Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1C.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1COCC1>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccccc1N=C=O
Reactant: CCOC(=O)Cc1ccc(N)c(C)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2OC)cc1
Reaction time: 23 h
Yield: 100.8 %

Procedure:
To a stirred solution of ethyl 4-amino-3-methylphenylacetate (1.32 g, 7.37 mmol) and triethylamine (205 ml, 1.47 mmol) in THF (20 ml) was added 2-methoxyphenyl isocyanate (980 ml, 7.37 mmol), and the resulting mixture was stirred for 23 h. The mixture was concentrated to a small volume in vacuo and hexane was added to the residue to give precipitate, which was collected to give ethyl 4-[N′-(2-methoxyphenyl)ureido]phenylacetate (2.44 g, quant.) as a white crystalline material. mp 107-109° C.; 1H-NMR (CDCl3) δ1.26 (t, J=7.1 Hz, 3 H), 3.56 (s, 3 H), 3.79 (s, 3 H), 4.15 (q, J=7.1 Hz, 2 H), 6.82-6.85 (m, 1 H), 6.91-7.00 (m, 2 H), 7.08 (s, 1 H), 7.17 (d, J=8.5 Hz, 2 H), 7.27 (d, J=8.6 Hz, 2 H), 7.33 (s, 1 H), 8.07-8.10 (m, 1H); MS (ESI) m/z 329 (M30 +H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1.N1C=CC=CC=1>CO>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:2]3[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])[CH:21]=2)[CH:17]=[N:18]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)O)c(Nc2ccc3cn[nH]c3c2)n1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To the solution of 2-chloro-6-methylnicotinic acid 10 g and 6-aminoindazole 8.6 g in methanol 100 ml was added pyridine 9.5 ml, and then the solution was refluxed for 3 days. The reaction mixture was cooled, added H20 30 ml slowly at 20° C., and then stirred for 2 hr. The reaction mixture was filtered and the obtained solid was washed with methaol 20 ml. The desired compound (13.3 g, yield 85%) was obtained by drying of the solid product at 40˜50° C. in vacuo.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>CC(C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[CH:18]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.8 %

Procedure:
Tert-butyl bromoacetate (1.88 mL, 12.69 mmol) and potassium carbonate (3.5 g, 25.38 mmol) were added to a solution of 3-bromophenol (2.09 g, 12.08 mmol) in acetone (30 mL), and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. The mixture was filtered, and the filtrate was evaporated to dryness to give (3-bromophenoxy)acetic acid tert-butyl ester as a colorless oil (3.53 g, 100%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:16]#[N:17])=[C:13]([CH3:15])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[SH2:25]>N1C=CC=CC=1>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:16](=[S:25])[NH2:17])=[C:13]([CH3:15])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: Cc1nc(CNC(=O)OC(C)(C)C)sc1C#N
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1nc(CNC(=O)OC(C)(C)C)sc1C(N)=S
Reaction time: 48 h

Procedure:
2-(N-BOC-Aminomethyl)-5-cyano-4-methylthiazole [sic] (7.5 g, 29.61 mmol) was dissolved in pyridine (30 ml), and triethylamine (27 ml) was added. The solution was saturated with hydrogen sulfide at 0° C. and then left to stand for 48 hours at room temperature. The solvent was subsequently removed on a rotary evaporator, and the residue was taken up in ethyl acetate, washed with 20% strength potassium hydrogen sulfate solution and dried over magnesium sulfate. The solvent was removed on a rotary evaporator, and the crude product was dissolved in dichloromethane and precipitated with petroleum ether. The product which had precipitated was filtered off with suction and dried in a vacuum drying oven [lacuna] 40° C. Yield: 7.1 g (24.7 mmol, 83%).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([O-:15])=[O:14])=O)(C)(C)C.[CH2:21]1COC[CH2:22]1>>[ClH:1].[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([O:15][CH2:21][CH3:22])=[O:14]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(=O)[O-]
Reactant: C1CCOC1
Agent: Cl
Product: CCOC(=O)c1cc(F)ccc1CN
Temperature: 50 °C

