Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[S:7])=[CH:4][C:3]=1[Cl:16].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(=O)CC>[CH3:17][S:7][C:6](=[N:8][CH2:9][Si:10]([CH3:12])([CH3:13])[CH3:11])[C:5]1[CH:14]=[CH:15][C:2]([Br:1])=[C:3]([Cl:16])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CNC(=S)c1ccc(Br)c(Cl)c1
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.5 %

Procedure:
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethylthiobenzamide (Example I13) (4.43 g) in butanone (80 ml) was added potassium carbonate (2.73 g) and methyl iodide (1.02 ml). The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:5) to give of 4-bromo-3-chloro-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (2.56 g). 1H-NMR (400 MHz, CDCl3): 7.55-7.15 (m, 3H), 3.55 (s, 2H), 1.98 (s, 3H), 0.00 (s, 9H) ppm.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: COC(=O)CBr
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: C1CCOC1
Product: COC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of benzyl piperazine-1-carboxylate (0.5 g, 2.270 mmol) and TEA (0.949 mL, 6.81 mmol) in THF (10 mL) was added methyl 2-bromoacetate (0.230 mL, 2.497 mmol) dropwise. The reaction was stirred at 65° C. After 1 hour, the reaction mixture was concentrated, and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to generate benzyl 4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate as a clear oil (0.61 g, 92% yield).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:8][CH:7]([C:9]([OH:11])=O)[CH2:6]1)[CH:2]([CH3:4])[CH3:3].Cl.[CH3:13][NH:14][O:15][CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.C(N(CC)CC)C.CN(C=O)C>[CH3:16][O:15][N:14]([CH3:13])[C:9]([CH:7]1[CH2:8][CH:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6]1)=[O:11]
Reactant: CNOC
Reactant: CC(C)CC1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)C1CC(CC(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.4 %

Procedure:
3-Isobutylcyclobutanecarboxylic acid (62.7 g) and DMF (500 mL) were mixed. To the mixture were added N,O-dimethylhydroxylamine hydrochloride (46.9 g), triethylamine (83.9 mL), HOBt.H2O (73.8 g) and WSC.HCl (92.3 g). The resulting mixture was stirred at RT overnight. To the reaction mixture was added water (500 mL). The mixture was extracted with ethyl acetate/hexane=1/1 (250 mL×2). The combined organic layer was washed with water (250 mL), aqueous 10 w/v % sodium carbonate (250 mL), water (250 mL), 1 N hydrochloric acid (500 mL), water, saturated aqueous sodium bicarbonate (250 mL) and then brine (250 mL). The organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (87.5 g) as a crude product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23]C(OC(C)(C)C)=O)[N:15](C(OC(C)(C)C)=O)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:38]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:38])[C:20]=3[CH2:22][NH2:23])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2C(=O)OC(C)(C)C
Solvent: ClCCl
Product: NCc1c(Cl)ccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Reaction time: 48 h
Yield: 51.5 %

Procedure:
To a stirred solution of tert-butyl 1′-benzyl-4-((tert-butoxycarbonylamino)methyl)spiro[indoline-3,4′-piperidine]-1-carboxylate (115 mg, 0.227 mmol) in DCM (2 mL) was added 1-chloropyrrolidine-2,5-dione (NCS) (66 mg, 0.50 mmol). The reaction mixture was stirred at about room temperature for 48 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was dissolved in DCM (2 mL) and treated with 4N HCl in dioxane (0.5 mL) overnight. The solvents were evaporated. The residue was taken up in DCM and basidified with saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated to give (1′-benzyl-5-chlorospiro[indoline-3,4′-piperidine]-4-yl)methanamine (40 mg, 52%) as an oil, which was used in the next step without further purification. LCMS (APCI+) m/z 342, 344 [M+H]+; Rt=1.71 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[C:21](F)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[O:40]([CH3:42])[K].CO>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[C:21]([O:40][CH3:42])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(CCCOc2cc3ncnc(C4CCN(C(=O)OC(C)(C)C)CC4)c3cc2F)CC1
Reactant: CO[K]
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 100 °C
Reaction time: 9 h
Yield: 55 %

