Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24]C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:26]>C1COCC1.[OH-].[NH4+]>[CH:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCCC1
Temperature: 35 °C
Yield: 70 %

Procedure:
A solution of 9-[(cyclohexyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (205 mg, 0.608 mmol) in 5 mL of THF and 20 mL of concentrated aqueous ammonium hydroxide was treated with a stream of NH3 gas to ensure saturation. The reaction vessel was capped, and the mixture was heated at 35° C. with stirring until tlc indicated complete consumption of starting material (20 hrs). The THF was evaporated, and the aqueous layer was filtered. The green solid precipitate was dissolved in THF and purified by radial chromatography on silica gel (elution with CH2Cl2). The resultant foam was triturated with ether to afford 138 mg (70%) of the title compound as an off-white solid. IR (KBr, cm−1) 3418, 3200, 3131, 1629, 1600, 1443, 1261, 778. 'FAB HRMS m/e, Calcd for C20H23N2O2: 323.1760. Found: 323.1760 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[NH:14][C:13](=O)[C:12]=2[CH2:11][CH2:10]1.[CH2:29]([N:31](CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[C:15]=3[N:14]=[C:13]([NH:31][CH3:29])[C:12]=2[CH2:11][CH2:10]1
Reactant: CCN(CC)CC
Reactant: Cc1cc(O)ccc1N1CCc2c1c1cccc(OCC(F)(F)F)c1[nH]c2=O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1CCN2c1ccc(O)cc1C
Temperature: -10 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
1-(2-Methyl-4-hydroxyphenyl)-4-oxo-6-β,β,β-trifluoroethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline (2.5 g, 6.4 mmol) was dissolved in dichloromethane, triethylamine(2.2 ml, 16.0 mmol), and methanesulfonyl chloride(1.1 ml, 13.5 mmol) was added at -78° C. The reaction mixture was stirred for 3 hours, then slowly warmed up to -10° C., and stirred for 1 hours. The reaction mixture was extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized in dichloromethane/hexane to obtain 2.3 g of desired compound as solid in 75% of yield.
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6](=[S:9])SC)([OH:3])=[O:2].[N-:10]=[N+:11]=[N-:12].[Na+]>O>[C:1]([CH2:4][N:5]1[C:6]([SH:9])=[N:12][N:11]=[N:10]1)([OH:3])=[O:2]
Reactant: CSC(=S)NCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cn1nnnc1S

Procedure:
A mixture of 16.5 g. (0.1 mol.) of methyl carboxymethyldithiocarbamate and 14.3 g. (0.22 mol.) of sodium azide in 150 ml. of water was heated at 56° for 12 hours. The reaction mixture was extracted with ether, then acidified to pH 1.5 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated to dryness to give 1-carboxymethyl-tetrazole-5-thiol, m.p. 178°-179°.
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[N:28][CH:29]=2)[N:14]=1)[CH3:4]>CN(C=O)C.CCN(CC)CC.[Pd]>[NH2:1][C:2](=[O:43])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[N:28][CH:29]=2)[N:14]=1)[CH3:4]
Reactant: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Reaction time: 112 h

