Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:21]2[CH2:26][CH2:25][CH:24]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)=[C:13]([C:15]#[C:16][CH:17]([OH:20])[CH2:18][CH3:19])[CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH3:40]I>>[F:37][C:2]([F:1])([F:36])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:21]2[CH2:22][CH2:23][CH:24]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:28])=[O:29])[CH2:25][CH2:26]2)=[C:13]([C:15]#[C:16][CH:17]([O:20][CH3:40])[CH2:18][CH3:19])[CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CCC(O)C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCC(S(=O)(=O)c2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCC(C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCC(S(=O)(=O)c2ccccc2)CC1)OC

Procedure:
Following the procedure described for Example 155, -(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)pent-1-yn-3-ol (Example 162) was reacted with sodium hydride and methyl iodide to afford 1,1,1,3,3,3-hexafluoro-2-(3-(3-methoxypent-1-ynyl)-4-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)-2-propanol as a mixture of enantiomers.
Reaction SMILES: [CH3:1][C:2](=[C:4]([CH3:6])[CH3:5])[CH3:3].[N+](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-]>>[CH3:1][C:2]1([CH3:3])[C:4]([CH3:6])([CH3:5])[CH:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)=C(C)C
Product: CCOC(=O)C1C(C)(C)C1(C)C

Procedure:
The method of Mesheheryakov, Chem. Abstr., 54, 24436d (1960) was employed. To a mixture of 19 g. (0.226 mole) of 2,3-dimethyl-2-butene and 2 g. of cupric sulfate is added at reflux a mixture of 51 g. (0.447 mole) ethyl diazoacetate and 19 g. of 2,3-dimethyl-2-butene. The resulting mixture is heated at reflux for 3 hours, cooled, filtered and distilled to afford 19.8 g. (26%) of the desired cyclic ester, B.P. 76-77° (15 mm.)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]2)=[O:22])=[C:8]([CH:19]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1)=[O:10])(=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:38][OH:39]>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:19]=[C:4]([C:1](=[N:38][OH:39])[CH3:2])[CH:5]=[CH:6][C:7]=2[NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:30])[CH3:31])[CH2:27][CH2:28]2)=[O:22])=[N:13][CH:14]=1
Reactant: NO
Reactant: CC(=O)c1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a stirring solution of 5-acetyl-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (0.25 g, 0.56 mmol) in methanol (2 mL) was added sodium acetate (0.1 g, 1.2 mmol) followed by hydroxylamine hydrochloride (46 mg, 0.67 mmol). The mixture was stirred overnight at room temperature and concentrated in vacuo. The resulting residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and the layers separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with 3% 2 M ammonia/methanol solution in dichloromethane to give 0.22 g (85%) of a white solid.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.CI>O1CCCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH3:1]
Reactant: Fc1cncc(Br)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CI
Product: Cc1c(F)cncc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (46 mL, 0.0738 mol, 1.6 M) was added to a solution of diisopropylamine (10.08 mL, 0.0738 mol) in tetrahydrofuran (80 mL) at −78° C. The reaction mixture was warmed to 0° C., stirred for 30 min, and then cooled to −78° C. 3-Bromo-5-fluoro-pyridine (10.0 g, 0.056 mol) in tetrahydrofuran (10 mL) was added to the reaction mixture and the reaction mixture was stirred for 30 min. Methyl iodide (4 mL, 0.062 mol) was added to the reaction mixture at same temperature and the reaction mixture was then allowed to warm to RT and stirred it for 2 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (150 mL) solution. Then aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulphate and concentrated to afford 3-bromo-5-fluoro-4-methyl pyridine. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.31 (s, 1H), 2.38 (s, 3H). MS (M+2): 192.0.
Reaction SMILES: O=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([OH:18])=[O:17]>C(O)(=O)C>[C:3]12[CH2:14][CH2:15][C:16](=[O:17])[O:18][C:2]=1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: O=C(O)CCC1CCCCCCCCCCC1=O
Solvent: CC(=O)O
Product: O=C1CCC2=C(CCCCCCCCCC2)O1
Reaction time: 5 h
Yield: 99 %

