Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:9])([CH3:6])([CH3:5])[CH3:4].IC.[C:30](O)(=O)C>C1COCC1>[C:3]([O:7][C:8]([N:10]([CH3:30])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCOCCC(=O)O
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCOCCOCCOCCOCCC(=O)O)C(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
85.4 mg of NaH are added portionwise to a solution, cooled to 0° C., of 520 mg of 3-[2-(2-{2-[2-((tert-butoxycarbonyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]propanoic acid in 14 ml of THF. After stirring for 5 min, 150 μl of iodomethane are added. The mixture is then stirred at AT for 2 h and then an additional 150 μl of iodomethane are added. After 12 h at AT, the mixture is hydrolysed and then brought to acidic pH by addition of aqueous acetic acid at 0° C. The aqueous phase is extracted 3× with AcOEt, the combined organic phases are dried over MgSO4 and concentrated under RP, and the crude product obtained is reacted again according to the same protocol with 85 mg of NaH and 176 μl of iodomethane for an additional 2 h. 500 mg of 3-[2-(2-{2-[2-((tert-butoxycarbonyl)(methyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]propanoic acid are thus obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1Cl
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1Cl
Temperature: 78 °C
Yield: 65.3 %

Procedure:
5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.150 g, 0.380 mmol) and ethyl formate (0.090 mL, 1.12 mmol) were dissolved in anhydrous ethanol (4 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.7 mL, 1.9 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered and the solids were subsequently washed with 0° C. EtOH to afford the pure 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.105 g, 0.248 mmol, 65%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[CH:30]=1>CCOCC.CCCCCC.CCOCC.C(#N)C>[I:25][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[CH:30]=1
Reactant: II
Reactant: COC(=O)c1ccc(CO)cc1-c1ccccc1C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC#N
Product: COC(=O)c1ccc(CI)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
Triphenylphosphine (5.16 g), and imidazole (1.34 g) were dissolved in 3:1 ether:acetonitrile (80 mL), and the reaction was cooled to 0° C. Iodine (5.0 g) was added with vigorous stirring, and the reaction was warmed to ambient temperature. After 1 h, the reaction was recooled to 0° C. and 4-hydroxymethyl-2-(2-methylphenyl)benzoic acid, methyl ester (example 1178C, 4.6 g) was added as a solution in ether (20 mL). After 4 h at ambient temperature, the reaction was diluted with hexane/ether (1:1, 200 mL) and filtered. The filtrate was washed with a dilute solution of Na2SO3 until colorless, then with water (2×50 mL). The organic extracts were washed with brine (20 mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexane to give a light yellow oil (4.7 g) which slowly crystalizes in the freezer. 1H NMR (300 MHz, CDCl3) δ2.06 (s, 3H), 3.60 (s, 3H), 4.45 (ABq, JAB=9.7 Hz, ΔνAB=6.7 Hz, 2H), 7.03 (brd, J=6.6 Hz, 1H), 7.17-7.29 (m, 4H), 7.41 (dd, J=8.1, 1.6 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H)). MS(CI/NH3) m/e: (M+NH4)+ 384.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[N:6]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1)(O)=[O:2].S(Cl)([Cl:26])=O>>[ClH:26].[Cl:26][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[N:6]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1)=[O:2]
Reactant: Cc1ccc2c(c1)c(C(=O)O)cn2-c1ccnc2ccccc12
Reactant: O=S(Cl)Cl
Product: Cc1ccc2c(c1)c(C(=O)Cl)cn2-c1ccnc2ccccc12
Product: Cl

Procedure:
10 cm3 of thionyl chloride are added at 22° C. under an argon atmosphere to 1 g (3 mmol) of 3-carboxy-5-methyl-1-(quinol-4-yl)-1H-indole. After stirring at reflux for 2.5 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated twice with 5 cm3 of dimethoxyethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1 g of 3-chlorocarbonyl-5-methyl-1-(quinol-4-yl)-1H-indole hydrochloride in the form of a yellow solid which is used directly in the following step.
Reaction SMILES: [C:1](=[S:3])=S.[S-2].[Na+].[Na+].[CH:7]1([NH:13][C:14](=[O:17])[CH:15]=C)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl>CO.O>[CH:7]1([NH:13][C:14](=[O:17])[CH2:15][CH2:1][SH:3])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: S=C=S
Reactant: C=CC(=O)NC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: O=C(CCS)NC1CCCCC1
Yield: 100.3 %