Procedure:
A mixture of tert-Butyl 4-(5-((4-((2-(1-amino-1-oxopropan-2-yl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A71 (0.139 g, 0.234 mmol) and 10% Pd/C (0.156 g) in DMF (3.0 mL) and Et3N (0.30 mL) was stirred under a hydrogen atmosphere for 112 hours. The mixture was filtered through Celite and concentrated under reduced pressure before being purified using silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., 0-20% MeOH in EtOAc) to give the title compound A72 (0.060 g, 42%). LCMS-D: rt 3.568 min; m/z 599.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[C:18]([CH3:30])[CH:17]=1)=O.[NH2:32][C:33]([NH2:35])=[O:34].[ClH:36].O1CCOCC1>C(O)C>[ClH:36].[OH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[CH:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH2:3][O:2][CH3:1])[NH:35][C:33](=[O:34])[N:32]=2)=[CH:17][C:18]=1[CH3:30]
Reactant: NC(N)=O
Reactant: COCCOc1ccccc1C(=O)CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COCCOc1ccccc1-c1cc(-c2ccc(O)c(C)c2)nc(=O)[nH]1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 1-(2-{[2-(methyloxy)ethyl]oxy}phenyl)-3-{3-methyl-4-[(phenylmethyl)oxy]phenyl}propane-1,3-dione (0.24 g, 0.56 mmol), urea (0.34 g, 5.6 mmol), 4.0M hydrochloric acid in dioxane (1.4 mL, 5.6 mmol) in ethanol (2 mL) was heated in a 110° C. oil bath for 12 h. The solution was allowed to cool to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate (10% methanol) and aqueous saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This crude mixture was taken up in 2.0 mL trifluoroacetic acid and heated in an 80° C. oil bath for 1 hour then concentrated. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% trifluoroacetic acid), followed by concentration in vacuo, treatment with methanol and 4.0 M hydrochloric acid in dioxane, and lyophilization gave the title compound 4-(4-hydroxy-3-methylphenyl)-6-(2-{[2-(methyloxy)ethyl]oxy}phenyl)pyrimidin-2(1H)-one hydrochloride (0.037 g, 19%). 1H NMR (400 MHz, d6-DMSO): 11.07 (s, 1H), 8.01 (d, 1H), 7.92 (dd, 1H), 7.74 (dd, 1H), 7.63 (dt, 1H), 7.47 (s, 1H), 7.29 (d, 1H), 7.19 (dt, 1H), 7.10 (d, 1H), 4.29 (m, 2H), 3.71 (m, 2H), 3.27 (s, 3H), 2.20 (s, 3H). MS (EI) for C20H20N2O4: 352 (MH+).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:10]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:6])[OH:3])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CCCCCO
Product: CCCCCOC(=O)CC(O)C(=O)OCCCCC
Temperature: 115 °C

Procedure:
Dipentyl-DL-malate was prepared using a procedure similar to that in Example 4. To the reaction flask, DL-malic acid (100.43 g), 1-pentanol (325 mL) and Amberlyst®15 ion exchange resin (14.2 g) were added. The mixture was placed under nitrogen and heated to reflux. At 108° C., two phases started to collect in the Dean-Stark trap. The reaction was maintained at 110-120° C. for 4 hr 15 min and water was continuously removed. The product was separated from the catalyst via filtration over silica using 300 mL diethyl ether. The organic layer was washed 4 times with saturated sodium bicarbonate, washed once with water, and dried over magnesium sulfate. Diethyl ether was removed via rotary evaporation. Dipentyl-DL-malate was obtained as a low viscosity, slightly hazy, very light yellow liquid with a slight pleasant odor (116.5 g, 55.6% yield) after pumping on the sample in vacuo to remove residual 1-pentanol.
Reaction SMILES: [NH2:1]/[C:2](/[CH2:10][F:11])=[C:3](/[F:9])\[C:4](OCC)=[O:5].[Cl:12][C:13]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:16]([N:23]=[C:24]=[O:25])=[C:15]([F:26])[CH:14]=1>>[Cl:12][C:13]1[C:18]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:17][C:16]([N:23]2[C:4](=[O:5])[C:3]([F:9])=[C:2]([CH2:10][F:11])[NH:1][C:24]2=[O:25])=[C:15]([F:26])[CH:14]=1
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C(F)=C(\N)CF
Product: CC(C)Oc1cc(-n2c(=O)[nH]c(CF)c(F)c2=O)c(F)cc1Cl