Procedure:
Into a column of 1.6 mm diameter was packed Amberlyst 15 and a solution composed of β-(2-oxocyclododecyl)propionic acid, acetic anhydride, and glacial acetic acid in the ratio of 1:1:10 parts by weight was flowed down through the column at a residence time of 5 hours. The effluent was fractionally cut each hour and each fraction was analyzed by gas chromatography. The gas chromatogram of the reaction solution after 5 hours from outset of the flow-down showed that β-(2-oxocyclododecyl)-propionic acid was not present and 13-oxabicyclo(10.4.0)hexadec-1(12)-en-14-one was produced in 99% yield.
Reaction SMILES: CC(S([NH:7][C:8]1([C:18]2[S:19][C:20]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:26]=[C:25]([CH3:40])[CH:24]=3)=[CH:21][N:22]=2)[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)=O)(C)C.C(Cl)(Cl)Cl.[N-:45]=[N+]=[N-].[Na+].CS(O)(=O)=O>O>[NH2:7][C:8]1([C:18]2[S:19][C:20]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:26]=[C:25]([CH3:40])[CH:24]=3)=[CH:21][N:22]=2)[CH2:17][CH2:16][NH:45][C:11](=[O:12])[CH2:10][CH2:9]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)CCC4(CC3)OCCO4)s2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)CCNC(=O)CC3)s2)c1
Temperature: 65 °C
Yield: 63.8 %

Procedure:
To the product of Step 2 (100 mg, 0.13 mmol) was added chloroform (630 pt), sodium azide (24.5 mg, 0.38 mmol), and methanesulfonic acid (98 μL, 1.51 mmol). The mixture was heated to 65° C. for 1.5 h., cooled to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (35:65 to 70:30 acetonitrile:water with a 0.1% trifluoroacetic acid modifier). The fractions containing the desired product were diluted with ethyl acetate and free based with saturated aqueous sodium bicarbonate. The separated organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (38 mg, 0.083 mmol, 66% yield) as an orange oil. MS ESI: [M+H]+ m/z 463. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.49 (s, 1H), 7.28 (d, J=4.7, 1H), 7.16 (s, 1H), 2.39-2.08 (m, 9H), 1.30-0.99 (m, 4H). rhSYK activity=+++
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][O:10][CH3:11].C([Li])CCC.[CH:17](=[O:26])[C:18]1[C:19]([O:24][CH3:25])=[CH:20][CH:21]=[CH:22][CH:23]=1.[Cl-].[NH4+]>CCCCCC.CN(C)CCN(C)C.O1CCCC1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:17]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[O:8][CH2:9][O:10][CH3:11])[OH:26]
Reactant: COCOc1ccccc1C
Reactant: COc1ccccc1C=O
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1c(C)cccc1C(O)c1ccccc1OC
Reaction time: 4 h
Yield: 137.2 %

Procedure:
1-Methyl-2-methoxymethoxybenzene (15.2 g) was added to a mixture of 75 ml of a 1.6 M solution of n-butyl lithium in hexane and 18.1 ml of tetramethylethylenediamine at 0° C. with stirring. After 4 hours, 13.6 g of o-anisaldehyde dissolved in 30 ml of tetrahydrofuran was added. The mixture was allowed to react for 0.5 hour and was then poured into a mixture of ice and saturated aqueous ammonium chloride. The resulting mixture was extracted with ether and the ether extract was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 39.5 g of the title compound as an off-white solid. The assigned structure was consistent with the proton NMR spectrum.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:14]([NH2:25])[C:15]1[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[C:17]([O:18][CH3:19])[CH:16]=1>C(N(CC)CC)C>[CH3:19][O:18][C:17]1[CH:16]=[C:15]([CH:24]=[CH:23][C:20]=1[O:21][CH3:22])[CH2:14][NH:25][C:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:12]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)C23CC4CC(CC(C4)C2)C3)cc1OC

