Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([O:12][CH:13]([F:15])[F:14])[CH:6]=1)=[O:4].[C:16]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([OH:27])=[O:26])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>CC#N.CCOC(C)=O>[N:23]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([O:27][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([O:12][CH:13]([F:15])[F:14])[CH:6]=1)=[O:4])=[O:26]
Reactant: O=C(CBr)c1ccc(Br)c(OC(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(Br)c(OC(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
2-Bromo-1-(4-bromo-3-(difluoromethoxy)phenyl)ethanone (6.65 mmol) and Boc-proline (1.72 g, 7.98 mmol) were suspended in MeCN (13 mL) and triethylamine (1.00 mL, 7.32 mmol) was added. The reaction mixture was stirred at RT for 14 h, then diluted with EtOAc. The organic solution was washed with water saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (19% to 40% EtOAc/Hex) to afford (S)-2-(2-(4-bromo-3-(difluoromethoxy)phenyl)-2-oxoethyl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate (2.48 g, 78% over 4 steps).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[O:39][C:38]([C:40]([O:42]CC)=[O:41])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[O:39][C:38]([C:40]([OH:42])=[O:41])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)cc3OC)c(C)o2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(C(=O)O)o4)oc3C)c(OC)c2)cs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a mixture of ethyl 5-[4-({4-[([4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-furancarboxylate (0.46 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the precipitated crystals were collected by filtration to give 5-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-furancarboxylic acid as colorless crystals (0.31 g, yield 84%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 154-155° C.
Reaction SMILES: [CH3:1][C:2]1[N:12]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:5]2[C:6](=[O:11])[N:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[C:3]=1[C:21](O)=[O:22].N[CH2:25][C:26]1[CH:31]=[C:30]([CH3:32])[NH:29][C:28](=[O:33])[C:27]=1[CH3:34].C[N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[NH:29][C:28](=[O:33])[C:27]=1[CH2:34][NH:36][C:21]([C:3]1[C:4]2[CH:9]=[CH:8][N:7]([CH3:10])[C:6](=[O:11])[C:5]=2[N:12]([CH:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[C:2]=1[CH3:1])=[O:22]
Reactant: Cc1c(C(=O)O)c2ccn(C)c(=O)c2n1C(C)c1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cc(CN)c(C)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3ccccc3)c3c(=O)n(C)ccc23)c(=O)[nH]1
Yield: 52.7 %

Procedure:
To a mixture of 2,6-dimethyl-7-oxo-1-(1-phenylethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (200 mg, 0.64 mmol) and 4-(aminomethyl)-3,6-dimethylpyridin-2(1H)-one (118 mg, 0.78 mmol) in N,N-dimethylformamide (20 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (365 mg, 0.96 mmol) and triethylamine (388 mg, 3.84 mmol) at room temperature. The resultant mixture was stirred at room temperature for 2 hours. Once starting material left was consumed, the reaction mixture was quenched with water (50 mL), and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (100 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:2) to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,6-dimethyl-7-oxo-1-(1-phenylethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (150 mg, 53%) as a white solid. LRMS (M+H+) m/z: calcd 444.22. found 444. HPLC purity (214 nm): 97%. 1H NMR (400 MHz, CD3OD): δ 7.22-7.13 (m, 4H), 7.01 (d, J=7.2 Hz, 2H), 6.69 (d, J=7.2 Hz, 1H), 5.99 (s, 1H), 4.35 (s, 2H), 3.50-3.21 (m, 4H), 2.26 (s, 3H), 2.13 (s, 3H), 2.06 (s, 3H), 1.82 (d, J=7.2 Hz, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=1.[N+:16]([O-])([OH:18])=[O:17]>O>[Cl:6][C:7]1[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=1
Reactant: Clc1ccc2c(c1)CCO2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc2c1OCC2
Temperature: 0 °C
Reaction time: 44 h
Yield: 40.5 %

