Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:15])=[CH:10][CH:9]=1.[OH:21]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:17][C:18]([OH:20])=[O:19])=[O:21])[CH3:15])=[CH:10][CH:9]=1
Reactant: OO
Reactant: CC(SCC(=O)O)c1ccc(-c2ccccc2Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(c1ccc(-c2ccccc2Cl)cc1)S(=O)CC(=O)O
Reaction time: 8 h

Procedure:
50 gm (0.163 mol) of [1-(2'-chloro-4-biphenylyl)-ethylthio]-acetic acid were suspended in 163 ml of glacial acetic acid and 16.0 gm (0.171 mol) of 36.3% hydrogen peroxide were added dropwise to the suspension at 10° C. while vigorously stirring. Afterwards, the mixture was allowed to stand overnight at room temperature, during which time the starting compound dissolved. Subsequently, 500 ml of water were added, the reaction product was extracted with ethyl acetate, and the organic solvent was removed from the extract in vacuo, leaving 45.1 gm (85% of theory) of the title compound, m.p. 144°-147° C. (from ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.ClCCCl>[CH2:1]([O:3][C:4]([CH:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:9][CH2:8][N:7]1[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1NCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1c2[nH]c3ccccc3c2CCN1C(=O)c1ccc(F)cc1
Temperature: 55 °C
Reaction time: 17 h
Yield: 93.4 %

Procedure:
The title compound was prepared by the addition of 2,3,4,9-tetrahydro-1H-betacarboline-1-carboxylic acid ethyl ester (102 mg, 418 μmol), DCE (5 mL), 4-fluorobenzoyl chloride (60 μL, 477 μmol), diisopropyl ethylamine (167 μL, 954 μmol), DMAP (6 mg, 10 mol %) to a 25 mL flask. The solution was allowed to stir at 55° C. under N2 for 17 hours. The solution was concentrated under reduced pressure, and the crude material was chromatographed (SiO2, 100% hexane to 25% EtOAc) to provide 143 mg (63% yield) of title compound; 1H NMR (CDCl3) δ 8.40 (1H, br s), 7.53-7.57 (3H, m), 7.41 (1H, d), 7.10-7.23 (4H, m), 6.19 (1H, s), 4.31 (2H, m), 4.10 (1H, dd), 3.63 (1H, m), 2.87-2.96 (1H, m), 2.78 (1H, dd), 1.36 (3H, t); 13C NMR (CDCl3) 6171, 169, 138, 130, 129, 126, 126, 123, 120, 116, 116, 112, 110, 62, 53, 45, 22, 14; MS (ESI): 367 (MH+).
Reaction SMILES: [SH:1][C:2]([CH3:14])([CH3:13])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]([CH3:12])([SH:11])[CH3:10].N.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CO>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][S:1][C:2]([CH3:14])([CH3:13])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]([CH3:12])([S:11][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH3:10])=[CH:20][CH:19]=1
Reactant: CC(C)(S)CNCCNCC(C)(C)S
Reactant: COc1ccc(CCl)cc1
Agent: N
Solvent: CO
Product: COc1ccc(CSC(C)(C)CNCCNCC(C)(C)SCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A solution of N,N′-bis(2-mercapto-2-methylpropyl)ethylenediamine (11.23 g, 47.5 mmol; see, DiZio et al., 1991, Bioconjugate Chem 2: 353 and Corbin et al., 1976, J. Org. Chem. 41: 489) in methanol (500 mL) was cooled in ice/water bath and then saturated with gaseous ammonia over 45 min. To this was added 4-methoxybenzyl chloride (17.0 mL, 125 mmol, 264 mol %). The reaction was allowed to warm to room temperature overnight with stirring under argon. The solution was concentrated to a paste and then partitioned between diethyl ether (150 mL) and 0.5 M KOH (200 mL). The aqueous layer was further extracted with diethyl ether (2×50 mL). The combined organic layers were washed with NaCl solution and concentrated to a clear colorless oil. The oil dissolved in diethyl ether (200 mL) and then acidified with 4.0 M HCl in dioxane until no further precipitation was seen. The white precipitate was collected by filtration and washed with diethyl ether. The white solid was recrystallized from hot water at a pH of ˜2. The product was collected by filtration to afford 29.94 g as a mix of mono- and di-HCl salts. The HCI salts were partitioned between 1 M KOH (100 mL) and ethyl acetate (100 nmL). The aqueous was extracted with ethyl acetate (2×30 mL) and the combined organic layers were washed with NaCl solution, dried with Na2SO4 and concentrated to give pure product as the free base as a light yellow oil (18.53 g, 82% yield). Nuclear magnetic resonance characterization experiments yielded the following molecular signature:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[NH2:15].[CH:16]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1.O>C(#N)C>[CH:16]1([CH2:21][C:22]([NH:15][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:5][C:4]=2[CH3:14])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(N2CCOCC2)cc(C)c1N
Reactant: O=C(Cl)CC1CCCC1
Solvent: O
Solvent: CC#N
Product: Cc1cc(N2CCOCC2)cc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 20 %