Procedure:
Carbon disulfide (76 g) was added to a mixture of sodium sulfide (55 g) in methanol (80 g) and water (80 g) and kept at 20° C. To this was slowly added N-cyclohexylacrylamide (100 g) maintaining the pot temperature at 20°-30° C. The resulting solution was stirred for an additional 2-3 hour and neutralized with concentrated hydrochloric acid. The organic layer was separated, washed with water and evaporated to dryness to afford 122.6 g of N-cyclohexyl-3-mercaptopropionamide (90.5% yield).
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]([O:14][CH2:15][C:16]([OH:18])=O)=[O:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C([Cl:22])=O>>[C:1]([O:10][CH2:11][C:12]([O:14][CH2:15][C:16]([Cl:22])=[O:18])=[O:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)OCC(=O)OCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: CCCCCCCC(=O)OCC(=O)OCC(=O)Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5.6 g (0.022 mole) octanoyl-oxyacetyl-oxyacetic acid, 50 ml hexame were placed in a 250 ml round bottom flask. 2.9 ml (0.03 mole) oxalyl chloride was added in one portion and the reaction stirred at room temperature for 6 hours. The reaction was then heated to 80° C., a distillation head attached with condenser and receiver, and the excess oxalyl chloride and solvent removed at reduced pressure. There remained 4.5 g of light yellow oil. IR spectrum reveals no free -OH and a broad v-c=o absorbance, with maxima at 1815, 1780 and 1755 cm-1.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:25])([F:26])[F:16])=[CH:23][CH:22]=3)[CH:6]=[N:5]2)[C:29]([OH:28])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccc(C(F)(F)F)cc2)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 4-trifluoromethyl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(4-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid as a white solid (715.2 mg, 88% for the final step); ES+-HRMS m/e calcd for C19H19N2O4F3 [M+H+] 397.1370, found 397.1371. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.20 (m, 2H), 1.34-1.79 (m, 7H), 1.91-2.05 (m, 1H), 2.12-2.26 (m, 1H), 5.33 (dd, J=10.8, 4.2 Hz, 1H), 6.01 (d, J=2.9 Hz, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.14 (d, J=2.9 Hz, 1H), 13.03 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[Br:13]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>ClCCCl>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH3:10])[C:6]=2[C:11]=1[Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nsc2cc(F)c(N)cc12
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClCCCl
Product: Cc1nsc2cc(F)c(N)c(Br)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 5-amino-6-fluoro-3-methyl-1,2-benzisothiazole (0.600 g, 0.00329 mol) in 1,2-dichloroethane is added N-bromosuccinimide (0.586 g, 0.00329 mol) followed by 1,1'-azobis(cyclohexanecarbonitrile) (0.0200 9). The mixture is stirred two hours at 70° C., additional N-bromosuccinimide (0.240 g, 0.00135 mol) is added, and the mixture is stirred 40 minutes at 70° C. The mixture is then cooled to room temperature, filtered and concentrated in vacua to obtain a residue. The residue is chromatographed on silica gel to give the title compound (0.870 g, 100%) which is identified by NMR spectral analysis.
Reaction SMILES: [C:1](=[O:4])([O-:3])[NH2:2].[NH4+].[CH2:6]([O:16][CH2:17][CH:18]1[CH2:20][O:19]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CCCCCC.C(OC)(C)(C)C>CO>[CH2:6]([O:16][CH2:17][CH:18]([OH:19])[CH2:20][NH3+:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:6]([O:16][CH2:17][CH:18]([OH:19])[CH2:20][NH:2][C:1](=[O:3])[O-:4])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCOCC1CO1
Reactant: NC(=O)[O-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: CO
Product: CCCCCCCCCCOCC(O)CNC(=O)[O-]
Product: CCCCCCCCCCOCC(O)C[NH3+]
Temperature: 25 °C
Reaction time: 120 h

