Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:43])=O>C(OCC)(=O)C>[Cl:43][CH2:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=1
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Yield: 67.4 %

Procedure:
To a mixture of methyl 5-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate (0.20 g) and toluene (10 mL) was added thionyl chloride (0.055 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate (0.14 g, yield 67%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-147° C.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][N:33]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccnc(-c2ccccc2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-phenylisonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 403.13 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]([CH:14]1[O:19][CH2:18][CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH2:24](N(CC)CC)C.CI>C1C=CC=CC=1>[CH3:24][N:16]1[CH2:17][CH2:18][O:19][CH:14]([CH:6]([O:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=2[O:2][CH3:1])[C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[CH2:15]1
Reactant: CCN(CC)CC
Reactant: COc1ccccc1OC(c1ccc(Cl)cc1)C1CNCCO1
Solvent: c1ccccc1
Solvent: CI
Product: COc1ccccc1OC(c1ccc(Cl)cc1)C1CN(C)CCO1
Reaction time: 20 h
Yield: 58.2 %

Procedure:
To a solution of 2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine (11.6 g) and triethylamine (3.5 g) in benzene (100 ml) a solution of CH3I (5.5 g) in benzene (20 ml) was added dropwise at room temperature over 1 hour. Stirring was continued at room temperature for 20 hours, the mixture was filtered and the solvent was evaporated to dryness so obtaining an oil which was separated on silica gel column to give 4-methyl-2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine (7 g; yield 57%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C@H:16]2[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]2[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@H](F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: F[C@@H]1CNCC[C@@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of cis-tert-butyl 4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (400 mg, 1.04 mmol) in CH2Cl2 (4 mL) was dropwise added TFA (1 mL, 13 mmol) at rt. The mixture was stirred at rt for 2 h and then concentrated. To the residue was added 50 mL of saturated aqueous sodium bicarbonate and the mixture was extracted with 3×60 mL of CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to yield 270 mg cis-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine (0.95 mmol, 91%). (M+H)+=286.25. 1H NMR (500 MHz, chloroform-d) δ 7.49-7.38 (m, 4H), 7.34 (t, J=7.5 Hz, 1H), 7.26-7.20 (m, J=8.5 Hz, 2H), 7.01-6.93 (m, 2H), 5.08 (s, 2H), 4.70 (d, J=49.0 Hz, 1H), 3.38 (t, J=12.5 Hz, 1H), 3.25 (dt, J=13.4, 2.0 Hz, 1H), 2.93 (d, J=14.3 Hz, 1H), 2.90-2.68 (m, 3H), 2.09 (qd, J=12.9, 4.1 Hz, 1H), 1.69 (d, J=14.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:10]=3[CH2:9][CH2:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(C(=O)O)c(CCc2cccc(Cl)c2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O

Procedure:
For the synthesis of the title compound, 16.6 g (0.057 mol) of [2-(3-chlorophenyl-ethyl]-4-methoxybenzoic acid, 7.25 g (0.06 mol) of SOCl2, 250 ml of methylene chloride and 10 g of AlCl3 (0.075 mol) are employed in method K. Purification is carried out by column chromatography (flash; SiO2; hexane 90%/ethyl acetate 10%). C16H13ClO2(Mr=272.73)
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][C:16]#[C:17][CH:18]([CH3:20])[CH3:19])=[O:12])=[CH:9][N:10]=2)[CH2:2]1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>C(O)C>[CH:21]([NH:24][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][C:16]#[C:17][CH:18]([CH3:20])[CH3:19])=[O:12])=[CH:9][N:10]=1)([CH3:23])[CH3:22]
Reactant: CC(C)N
Reactant: CC(C)C#CCCNC(=O)c1cnc(OCC2CO2)s1
Solvent: CCO
Product: CC(C)C#CCCNC(=O)c1cnc(OCC(O)CNC(C)C)s1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
This example illustrates methods for preparing the compounds of the present invention. In this example a mixture containing 12 g. (0.0314 mole) of 1,2-epoxy-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]propane, 12 g. (0.203 mole) of isopropylamine and 20 ml. of ethanol is allowed to stand at room temperature for 12 hours. The mixture is then evaporated under vacuum to remove the solvent and the resulting residue dissolved in 50 ml. of ethyl acetate and cooled to -20° C, and maintained at this temperature for 2 hours. The mixture is then filtered and the resulting filter cake washed with cold (about 0° C) ethyl ether and then recrystallized from ethyl acetate affording 1-isopropylamino-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]-propan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C1C[O:14][CH2:13]C1.CN(C=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:13]=[O:14])[S:10][C:3]=12
Reactant: C1CCOC1
Reactant: Clc1ccnc2ccsc12
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2nccc(Cl)c2s1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine (2) (2 g, 11.83 mmol) in THF (40 mL) n-BuLi (2.5M in hexanes, 5.7 mL, 14.2 mmol) was added dropwise at −78° C. and the reaction mixture stirred 1 h. DMF (2.7 mL, 35.5 mmol) was added and stirring continued 1 h more. The reaction mixture was poured into water, extracted with EtOAc, the combined organics dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was triturated with ether and filtered affording title compound 232 (2 g, 10.12 mmol, 86% yield). MS (m/z): 197.9 (36%), (M+MeOH+1) 230.0 (100%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][N:26]4C(OC(C)(C)C)=O)=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]4)=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]c(C3CCCCN3)cc2c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamido)-1H-indol-2-yl)piperidine-1-carboxylate (55 mg, 0.11 mmol) was dissolved in dichloromethane (2.5 mL) containing trifluoroacetic acid (1 mL). The reaction mixture was stirred for 6 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(piperidin-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 403.2. found 404.4 (M+1)+. Retention time of 0.95 minutes.
Reaction SMILES: [Br:1][CH2:2][CH:3]([S:6]([C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:8])=[O:7])[CH2:4]Br.N1C(C)=CC=CC=1C>C(Cl)Cl>[C:9]([S:6]([C:3](=[CH2:4])[CH2:2][Br:1])(=[O:7])=[O:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)S(=O)(=O)C(CBr)CBr
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=C(CBr)S(=O)(=O)C(C)(C)C
Temperature: 25 °C
Yield: 91390.6 %