Procedure:
To a stirred and cooled mixture of 32 nil of sulfuric acid and 14 ml of water there were added 17 g of 2,3-dihydro-5-chlorobenzofuran, while keeping the temperature at 25° C. After cooling to 0° C., there were added dropwise 14 ml of nitric acid. Stirring and cooling at 0° C. was continued for 44 hours. The reaction mixture was diluted with water (temp. <10° C.) and stirred for 15 min. The precipitate was filtered off, washed with water and recrystallized from a mixture of ethyl acetate and hexane (30:70), yielding 8.9 g (40.5%) of 5-chloro-2,3-dihydro-7-nitrobenzofuran (interm. 3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][CH:11]=[CH:10][N+:9]=2[O-])=[CH:4][CH:3]=1.[CH2:20]([N:22](CC)CC)C.CN(C)C(Cl)=O.C[Si](C#N)(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:20]#[N:22])[CH:11]=[CH:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: [O-][n+]1cccc(OCC2CC2)c1-c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: N#Cc1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
To a solution of 25 g 2-(4-chloro-phenyl)-3-cyclopropylmethoxy-pyridine 1-oxide in 500 mL acetonitrile, 9.23 g triethylamine and 10.73 g dimethylcarbamoylchlorid were added. After 5 minutes at room temperature, 27.88 g trimethylsilylcyanid was added. The reaction mixture was stirred at 90° C. over 15 h. The reaction mixture was partitioned between water and ethyl acetate; then extracted. The organic phase was washed with brine; then dried over MgSO4 and purified by chromatography on silica gel with a gradient of heptane to heptane:ethyl acetate 2:1 to yield 15.30 g (59.26%) of the title compound as light yellow solid, MS 285.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[CH:3]=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 15 %

Procedure:
5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine (2.6 mmol) is dissolved in DMF (12 ml), 4-(methylsulfonyl)phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction is heated to 120° C. in the microwave for 45 min. The reaction solution is pored into water and extracted with Methyltert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-2-nitro-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow oil in a yield of 15%. HPLC (method C): 1.65 min; LC-MS (method A): 1.534 min, 369.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13]Cl.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].[I-].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:19]1[C:15](=[O:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18]1=[O:20]
Reactant: ClCCCc1c[nH]c2ccc(Br)cc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCc1c[nH]c2ccc(Br)cc12
Temperature: 105 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
A mixture of 5-bromo-3-(3-chloropropyl)-1H-indole (1.35 g), potassium phthalimide (0.93 g) and potassium iodide (1.3 g) in dry dimethylformamide (20 ml) was warmed with stirring at 105° C. for 3 hours. The mixture was cooled and diluted with water (30 ml). An oil precipitated which crystallised over the next 5 min. The resulting solid was collected and washed thoroughly with water. The product was recrystallised from 2-propanol (50 ml) to afford the title compound as a pale yellow crystalline solid (1.1 g) m.p. 168.5°-170° C.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:30][CH2:31][C@H:32]([OH:34])[CH3:33]>C1(C)C=CC=CC=1>[CH3:16][O:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH3:14])([CH3:13])[C:4]3[CH:3]=[CH:2][N:30]([CH2:31][C@H:32]([OH:34])[CH3:33])[C:5]=32)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2(C)C
Yield: 59.3 %

Procedure:
A solution of 4.94 g of (RS)-2-(2-oxoethyl)-6-methoxy-3,3-dimethyl-1-indanone and 220 ml of p-toluenesulfonic acid in 200 ml of anhydrous toluene was heated on a water separator. A solution of 6.39 g of (R)-1-amino-2-propanol in 40 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes, during which the solvent was reduced to a volume of 40 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 3.42 g (60%) of (R)-1-(7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: CO.C(Cl)(Cl)[Cl:4].[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([CH2:22][N:23]([C:34]3[CH:42]=[CH:41][C:37]4[N:38]=[CH:39][S:40][C:36]=4[CH:35]=3)[C:24]([CH2:26][CH:27]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]3)=[O:25])=[O:21])=[CH:15][CH:14]=2)[N:12]=1.[BH4-].[Na+]>O>[ClH:4].[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([CH2:22][N:23]([C:34]3[CH:42]=[CH:41][C:37]4[N:38]=[CH:39][S:40][C:36]=4[CH:35]=3)[C:24]([CH2:26][CH:27]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]3)=[O:25])=[O:21])=[CH:15][CH:14]=2)[N:12]=1
Reactant: ClC(Cl)Cl
Reactant: Nc1nc(-c2ccc(NC(=O)CN(C(=O)CC3CCC(=O)CC3)c3ccc4ncsc4c3)cc2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cl
Product: Nc1nc(-c2ccc(NC(=O)CN(C(=O)CC3CCC(O)CC3)c3ccc4ncsc4c3)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A methanol-chloroform (40 ml-20 ml) solution of N-({[4-(2-aminothiazol-4-yl)phenyl]carbamoyl}methyl)-N-benzothiazol-6-yl-4-oxocyclohexanecarboxyamide (430 mg) was mixed with sodium borohydride (0.19 g) at 0° C. and then stirred at room temperature for 1 hour. The reaction solution was mixed with water and extracted with chloroform, the organic layer was dried with anhydrous sodium sulfate and filtered, and then the solvent was evaporated under a reduced pressure. The thus obtained crude product was purified by SCG (chloroform/methanol/27% aqueous ammonia=94.8/5/0.2). This was dissolved in chloroform-methanol (10 ml-10 ml) and mixed with 4 M hydrogen chloride in ethyl acetate (1 ml), and then the solvent was evaporated under a reduced pressure. By recrystallizing the thus obtained crude crystals from isopropyl alcohol-ethyl acetate (3/1), 259 mg of N-({[4-(2-aminothiazol-4-yl)phenyl]carbamoyl}methyl)-N-benzothiazol-6-yl-4-hydroxycyclohexanecarboxyamide monohydrochloride (pale yellow crystals) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>ClC(Cl)C.C1(C)C=CC=CC=1>[S:28]1[CH2:2][CH2:3][N:4]=[C:5]1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17]
Reactant: O=C(NCCCl)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1cccc2cc(C3=NCCS3)[nH]c12
Yield: 60 %