Procedure:
2,6-Dimethyl-4-morpholin-4-yl-phenylamine (0.50 g) and cyclopentylacetyl chloride (0.53 mL) were dissolved in acetonitrile (5 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. Water (25 mL) was added and the product was extracted with ethyl acetate (3×25 mL). The organic phases were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 0.138 g (20%) of the title compound as an off-white solid. LC-MS-TOF (m/z) 317 (MH+); tR=1.93, (UV, ELSD) 95%, 100%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1.52 (m, 2H), 1.61 (m, 2H), 1.76 (m, 2H), 2.07 (s, 6H), 2.11 (m, 1H), 2.25 (d, 2H), 3.05 (dd, 4H), 3.71 (dd, 4H), 6.63 (s, 2H), 8.94 (s, 1H).
Reaction SMILES: C(OP([C:9]([O:25][CH3:26])([O:23][CH3:24])[CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(OCC)=O)C.[Li]CCCC.CCCCCC.[C:38]1([CH3:58])[CH:43]=[CH:42][C:41]([C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[C:51]([CH:54]=O)[CH:52]=3)[C:47]([CH3:57])([CH3:56])[CH2:46][CH:45]=2)=[CH:40][CH:39]=1>C1COCC1>[CH3:26][O:25][CH:9]([O:23][CH3:24])[CH2:10]/[C:11](/[C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1)=[CH:54]\[C:51]1[CH:52]=[C:53]2[C:48]([C:47]([CH3:57])([CH3:56])[CH2:46][CH:45]=[C:44]2[C:41]2[CH:40]=[CH:39][C:38]([CH3:58])=[CH:43][CH:42]=2)=[CH:49][CH:50]=1
Reactant: CCOC(=O)c1ccc(CCC(OC)(OC)P(=O)(OCC)OCC)cc1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C(=C/c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)CC(OC)OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (-78° C.) solution of ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 350 mg, 0.9 mmol, available in accordance with EPO Application No. 0 210 929 published on Feb. 4, 1987), in THF (9 mL), was added n-BuLi in hexane (1.6M solution, 0.7 mL, 1.1 mmol). The mixture was stirred for 1.5 hours. To this solution 1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde (Compound C, 200 mg, 0.72 mmol), in THF (1 mL) was added and the mixture was gradually warmed to ambient temperature (4 h). The reaction was quenched by adding water (5 mL), and extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine (10 mL), dried with MgSO4 and the solvent was removed by distillation. The crude material was purified by silicagel chromatography to afford the title compound as a colorless off.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][S:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1
Reactant: OCCO
Reactant: CSCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CSCCC1OCCO1

Procedure:
A solution of 3-(methylthio)propanal (5.2 g, 0.05 mol) and ethyleneglycol (3.4 g. 0.055 mol) in 100 mL of benzene was treated with 300 mg p-toluenesulfonic acid and heated at reflux for 4 hrs. The solution was cooled and decanted. Concentration and drying in vacuo provided the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm:4.93 (1H, t, J=0.76 Hz) 3.74-4.03 (4H, m) 2.46-2.68 (2H, m) 2.08 (3H, s) 1.83-2.00 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][CH2:11][CH2:12][OH:13])=[C:4]([N+:14]([O-])=O)[CH:3]=1.[H][H]>[Ni].CO>[ClH:1].[NH2:14][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCO
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cl
Product: Nc1cc(Cl)c(Cl)cc1NCCCO