Procedure:
Concentrated HCl (37%; 16 ml) was added dropwise to a solution of thyl 2-((tert-butoxycarbonylamino)methyl)-5-fluorobenzoate (Example 3; 15.9 g; 53.6 mmol) in THF (96 ml). The mixture was heated at 50° C. for 2 hours. The mixture was concentrated to dryness. The residue was taken up in ethanol (200 ml) and concentrated again. The solid was triturated from ether (100 ml). The precipitate was filtered off and washed with diethyl ether (2×50 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][CH:34]=[CH:33][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=2)[CH2:17][NH:18]C(=O)OC(C)(C)C)[N:12]=[C:11]([C:29]([F:32])([F:31])[F:30])[CH:10]=1)=[O:8].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:18][CH2:17][C:16]1[CH:15]=[C:14]([N:13]2[C:9]([C:7]([NH:6][CH2:5][C:4]3[CH:33]=[CH:34][CH:35]=[CH:36][C:3]=3[O:2][CH3:1])=[O:8])=[CH:10][C:11]([C:29]([F:31])([F:32])[F:30])=[N:12]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CN)c1
Temperature: 21 °C
Reaction time: 2 h
Yield: 128.2 %

Procedure:
To a stirred solution of 57 (900 mg, 1.784 mmol) in CH2Cl2 (3.4 mL) was added TFA (2.8 mL, 35.7 mmol). The mixture was allowed to stir at 21° C. for 2 h. A saturated NaHCO3 aqueous solution was added and followed by extractions with CH2Cl2. It was then dried over Na2SO4 and evaporated. The crude was used without any further purification. The title product 58 (925 mg, 100% yield) was isolated as a beige powder. LRMS (ESI): calc. 404.4; found 405.6 (MH)+.
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1>CC(O)C>[ClH:13].[Br:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: Cc1c(Br)ccc2c1NCC2
Reactant: COc1ccc2c(Cl)ncnc2c1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(N3CCc4ccc(Br)c(C)c43)ncnc2c1
Yield: 49 %

Procedure:
Utilizing a procedure analogous to that described in Example 1 (with conversion to the HCl salt as outlined for Example 2), this product was prepared in 49% yield from 6-bromo-7-methyl-indoline (1.1 eq.), and 4-chloro-7-methoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 200°-205° C. (dec); LC-MS: 370, 372 (MH+); anal. RP18-HPLC RT: 5.76 min.).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[CH2:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][O:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH2:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][O:19]1
Reactant: c1cc2c(c(N3CCNCC3)c1)COC2
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5c4COC5)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.3 %

Procedure:
To a suspension of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.257 g, 1.107 mmol, 1.1 eq) and 1-(1,3-dihydro-isobenzofuran-4-yl)-piperazine (0.204 g, 0.998 mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.433 g, 2.043 mmol, 1.84 eq). The slurry was allowed to stir overnight at room temperature (18 h). The mixture was diluted with EtOAc and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.064 g, 12%). CHN Found: C, 64.37; H, 6.54; N, 12.13. This calculates out for C24H28N4O3×0.74HCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:11]1[CH:12]=[C:13]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:15][CH:16]=1)=[O:10].N1C=CC=CC=1.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:11]1[CH:12]=[C:13]([N:17]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])[CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: COc1ccccc1S(=O)c1cccc(NCc2cccnc2)c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(S(=O)c2ccccc2OC)c1
Temperature: 0 °C
Yield: 8.4 %