Procedure:
The ammonium carbamate prepared as described above was dissolved in anhydrous methanol (a total of 3.5 L) and transferred to a five liter three-necked round bottom flask equipped with thermometer and magnetic stirrer. (Decyloxy)methyloxirane (150 g, 0.7 mole) was added and the mixture was stirred at ambient temperature for five days, after which no more epoxide could be detected by TLC (silica gel, 4:1 hexane:methyl t-butyl ether, Rf =0.62). A small amount of precipitate was observed. The mixture was cooled to 5° C. and suction filtered on a coarse frit. After drying, 8.2 g of white solid was obtained. The methanol solution was evaporated to dryness on a rotary evaporator at about 5 mm Hg and a bath temperature of about 40° C. The crude substituted ammonium carbamate was obtained as a white solid (161 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2(C(OCC)=O)[NH:17][C:16]([CH3:18])=[CH:15][S:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-:24].[Na+].Cl.[CH2:27]([OH:29])C>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[S:14][C:15]([C:27]([OH:29])=[O:24])=[C:16]([CH3:18])[N:17]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C1(c2cc(OC)c(OC)c(OC)c2)NC(C)=CS1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: COc1cc(-c2nc(C)c(C(=O)O)s2)cc(OC)c1OC
Yield: 90 %

Procedure:
Ethyl 2-(3,4,5-trimethoxyphenyl)-4-methylthiazolecarboxylate (10.1 g corresponding to its 0.03mol), 150 ml of ethanol and 50 ml of an aqueous 10% solution of sodium hydroxide were heated for 1.5 hours under a reflux condenser. After condensing the reaction mixture to 40 ml and neutralizing the condensate with 6 N hydrochloric acid, the precipitate which separated was washed with water and recrystallized from an aqueous 50% ethanolic solution to obtain the product amounting to 8.3 g, consisting of faintly yellow needle-like crystals, melting at 205° to 207° C. at a yield of 90%.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:11]=[C:12]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:14][CH2:13]1.CI.[CH3:30]C(O)=O>C1COCC1>[CH3:30][C@H:13]1[C:12](=[O:11])[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:14]1
Reactant: CC(=O)O
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](C)C(=O)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
This compound is prepared as described by Gu et al, Tetrahedron Lett., 2003, 44, 3203-3205. Lithium hexamethyldisilazide in THF (1.0 M; 8.47 mL, 8.47 mmol) was added dropwise over 30 min. to a solution of 1-tert-butyl 2-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (2.0 g, 8.2 mmol) in THF (20 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 h. Methyl iodide (1.30 mL, 20.9 mmol) was then added dropwise over 10 min. After stirring at −78° C. for 2 h, the reaction mixture was allowed to warm to room temperature and stirred for 14 h. The reaction was then quenched by the addition of AcOH (1.00 mL, 17.6 mmol), and the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound (0.47 g, 22%). LCMS calc. for C12H19NNaO5 (M+Na)+: m/z=280.1. found 280.1. 1H NMR (CDCl3, 400 MHz) δ 4.57 (1H, dd, J=1.6 and 9.6 Hz), 3.77 (3H, s), 2.68 (1H, m), 2.27 (1H, m), 1.93 (1H, m), 1.49 (9H, s), 1.21 (3H, d, J=6.8 Hz) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:16][C:17]([NH2:19])=[S:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24](S(O)(=O)=O)=[CH:23][CH:22]=1.[C:32](O)(=O)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:16][C:17]2[S:18][C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:21][CH3:31])=[CH:32][N:19]=2)[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1cc(NC(N)=S)cc(C(C)(C)C)c1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCCCc1cnc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Temperature: 90 °C

Procedure:
3,5-Di-tert-butyl-4-hydroxyphenylthiourea (2.00 g), 1.81 g of α-bromooctylaldehyde dimethyl acetal and 0.06 g of p-toluenesulfonic acid monohydrate were dissolved in 12 ml of acetic acid, and the solution was heated at 90° C. for 1 hour. The reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution was added, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. Purification of the crude product by silica gel column chromatography (diethyl ether-hexane=1:3) gave 1.56 g of the desired compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N(CC)(CC)CC.Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].O>C(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[CH2:16][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: COC(=O)CBr
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
Treat a 0° C. solution of 4-hydroxy-piperidine (20.0 g, 0.19 mol) and (CH3CH2)3N (24.0 g, 0.24 mol) in CH2Cl2 (200 mL) with methyl bromoacetate (30.21 g, 0.197 mol), warm to room temperature, and stir 2 hours at room temperature under N2. Dilute the reaction with water and extract with 3:1 chloroform:isopropanol. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 5% methanol in CH2Cl2 to afford 20.13 g (59%) of the titled product. Rf=0.13 (9/1 CH2Cl2/methanol). ES MS (m/z): 174 (M+).
Reaction SMILES: [C:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:18])[CH2:15][C:16]#[N:17])[CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]=[C:30](Cl)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:18])[C:15](=[C:30]([NH:29][S:26]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:16]#[N:17])[CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Oc1cccc(NC(=O)CC#N)c1
Reactant: Cc1ccc(S(=O)(=O)N=C(Cl)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1cccc(NC(=O)C(C#N)=C(NS(=O)(=O)c2ccc(C)cc2)c2ccccc2)c1
Reaction time: 1 h