Procedure:
A mixture of 4-{6-Fluoro-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester (32.6 mg, 66.9 μmol), as prepared in Example 205d, DMSO (50 μL), and 0.31M KOMe/MeOH (270 μL, 83.9 μmol KOMe in 6.4 mmol MeOH) was stirred at 100° C. for 9 hr, and then 110° C. for 2 hr. The resulting pale yellow homogeneous solution was allowed to cool to rt, diluted with DCM (2 mL), and washed with 4M NaCl (1×2 mL). The aq layer was back-extracted with DCM (1×2 mL), and the combined organic layers were dried (Na2SO4) and concentrated. Purification of the residue by silica flash chromatography (1:2 hex/EtOAc→1:2 hex/EtOAc/3% DMEA→9:1 EtOAc/acetone/3% DMEA eluent) afforded the title compound (18.4 mg, 55%). NOe experiments support the assigned regioisomer. Select 1H-NMR resonances and nOes (300 MHz, CDCl3) δ 7.34 (s, 1H), 7.24 (s, 1H), 4.04 (s, 3H), 3.51 (m, 1H). Irradiation of the diagnostic methine proton at δ 3.51 generates an nOe to the quinazoline C5 proton at δ 7.24, but not to the quinazoline C8 proton at δ 7.34. Irradiation of the methoxy protons at δ 4.04 generates an nOe to the C5 proton at δ 7.24, but not to the C8 proton at δ 7.34. This indicates methoxy substitution at C6 of the quinazoline. LC/MS (ESI): calcd mass 499.3, found 500.4 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:20]([O-:22])=[O:21])[C@H:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]CN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:10]([NH:12][C@H:13]([C:20]([OH:22])=[O:21])[C@H:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[O:11])[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)[C@@H](O)[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](O)[C@H](NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound of example 255A (470 mg, 1.32 mmol) and (2S,3S)-2-amino-3-hydroxy-4-methoxy-4-oxobutyric acid hydrochloride (see example 33A for preparation, 407 mg, 2.04 mmol, 1.6 equivalents) are dissolved in DMF (20 ml) at 0° C., and DIPEA (1.78 ml, 10.20 mmol, 7.7 equivalents) are added. The mixture is stirred at room temperature for about 16 h and then chromatographed according to method 45 and fine purified by method 32. Yield: 200 mg (29% of theory).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(COCC2OCCO2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A mixture of benzyloxyacetaldehyde (3 g, 20 mmol), ethylene glycol (1.23 ml, 22 mmol), p-toluenesulfonic acid monohydrate (344 mg, 1.8 mmol), and toluene (15 ml) was stirred at 140° C. for 2 hours and further stirred at 150° C. for 3 hours. After cooled on ice, a 2N aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture. An organic layer was separated, washed with water (three times) and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=1/0 to 9/1 gradient). Desired fractions were concentrated to obtain the title compound (3.01 g, 77.5% yield) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([OH:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)N.Cl[C:19](OCC)=[O:20]>>[C:2]1([N:1]2[C:19](=[O:20])[O:17][C:8](=[O:16])[C:9]3=[CH:10][CH:12]=[CH:13][CH:14]=[C:15]23)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1C(=O)O
Product: O=c1oc(=O)n(-c2ccccc2)c2ccccc12

