Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:35]1[CH:36]=[CH:37][C:38]2[S:42][CH:41]=[N:40][C:39]=2[CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[S:42]1[C:38]2[CH:37]=[CH:36][C:35]([C:21]3[CH:22]=[CH:23][C:18]([N:13]4[C:12]([CH2:11][C@@H:8]5[CH2:9][CH2:10][N:6]([C:4]([CH:1]6[CH2:3][CH2:2]6)=[O:5])[CH2:7]5)=[N:16][NH:15][C:14]4=[O:17])=[C:19]([F:33])[CH:20]=3)=[CH:43][C:39]=2[N:40]=[CH:41]1
Reactant: CC1(C)OB(c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)c(F)c2)OC1(C)C
Reactant: Brc1ccc2scnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4scnc4c3)cc2F)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.230 mmol) in dioxane (1.5 mL) was treated with 5-bromo-1,3-benzothiazole (0.230 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (9 mg), and 2M aq potassium carbonate (0.690 mmol). The reaction mixture was purged with nitrogen, sealed, and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, treated with Si-Thiol (Silicycle, 20 mg), filtered, and concentrated in vacuo. Silica gel chromatography (0-8% methanol/dichloromethane) and reverse phase HPLC (20-50% acetonitrile w/0.1% TFA/water w/0.1% TFA) were utilized in purifying this compound. The product fractions from the HPLC were combined, adjusted to pH˜5 with the addition of saturated aq sodium bicarbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo, providing the title compound as an amorphous off-white solid (39%). MS(ES)+ m/e 464.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3][CH:2]=1.[H-].[Na+].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>O1CCCC1>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:8][CH2:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2cncnc2)cc1
Reaction time: 0.08 h

Procedure:
Pyrimidin-5-ylmethanol (510 mg, 4.63 mmol) in tetrahydrofuran (8 mL) at room temperature was treated with sodium hydride (185 mg, 4.63 mmol) and stirred for 5 minutes. p-Toluenesulfonyl chloride (883 mg, 4.63 mmol) was added, and the resulting mixture stirred for one hour to form pyrimidin-5-ylmethyl 4-methylbenzenesulfonate. In a separate flask 3-methyloxindole (682 mg, 4.63 mmol) and N,N′-dimethylethylenediamine (1.538 mL, 10.19 mmol) in tetrahydrofuran (16 mL) were cooled to −78° C. and treated dropwise with n-butyllithium (2.5M in hexanes, 4.08 mL, 10.2 mmol). The mixture was allowed to warm to 0° C. and stirred for 15 minutes. The mixture was recooled to −78° C. To this mixture was added the tetrahydrofuran solution of pyrimidin-5-ylmethyl 4-methylbenzenesulfonate via cannula; the resulting reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. Water (50 mL) was added, and the mixture extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 25S, eluting with 0-100% ethyl acetate/hexane to afford 3-methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one as a white solid.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[C:9]([F:15])[CH:8]=1)C.C(OC(OCC)CSC1C=CC(C)=C(F)C=1)C>>[F:13][C:11]1[C:12]2[CH:4]=[CH:5][S:6][C:7]=2[CH:8]=[C:9]([F:15])[C:10]=1[CH3:14]
Reactant: CCOC(CSc1cc(F)c(C)c(F)c1)OCC
Agent: CCOC(CSc1ccc(C)c(F)c1)OCC
Product: Cc1c(F)cc2sccc2c1F

Procedure:
The same procedure as in Reference Example 1 (3) is repeated, except that 1,1-diethoxy-2-(3,5-difluoro4-methylphenylthio)ethane is substituted for the 1,1-diethoxy-2-(3-fluoro-4-methylphenylthio)ethane, to obtain 4,6-difluoro-5-methylbenzo[b]thiophene.
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1.[Br:17]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1
Reactant: CCOC(=O)COc1ccc(CO)cc1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(CBr)cc1C
Yield: 54.1 %

