Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][CH:9]=1)(=[O:3])[CH3:2].S(Cl)([Cl:17])(=O)=O>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][C:9]=1[Cl:17])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cscc1NC(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1csc(Cl)c1NC(C)=O
Temperature: 0 °C

Procedure:
40 g. of methyl 4-acetylamino-3-thiophene carboxylate are dissolved in 1 liter of absolute chloroform, and a solution of 27 g. of sulfuryl chloride in 100 ml. of absolute chloroform is then added dropwise within 20 minutes. The reaction solution is then boiled under reflux for 1 hour. The brownish colored solution obtained is cooled and when its temperature is 10°, 1 liter of ice water is added. The organic solution is then washed with 200 ml. of 5% sodium bicarbonate solution, dried over sodium sulfate, and evaporated to dryness in vacuo. The oily residue is triturated with 100 ml. of ether, whereupon crystallization takes place. The product is suction filtered and recrystallized from ethyl acetate, and methyl 4-acetylamino-5-chloro-3-thiophene carboxylate having a melting point of 119°-121° is obtained. The ethereal filtrate and the mother liquor from the ethyl acetate recrystallization are combined, evaporated to dryness, and the oil that remains is chromatographed on 300 g. of silica gel using methylene chloride/ethyl acetate (4:1) as eluent. An additional portion of methyl 4-acetylamino-5-chloro-3-thiophene carboxylate having a melting point of 119°-121° is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]([NH2:48])[CH3:47])=[CH:42][CH:41]=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:7])[NH:48][CH:46]([C:43]2[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=2)[CH3:47])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(N)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(C(=O)NC(C)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
A mixture of 3-bromo-5-(methoxycarbonyl)benzoic acid (0.60 g, 2.32 mmol) and HATU (1.06 g, 2.78 mmol) in DMF (15 mL) was stirred at room temperature for 10 min. Then 1-(4-fluorophenyl)ethanamine (0.323 g, 0.3 mL, 2.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with H2O (3 times) and brine, dried over sodium sulfate, and concentrated under vacuum to give the title compound (0.880 g, 99.9% yield): HPLC retention time: 2.098 min (method A). MS (ESD) (M+H)+ 380/382.
Reaction SMILES: [OH:1][N:2]1[C:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=[N:3]1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[C:8]1([S:7][C:6]2[N:2]([O:1][C:16](=[O:17])[N:15]([CH3:14])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:3]=[CH:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1nccc1Sc1ccccc1
Product: CN(C(=O)On1nccc1Sc1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-5-phenylsulfanylpyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (80%, oil).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CSc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1
Reactant: CN(CCCN)c1ccccn1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (1.0 g) and 2-methylthio-5-(4-fluorobenzyl)pyrimid-4-one (1.25 g) were heated together under reflux in pyridine (3 ml) for 24 hr. The mixture was stripped and the residue recrystallised twice from ethanol/water to give 2-[3-(N-methyl-N-pyrid-2-ylamino) propylamino]-5-(4-fluorobenzyl)-pyrimid-4-one 0.5H2O, 1.2 g (64%) mp ca. 70° C. (softens).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:16](OC=C)(=O)[CH3:17]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([O:14][CH:16]=[CH2:17])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: C=COC(C)=O
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Product: C=COC(=O)C(C)c1ccc(CC(C)C)cc1
Reaction time: 8 h
Yield: 82 %

Procedure:
100 g of 2-(4'-isobutylphenyl)propionic acid (ibuprofen) were taken up in 1 l of vinyl acetate and heated under reflux to boiling in the presence of 2 g of Li2PdCl4 and 20 g of active carbon. The reaction was followed by thin layer chromatography. After 8 hours, the catalyst was filtered off and the filtrate was concentrated to dryness. After filtration through silica gel using hexane:ethyl acetate (10:1), 92.7 g (39.9 mmol; 82%) of vinyl 2-(4'-isobutylphenyl)propionate were obtained as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][N:7]=1)=[O:5])[CH3:2].[Cl-].[Li+].N1C=CC=CC=1.C1(C)C=CC(S([Cl:34])(=O)=O)=CC=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]=1[Cl:34])=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1n[nH]c2c(c1=O)CCCC2
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2c(c1Cl)CCCC2
Yield: 60.6 %