Procedure:
using ethyl 3-amino-2,4-difluorocrotonate and 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-fluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 152°-154° C.;
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([OH:14])=[O:13])[NH:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>[OH-].[Na+]>[C:15]([N:3]1[CH:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1Cc2ccccc2CN1C(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
This compound was prepared according to Hein et. al., J. Amer. Chem. Soc.; 1962, 84, 4487-4494, incorporated by reference herein in its entirety. Thus, a slurry of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride (20.3 g, 95 mmol) in 2N NaOH (150 ml) was treated with benzoyl chloride (13.4 ml, 114 mmol) dropwise over 30 minutes. The mixture was stirred a further 1.5 hours, acidified to pH 2-3 (4N HCl), and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 16.4 g (61) of the title compound following recrystallization (acetone/water); MS: 280 m/z (M-H)-.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-])=O)[C:7]=1[OH:16])(=[O:5])=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:16])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a solution of N,N-dimethyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (2.3 g, 8.2 mmol) in ethyl acetate, was added 10% Pd/C (2.0 g). The mixture was flushed with argon, and then stirred under a hydrogen atmosphere at balloon pressure for 3 hours at room temperature. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated to give the desired product (2.0 g, 97%). EI-MS (m/z) 249.5 (M−).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([F:19])[CH:10]=1.[CH3:20]O>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:20])=[O:17])=[C:11]([F:19])[CH:10]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(Br)cc1F
Yield: 91 %

Procedure:
Trimethylsilyl diazomethane (11.6 mL of 2 M in toluene, 23.2 mmol) was added dropwise to a solution of 2-(4-bromo-2-fluoro-phenyl)acetic acid (4.5 g, 19.3 mmol) in a mixture of toluene (7.65 mL)/methanol (7.65 mL) under a nitrogen atmosphere at room temperature. The reaction mixture was then quenched with a few drops of acetic acid and the solvents were concentrated in vacuo. The residue was purified by silica gel column chromatography using 0-10% EtOAc-hexanes as eluent to yield methyl 2-(4-bromo-2-fluoro-phenyl)acetate (4.3 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.28-7.22 (m, 2H), 7.15 (t, J=8.0 Hz, 1H), 3.71 (s, 3H), 3.63 (d, J=1.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7][C@H:6]1[CH:13]=[CH2:14])C=C>C(Cl)Cl>[CH3:12][C:8]1([CH3:11])[O:7][C@H:6]2[CH:13]=[CH:14][CH2:1][O:4][C@H:5]2[CH2:10][O:9]1
Reactant: C=CCO[C@H]1COC(C)(C)O[C@H]1C=C
Solvent: ClCCl
Product: CC1(C)OC[C@@H]2OCC=C[C@@H]2O1
Temperature: 25 °C

Procedure:
To a solution of cis-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane (300 mg, 1.52 mmol) in dry CH2Cl2 (10 mL) was added bis-(tricyclohexylphosphine)benzylidine ruthenium (IV) chloride (120 mg, 0.14 mmol). The mixture was stirred at ambient temperature for ca. 8 H, filtered through filter paper and concentrated in vacuo to 1 mL. The residue was purified by flash chromatography with 15% EtOAc-hexane
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f19) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[NH:6][CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11]CC)=O)([O-:3])=[O:2].C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH2:17]([O:16][C:14]([CH:8]1[C:9](=[O:11])[C:19]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:22]=[CH:21][CH:20]=2)[N:6]=[CH:7]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C(=CNc1ccccc1[N+](=O)[O-])C(=O)OCC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1C=Nc2c(cccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
Diethyl (2-nitroanilino)methylenemalonate (43 g) was added to refluxing diphenyl ether (600 ml). The mixture was stirred at reflux for 1.5 hours, then cooled to ambient temperature. Diethyl ether (600 ml) was added and the mixture filtered. The solid so obtained was washed with diethyl ether to give 3-ethoxycarbonyl-8-nitro-4-oxo-3,4-dihydroquinoline in 85% yield, mp 241-243° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8](=[O:24])[C@@H:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6])[CH:2]=[CH2:3].B.C(=O)(O)[O-:27].[Na+].OO>O1CCCC1.C(O)C>[CH:11]1([CH2:10][C@H:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:7][C:5]([NH:4][CH2:1][CH:2]([OH:27])[CH3:3])=[O:6])=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C([O-])O
Reactant: C=CCNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)CNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 11 %