Procedure:
N-(3-(2-Methoxyphenylsulfinyl)phenyl)pyrid-3-ylmethylamine (159 mg, 0.44 mmol) was taken up in 1,2-dichloroethane (2.0 ml) and anhydrous pyridine (1.0 ml) and cooled under nitrogen to 0° C. Ethanesulfonyl chloride (103 mg, 0.80 mmol) is added dropwise via syringe and the reaction allowed to stir at 0° C. for thirty minutes. The ice bath is removed and the mixture stirred 88 hours at room temperature, as a matter of convenience. Solid potassium carbonate was added, the reaction stirred an additional hour, and then filtered and concentrated to a dark oil. Radial silica gel chromatography (2 mm Chromatotron® plate, eluting with 20/1 methylene chloride/methanol) afforded the title compound (16 mg, 8%). 1H NMR(400 MHz): 1.39(3H,t,J=7.3), 3.04(2H,q,J=7.3), 3.78(3H,s), 4.88(2H,s), 6.86(1H,d,J=7.8), 7.11-7.21(2H,m), 7.25-7.30(1H,m), 7.35(1H,t,J=7.8), 7.42(1H,dt,J=7.3, 2.0), 7.56-7.62(2H,m), 7.68(1H,m), 7.81(1H,dd,J=7.3, 1.5), 8.31(1H,br s), 8.46(1H,br s); MS(HRMS)m/z 431.1116([M+H]+calcd for C21H23N2O4S 431.1099).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22](=O)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]([S@@:29]([NH2:31])=[O:30])([CH3:28])[CH3:27].C(Cl)Cl>[Cl-].[Na+].O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17](/[C:22](=[N:31]\[S@@:29]([C:26]([CH3:28])([CH3:27])[CH3:25])=[O:30])/[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(=O)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C/C(=N/[S@](=O)C(C)(C)C)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethanone (0.2227 g, 0.0006843 mol) and (s)-(−)-2-Methyl-2-propanesulfinamide (0.0829 g, 0.000684 mol) in Methylene chloride (1.4 mL, 0.021 mol) was added Ti(OEt)4 (0.488 mL, 0.00171 mol). The reaction was stirred at room temperature for 1 d. The mixture was then cooled to 0° C., added equal volume brine, filtrate through celite, and extracted with EtOAc. After died over Na2SO4, the residue was chromatographed 0-50% EA/HE gave product (132 mg, 45%). LCMS 2.39 min m/z 429.30 ([M+1], 100%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][CH2:17][O:18][CH3:19])=O.[CH:20]1([NH:23][C:24]2[S:25][CH2:26][C:27](=[O:29])[N:28]=2)[CH2:22][CH2:21]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:20]1([NH:23][C:24]2[S:25]/[C:26](=[CH:1]\[C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]4[O:15][CH2:16][CH2:17][O:18][CH3:19])/[C:27](=[O:29])[N:28]=2)[CH2:22][CH2:21]1
Reactant: O=C1CSC(NC2CC2)=N1
Reactant: COCCOc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCCOc1c(C#N)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-(2-methoxy-ethoxy)-quinoline-3-carbonitrile (example 77b), 2-cyclopropylamino-thiazol-4-one (example 37c), sodium acetate and acetic acid to give 6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(2-methoxy-ethoxy)-quinoline-3-carbonitrile. LC-MS m/e 395 (MH+).
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])/[CH:12]=[CH:13]\[C:14]([OH:16])=O)=[CH:6][CH:5]=1)(O)=O.[C:18]([O:21]C(=O)C)(=[O:20])C.C([O-])(=O)C.[Na+]>>[O:16]=[C:14]1[CH:13]=[CH:12][C:11](=[O:17])[N:10]1[C:7]1[C:6]([C:18]([OH:21])=[O:20])=[CH:5][CH:4]=[CH:9][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C(O)c1ccccc1N1C(=O)C=CC1=O
Temperature: 80 °C
Yield: 33 %

Procedure:
A mixture of N-(4-carboxyphenyl)maleamic acid (5.0 g, 21.2 mmol), acetic anhydride (4 ml, 42.5 mmol) and sodium acetate (3.48 g, 42.5 mmol) Was heated at 80° C. for 3h. After heating, excess acetic anhydride was removed under reduced pressure and the residue purified by column chromatography using 0-4%. MeOH/DCM as an eluent to give 3k (33%) as a solid.15 mp: 165-168° C.; 1H NMR (400 MHz, DMSO-d6): δ 7.20 (s, 2H), 7.47 (d, J=8.4 Hz, 2H), 8.02 (d, 8.0 Hz, 2H), 12.75 (brs, 1H); HRMS (m/z): [M−H]− calcd for C11H6NO4, 216.0302; found, 216.0296.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1>C(O)(=O)C>[C:22]([C:21]1[CH:25]=[CH:26][C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:19][CH:20]=1)([OH:24])=[O:23]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1

Procedure:
A solution of 10.8 g. (0.05 mole) of 2-phenacylcyclohexanone, 6.85 g. (0.05 mole) of p-aminobenzoic acid and 30 ml. of glacial acetic acid was heated under reflux for 5 hours and cooled. The solid which separated was collected and recrystallized from ethanol to provide 5.85 g. (37%) of pale yellow crystals, m.p. 244°-246°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:23])[CH:13]([OH:14])[CH:12]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:22])[CH:10]=2)[O:5]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1([CH3:23])[CH:13]([OH:14])[CH:12]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:22][C:24](=[O:26])[CH3:25])[CH:10]=2)[O:5]1
Reactant: COCC1(C)Oc2ccc(N)cc2C(n2ccccc2=O)C1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COCC1(C)Oc2ccc(NC(C)=O)cc2C(n2ccccc2=O)C1O
Reaction time: 24 h