Procedure:
7-Nitro-1H-indole-2-carboxylic acid (2-chloro-ethyl)-amide (267 mg, 1 mmol) prepared in Step B was dissolved in dichloroethane (10 mL) and toluene (10 mL), and Lawesson's Reagent (1.29 g, 3.2 mmol) was added thereto. The mixture was refluxed for 4 h, and distilled under reduced pressure. Water was added thereto, and the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and the concentrate was purified by column chromatography to give the title compound as a product of the cyclization reaction (148 mg, Yield 60%).
Reaction SMILES: C[C:2]1([C:28]2C=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6](=O)[CH:5]=[C:4]([C:8](=NOC(NCCCCCCCC)=O)[C:9]2C=CC=C[CH:10]=2)O1.[CH:34]1([C:40]2([CH3:66])[C:44](=[O:45])[CH:43]=[C:42]([C:46](=[N:53][O:54][C:55]([NH:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]CC)=[O:56])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:41]2)CCCCC1.ClC1C=CC(C2(C)C(=O)C=C(C(=NOC(NCCCCCCCC)=O)C3C=CC=CC=3)O2)=CC=1.CC(C1C=CC(C2(C)C(=O)C=C(C(=NOC(NCCCCCCCC)=O)C3C=CC=CC=3)O2)=CC=1)(C)C>>[CH3:66][C:40]1([CH3:34])[C:44](=[O:45])[CH:43]=[C:42]([C:46](=[N:53][O:54][C:55]([NH:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:32][CH2:31]/[CH:30]=[CH:29]/[CH2:28]/[CH:2]=[CH:6]/[CH2:5][CH2:4][CH2:8][CH2:9][CH3:10])=[O:56])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[O:41]1
Reactant: CCCCCCCCNC(=O)ON=C(C1=CC(=O)C(C)(C2CCCCC2)O1)c1ccccc1
Reactant: CCCCCCCCNC(=O)ON=C(C1=CC(=O)C(C)(c2ccccc2)O1)c1ccccc1
Agent: CCCCCCCCNC(=O)ON=C(C1=CC(=O)C(C)(c2ccc(C(C)(C)C)cc2)O1)c1ccccc1
Agent: CCCCCCCCNC(=O)ON=C(C1=CC(=O)C(C)(c2ccc(Cl)cc2)O1)c1ccccc1
Product: CCCCC/C=C/C/C=C/CCCCCCCCNC(=O)ON=C(C1=CC(=O)C(C)(C)O1)c1ccccc1

Procedure:
2-cyclohexyl-2-methyl-5-[[[[(octylamino)carbonyl]oxy]imino]phenylmethyl]-3(2H)-furanone 2-methyl-2-phenyl-5-[[[[(octylamino)carbonyl]oxy]imino]phenylmethyl]-3(2H)-furanone; 2-(4-chlorophenyl)-2-methyl-5-[[[[(octylamino)carbonyl]oxy]imino]phenylmethyl]-3(2H)-furanone; 2-[4-(1,1-dimethylethyl)phenyl]-2-methyl-5-[[[[(octylamino)carbonyl]oxy]imino]phenylmethyl]-3(2H)-furanone;
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22](OC)=[O:23].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23]
Reactant: COC(=O)c1nc(C)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)NCC(=O)O)nc(C)c3c2)cc1
Temperature: 110 °C