Procedure:
Subject 4.0 g. (20 mmoles) of adamantane carboxylic acid chloride, 3.3 g. (20 mmoles) of veratrylamine and 10.0 ml. of triethylamine to the process of Example 11 and obtain thereby the title product, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[C:5](=[O:12])[NH:4][C:3]1=[O:13].[H-].[Na+].[CH2:16]([O:19][C:20](=[O:43])[CH:21]([CH2:40][CH2:41]Br)[N:22]([CH3:39])[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:17]=[CH2:18].[Cl-].[NH4+]>CN(C)C=O>[CH2:16]([O:19][C:20](=[O:43])[CH:21]([CH2:40][CH2:41][N:4]1[C:5](=[O:12])[C:6]2[N:7]([CH3:11])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:13])[N:22]([CH3:39])[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)C(CCBr)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCn1c(=O)c2c(ncn2C)n(C)c1=O)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
After addition of 3,7-dimethylxanthin (1.10 g, 6.1 mmol) to a suspension of sodium hydride (60%, 0.24 g, 6.0 mmol) in N,N-dimethylformamide (20 ml), the mixture was stirred at 50° C. for 2 hours. After cooling it to room temperature, a solution of (±)-2-(2-bromoethyl)-N-methyl-N-(4-phenoxybenzenesulfonyl)glycine allyl ester (2.34 g, 5.0 mmol) in N,N-dimethylformamide (10 ml) was added to the reaction mixture. This was heated at 80° C. for 2 hours. After cooling it to room temperature, a saturated aqueous solution of ammonium chloride was added and then this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate 3/1 as the eluant to afford the desired compound (0.86 g, yield 30%) as a colorless amorphous solid.
Reaction SMILES: Br[CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5].[C:12]([NH:15][CH2:16][CH2:17][SH:18])(=[O:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([NH:15][CH2:16][CH2:17][S:18][CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: O=C(O)CC(Br)C(=O)C(=O)O
Reactant: CC(=O)NCCS
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCSC(CC(=O)O)C(=O)C(=O)O
Yield: 60.7 %

Procedure:
In 20 ml of dichloromethane was suspended 1.0 g of 3-bromo-2-oxoglutaric acid. To the suspension was added, while stirring under ice-cooling, 0.5 g of 2-acetamidoethanethiol, followed by addition of 1.83 ml of triethylamine. The reaction solution was stirred at room temperature for one hour, then the solvent was evaporated off. To the residue were added ethyl acetate and water. The aqueous layer was taken, which was adjusted to pH 1~2 with 1N-HCl, followed by extraction with ethyl acetate. The extract solution was washed with water and dried (MgSO4), followed by evaporating off the solvent to give 0.67 g of 3-(2-acetamidoethylthio)-2-oxoglutaric acid as a pale yellow oily product. To this product were added, while stirring under ice-cooling, 0.32 ml of dicyclohexylamine and 0.34 g of 4-nitrobenzyl bromide. The reaction solution was stirred for 15 hours at room temperature, followed by dilution with ethyl acetate. The crystals which separated out were filtered off, and the filtrate was washed with water and dried (MgSO4), followed by evaporating off the solvent. The residue was subjected to a silica gel column chromatography, followed by elution with ethyl acetate then with ethyl acetate--acetic acid (100:3) to give 0.4 g of the subject Compound (70) as a pale yellow oily product.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][CH:8](CO)[CH2:9][CH2:10][CH2:11][N:12]1[CH:20]=[N:19][C:18]2[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]1=2.C(Cl)(Cl)Cl.CO>O>[NH:16]1[C:17](=[O:21])[C:18]2[N:19]=[CH:20][N:12]([CH2:11][CH2:10][CH2:9][CH:8]=[O:7])[C:13]=2[N:14]=[C:15]1[NH2:22]
Reactant: Nc1nc2c(ncn2CCCC(O)CO)c(=O)[nH]1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(ncn2CCCC=O)c(=O)[nH]1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a vigorously stirred solution of 113 mg (0.53 mmole) of sodium periodate in 1.1 ml of H2O at room temperature was added 101 mg (0.4 mmole) of (±)-9-(4,5-dihydroxypentyl)guanine. After 2 hours, TLC (silica gel, 70:30:3 CHCl3 --MeOH--H2O) showed complete conversion to a faster-moving product. The white solid was collected on a filter and washed with some H2O, then with diethyl ether, to give 79 mg of white solid. Recrystallization from H2O--MeOH yielded 29 mg (33%) of white solid, m.p. not less than 300° C. By 200 MHz NMR (DMSO-d6), the material consisted of a mixture of the free aldehyde and the covalent hydrate. A similar preparation showed only the free aldehyde by NMR.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]1([C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:17])[CH2:15]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C)C=O>[C:18]1([C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([OH:17])[CH2:15][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1nc[nH]n1
Reactant: OC(CCl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(Cn1cncn1)(c1ccccc1)c1ccccc1