Procedure:
A mixture of 16.78 g (0.052 mmol) of 1,3-dibromo-2- (t-butylsulfonyl) propane and 14 mL (0.12 mol) of 2,6-lutidine in 55 mL of CH2Cl2 was refluxed for 75 minutes. The solution was allowed to cool to room temperature and extracted with three 80-mL portions of 5% HCl followed by 80 mL of water. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. to give 11.46 g (91%) of the allyl bromide as a white solid, mp 40.5-°42.0° C., which was used without further purification; IR (KBr) 2980 cm-1, 1480, 1395, 1230, 1100, 970, 730, 640; 1H NMR (CDCl3)δ 1.40 (s, 9H, t-butyl), 4.30 (s, 2H CH2Br), 6.50 (s, 2H, vinyl).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]#[N:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[N:13][S:14][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:28][NH:29][CH3:30].C([O-])(O)=O.[Na+]>CN(C=O)C.C1COCC1>[C:26]([CH2:25][NH:24][C:22](=[O:23])[C@H:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:16][C:12]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:29]([CH3:30])[CH3:28])=[CH:6][CH:7]=2)=[CH:15][S:14][N:13]=1)#[N:27]
Reactant: CC(C)C[C@H](Nc1nscc1-c1ccc(C(=O)CBr)cc1)C(=O)NCC#N
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Nc1nscc1-c1ccc(C(=O)CN(C)C)cc1)C(=O)NCC#N

Procedure:
N2-{4-[4-(bromoacetyl)phenyl]isothiazol-3-yl}-N1-(cyanomethyl)leucinamide (29 mg, 0.064 mmol) was dissolved in DMF (0.6 mL) and dimethylamine (0.13 mL of a 2 M solution in THF, 0.26 mmol) was added. The reaction mixture was stirred until disappearance of the starting material was observed by TLC (˜1 h). Aqueous sat. NaHCO3 was added, the product was extracted with EtOAc (3×), dried over MgSO4, concentrated in vacuo and purified by flash chromatography with dichloromethane, methanol and ammonium hydroxide to yield N1-(cyanomethyl)-N2-{4-[4-(N,N-dimethylglycyl)phenyl]isothiazol-3-yl} leucinamide.
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17].[CH3:30][NH2:31]>CO>[CH3:30][NH:31][C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(Cl)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CN
Solvent: CO
Solvent: CC(=O)O
Product: CNC1=C2CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reaction time: 0.5 h

Procedure:
To obtain the corresponding 4-methylamino compound, a suspension of (20S)-4-chloro-21-hydroxy-20-methylpregn-4-en-3-one acetate in methanol was mixed with 40% aqueous methylamine and refluxed for 30 minutes. Additional 40% aqueous methylamine was added and refluxing was continued for another 30 minutes. The solvent was then evaporated and the residue was purified as described above for the 4-amino compound to give (20S)-4-(methylamino)-21-hydroxy-20-methyl-pregn-4-en-3-one.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH+:14]=[CH:13]1)([OH:10])=O.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25]>>[N:12]1([CH2:11][C:8]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:22]([F:21])[CH:23]=2)=[O:10])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: Cc1ccc(N)cc1F
Reactant: O=C(O)Cn1c[nH+]c2ccccc21
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccc(NC(=O)Cn2cnc3ccccc32)cc1F