Procedure:
To a solution of ethyl [4-(hydroxymethyl)-2-methylphenoxy]acetate (4.27 g, 19 mmol) in dry CH2Cl2 (150 mL) under nitrogen at 5° C., was added tetrabromomethane (6.91 g, 20.9 mmol) then triphenylphosphine (5.71 g, 21.8 mmol) portion wise over 0.5 h. The resultant mixture was then stirred for 16 h at room temperature. The solvents were removed in vacuo. Purification by Biotage™ chromatography (silica, 2×90 g) eluting with 30:1 cyclohexane:EtOAc afforded the title compound as a yellow solid (2.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:23][C:24]1([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][O:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:23][C:24]3([CH3:28])[CH2:27][O:26][CH2:25]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCC1(C)COC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
Using an analogous procedure to that described in Example 5 except that the reaction mixture was stirred at ambient temperature for 72 hours, 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline was reacted with 3-methyl-3-(4-toluenesulphonyloxymethyl)-oxetane (Chem. Pharm. Bull., 1985, 33, 1707) to give 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-methyloxetan-3-ylmethoxy)quinazoline in 24% yield, m.p. 226°-227° C. (recrystallised from ethanol); NMR Spectrum: 1.43 (s, 3H), 3.93 (s, 3H), 4.23 (s, 2H), 4.37 (d, 2H), 4.53 (d, 2H), 7.2 (s, 1H), 7.43 (t, 1H), 7.78 (m, 1H), 7.88 (s, 1H), 8.11 (m, 1H), 8.49 (s, 1H), 9.49 (s, 1H); Elemental Analysis: Found C, 59.5; H, 4.7; N, 10.2; C20H19ClFN3O3 requires C, 59.5; H, 4.7; N, 10.4%.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH2:13]=O>C(O)=O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][N:8]([CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)CCNCC2
Reactant: C=O
Solvent: O=CO
Product: CN1CCc2ccc(Br)cc2CC1
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
2.43 g 7-Bromo-2,3,4,5-tetrahydro-1H-benzo[d]azepine are dissolved in 4.055 g of formic acid and 3.2 mL of formaldehyde solution was added. The mixture was stirred at 70° C. for 3.5 h and continued overnight at 25° C. The mixture was concentrated, diluted with water and 10 N NaOH to adjust to a basic pH. The mixture was then extracted with tertbutylmethylether (3×) and the organic phase dried (Na2SO4), filtered and concentrated to yield 2.48 g 7-bromo-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[CH2:13]([N:20]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[NH:21][C:22](=[O:49])[CH:23]([OH:48])[CH:24]([NH:32][C:33]([C@H:35]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]1[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+].O>CS(C)=O>[CH2:13]([N:20]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[NH:21][C:22](=[O:49])[C:23](=[O:48])[CH:24]([NH:32][C:33]([C@H:35]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]1[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)NC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
IBX (189 mg, 0.303 mmol, 45 wt %) was added a solution of tert-butyl 1-benzyl-2-(3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoyl)-hydrazinecarboxylate (130 mg, 0.216 mmol) in DMSO (3 mL). After stiffing overnight saturated aqueous NaHCO3 solution (15 mL) and water (15 mL) were added. The mixture was extracted with EtOAc, the combined organic layers were washed with saturated aqueous NaHCO3 solution, water and dried (MgSO4). Purification by flash column chromatography (gradient 1-10% MeOH in DCM) provided the title compound (110 mg, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH3:24])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2].[CH2:25](Br)C=C>>[CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH:24]=[CH2:25])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CC)CCCN(CC2COc3ccccc3O2)C1
Reactant: C=CCBr
Product: C=CCC1(C(=O)OCC)CCCN(CC2COc3ccccc3O2)C1