Procedure:
To a mixture of 4.89 g (20 mmol) of 3-(2-cyanoacetamido)phenyl methacrylate, 5.88 g (20 mmol) of N-(4-methylphenylsulfonyl)benzenecarboximidoyl chloride and 200 ml of methylene chloride was added dropwise 4.05 g (40 mmol) of triethylamine with 10 ml of methylene chloride rinse. The resultant solution was stirred for 1 hr and washed twice with 10% HCl and once with water. The solution was dried over magnesium sulfate and concentrated after adding t-butylpyrocatechol inhibitor. The solid residue was treated with ligroine, collected and recrystallized from ethanol.
Reaction SMILES: C(OC1C=CC=CC=1C([NH:10][CH:11]([CH3:25])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1)=O)CCC.N1CCOCC1.[S].Cl>>[NH2:10][CH:11]([CH3:25])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1
Reactant: CCCCOc1ccccc1C(=O)NC(C)Cc1ccc(CC(=O)OCC)cc1
Agent: Cl
Agent: [S]
Solvent: C1COCCN1
Product: CC(N)Cc1ccc(CC(=O)O)cc1

Procedure:
The preparation of the ethyl 4-(2-aminopropyl)phenylacetate used as starting material is carried out in the following manner: 4-(2-acetamidopropyl)-acetophenone (m.p. 99°-100° C.) is reacted with morpholine and sulfur to give the thiomorpholide of 4-(2-acetamidopropyl)-phenyl-acid acid (m.p. 147° C.). By boiling with 6 N hydrochloric acid, there is obtained 4-(2-aminopropyl)-phenylacetic acid (oily), which is esterified with hydrogen chloride and ethanol. By treating the initially formed hydrochloride with dilute aqueous sodium hydroxide solution, there is obtained the free amino compound in the form of an oil.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](SC)=[CH:26][CH:25]=3)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].O.O[O:34][S:35]([O-:37])=O.[K+].O1CCC[CH2:40]1>CO>[CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([S:35]([CH3:40])(=[O:37])=[O:34])=[CH:26][CH:25]=3)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CSc1ccc(-c2cccc(-n3cc(C(=O)NC(C)C)c(=O)c4cccnc43)c2)cc1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)NC(=O)c1cn(-c2cccc(-c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of N-isopropyl-1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 22 in tetrahydrofuran (24 ml/mmol), methanol (12 ml/mmol), and water (12 ml/mmol), was added oxone (2.24 eq) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with 30% ether in methylene chloride to afford the title compound as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH:11]([CH2:23][CH3:24])[CH:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[OH:13].[C:25]([O:29][C:30](=[O:32])N)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30](=[O:32])[NH:10][CH:11]([CH:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[OH:13])[CH2:23][CH3:24])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCC(N)C(O)c1nc2ccccc2o1
Reactant: CC(C)(C)OC(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(NC(=O)OC(C)(C)C)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DIPEA (0.35 ml, 2 mmol) and di-tret-butyl dicarbonate (355 mg, 1.63 mmol) were added to a solution of 2-Amino-1-benzooxazol-2-yl-butan-1-ol (320 mg, 1.55 mmol) in dry methylene chloride (10 ml) and stirred at room temperature for 4 hrs. The reaction was quenched with saturated aqueous NH4Cl and the pH was adjusted to neutral. Oraganic layer separated and the aqueous layer extracted with methylene chloride. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give, 1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid tert-butyl ester (500 mg).
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[CH3:29]>>[NH2:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:14]([C:10]2[CH:9]=[C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH3:17])[N:13]=[CH:12][N:11]=2)=[O:16])=[C:20]([CH3:29])[CH:21]=1)(=[O:26])=[O:27]
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(N(C)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 4-amino-3-methyl-benzenesulfonamide (Biofine), the title compound was obtained as a white solid after purification by preparative HPLC.