Procedure:
A solution of 1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-urea (prepared in Example 24, 765 mg, 2.07 mmol) in tetrahydrofuran (50 mL) cooled to 0° C. was treated with a 1.0M borane solution in tetrahydrofuran (4.14 mL, 4.14 mmol). The reaction was allowed to warm from 0° C. to 25° C. over 1 h. At this time, the reaction was re-cooled to 0° C. and treated with ethanol (15 mL) followed by a mixture of a saturated aqueous sodium bicarbonate solution (45 mL) and hydrogen peroxide (15 mL). The resulting mixture was allowed to warm from 0° C. to 25° C. over 1 h. The reaction was then slowly quenched with a saturated aqueous sodium sulfite solution and then extracted with ethyl acetate (3×30 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-(2-hydroxy-propyl)-urea (103 mg, 11%) as a white foam: [α]23589=−33.0° (c=0.094, chloroform); EI-HRMS m/e calcd for C18H24Cl2N2O3 (M+) 386.1164, found 386.1151.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33](=[O:56])[C@@H:34]([NH:43][C:44]([C:46]2[NH:55][C:49]3=[CH:50][N:51]=[C:52]([Cl:54])[CH:53]=[C:48]3[CH:47]=2)=[O:45])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([NH:26][CH:27]1[CH2:28][CH2:29][N:30]([C:33](=[O:56])[C@@H:34]([NH:43][C:44]([C:46]2[NH:55][C:49]3=[CH:50][N:51]=[C:52]([Cl:54])[CH:53]=[C:48]3[CH:47]=2)=[O:45])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:31][CH2:32]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of acetic acid (7.5 μL, 0.13 mmol) in DMF (5 mL) was added EDCI (33 mg, 0.17 mmol), HOBt (19.5 mg, 0.14 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [2-(4-aminopiperidin-1-yl)-1(S)-(4-fluorobenzyl)-2-oxoethyl]amide (EXAMPLE 180, 70 mg, 0.16 mmol) and DIPEA (57 μL, 0.33 mmol), and the reaction stirred at rt for 16 h. Solvent was removed in vacuo then crude material partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was washed with NaHCO3 (2×20 mL) and brine (2×30 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography using dichloromethane/methanol (95:5) as the eluent gave the title compound as an off-white powder. m/z (ES+)=486.27 [M+H]+; RT=3.16 min.
Reaction SMILES: COCCOCCOC.N.[C:11](#[N:20])[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[H][H]>O>[C:12]1([CH2:11][NH2:20])[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C#N)cc1
Agent: N
Solvent: COCCOCCOC
Solvent: O
Product: NCc1ccc(CN)cc1
Temperature: 125 °C

Procedure:
A stirred autoclave is charged with 900 ml. of diethylene glycol dimethyl ether (Diglyme), 100 ml. ammonia, 100 g. terephthalonitrile (TPN) and the desired amount of catalyst and 100 ml of water. The autoclave is heated to 125° C. Hydrogen is introduced rapidly until the selected pressure is reached. The absorption of hydrogen starts immediately and additional hydrogen is added to keep the pressure at the selected level. The course of the reaction is monitored by measuring the volume of hydrogen consumed and by periodic withdrawal of a small sample of the reaction mixture for analysis. When the analysis indicates that all of the terephthalonitrile is reacted, the agitation is stopped and the reactor is cooled rapidly and vented. The reaction mixture is filtered to recover the catalyst and then is flash evaporated to remove solvent. The residual oil is distilled at about 100° C. and 0.5 mm Hg. to give practically pure p-xylylene diamine. A small amount of high boiling residue remains in the distillation pot.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([O:10][CH2:11][CH:12]=[CH2:13])[CH:6]([OH:9])[CH:7]=[CH2:8])[CH3:2].[CH3:15][C:16](OC(C)=O)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCN(CC)CC.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([O:10][CH2:11][CH:12]=[CH2:13])[CH:6]([O:9][C:16](=[O:17])[CH3:15])[CH:7]=[CH2:8])[CH3:2]
Reactant: C=CCOC(C(=O)OCC)C(O)C=C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(C(=O)OCC)C(C=C)OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of 2-allyloxy-3-hydroxy-pent-4-enoic acid ethyl ester (100 mg, 0.5 mmol) and DMAP (30 mg, 0.25 mmol) in CH2Cl2-Et3N (9:1, 10 mL) was added Ac2O (76 mg, 0.75 mmol). The resulting solution was stirred at ambient temperature for 1H. The solution was diluted with CH2Cl2 (40 mL), washed with H2O (20 mL×2), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.N([O-])=[O:35].[Na+]>CC(O)=O.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C@:19]2([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([OH:35])[N:7]=4)=[CH:13][CH:12]=3)[CH3:15])[CH2:21][CH2:20]2)=[CH:27][CH:28]=1
Reactant: O=N[O-]
Reactant: C[C@@H](c1ccc(-c2ccnc(N)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](c1ccc(-c2ccnc(O)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 8 %