Procedure:
1,2,4-Triazole (0.03 mol, 2.07 g) was added portionwise to a suspension of sodium hydride (0.03 mol, 0.72 g) in DMF (30 ml) and the solution stirred until effervescence ceased. 1,1-Diphenyl-2-chloro-ethan-1-ol (0.015 mol, 2.94 g) in dimethylformamide (DMF; 10 ml) was added dropwise and the solution warmed at 100° for six hours. The reaction mixture was poured into water and a white solid crystallised out. This was filtered off, washed with water, dried, and recrystallised from ethanol to give the title compound as a white crystalline solid, m.p. 128°-129°.
Reaction SMILES: C([O:4][N:5]1[C:10](=[O:11])[C:9]2[S:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=2)[C:6]1=[O:23])C=C.BrCC1O[C:30]2[CH:32]=CC=[CH:35][C:29]=2OC1>>[OH:4][N:5]1[C:10](=[O:11])[C:9]2[S:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]3[C:18](=[CH:35][CH:29]=[CH:30][CH:32]=3)[CH:17]=2)[C:6]1=[O:23]
Reactant: BrCC1COc2ccccc2O1
Reactant: C=CCOn1c(=O)c2sccc2n(Cc2cccc(Br)c2)c1=O
Product: O=c1c2sccc2n(Cc2ccc3ccccc3c2)c(=O)n1O

Procedure:
3-Allyloxy-1-(3-bromo-benzyl)-1H-thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-bromomethyl-2,3-dihydro-benzo[1,4]dioxine via general procedure B2. The crude intermediate was deprotected via general procedure D2. The final product was purified by mass triggered preparative HPLC. Electrospray MS: 333 (M+H); retention time: 2.05 min.
Reaction SMILES: C([NH:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH2:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[Cl:26])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=O.[OH-].[K+]>C(O)C.O>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[CH2:18][N:9]1[C:8]2[CH:7]=[N:6][C:5]([CH2:4][NH2:3])=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=CNCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C