Procedure:
A mixture of 1 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-amino-3-chromanol, 10 ml of acetic anhydride and 10 ml of pyridine is allowed to stand at 20° C. for 24 hours. The mixture is evaporated, worked up in the customary manner and 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-acetamido-3-chromanol is obtained.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17](O)[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH3:3])[C:4]([O:6][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7])=[O:5]
Reactant: CC(N)C(=O)O
Reactant: CCCCCCCCCCC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(C)N
Yield: 110.8 %

Procedure:
To a stirred solution of DL-alanine 1 (5 g, 56.1 mmol) in toluene (100 mL) was added dodecanol 2 (9.42 g, 50.5 mmol) in one lot, followed by pTSA (11.75 g, 61.7 mmol). After addition, the temperature of the reaction mixture was slowly raised to reflux temperature, the water was separated azeotropically, and the reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum, the obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude dodecyl 2-aminopropanoate 3 (14.4 g, yield: 100%) as a liquid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][C@@H:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:15]([CH2:26][CH2:27][C@@H](O[Si](C(C)(C)C)(C)C)CCCCC)[C@H:14]2[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([OH:49])[CH:44]=2)(=O)=O)=CC=1.[H-].[Na+].C([O:55][CH2:56][CH3:57])(=O)C>C1COCC1>[Si:19]([O:18][C@H:16]1[C@H:15]([CH2:26][CH2:27][C@@H:56]([O:55][Si:19]([C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:21])[CH3:20])[CH2:57][CH2:15][CH2:14][CH2:13][CH3:12])[C@H:14]2[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([OH:49])[C:44]=3[CH2:12][C@H:13]2[CH2:17]1)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:20])[CH3:21]
Reactant: CCOC(C)=O
Reactant: CCCCC[C@@H](CC[C@@H]1[C@@H](Cc2cccc(O)c2)[C@@H](COS(=O)(=O)c2ccc(C)cc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC[C@@H](CC[C@@H]1[C@H]2Cc3cccc(O)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A degassed solution of ((1S,2S,3R,4R)-2-(3-hydroxybenzyl)-4-(tert-butyldimethylsilyoxy)-3-((S)-3-(tert-butyldimethylsilyoxy)octyl)cyclopentyl)methyl 4-methylbenzenesulfonate (12.4 g, 0.017 mol) in anhydrous THF (250 ml) at 0° C. under nitrogen was treated with 60% sodium hydride (2.04 g, 0.051 mol). The resulting suspension was stirred for 4 hr at reflux. The reaction was then cooled to 10° C., diluted with ice cold brine (250 ml) and ethyl acetate (500 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield: 87%.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=[O:28])[CH2:26]Br)=[CH:23][CH:22]=1>ClCCl>[C:1]1([CH:7]2[N:12]([CH2:26][C:25]([C:24]3[CH:29]=[CH:30][C:21]([Cl:20])=[CH:22][CH:23]=3)=[O:28])[CH2:11][CH2:10][NH:9][C:8]2=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=C1NCCNC1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CN1CCNC(=O)C1c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A stirred mixture of 58.0 g (0.33 mol) of 3-phenyl-2-piperazinone, 85 g (0.62 mol) of blended potassium carbonate, and 76.9 g (0.33 mol) of 4-chlorophenacyl bromide in 400 ml of dichloromethane was heated at reflux for 12 hours. The mixture was cooled to ambient temperature, filtered, and the solid washed thoroughly with dichloromethane. The filtrate was concentrated to dryness, isopropanol added and stirred, the solid collected by filtration, washed thoroughly with isopropanol and dried in a vacuum oven at 50° C. to give 92.5 g (85 %) of 3-phenyl-4-(4-chlorophenacyl)-2-piperazinone. This material was used in Example 2 of the process. Pure material could be obtained by recrystallization from methanol to give a white solid (mp. 157°-158° C. dec.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]2([CH2:17][CH3:18])[CH2:15][CH3:16].CS(C1C=C(C=CC=1OC(F)(F)F)C[O:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]([C:39]2[CH:43]=[CH:42][O:41][N:40]=2)[CH2:35][C:36]([OH:38])=[O:37])=[CH:30][CH:29]=1)(=O)=O.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:15]([C:6]1([CH2:17][CH3:18])[C:5]2[CH:4]=[C:3]([CH2:2][O:27][C:28]3[CH:33]=[CH:32][C:31]([C@@H:34]([C:39]4[CH:43]=[CH:42][O:41][N:40]=4)[CH2:35][C:36]([OH:38])=[O:37])=[CH:30][CH:29]=3)[CH:12]=[CH:11][C:10]=2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7]1)[CH3:16]
Reactant: CS(=O)(=O)c1cc(COc2ccc([C@H](CC(=O)O)c3ccon3)cc2)ccc1OC(F)(F)F
Reactant: CCC1(CC)CCC(C)(C)c2ccc(CBr)cc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1(CC)CCC(C)(C)c2ccc(COc3ccc([C@H](CC(=O)O)c4ccon4)cc3)cc21