Procedure:
To a solution of (R)-3-((S)-1-(4-(2-aminopyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (40 mg, 0.089 mmol) in CH3COOH (0.3 mL) and H2O (0.13 mL) was added an aqueous solution of NaNO2 (2 mol/L, 0.5 mL) dropwise at 0° C. The reaction was stirred for 10 min at this temperature before heating at 60° C. for 3 h. After the mixture was evaporated to dryness, the mixture was adjusted pH 9 with aqueous NaHCO3 solution. The mixture was extracted with EtOAc, and the organic layer was dried and concentrated to give the residue, which was purified by preparative TLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-hydroxypyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one (3.18 mg, 8%). LC-MS Method 2 tR=0.87 min, m/z=452. 1H NMR (CD3OD): 1.19-1.23 (m, 2H), 1.48 (d, 3H), 1.82-1.86 (m, 2H), 2.05-2.41 (m, 3H), 3.01-3.10 (m, 1H), 3.37 (t, 2H), 5.50 (q, 1H), 6.90 (d, 1H), 6.95-7.02 (m, 4H), 7.18-7.22 (m, 2H), 7.00-7.05 (m, 3H), 7.21-7.24 (m, 2H), 7.80 (d, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:10])[O:6][C:7]=1[CH2:8][Br:9].[CH:11]([O-:13])=[O:12].[K+]>C(#N)C>[Br:9][CH2:8][C:7]1[O:6][C:5](=[O:10])[O:4][C:3]=1[CH2:2][O:13][CH:11]=[O:12]
Reactant: O=c1oc(CBr)c(CBr)o1
Reactant: O=C[O-]
Agent: [K+]
Solvent: CC#N
Product: O=COCc1oc(=O)oc1CBr
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
4,5-Dibromomethyl-2-oxo-1,3-dioxolene (150 mg, 0.55 mmol) was dissolved in acetonitrile (4.0 mL). Potassium formate (46 mg, 0.55 mmol) was added thereto. This mixture was stirred at 25° C. for 5 hours. Through the ordinary post-treatment, crude Compound S-30 (85 mg, yield 65%) was obtained.
Reaction SMILES: O[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(O)=O>[C:24]1([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NS(=O)(=O)c1ccc(CCN2C(=O)c3ccccc3C2(O)c2ccccc2)cc1
Solvent: O=CO
Product: NS(=O)(=O)c1ccc(CCN2C(=O)c3ccccc3C2c2ccccc2)cc1

Procedure:
12 parts of para-[β-(2,3-dihydro-3-hydroxy-3-phenyl-(1H)-isoindol-1-on-2-yl)ethyl]benzenesulphonamide are refluxed for 7 hours with 120 parts of 98% formic acid. After concentration in vacuo, the residue is recrystallized in 110 parts of ethyl acetate to give 8 parts of the desired product, m.p.: 218° C.