Procedure:
The procedure described above for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine-3-carboxylic acid ethyl ester was repeated except that allyl bromide was used instead of methyl iodide.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH3:15])=[N:9][C:8]=1[NH2:16].O1CCCC1.C(O)(=O)C>O.CO>[NH2:16][C:8]1[N:9]=[C:10]([CH2:13][O:14][CH3:15])[CH:11]=[CH:12][C:7]=1[C:6]([OH:17])=[O:5]
Reactant: COCc1ccc(C(=O)OC)c(N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc(C(=O)O)c(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Lithium hydroxide monohydrate (1.2 g, 29 mmol) was added to a mixture of 2-amino-6-methoxymethyl-nicotinic acid methyl ester described in Preparation Example A-10 (2.9 g, 15 mmol), tetrahydrofuran (30 mL), methanol (7.5 mL), and water (7.5 mL), which was then stirred overnight at room temperature. Acetic acid (1.7 mL, 29 mmol) was added to the reaction solution and the solvent was evaporated in vacuo. After filtration using silica gel (methanol/ethyl acetate=1/3) and the solvent was evaporated in vacuo, the residue was washed with water, and the title compound (2.1 g, 12 mmol, 80%) was obtained as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1([O:22][Si](C)(C)C)[C:15]2[NH:14][C:13]3[C:8](=[CH:9][C:10]([C:20]#[N:21])=[CH:11][C:12]=3[C:16]([F:19])([F:18])[F:17])[C:7]=2[CH2:6][CH2:5][CH2:4]1.[OH-].[K+]>C1COCC1.O>[OH:22][C:3]1([C:2]([F:28])([F:1])[F:27])[C:15]2[NH:14][C:13]3[C:8](=[CH:9][C:10]([C:20]#[N:21])=[CH:11][C:12]=3[C:16]([F:17])([F:18])[F:19])[C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)CCCc2c1[nH]c1c(C(F)(F)F)cc(C#N)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)c2[nH]c3c(c2c1)CCCC3(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
1,8-bis(Trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile (100 mg, 0.23 mmol) was dissolved in THF (5 mL) and KOH (66 mg, 1.19 mmol), in H2O (5 mL), was added. The reaction mixture was stirred at room temperature for 1 h, diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography [EtOAc-hexane (17:3) as eluant] to afford the title compound as a white solid (30 mg, 36.58%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.75 (br s, 1H), 8.067 (s, 1H), 7.75 (s, 1H), 2.91-2.86 (m, 1H), 2.80-2.74 (m, 1H), 2.55 (s, 1H), 2.37-2.32 (m, 1H), 2.16-2.05 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[C:11](=[O:17])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:28]([O:27][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[C:11](=[O:17])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCN1CCN(c2ccc(N)cc2F)CC1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1=O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
5-Amino-2-(4-ethyl-3-oxopiperazin-1-yl)fluorobenzene (2.95 g) was dissolved in dry dichloromethane (50 ml) under argon. Pyridine (1.26 ml) was added, and the mixture cooled to -20° C. Benzyl chloroformate (1.95 ml) was added, and the mixture stirred for 10 minutes at -20° C., before allowing the temperature to rise to ambient over 1.5 hours. Solvents were evaporated, the residue dissolved in dichloromethane and washed with sodium bicarbonate solution. After drying (MgSO4) and evaporation of solvent, the residue was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 4% methanol in dichloromethane. Relevant fractions were combined and evaporated to give 5-benzyloxycarbonylamino-2-(4-ethyl-3-oxopiperazin-1-yl)fluorobenzene (3.3 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].I[C:13]1[CH:14]=[C:15]([Br:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1
Reactant: Brc1cccc(I)c1
Reactant: Sc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(Sc2ccc3ccccc3c2)c1
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of 2-naphthalenethiol (3.2 g), 3-iodobromobenzene (6.7 g), potassium carbonate (1.4 g), cuprous chloride (0.4 g) and DMF (4 ml) was heated to reflux for 1 hour. The mixture was allowed to cool to ambient temperature and was partitioned between diethyl ether and water. The mixture was filtered and the organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up in ethyl acetate, decolourised by treatment with charcoal, reisolated and purified by recrystallisation from methanol to give 3-bromophenyl 2-naphthyl sulphide (3.9 g, 65%), m.p. 68°-70° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][CH:31]=[C:32]([CH2:34]Cl)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=3)[S:30][CH:31]=2)=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Reactant: CC(C)(C)c1ccc(-c2nc(CCl)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(C)(C)C)cc3)n2)c(C)c1)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
A mixture of 150 mg of [rac]-2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (0.59 mmol), 190 mg of 2-(4-tert-butyl-phenyl)-4-chloromethyl-thiazole (0.71 mmol) and 325 mg of cesium carbonate (1 mmol) in 5 ml of acetonitrile was stirred at 60° C. for 1 h. The solvent was then evaporated and the residue obtained was chromatographed on silicagel using a 98:2 (v/v) mixture of dichloromethane and diethyl ether as the eluent. Thus, 150 mg (52% of theory) of [rac]-3-{4-[2-(4-tert-butyl-phenyl)-thiazol-4-ylmethoxy]-3-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was obtained as a colorless viscous oil.
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[NH:14][C:15](=O)[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=2)[CH2:4][CH2:3]1.[O:24]1[CH2:27][C:26]([CH2:30][NH2:31])([CH2:28][NH2:29])[CH2:25]1>>[NH2:29][CH2:28][C:26]1([CH2:30][NH:31][C:15]2[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=[C:13]([N:5]3[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[S:2](=[O:1])[CH2:3][CH2:4]3)[N:14]=2)[CH2:27][O:24][CH2:25]1
Reactant: NCC1(CN)COC1
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC3(CN)COC3)c2s1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 3 by using 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one and 3,3-oxetanedimethanamine. MS obsd. (ESI+) [(M+H)+] 444, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.74 (t, J=8.7 Hz, 2H), 7.43-7.51 (m, 2H), 6.83 (s, 1H), 5.21 (d, J=15.2 Hz, 1H), 4.68-4.75 (m, 1H), 4.64 (d, J=6.6 Hz, 2H), 4.50 (t, J=6.2 Hz, 2H), 4.01 (br. s., 2H), 3.09 (s, 2H), 2.56 (s, 3H), 2.06 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19](COC)[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8](=[O:18])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])=[N:6][CH:7]=1.Cl>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8](=[O:18])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])=[N:6][CH:7]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(F)cccc1OC)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(F)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
N-[5-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (180 mg, 0.313mmol) was magnetically stirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL) and heated at 85° C. for 7 h. The reaction was subsequently concentrated and the residue was neutralized (pH 7) with aqueous sodium bicarbonate and extracted with EtOAc (3×80 mL). The extracts were dried (MgSO4), filtered, and chromatographed on silica gel using EtOAc-hexane (gradient, 0:100 to 50:50) to provide N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: MS m/z 489.1 (M+H); 511.0 (M+Na).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](OC)=[C:8]([Cl:14])[C:7]=1[CH3:15].[C:17]1(O)C=CC=CC=1>>[NH2:1][CH2:2][C@@H:3]([OH:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:17])=[C:8]([Cl:14])[C:7]=1[CH3:15]
Reactant: Oc1ccccc1
Reactant: COc1ccc(OC[C@H](O)CN)c(C)c1Cl
Product: Cc1ccc(OC[C@H](O)CN)c(C)c1Cl

