction solution was allowed to cool, the deposited salt was separated by filtration and the filtrate was concentrated to obtain crude crystals, which were then recrystallized from ethyl acetate-n-hexane to obtain 0.35 g of the desired compound in the form of crystals: melting point 115.7° C., yield 79%.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[C:26](/[C:43]2[CH:48]=[CH:47][C:46](I)=[CH:45][CH:44]=2)=[CH:27]/[CH2:28][O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:32]([CH3:42])[CH:31]=2)=[CH:22][CH:21]=1>O1CCCC1.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.[Cu]I>[Cl:19][C:20]1[CH:21]=[CH:22][C:23](/[C:26](/[C:43]2[CH:44]=[CH:45][C:46]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]3)=[CH:47][CH:48]=2)=[CH:27]/[CH2:28][O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:32]([CH3:42])[CH:31]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCN1CCC(CO)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCC(CO)CC3)cc2)cc1C
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, (1-propargylpiperidin-4-yl)methanol (122 mg, 0.8 mmol) and diisopropylamine (370 mg, 0.56 mmol) were added to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (220 mg, 0.4 mmol; prepared as described in example 7) in tetrahydrofuran (15 mL). Subsequently, bis(triphenylphosphine)palladium(II) dichloride (30 mg, 0.042 mmol) and copper(I) iodide (15 mg, 0.075 mmol) were added; the reaction mixture was degassed again and then stirred under inert atmosphere at ambient temperature over night. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a paddle of silica gel. The paddle was thoroughly washed with ethyl acetate (4×20 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform/methanol 95:5) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-[4-(hydroxymethyl)-piperidin-1-yl]propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:23])=O>C(Cl)Cl.CN(C)C=O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:20]=[CH:19][CH:18]=1)[CH2:2][Cl:23]
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
25.6g (93.5 mmoles) of 2-(3-hydroxymethylphenoxy)methylquinoline is dissolved in 30 ml of methylene chloride and 3 drops of dimethylformamide is added. 60.7 ml of a 2.0M solution of thionyl chloride in methylene chloride is then added dropwise at 0° C. The mixture is allowed to warm to room temperature and stirred for 5 hours. The solution is washed with sodium bicarbonate solution, dried, concentrated in vacuo and the crude product purified by silica gel HPLC to yield 12.1 g 3-(2-quinolinylmethyloxy)benzylchloride as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[O:4].B.O1CCCC1.Cl>O1CCCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3 %