Procedure:
To a slurry of 4-oxo-1,4,5,6,7,8-hexahydrocinnoline-3-carboxylic acid ethyl ester (1 g), lithium chloride (0.19 g) and pyridine (0.36 ml) in dichloromethane (30 ml) was added p-toluenesulphonyl chloride (0.85 g). The reaction mixture was heated at reflux for 20 h. The solid was collected by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography using a gradient elution: CH2Cl2 (500 ml), CH2Cl2/MeOH 99:1 (500 ml), CH2Cl2/MeOH 98:2 (1 liter). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (0.65 g, 61%). δH (360 MHz; CDCl3) 1.44 (3H, t, J=7 Hz, CH3), 1.89 (4H, m, CH2), 2.85 (2H, t, J=5.7 Hz, CH2), 2.62 (2H, t, J=5.7 Hz, CH2), 4.51 (2H, t, J=7 Hz, CH2), m/z (ESP+) 241/243 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)cc1OCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
Methyl 4-methoxysalicylate (7.91 g, 43.4 mmol), 2-(4-tert-butoxycarbonylpiperazin-1-yl)ethanol (10.0 g, 43.4 mmol), and triphenylphosphine (PPh3) (11.3 g, 43.4 mmol) in THF (190 ml) were cooled to 0° C. under N2. DIAD (8.54 ml, 43.4 mmol) was added dropwise, and the reaction allowed to warm to room temperature. After stirring for 18 h, the THF was removed in vacuo, the residue taken up in dichloromethane, and washed with water, dried, and the solvent removed in vacuo to give a yellow oil. After the oil was dissolved in diethyl ether and the solution allowed to stand for 18 h, the triphenylphosphine oxide was filtered, the solvent removed in vacuo, and the crude product purified on silica gel using preparative HPLC and a gradient of hexane and EtOAc to give 11.0 g (64.3%) of a pale yellow oil.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]1[CH:17]([N:18](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:16](=[O:33])[NH:15][C:14]2[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:13]=2[O:12]1)C1C=CC=CC=1>CO.[Pd]>[NH2:18][CH:17]1[C:16](=[O:33])[NH:15][C:14]2[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:13]=2[O:12][CH:11]1[CH2:10][CH2:9][OH:8]
Reactant: O=C1Nc2cc(F)ccc2OC(CCOCc2ccccc2)C1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1C(=O)Nc2cc(F)ccc2OC1CCO
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield by hydrogenation of (−)-(6R,7R or 6S,7S)-6-(2-benzyloxy-ethyl)-7-dibenzylamino-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 241.3 (M+H+, 100).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.FC(F)(F)S([O-])(=O)=O.[N:16]1([S:21](N2C=C[NH+](C)C2)(=[O:23])=[O:22])[CH:20]=[CH:19][N:18]=[CH:17]1>>[N:16]1([S:21]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)(=[O:23])=[O:22])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Reactant: OC1CCNCC1
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=S(=O)(N1CCC(O)CC1)n1ccnc1

Procedure:
1-(Imidazole-1-sulfonyl)-piperidin-4-ol was prepared in accordance with step A of the general method described in example 76 from 4-hydroxypiperidin and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=232.5 (M+H+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:9].[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][C:19]=1[S:28]([N:6]1[CH2:5][CH2:4][N:3]([C:8]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[O:9])[C@@H:2]([CH3:1])[CH2:7]1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Reactant: Cc1ccc(C(=O)N2CCNC[C@@H]2C)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)C[C@@H]2C)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.8 %