Procedure:
A mixture of 39.7 parts of 3[(4,5-dichloro-2-nitrophenyl)amino]-1-propanol and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off. The filtrate is acidified with 24 parts of a hydrochloric acid solution while stirring. The solvent is evaporated and the solid residue is stirred in 2-propanol. The product is filtered off and dried in vacuo, yielding 31.5 parts of 3-[(2-amino-4,5-dichlorophenyl)amino]-1-propanol hydrochloride; mp. 185° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][C:10]1[CH:15]=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=1.I[C:26]1[CH:39]=[N:38][C:29]2[NH:30][C:31]3[CH:36]=[N:35][C:34]([Br:37])=[CH:33][C:32]=3[C:28]=2[CH:27]=1>C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.C(Cl)Cl>[Br:37][C:34]1[N:35]=[CH:36][C:31]2[NH:30][C:29]3[N:38]=[CH:39][C:26]([C:13]4[CH:12]=[CH:11][C:10]([CH2:9][N:3]5[C@H:4]([CH3:8])[CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[CH:15][CH:14]=4)=[CH:27][C:28]=3[C:32]=2[CH:33]=1
Reactant: C[C@@H]1CCC[C@H](C)N1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1Cc1ccc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)cc1
Yield: 38.7 %

Procedure:
A degassed mixture of (2S,6R)-2,6-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]piperidine (685 mg, 2.08 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (389 mg, 1.04 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (127 mg, 0.16 mmol) in saturated sodium carbonate solution (1 mL) and THF (10 mL) was heated under reflux for 18 h. The cooled reaction mixture was diluted with DCM (50 mL) and washed with water (25 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g column, ISCO, 0-15% methanol in DCM) to afford the title compound as an off-white solid (181 mg, 39%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=2.2 Hz, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.69 (d, J=0.9 Hz, 1H), 8.29 (d, J=0.9 Hz, 1H), 7.68-7.63 (d, J=8.1 Hz, 2H), 7.56-7.50 (m, 2H), 4.00 (s, 2H), 2.65-2.51 (m, 2H), 1.72-1.56 (m, 4H), 1.46-1.30 (m, 2H), 1.25 (d, J=6.2 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:16]([O:19][C:20]1[C:29]2[C:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][C:25]([CH3:33])([CH3:32])[C:24]=2[CH:23]=[C:22](B(O)O)[CH:21]=1)[CH2:17][CH3:18]>>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:3][C:2]=1[C:22]1[CH:21]=[C:20]([O:19][CH2:16][CH2:17][CH3:18])[C:29]2[C:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][C:25]([CH3:32])([CH3:33])[C:24]=2[CH:23]=1
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Reactant: CCCOc1cc(B(O)O)cc2c1C(C)(C)CCC2(C)C
Product: CCCOc1cc(-c2cc(C=CC(=O)O)ccc2O)cc2c1C(C)(C)CCC2(C)C
Yield: 42.3 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 1.61 g (5.5 mmol) of 4-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid obtained in Example 43(c), 640 mg (40%) of the expected compound were obtained in the form of a white powder having a melting point of 114°-116° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.FC1C=CC(O)=CC=1.[C:21](#[N:24])C=C.[CH3:25][Si:26](C#N)([CH3:28])[CH3:27]>C(Cl)Cl.[I-].[Zn+2].[I-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7]([C:21]#[N:24])([O:11][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:6]=2[CH:12]=1
Reactant: C=CC#N
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCOc2ccc(F)cc21
Agent: Oc1ccc(F)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: C[Si](C)(C)OC1(C#N)CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 20 g (0.12 moles) of 2,3-dihydro-6-fluoro-4H-benzopyran-4-one (prepared from 4-fluorophenol and acrylonitrile as described in J. Med. Chem., 28, 1716 (1985) and 23 mL (0.18 moles) of trimethylsilyl cyanide in 220 mL of CH2Cl2 was added 500 mg of zinc iodide. The reaction was stirred at room temperature for 20 hours then poured onto ice-water. The CH2Cl2 layer was washed with water, 10% aqueous NaHCO3 and brine then dried over MgSO4, filtered and evaporated to give 32 g of crude product which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:20]([O:23][CH2:24][CH2:25]Br)(=[O:22])[CH3:21]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:25][CH2:24][O:23][C:20](=[O:22])[CH3:21])=[C:6]([Br:12])[CH:5]=1
Reactant: COC(=O)c1cc(F)c(O)c(Br)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(OCCOC(C)=O)c(Br)c1