Procedure:
(R)-1-Amino-3-(3-chloro-4-methoxy-2-methyl-phenoxy)-propan-2-ol tan solid, 0.51 g (starting from 3.0 mmol of phenol).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([O:18]CC)=[O:17].[OH-].[Li+]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)[C@@H]1CCCCN1c1nc2ccccc2s1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2s1

Procedure:
The title compound was prepared by a similar method to Preparation 3 from ethyl (2S)-1-(1,3-benzothiazol-2-yl)-2-piperidinecarboxylate [see Preparation 42] and 1N aqueous lithium hydroxide solution. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 10:1, by volume, dichloromethane: methanol to afford (2S)-1-(1,3-benzothiazol-2-yl)-2-piperidinecarboxylic acid as a solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[CH:24]=[CH:23][C:13]2[CH2:14][CH:15]3[CH:20]([CH3:21])[C:19]([CH3:22])([C:12]=2[CH:11]=1)[CH2:18][CH2:17][NH:16]3)=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39][CH2:40]Br>C(#N)C>[CH3:2][O:3][C:4]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[CH:24]=[CH:23][C:13]2[CH2:14][C@@H:15]3[C@H:20]([CH3:21])[C@:19]([CH3:22])([C:12]=2[CH:11]=1)[CH2:18][CH2:17][N:16]3[CH2:40][CH2:39][O:38][CH3:37])=[O:9]
Reactant: COc1ccc(CNC(=O)c2ccc3c(c2)C2(C)CCNC(C3)C2C)c(OC)c1
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CC[C@@]2(C)c3cc(C(=O)NCc4ccc(OC)cc4OC)ccc3C[C@@H]1[C@@H]2C
Temperature: 65 °C
Yield: 85.5 %

Procedure:
A mixture of 2R,6R,11R)—N-(2,4-dimethoxybenzyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide hydrochloride (400 mg, 0.93 mmol), potassium carbonate (385 mg, 2.78 mmol), and bromoethyl methyl ether (142 mg, 1.02 mmol) in acetonitrile (15 mL) was heated at 65° C. overnight. Further bromoethyl methyl ether was added (70 mg, 0.50 mmol) and the reaction heated at 65° C. for 24 hours. The reaction mixture was allowed to return to ambient temperature before partitioning between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave (2R,6R,11R)—N-(2,4-dimethoxybenzyl)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide (360 mg, 86% yield); LC/MS (M+H)+=453.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:29]12[CH2:37][C:33]([CH2:38][NH2:39])([CH2:34][CH2:35][CH2:36]1)[CH2:32][CH2:31][CH2:30]2>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:39][CH2:38][C:33]23[CH2:37][N:29]([CH2:30][CH2:31][CH2:32]2)[CH2:36][CH2:35][CH2:34]3)=[O:8])=[C:4]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:3]=1
Reactant: COCCOc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCC12CCCN(CCC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCOc1cc(N)c(Cl)cc1C(=O)NCC12CCCN(CCC1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of 4-amino-5-chloro-2-(2-methoxyethoxy)benzoic acid (2.09 g, 8.5 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.46 g, 9.0 mmol), stirred for one hour, degassed under a stream of nitrogen over 10 minutes, and cooled (0° C.). A solution of 1-azabicyclo[3.3.1]nonane-5-methanamine (1.36 g, 8.8 mmol) in tetrahydrofuran (5 mL) was added dropwise, and stirring was continued at room temperature for 18 hours. The solution was concentrated in vacuo and the residue was taken up in methylene chloride (100 mL) and washed with saturated sodium carbonate (50 mL). The organic solution was dried (Na2SO4), concentrated in vacuo, and passed through a short column of alumina (eluted with 5% methanol/methylene chloride). The filtrate was concentrated in vacuo and, at this point, appeared to be contaminated with some highly insoluble impurity. The residue was taken up in tetrahydrofuran and filtered, and the filtrate was concentrated in vacuo, triturated from cold ether, and recrystallized from acetonitrile (2 crops) to afford 1.59 g (49%) of colorless crystals; mp 154.0°-155.5° C.