Procedure:
The title compound was synthesised according to the procedure described in Example 89, from 3-carboxymethyl-3H-benzoimidazol-1-ium trifluoro-acetate and 3-fluoro-4-methyl-aniline. Yield 12 mg (35%). Calculated for C16H14FN3O m/z: 283.3, found 284.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ ppm 2.2 (s, 3H), 5.1 (s, 2H), 7.1 (m, 2H), 7.3 (m, 2H), 7.4 (d, J=11.6 Hz, 1H), 7.5 (d, J=8.6 Hz, 1H), 7.7 (m, 1H), 8.1 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][CH3:23])[CH2:18][CH:19]=2)=[CH:10][C:9]=1[N+:24]([O-])=O)=[O:6]>CO.C(O)(=O)C.[Zn]>[NH2:24][C:9]1[CH:10]=[C:11]([C:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][CH3:23])[CH2:16][CH:15]=2)[CH:12]=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[C:4]1[CH:27]=[CH:28][CH:29]=[CH:30][C:3]=1[O:2][CH3:1]
Reactant: CNCCN1CC=C(c2ccc(NC(=O)c3ccccc3OC)c([N+](=O)[O-])c2)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CNCCN1CC=C(c2ccc(NC(=O)c3ccccc3OC)c(N)c2)CC1
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of 203 (143.9 mg, 0.225 mmol) in MeOH (4.5 mL) and Acetic Acid (1.1 mL) at room temperature was added Zinc dust (85 mg, 1.307 mmol). The solution was stirred 1 h and then filtered and concentrated and the crude residue was purified by flash chromatography (10 to 30% MeOH in DCM) and the material was further triturated with hexane to afford 205 (30 mg, 0.060 mmol, 27%) as a yellow solid. LRMS (ESI): calc. 380.2, found 381.2 (MH)+. 1H-NMR (CDCl3+CD3OD) δ(ppm): 8.15 (dd, J=8.0, 2.2 Hz, 1H), 7.46 (ddd, J=8.8, 8.8, 2.3 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.07 (dd, 7.4, 7.4 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.82-6.79 (m, 2H), 3.98 (s, 3H), 3.19-3.16 (m, 2H), 3.08-3.04 (m, 2H), 2.79-2.71 (m, 4H), 2.64 (s, 3H), 2.52-2.47 (m, 2H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH2:13]>>[CH2:11]([OH:12])[C@H:9]1[O:10][C@H:2]([O:1][C@H:7]2[C@H:5]([OH:6])[C@@H:3]([OH:4])[C@H:2]([OH:1])[O:13][C@@H:9]2[CH2:11][OH:12])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 130 °C

Procedure:
A suspension containing 2 parts by weight of corn starch and 7 parts by weight of water was added with a commercially-available liquefying α-amylase derived from a microorganism, and heated to 90°-100° C. to effect gelatinization and liquefaction. Thereafter, the mixture was heated at 130° C. to cease the enzymatic reaction, followed by recoverying a liquefied solution with a dextrose equivalent (DE) of about 2. The resultant solution was first cooled to 55° C., then added with 150 units per g starch of isoamylase (EC 3.2.1.68) derived from a microorganism of the species Pseudomonas amyloderamosa commercialized by Hayashibara Biochemical Laboratories Inc., Okayama, Japan, and 40 units per g dextrin of β-amylase (EC 3.2.1.2) commercialized by Nagase Biochemicals Ltd., Kyoto, Japan. The resultant mixture was kept at pH 5.0 and subjected to an enzymatic reaction for 24 hours to obtain a maltose-rich saccharide solution which was then heated to inactivate the remaining enzyme. Thus, a maltose-rich saccharide solution was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)CCCN
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(NCCCN(C)C)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide (100 mg, 0.20 mmol), N,N-dimethyl-1.3-propanediamine (260 μL, 2.0 mmol) and K2CO3 (283 mg, 2.0 mmol) in 1-butanol (5 mL) the title compound was obtained as a white powder (84 mg, 0.15 mmol, 75.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J=5.1 Hz, 1H), 7.45-7.63 (m, 4H), 7.28-7.32 (m, 2H), 7.15-7.20 (m, 3H), 6.04 (s, 1H), 3.24-3.31 (m, 3H), 2.31 (t, J=7.1 Hz, 2H), 2.17 (s, 6H), 1.66 (t, J=7.0 Hz, 2H), 1.35 (d, J=6.8 Hz, 6H). MS (ESI): 555.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[CH:3]=1.[C:8]1([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(N(CCCC)CCCC)CCC>[CH3:7][C:4]1[CH:3]=[C:2]2[N:1]=[C:15]([OH:16])[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:20]([OH:21])[N:6]2[N:5]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Cc1cc(N)[nH]n1
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cc2nc(O)c(-c3ccccc3)c(O)n2n1
Temperature: 25 °C