Procedure:
The novel 1,2-diphenylquinolones of formula IV, where m is the interger 0, are prepared by three methods. In a first method the 1,2-diphenylquinolones (IV, m=0) are prepared by reaction of an appropriate N-phenylisatoic anhydride with an appropriate lower-alkyl benzoylacetate, hydrolysis of the resulting 1,2-phenylquinolone-3-carboxylate to the corresponding 3-carboxy compound and pyrolytic elimination of the carboxyl group. In a second method the 1,2-diphenylquinolones (IV, m=0) are prepared by reaction of an appropriate N-phenylisatoic anhydride with sodium methylsulfinylmethide (hereinafter dimsyl sodium), and reaction of the methylsulfinylacetophenone so obtained with an appropriate benzaldehyde. The N-phenylisatoic anhydride is prepared by reacting an appropriate 2-bromo (or chloro)benzoic acid with an appropriate aniline and reacting the resulting anthranilic acid with ethyl chloroformate. These steps are illustrated by the following equations: ##SPC8##
Reaction SMILES: [Na+].[F:2][C:3]([F:25])([F:24])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]([O-:19])=[O:18])=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][O:31][C:30]1=[O:34]>CN(C)C=O>[O:34]=[C:30]1[N:29]([CH2:28][CH2:27][O:18][C:17](=[O:19])[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:14][C:8]2[C:7]3[C:12](=[CH:13][C:4]([C:3]([F:24])([F:2])[F:25])=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)[CH2:33][CH2:32][O:31]1
Reactant: O=C([O-])c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Reactant: O=C1OCCN1CCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCN1CCOC1=O)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
A mixture comprising 10.62 g of N-(7-trifluoromethyl-4-quinolyl)-anthranilic acid sodium salt, 4.98 g of 90% 3-(β-chloroethyl)-oxazolidin-2-one and 60 ml of dimethylformamide was heated under stirring at 120° C. for five hours. Upon completion of the reaction, the mixture was cooled, insoluble sodium chloride was filtered off, and the solvent was evaporated off in vacuo. The residue was treated with 200 ml of water and the solid, collected by filtration, crystallized from methylene dichloride: petroleum ether. 8.7 g of N-(7-trifluoromethyl-4-quinolyl)-anthranilic acid β-(2-oxo-3-oxazolidinyl)-ethyl ester, melting at 124°-125° C., were obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([OH:38])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].Cl>O.CN(C)C=O>[C:15]([O:14][C:13]([N:12]([CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)[CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]2[C:37]3[C:32](=[C:33]([O:38][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]2=[O:39])[CH2:22][CH2:21]1)=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(O)cccc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3 mL of an N,N-dimethylformamide solution containing 166 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-hydroxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 65 mg of potassium carbonate and 43 μL of ethyl bromoacetate were added, and stirred at room temperature for 2 hours. After water was added to the reaction mixture and acidified with hydrochloric acid, the mixture was extracted with a mixture of ethyl acetate: toluene=5:1. The extracts were washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1], to give 196 mg of ethyl (1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetate as a pale brown oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[C:7](Cl)(Cl)=[O:8].Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[NH2:35][C:21]1[N:22]=[C:23]([C:25]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][N:31]([C:7]([NH:6][C:2]4[S:1][CH:5]=[CH:4][N:3]=4)=[O:8])[CH2:32]3)=[CH:27][CH:26]=2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)Cl
Reactant: Nc1nccs1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3nccs3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 1,3-thiazol-2-amine (Aldrich, Cat. #123129), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=451.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(Cl)Cl>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:23][N:22]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:21][CH2:20][C:6]1=2
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC(O)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a stirred solution of 2-(1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol (300 mg, 0.977 mmol) and triethyl amine (0.18 mL, 1.27 mmol) in DCM (6 mL) was added ethyl chloroformate (138 mg, 1.27 mmol), and the reaction mixture stirred at RT for 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH-DCM) to yield ethyl 3,4-dihydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-8-methyl-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (170 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.4 (d, 2H), 7.21 (m, 4H), 7.0 (d, 1H), 5.03 (t, 1H), 4.6 (m, 2H), 4.21 (m, 4H), 3.78 (m, 2H), 3.6 (m, 1H), 2.75 (m, 1H), 2.4 (s, 3H), 1.28 (t, 3H). Separation by chiral HPLC provides enantiomers 72a and 72b.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.[C:17]([O-])(=[O:19])[CH3:18].[Na+].C(O)C.C(OC(=O)C)(=O)C>O>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:6][CH:5]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2cccc(CCN)c2c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2cccc(CCNC(C)=O)c2c1

Procedure:
In a reactor, 5 g of the compound obtained in Step C and 2 g of sodium acetate are introduced into ethanol. The mixture is stirred, 2.3 g of acetic anhydride are then added, the reaction mixture is heated to reflux and 20 ml of water are added. The reaction mixture is allowed to return to ambient temperature and the precipitate obtained is filtered off and washed with an ethanol/water 35/65 mixture to yield the title product.
Reaction SMILES: [O:1]1[C:3]2[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]1=2.[H][H]>[Pd]>[CH:2]1([OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1=CC2=C(CCCCCCCC1)O2
Reactant: [H][H]
Agent: [Pd]
Product: OC1CCCCCCCCCCC1
Yield: 20 %