Procedure:
This formamide (2.90 g, 7.5 mmol) was treated with potassium hydroxide (5.40 g, 9.4 mmol) in ethanol/water (5:1, 48 mL) at reflux for 6 hours. The resulting suspension was cooled to room temperature, concentrated, and diluted with CH2Cl2 (50 mL). The organic phase was washed with water (2×25 mL), dried (Na2SO4), filtered and concentrated to give [9-(2,5-dichlorobenzyl)-9H-β-carbolin-3-yl]methylamine as a yellow solid. The crude material was recrystallized from ethyl acetate/hexane to give 1.48 grams (55%) of a pale-yellow solid. 1H NMR (CDCl3) δ8.70 (s, 1H), 8.18 (d,J=7.9 Hz, 1H), 8.03 (s, 1H), 7.58 (td,J=7.2, 1.1 Hz, 1H) 7.32-7.42 (6-line m, 3H), 7.20 (dd, J=9.6, 2.6 Hz, 1H), 6.55 (d, J=2.6 Hz, 1H), 5.60 (s, 2H), 4.28 (d, 1H), 1.96 (br s, 2H); MS monoisotopic mass (calculated) 355.1, MH+ (observed) 356.7.
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]=[CH:13][S:14][C:15]=1[CH2:16][CH2:17][NH:18][C:19](=[O:43])[C@H:20]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:21][C@H:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:10])C1C=CC=CC=1.Br.C(O)(=O)C>>[C:9]([C:11]1[N:12]=[CH:13][S:14][C:15]=1[CH2:16][CH2:17][NH:18][C:19](=[O:43])[C@H:20]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:21][C@H:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([OH:10])=[O:8]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)NCCc1scnc1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)NCCc1scnc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
A mixture of 2.2 g of 4-benzyloxycarbonyl-5-{2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)-(L)-phenylalanyl]aminoethyl}thiazole and 30 ml of a 25% hydrogen bromide-acetic acid solution was stirred at room temperature for one day. After removing the solvent, the mixture was neutralized with a 10% potassium carbonate aqueous solution. The crystals obtained were recrystallized from a methanol-isopropyl ether mixed solution to obtain 1.27 g of 4-carboxy-5-{2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)-(L)-phenylalanyl]aminoethyl}thiazole.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([OH:41])[CH2:36]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH:37]([OH:41])[CH2:36]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCCN1CCCC(O)C1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC(O)C3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-(4-amino-butyl)-piperidin-3-ol by the procedure analogous to Example 6. HPLC ret. time: 3.3 minutes. 1H NMR (400 MHz, CD3OD) δ 7.18 (dd, 1H, J=6.8, 9.6 Hz), 7.04 (dd, 1H, J=5.6, 10 Hz), 5.45 (s, 2H), 3.64 (m, 1H), 3.24-3.22 (m, 2H), 2.90 (m, 1H), 2.73 (m, 1H), 2.37 (m, 2H), 2.25 (d, 3H, J=1.6 Hz), 1.99-1.87 (m, 3H), 1.74 (m, 1H), 1.74-1.53 (m, 6H) ppm; MS (APCl, m/z): 498 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:15]([CH3:24])=[CH:16][C:17]([NH2:23])=[C:18]3[C:22]=2[CH2:21][CH2:20][CH2:19]3)=[CH:11][C:10]=1[I:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([N:23]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:17]1[CH:16]=[C:15]([CH3:24])[C:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([I:27])[CH:11]=2)=[C:22]2[C:18]=1[CH2:19][CH2:20][CH2:21]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(N)c2c(c1Oc1ccc(OCc3ccccc3)c(I)c1)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c2c(c1Oc1ccc(OCc3ccccc3)c(I)c1)CCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 7-(4-benzyloxy-3-iodophenoxy)-6-methylindan-4-ylamine (3.80 g) in N,N-dimethylformamide (15 mL) were added benzyl bromide (2.30 mL) and potassium carbonate (2.67 g), and the mixture was stirred under an argon atmosphere at room temperature for 2 days. Adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) to give the title compound (4.50 g).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH:36]([CH3:38])[CH3:37])=[N:13][C:14]2[C:15]([CH3:35])([CH3:34])[CH2:16][N:17](C(=O)C(F)(F)F)[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.CCOCC>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH:36]([CH3:38])[CH3:37])=[N:13][C:14]2[C:15]([CH3:35])([CH3:34])[CH2:16][NH:17][CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(C(=O)C(F)(F)F)CC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A mixture of methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2,2,2-trifluoroacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 4) (0.250 g, 0.464 mmol) and K2CO3 (0.064 g, 0.464 mmol) in MeOH was stirred at room temperature for 24 h. The reaction was diluted with Et2O (50 mL), washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated to give a pale yellow residue which was purified by reverse phase preparative-HPLC, eluting with MeCN/H2O, to afford methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (0.117 g, 57% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.28-7.32 (1H, m), 7.15-7.20 (1H, m), 7.13 (2H, d, J=6.7 Hz), 4.79 (1H, s), 3.75 (1H, d, J=16.2 Hz), 3.69 (3H, s), 3.48 (1H, quin, J=6.6 Hz), 3.42 (1H, d, J=16.5Hz), 2.94-3.05 (2H, m), 2.17 (1H, br. s.), 1.39 (6H, s), 1.26 (3H, d, J=6.4 Hz), 1.09 (3H, d, J=6.7 Hz), 0.95 (9H, s). LCMS (M+H) calcd for C26H36FN2O3: 443.2. found: 433.3.