Procedure:
3-Bromo-5-fluoro-4-hydroxybenzoic acid methyl ester (500 mg, 2.01 mmol; T. Kline et al., J. Med. Chem. 45 (2002), 3112-3129), potassium carbonate (971 mg, 7.03 mmol) and 2-bromoethyl acetate (503 mg, 3.01 mmol) were reacted in DMF (5 ml) at room temperature for 72 h. Then the mixture was partitioned between EA and 2 N hydrochloric acid, and the combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness. The raw material was purified by silica gel chromatography (EA/HEP gradient 0:1 to 4:6) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: Cc1ccc(F)c(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cc(C)ccc3F)cccc2c1N
Yield: 77.4 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro-5-methyl-phenylboronic acid (154 mg, 1.000 mmol) were reacted to afford the title compound (127 mg, 77% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (br, 1H), 7.91 (m, 1H), 7.81-7.68 (m, 2H), 7.28 (m, 1H), 7.24-7.17 (m, 1H), 7.13-7.05 (m, 1H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 2.39 (s, 3H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=339 (M+H). HPLC 1.86 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1C(O)=O.[CH2:21]([O:23][C:24]([N:26]=[C:27]=NC(C)(C)C)=[O:25])[CH3:22].[O:33]1CCCC1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:14])([F:13])[F:15])[C:3]=1[C:27]([NH:26][C:24]([O:23][CH2:21][CH3:22])=[O:25])=[O:33]
Reactant: CCOC(=O)N=C=NC(C)(C)C
Reactant: C1CCOC1
Reactant: COc1ccc2c(C(=O)O)c(Br)ccc2c1C(F)(F)F
Product: CCOC(=O)NC(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12

Procedure:
According to the procedure of O. Mitsunobu et al, Bull. Chem. Soc., Japan, 45, 3607 (1972), a solution of 2-bromo-6-methoxy-5-trifluoromethyl-1-naphthoic acid (4.50 g, 12.9 mmol, prepared by the process of Step 2, Example (11), and ethoxycarbonyl-t-butylcarbodiimide (2.40 g, 14.1 mmol) in dry tetrahydrofuran (80 mL) was heated to reflux under a dry nitrogen atmosphere for 21/3 hours. The THF was removed and the residue was dissolved in chloroform and the solvent evaporated. The resultant solid was triturated with ether (2×5 mL) and dried in vacuo to provide the title compound as an off white solid (4.61 g, 85%), m.p. 169°-171° C.
Reaction SMILES: [C:1]1([N:7]2[C:19](=[O:20])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C2C(=CC=C([F:32])C=2)N=CC=1C(OCC)=O.C1(NN)C=CC=CC=1>>[F:32][C:16]1[CH:15]=[CH:14][C:13]2[NH:12][CH:11]=[C:10]3[C:19](=[O:20])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[C:18]=2[CH:17]=1
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1Cl
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Solvent: NNc1ccccc1
Product: O=c1c2c[nH]c3ccc(F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 3 of the synthesis of 4a, using 3b and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 7.16 (1H, t, J=13.67 Hz), 7.41 (2H, t, J=7.56 Hz), 7.55 (1H, dt, J=8.54, 2.93 Hz), 7.77 (1H, dd, J=9.27, 4.88 Hz), 7.90 (1H, dd, J=9.27, 2.93 Hz), 8.18 (2H, dd, J=7.58, 1.95 Hz), 8.73 (1H, s). m/z 280.5 (MH+).
Reaction SMILES: [N:1]1([S:9]([C:12]2[CH:25]=[CH:24][C:23]3[C:22](=[N:26][OH:27])[C:21]4[C:16](=[CH:17][C:18]([S:28]([N:31]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)(=[O:30])=[O:29])=[CH:19][CH:20]=4)[C:15](=[N:39][OH:40])[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:41][CH2:42][N:43]=[C:44]=[N:45][CH2:46][CH2:47][CH2:48][N:49]([CH3:51])[CH3:50].C(Cl)(Cl)[Cl:53]>>[ClH:53].[ClH:53].[ClH:53].[ClH:53].[CH3:50][N:49]([CH3:51])[CH2:48][CH2:47][CH2:46][N:45]=[C:44]([O:40][N:39]=[C:15]1[C:14]2[CH:13]=[C:12]([S:9]([N:1]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:10])=[O:11])[CH:25]=[CH:24][C:23]=2[C:22](=[N:26][O:27][C:44](=[N:45][CH2:46][CH2:47][CH2:48][N:49]([CH3:51])[CH3:50])[NH:43][CH2:42][CH3:41])[C:21]2[C:16]1=[CH:17][C:18]([S:28]([N:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)(=[O:29])=[O:30])=[CH:19][CH:20]=2)[NH:43][CH2:42][CH3:41]
Reactant: O=S(=O)(c1ccc2c(c1)C(=NO)c1cc(S(=O)(=O)N3CCCCCCC3)ccc1C2=NO)N1CCCCCCC1
Reactant: ClC(Cl)Cl
Reactant: CCN=C=NCCCN(C)C
Product: CCNC(=NCCCN(C)C)ON=C1c2ccc(S(=O)(=O)N3CCCCCCC3)cc2C(=NOC(=NCCCN(C)C)NCC)c2cc(S(=O)(=O)N3CCCCCCC3)ccc21
Product: Cl
Yield: 68 %