Procedure:
In a reaction example shown in this report, when epoxycyclododecadiene is subjected to a reduction reaction with a hydrogen gas in the presence of a palladium catalyst carried on γ-alumina under a reduced pressure of 1.3 MPa at a reaction temperature of 90° C., cyclododecanol is obtained at a yield of 20%. In the report, a palladium catalyst carried on titania and a palladium catalyst carried on silica were employed. In each case, the yield of the cyclododecanol was less than 20%.
Reaction SMILES: Cl.[N:2]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6][NH:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21]>CO>[CH3:24][O:23][C:19](=[O:22])[CH2:20][CH2:21][N:5]1[CH2:6][CH2:7][N:2]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH:4]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=CC(=O)OC
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: CO
Product: COC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate hydrochloride, (200 g, 0.82 mol) in methanol (1 L) was added methyl acrylate (214 g, 2.46 mol) with stirring at approximately 25° C. under N2 atmosphere, and the reaction mixture was refluxed at 70° C. for 48 hours. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (1.2 L) and water (2 L). The organic layer was separated and washed with water (1 L×2) and brine (500 mL), dried over Na2SO4, filtered and concentrated. The crude obtained was purified by column chromatography over silica gel using 30-40% ethyl acetate in petroleum ether to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 11.43 (s, 9H), 2.20-2.34 (m, 1H), 2.35-2.46 (m, 1H), 2.48 (t, 2H, J=7.2 Hz), 2.76-2.90 (m, 1H), 2.90-3.12 (m, 2H), 3.12-3.30 (m, 1H), 3.32 (t, 1H, J=4.5 Hz), 3.35-3.44 (m, 1H), 3.67 (s, 3H), 3.71 (s, 3H) 3.83-3.94 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>>[CH:18]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(C)n1nc2c(c1-c1ccc(C#N)cc1)CCNCC2
Yield: 70.7 %

Procedure:
The title compound (95 mg) was prepared as in Example 177, Steps C and D, using 205 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 211 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C17H20N4, 280.17; found, m/z 281.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 4.36 (m, 1H), 3.42-3.40 (m, 2H), 3.19-3.17 (m, 2H), 2.79-2.77 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:23]([CH3:30])[CH2:24][O:25]C(C)(C)C)[CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)=[O:4].C(OCC)(=O)C.O>C(O)=O.[Cl-].[Na+].O>[CH3:31][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:23]([CH3:30])[CH2:24][OH:25])[CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(C)(C)C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: O
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)CO)c1
Yield: 101.1 %

Procedure:
A solution of methyl 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(2S)-1-[(2-methylpropan-2-yl)oxy]propan-2-yl]oxy-benzoate (170 g, 0.39 mol) in formic acid (850 mL) was heated to 90° C. for 3 hours. Ethyl acetate (1700 mL), water (1700 mL) and saturated aqueous brine (850 mL) was added and the aqueous layer separated and extracted with ethyl acetate (850 mL) and the combined organic layers were washed with saturated aqueous brine (850 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved with ethyl acetate (1500 mL), water (1500 mL) and methanol (150 mL). Sodium carbonate (170 g) was added and the biphasic solution heated to reflux for 2 hours. The aqueous layer was separated and the organic layer washed with water (1700 mL). The combined aqueous phases were extracted with ethyl acetate (850 mL) and the combined organic layers dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with 100% ethyl acetate to obtain a the title compound (148 g).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([OH:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[CH3:24]O>>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH3:24])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccccc1Oc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1ccccc1Oc1ccccc1
Yield: 91 %

Procedure:
A solution of 2-phenoxyphenylacetic acid (2.75 g) in dry methanol (30 ml) containing concentrated sulphuric acid (0.3 ml) was heated under reflux for 2 hours then allowed to cool, poured into water and extracted with ether. The extracts were washed with water, dried and concentrated under reduced pressure to give methyl 2-phenoxyphenylacetate (2.65 g, 91%) as a pale yellow oil.