Procedure:
To a solution of 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (30 mmol, 7 g) in anhydrous tetrahydrofuran (40 ml) was added borane-tetrahydrofuran solution (1M, 50 mmol, 50 mL) at ambient temperature. When gas evolution had subsided the solution was heated under reflux for 75 min then stirred for 16 hr at ambient temperature. Hydrochloric acid (6M) was added dropwise (ca. 5 mL) and the mixture was stirred at ambient temperature for 1 hr before removing the solvent under vacuum. The residue was dissolved in dichloromethane and the solution was washed with dilute sodium hydroxide solution. The dichloromethane solution was then extracted with dilute hydrochloric acid (×3), the extracts combined, made basic by addition of sodium hydroxide and extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The product was purified by chromatography on silica gel eluting with 5% methanol-dichloromethane to give 1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (200 mg, 3%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([CH:11]=[C:12]([CH3:26])[CH2:13][CH2:14][CH2:15][P:16]([O:22][CH:23]([CH3:25])[CH3:24])([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C([OH:31])(C)C.C(OCC)(=O)C.[Cl-].[Na+]>[O-2].[O-2].[O-2].[Cr+6].S(=O)(=O)(O)O.CC(C)=O>[C:1]([O:5][C:6]([NH:7][C@H:8]([CH:11]=[C:12]([CH3:26])[CH2:13][CH2:14][CH2:15][P:16]([O:18][CH:19]([CH3:20])[CH3:21])([O:22][CH:23]([CH3:25])[CH3:24])=[O:17])[C:9]([OH:31])=[O:10])=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)O
Reactant: CC(=C[C@H](CO)NC(=O)OC(C)(C)C)CCCP(=O)(OC(C)C)OC(C)C
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(=C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)CCCP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.84 ml of a solution which is 3.25 molar in chromium trioxide and 5.29 molar in sulphuric acid is added dropwise at 0°-5° to a solution of 0.5 g of alcohol 8 according to h) in 15 ml of acetone. The mixture is stirred at 0° for 30 minutes and at room temperature for35 minutes, and then 4 ml of isopropanol, 80 ml of ethyl acetate and 30 ml of 20% sodium chloride solution are added thereto, and the mixture is filtered. The aqueous phase is extracted three times with 20 ml of ethyl acetate each time. The organic phase is dried over sodium sulphate and concentrated by evaporation. Chromatography on 20 g of silica gel using hexane/ethyl acetate/acetic acid 16:10:1 yields 0.34 g of 9, [α]D =-35.25° (c=1.39, CHCl3), --C-NMR (75 MHz, CDCl3): 173.8 (CO2H); 155.0 (OCON); 140.4 (C(4)); 121.1 (C(3)); 79.5 (OC(CH3)3); 70.3 (OCH); 52.1 (C(2)); 39.7 (d, J=18, C(5)); 28.3 ((CH3)3C); 25.7 (d, J=142, C(7)); 24.0 ((CH3)2CH); 20.2 (d, J=5, C(6)).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:29](Cl)(=[O:33])[O:30][CH2:31][CH3:32].[Cl-].[NH4+]>C1COCC1.CCCCCCC>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:29]([O:30][CH2:31][CH3:32])=[O:33])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
A heptane solution of LDA (2.0 M, 36.4 ml, 72.8 mmols) was dropwise added to a THF (130 ml) solution of ethyl 4-benzyloxyphenylacetate (13.1 g, 48.5 mmols) and ethyl chlorocarbonate (9.25 ml, 97.0 mmols), under a nitrogen stream at −70° C. or lower. The reaction mixture was stirred for 15 minutes, then a saturated aqueous ammonium chloride solution was added thereto, and the resulting mixture was allowed to warm to room temperature, and then extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting residue was washed with hexane to obtain the entitled compound (13.8 g) as crystals, which were further recrystallized from hexane.
Reaction SMILES: [N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][N:7]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH:6]=2)([O-])=O>CCOC(C)=O.[Pd]>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=[C:4]2[NH2:1])=[N:8]1
Reactant: O=[N+]([O-])c1cccc2nn(C3CCCCO3)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc2nn(C3CCCCO3)cc12
Reaction time: 16 h
Yield: 28.4 %

Procedure:
A solution of 4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (2.336 g, 9448 μmol) was dissolved in EtOAc (100 mL) and treated with 10% Pd/C (100 mg). The resulting suspension was stirred under an atmosphere of H2. for 16 h after which time reduction was complete. The reaction mixture was filtered, concentrated and purified by flash chromatography on silica (50% EtOAc/hexane) to give 2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (584 mg, 28.5% yield) as a dry orange foam. 1H NMR (400 MHz, d6-DMSO) δ 8.47 (s, 1H); 6.92 (t, J=7.82 Hz, 1H); 6.72 (d, J=8.61 Hz, 1H); 5.99 (d, J=7.04 Hz, 1H); 5.54-5.69 (m, 3H); 3.98 (d, J=11.74 Hz, 1H); 3.63-3.78 (m, 1H); 2.02-2.13 (m, 2H); 1.87-2.00 (m, 1H); 1.65-1.80 (m, 1H); 1.59 (br. s., 2H). m/z (ESI, +ve) Found 218.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].[C:12](Cl)(=[O:14])[CH3:13]>C1COCC1>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C(=O)O)cc1Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.2 %

Procedure:
To a solution of 4-amino-3-chloro-benzoic acid (10.0 g, 58.3 mmol) in anhydrous THF (100 mL) was added acetyl chloride (20.7 ml, 291.1 mmol) and the solution stirred at room temperature for 48 hours. The solvent was evaporated and the product precipitated from hexanes then filtered and dried to give a white solid (11.73 g, 94% yield). 1H-NMR (500 MHz, CD3OD) δ 2.28 (s, 3H), 7.92 (dd, 1H), 7.99-8.16 (m, 2H). Analytical HPLC (cyano column) 7.84 min.