Procedure:
6-(Bromomethyl)-4,4-diethyl-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (44.2) Starting material 44.1 was prepared according to the published procedure of Kim, C. et al. (Tetrahedron. Lett. 1994, 35 (19), 3017-3020). A mixture of 44.1 (0.5 g, 2.17 mmol), NBS (0.58 g, 3.25 mmol), and dibenzoyl peroxide (53 mg) in CCl4 (10 mL) was heated at reflux for 5 hours. The reaction was cooled, and the precipitate was filtered out. The solvent was removed providing crude 44.2, which was used directly in the next step.
Reaction SMILES: [H-].[Na+].[Si]([CH:10]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:12]=2[O:11]1)(C(C)(C)C)(C)C.[CH3:23][O:24][C:25](=[O:28])[CH2:26]Cl.Cl>CN(C=O)C.O>[CH3:23][O:24][C:25](=[O:28])[CH2:26][N:14]1[C:13]2[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:12]=2[O:11][CH2:10][C:15]1=[O:16]
Reactant: COC(=O)CCl
Reactant: CC(C)(C)[Si](C)(C)C1Oc2ccc(CO)cc2NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)COc2ccc(CO)cc21
Temperature: 0 °C
Yield: 70.2 %

Procedure:
To a suspension of NaH (0.3 g, 0.01 mol) in dry DMF (15 mL) was added TBDMS-6-(hydroxymethyl)2H-1,4-benzoxazin-3(4H)-one (2 g, 0.0068 mol) at 0° C. with stirring and allowed to stir at RT for 2 h. The reaction mixture was cooled to 0° C., added methylchloroacetate (1 g, 0.0088 mol) and stirred at RT for 12 h. The reaction mixture was further cooled to 0° C., added 50 mL of 1.5N HCl solution and stirred at RT for 12 h. The reaction mixture was diluted with water (200 mL), extracted with ethylacetate (3×150 mL). The combined organic layer was washed with 10% aqueous NaHCO3 solution, brine and dried. The solvent was removed under vacuum and crude purified by column chromatography over silica gel (CHCl3/Methanol, 99.5:0.5) to give methyl-[6-(hydroxymethyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate (1.2 g, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=2[CH3:18])[O:3]1>CO>[CH3:18][C:10]1[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:19])([CH3:1])[O:3]2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:15]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Solvent: CO
Product: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 13 h
Yield: 109 %

Procedure:
A 500-mL round-bottomed flask equipped with a magnetic stirrer was charged with 4,4,5,5-Tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane 101e (8.44 g; 32.1 mmol) and methanol (150 mL). The reaction flask was twice evacuated and back-filled with argon. 10% Palladium on charcoal (50% wet, 425 mg dry weight) was then added to the solution, and the reaction flask evacuated and back-filled with hydrogen three times. The reaction was then stirred under balloon pressure of hydrogen at room temperature for 13 h. After this time, the flask was twice evacuated and back-filled with argon, then filtered through a pad of Celite 521 and the filtrate concentrated in vacuo. The resulting residue was dried under high vacuum for 1 d to afford a quantitative yield (8.16 g) of 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine 101f as a white solid: mp 110-112° C.; MS (ESI+) m/z 234 (M+H).