Procedure:
Compound 2-22 (442 mg, 0.75 mmole), 4 mL of anhydrous chloroform and 400 mg of EDAC were stirred at 60° C. for 1 hr. The reaction mixture was condensed and chromatographed by HPLC. Combined fractions containing the desired product (MH+=899) were acidified by addition of 5 mL of 1N HCl and evaporated to dryness. The product was dissolved in distilled water and lyophilized to give 530 mg (68%) of white title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:27][CH3:28])=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1.S(OC)(O[CH3:33])(=O)=O.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CC(C)=O>[CH3:28][O:27][C:3]1[C:2]([O:1][CH3:33])=[CH:26][N:5]2[C:4]=1[C:9]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=1)=[C:8]([C:24]#[N:25])[CH:7]=[N:6]2
Reactant: COc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of compound from Example 399 (14 mg, 0.038 mmol), dimethyl sulfate (4 μl, 0.042 mmol), K2CO3 (14 mg, 0.101 mmol) in acetone (0.5 ml) was stirred at rt overnight. After regular workup, the title compound (13 mg, 88%) was obtained after silica gel flash column chromatography (100% CH2Cl2). LCMS Found: (M+H)+=387.1
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=2[F:29])CC2CCCC2)=[O:14])=[N:9][CH:8]=1)C.[CH:31]1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)[CH2:35][CH2:34][CH2:33][CH2:32]1.[CH:60]1(CNC2C=CC=C(C)C=2F)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:31]1([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=2[F:29])[C:13](=[O:14])[N:12]([CH3:60])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:30])=[CH:8][N:9]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1cccc(NCC2CCCC2)c1F
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C)c2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: Cc1cccc(N(C(=O)N(C)c2ncc(SCC(=O)O)s2)C2CCCC2)c1F

Procedure:
The title compound was prepared via {2-[3-(2-fluoro-3-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2-fluoro-3-methyl-phenyl)amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl>CO>[N:8]1([C:5]([CH3:7])([CH3:6])[C:4]([OH:13])=[O:3])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CCOC(=O)C(C)(C)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)n1ccnc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
1.54 g of 2-imidazol-1-yl-2-methyl-propionic acid ethyl ester (73828-88-3) are dissolved in 20 ml of methanol. 20 ml of a 3M NaOH are added and the mixture is stirred for 16 hours at 60° C. The reaction mixture is then neutralised with 1M HCl and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on its Rf value.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:20][NH2:21])[CH3:19].N1C=CC=CC=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:21][O:20][CH2:18][CH3:19])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCON
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Yield: 91.8 %

Procedure:
A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 22 mmol) and O-ethylhydroxylamine hydrochloride (6.4 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The reaction was heated to reflux for 2.5 h before cooling and removal of solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo. The desired product (5.5 g, 93%) was isolated as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](#N)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([C:5]2[NH:3][CH2:2][CH2:1][N:4]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1ccccc1
Reactant: NCCN
Product: c1ccc(C2=NCCN2)cc1
Yield: 95 %

Procedure:
The procedure described in Example 5 is followed except that 206 parts of benzonitrile and 132 parts of ethylenediamine are employed. 273.6 parts (95% of theory) of 2-phenylimidazoline, of boiling point 295° C./1,013 mbar, are obtained.