Procedure:
To a solution of (2S)-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (may be prepared as described in Description 13) (200 mg, 0.912 mmol) in DCM (10 mL) was added 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (295 mg, 0.912 mmol) followed by DIPEA (0.159 mL, 0.912 mmol). The reaction mixture was left stirring at room temperature for 15 h. The solvent was removed by evaporation and the crude residue was dissolved in DCM (30 ml), washed with saturated sodium bicarbonate (40 ml), dried (hydrophobic frit) and evaporated under vacuum. The crude product was purified by silica chromatography using a gradient EtOAc/iso-hexane from 20/80 to 100/0. The desired fractions were combined and concentrated under vacuum to give the title compound (216 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[C:31](=[O:32])[C:30]([CH3:33])=[CH:29][N:18]([C@@H:19]2[O:25][C@H:22]([CH2:23][OH:24])[C@@H:21]([N:26]=[N+:27]=[N-:28])[CH2:20]2)[C:17]1=[O:34].CCN(CC)CC>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:13][CH2:14][CH2:15][N:16]2[C:31](=[O:32])[C:30]([CH3:33])=[CH:29][N:18]([C@@H:19]3[O:25][C@H:22]([CH2:23][OH:24])[C@@H:21]([N:26]=[N+:27]=[N-:28])[CH2:20]3)[C:17]2=[O:34])=[O:12])=[CH:6][CH:7]=1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCN)c1=O
Reactant: O=C(O)CCc1ccc(O)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCNC(=O)CCc2ccc(O)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10 mg 3-(4-hydroxyphenyl)-propionic acid N-hydroxysuccinimideester (HPP:NOS) in MeOH was mixed with 10 mg of 3-AE-AZT (Example 27) dissolved in 100 ul MeOH. The mixture was stirred 30 minutes at room temperature, followed by addition of 2.5 ul of Et3N. This mixture was incubated overnight at room temperature, and then chromatographed by TLC on silica gel-F 250 um using the solvent system CHCl3 /MeOH/HOAc (90+10+1). The following Rf values were observed upon visualization by UV at 254 nm: 3-AE-AZT, 0.034;NOS, 0.28; product, 0.35; HPPA, 0.37; andHPP:NOS, 0.55. The product, unlike 3-(4-hydroxyphenyl)propionic acid (HPPA), was an effective inhibitor of polarization in a FPIA for AZT.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Br:9]Br>ClCCl>[Br:9][CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8]
Reactant: O=C1CCCC(=O)C1
Reactant: BrBr
Solvent: ClCCl
Product: O=C1CCCC(=O)C1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
To a stirred solution of 1,3 Cyclohexandione (10 g, 89 mmol) in dichloromethane (22 mL) at 0° C. was added a solution of bromine (3.8 mL, 89 mmol) in dichloromethane (3 mL) over a period of 10 minutes. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered and the residue washed with hexane (200 mL). The residue was taken into water (75 mL) and heated at 80° C. for 30 minutes. It was cooled to room temperature, filtered and dried under reduced pressure to give the desired product (14 g, 82%) as a solid. ESMS [M+H]: 191.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)=[O:5])C.[OH-].[Na+]>CO.O>[S:11]1[CH:12]=[CH:13][N:9]2[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]12
Reactant: CCOC(=O)c1ccn2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccn2ccsc12
Temperature: 55 °C

Procedure:
A mixture of pyrrolo[2,1-b]thiazole-7-carboxylic acid ethyl ester (5.12 mmol) and sodium hydroxide (7.68 mmol) in MeOH (5.8 mL) and water (5.8 mL) is heated to 55° C. for 23 h. The mixture is concentrated in vacuo and made acidic by addition of hydrochloric acid (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product. LC-MS: tR=0.87 min; [M+H]+=168.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:15][Cl:16])[CH2:13][C:12](=O)[CH2:11][O:10]1.[CH2:17]([OH:20])[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:16][CH2:15][C:9]1([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:13][CH2:12][C:11]2([O:20][CH2:17][CH2:18][O:19]2)[O:10]1
Reactant: O=C1COC(CCl)(c2ccc(Cl)cc2Cl)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: ClCC1(c2ccc(Cl)cc2Cl)CCC2(OCCO2)O1