Procedure:
A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 5e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 5e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-[4-hydroxy-1-methyl-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxamido]acetic acid.
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]>>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9]
Reactant: O=C1OCCC1=CO
Reactant: NCc1ccccc1Cl
Agent: [Na]
Product: O=C1OCCC1=CNCc1ccccc1Cl
Yield: 64.8 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (10 mmol) and 2-chlorobenzylamine (11 mmol) and proceeding according to the abovementioned method A2, 3-(2-chlorobenzylamino)methylenedihydrofuran-2-one (1.54 g, efficiency: 75%) is produced in the form of a white powder.
Reaction SMILES: C1(C2C([CH:11]=[O:12])=CC(C(N3CCC(C4C=CC(C#N)=CC=4)CC3)=O)=C(C)C=2)CCC1.[Cl:30][C:31]1[C:39](I)=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[C:33]([CH3:41])[CH:32]=1.C1(C2C(C=O)=CC(C(O)=O)=C(C)C=2)CCC1>>[Cl:30][C:31]1[C:39]([CH:11]=[O:12])=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[C:33]([CH3:41])[CH:32]=1
Reactant: Cc1cc(Cl)c(I)cc1C(=O)O
Reactant: Cc1cc(C2CCC2)c(C=O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: Cc1cc(C2CCC2)c(C=O)cc1C(=O)O
Product: Cc1cc(Cl)c(C=O)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 392.2, except 4-chloro-5-iodo-2-methylbenzoic acid (compound 471.1) was used in place of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 392.1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][N:32]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:18]>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH:30]=[CH:31][N:32]=3)[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[O:18])[CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccnc(Br)c1
Reactant: CSc1ncc2c(n1)CCNC2
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccn1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 2-bromo-N-(3-trifluoromethyl-phenyl)-isonicotinamide were converted to the title compound.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[C:34]5[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=5[O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5]C[CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:59])CC2)CC1>>[OH:59][CH:5]1[CH2:6][CH2:7][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[C:34]5[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=5[O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:2][CH2:3]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: COc1ccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCCCCC6)CC5)cc34)c2c1
Agent: Cl
Product: COc1ccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCC(O)CC6)CC5)cc34)c2c1

Procedure:
This compound is synthesized from 4-(5-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (121, see example 92) and amine 21 analogously to the method described in example 1.
Reaction SMILES: Cl.[CH2:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][C:11]1[N:15]=[C:14]([CH2:16][C:17](O)=[O:18])[O:13][N:12]=1>O>[CH3:10][C:11]1[N:15]=[C:14]([CH2:16][C:17]([O:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:18])[O:13][N:12]=1
Reactant: Cc1noc(CC(=O)O)n1
Reactant: CCCCCCCO
Agent: Cl
Solvent: O
Product: CCCCCCCOC(=O)Cc1nc(C)no1

Procedure:
Under anhydrous conditions, a stream of gaseous hydrochloric acid was passed through 25 ml of n-heptanol and as soon as a saturated solution was reached at room temperature, 5.7 g (0.04 mol) of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid were introduced. Introduction of a slow stream of hydrochloric acid was continued for two hours and the reaction mixture was then stirred for 60 hours at room temperature whereby conversion of the carboxylic acid was virtually completed. The reaction mixture was thoroughly mixed with 75 ml of cold water and the layers were separated. The organic layer was washed three times with 10 ml volumes of a saturated solution of sodium bicarbonate in water, and two times with 10 ml of cold water. All water-layers were combined and extracted twice with 20 ml volumes of ethyl acetate. The combined ethyl acetate extracts were once washed with 10 ml of iced water and the water-layers were discarded. The two organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was distilled and fractionated at reduced pressure to obtain 6.8 g of n-heptyl 3-methyl-1,2,4-oxadiazol-5-yl-acetate of about 95% molar purity (impurity mainly a small amount of n-heptanol with a b.p. of 108° C. at 0.25 mm Hg and a refractive index nD20 =1.450.
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>>[CH3:17][C:2]1([CH2:3][O:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:1][O:26]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)COCc1ccc(OC(F)(F)F)cc1
Product: CC1(COCc2ccc(OC(F)(F)F)cc2)CO1
Yield: 93 %

Procedure:
Epoxidation of alkene 121 with 3-chloroperbenzoic acid as in Example 2G, followed by chromatography of the product on silica gel, eluting with 0-15% CH2Cl2/petroleum ether (foreruns) and then with 15-75% CH2Cl2/petroleum ether and CH2Cl2, gave 2-methyl-2-({[4-(trifluoromethoxy)benzyl]oxy}methyl)oxirane (123) (93%) as an oil; 1H NMR (CDCl3) δ 7.37 (dt, J=8.7, 2.4 Hz, 2H), 7.19 (br d, J=7.9 Hz, 2H), 4.59 (d, J=12.1 Hz, 1H), 4.54 (d, J=12.1 Hz, 1H), 3.61 (d, J=11.1 Hz, 1H), 3.44 (d, J=11.1 Hz, 1H), 2.75 (d, J=4.9 Hz, 1H), 2.64 (d, J=4.9 Hz, 1H), 1.40 (s, 3H); HRCIMS (NH3) calcd for C12H17F3O3N m/z [M+H+NH3]+ 280.1161. found 280.1144.