Procedure:
A solution of 4.5 g 5-amino-3-methylpyrazole and 12.2 mL diethyl phenylmalonate in N,N-dibutylbutan-1-amine was stirred at 185° C. over night. After cooling to room temperature the reaction mixture forms two layers. The top layer was removed and the lower layer was diluted with dichloromethane and methanol. The resulting solution was concentrated and extracted with a mixture of diethyl ether and 10% w/w NaOH solution. The organic layer was discarded and aqueous layer acidified with concentrated HCl. The precipitated product was collected by filtration.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:35]1[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]1=[O:36])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1c(CCl)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Yield: 82.2 %

Procedure:
A solution of 6-benzyloxy-4-butoxy-3-chloromethyl-2-isobutyl-1(2H)-isoquinolinone (6.85 g, 16 mmol) and potassium phthalimide (4.44 g, 24 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-[(6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione (7.08 g, 82.2%) as an amorphous.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[N:24]=[C:25]=[O:26])[CH3:14]>C(OCC)(=O)C>[CH3:14][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1)=[O:26])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NC1COc2ccccc2C1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NC1COc2ccccc2C1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a solution of 3,4-dihydro-3-amino-2H-benzopyran (0.9 g, 6 mmole) in 50 ml of ethyl acetate, there was added 1.22 g (6 mmol) of 2,6-bis(1-methylethyl)phenyl isocyanate. The resulting mixture was stirred at room temperature for twenty hours. The solvent was removed under vacuum and the residue was suspended in 20% ethyl acetate/hexane. The precipitated solid was collected by filtration and dried to yield 1.25 g of N-[2,6-bis-(1-methylethyl)phenyl]-N'-(3,4-dihydro-2H-1-benzopyran-3-yl)urea, mp 186°-188° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[O-]CC.[Na+].[CH2:14]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[OH:29])[C:25](=[O:30])[CH2:24][CH2:23]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>C(O)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][O:29][C:28]1[CH:27]=[C:26]2[C:22](=[CH:21][C:20]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:23][CH2:24][C:25]2=[O:30])[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: CCCCCCc1cc2c(cc1O)C(=O)CC2
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCc1cc2c(cc1OCCCC(=O)OCC)C(=O)CC2

Procedure:
3.6 ml of ethyl4-bromobutyrate dissolved in 15 ml of ethanol are added to a mixture of sodium ethoxide (1.6 g, 0.0233 mol) and 5-hexyl-6-hydroxyindan-1-one (4.5 g, 0.0194 mol) in 45 ml of ethanol. The reaction medium is heated for 5 hours at reflux. The mixture is poured into water and extracted with ether. The organic phase is dried (Na2SO4) and the solvents are evaporated off (5.9 g; 60%).
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C@@H:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO.C[C@@H](N)C1C=CC=CC=1>[N:1]1[C:10]2[C:9](=[N:20][C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:12])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C1CCCc2cccnc21
Solvent: CO
Product: C[C@@H](N=C1CCCc2cccnc21)c1ccccc1
Reaction time: 24 h
Yield: 104.8 %

Procedure:
To a stirred solution of 6,7-dihydro-5H-quinolin-8-one (3.02 g, 20.5 mmol) in dry MeOH (100 mL) was added (R)-(+)-α-methylbenzylamine (2.61 mL, 20.5 mmol) via syringe. The resulting mixture was stirred 24 h, at which point additional (R)-(+)-α-methylbenzylamine (0.26 mL, 2.0 mmol) was added and the reaction was stirred for an additional 24 h. The solvent was removed in vacuo and dried for 3 days at room temperature under reduced pressure (0.1 Torr) to afford 5.38 g (95%) of the title compound as a red/brown solid. [α]D=−126.0 (c 1.04, CHCl3); 1H NMR (CDCl3) δ 1.55 (d, 3H, J=6.9 Hz), 2.17-2.29 (m, 2H), 7.35 (t, 2H, J=7.8 Hz), 4.39 (q, 1H, J=6.6 Hz), 4.72 (t, 1H, J=4.7 Hz), 5.50 (br s, 1H), 7.07 (dd, 1H, J=7.5, 5.1 Hz) 7.20-7.47 (m, 6H), 8.37 (d, 1H, J=2.4 Hz); 13C NMR (CDCl3) δ 21.99, 25.68, 28.29, 53.79, 98.12, 122.43, 126.33, 127.03, 128.92, 132.63, 135.09, 139.47, 146.36, 150.48. ES-MS m/z 251 (M+H).