Procedure:
The furanone obtained in stage b) (4.2 g), in toluene (50 cc), is heated at reflux temperature in the presence of ethylene glycol (6.5 cc) and p-toluenesulphonic acid (0.1 g), with the separation of the water formed, until the disappearance of the starting product.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>N.CO>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:39])=[O:38])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30.7 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 4-Methoxybenzenesulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (5.5 mg). MS m/z 359 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].O[NH:23][C:24](=[NH:31])[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1>>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:31]=[C:24]([CH2:25][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[N:23]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)O
Reactant: N=C(Cn1cncn1)NO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cn2cncn2)no1

Procedure:
Method as for preparation 2 and 3 combined using 2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (preparation 168) (2.98 g, 10 mmol) and N-hydroxy-2-(1H-1,2,4-triazol-1-yl)ethanimidamide (preparation 148) (1.01 g, 10 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.[C:29]1(=O)[CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:29]1([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([C:11]([C:10]3[C:5]([O:4][C:3]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=4[Cl:1])=[N:6][CH:7]=[C:8]([F:23])[CH:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH2:32][CH2:31][CH2:30]1
Reactant: O=C1CCC1
Reactant: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 5.6 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (52.3 mg, 0.125 mmol, 1.0 equiv; Example 147) in methanol (0.5 mL) was added cyclobutanone (188 mg, 0.2 mL, 2.68 mmol, 21.4 equiv; [CAS RN 1191-95-3]), acetic acid (28 mg, 27 μL, 0.5 mmol, 4.0 equiv; [CAS RN 64-19-7]) and the reaction mixture stirred at rt. After 90 min, sodium cyanoborohydride (15.7 mg, 0.25 mmol, 2.0 equiv; [CAS RN 25895-60-7]) was added and stirring at rt continued for 18 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 3.3 mg (6%) of the title compound. MS (ISP): 474.1 [M+H]+.
Reaction SMILES: [Na].[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([S:11]([O-:14])(=O)=[O:12])=[CH:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][S:11]([C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:2][CH:3]=1)(=[O:14])=[O:12]
Reactant: O=S(=O)([O-])c1csc2ccccc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1csc2ccccc12

Procedure:
180 g of sodium-benzothiophene-3-sulphonate are placed in 650 ml of phosphorus oxychloride and then combined with 156 g of phosphorus pentachloride. The reaction mixture is refluxed for 3.5 hours before the excess phosphorus oxychloride is eliminated by distillation in vacuo. The residue is taken up in 800 ml of chloroform and the precipitate formed is separated off by filtering. The filtrate is concentrated by evaporation and stirred into 800 ml of petroleum ether with heating. The crystalline substance thus precipitated is filtered off, washed with petroleum ether and dried at 35° C.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>C(Cl)(Cl)Cl>[Br:1][C:10]1[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: BrBr
Reactant: COc1ccccc1C#N
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1C#N
Temperature: 25 °C
Yield: 71.4 %

Procedure:
Bromine (13.7 g, 86.0 mmol) in CHCl3 (20 mL) was added to the solution of 2-(methyloxy)benzonitrile (10.9 g, 81.9 mmol) in CHCl3 (50 mL). The mixture was refluxed for 29 h. The reaction was allowed to cool to room temperature, and washed with saturated sodium bisulfite (50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 5-bromo-2-(methyloxy)benzonitrile (12.4 g, 71%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:16]=1>>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:28]3[CH2:29][CH2:30][CH:25]([C:17]4[CH:16]=[N:15][C:24]5[C:19]([CH:18]=4)=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:26][CH2:27]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2ncc(C3CCNCC3)cc2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Product: c1ccc2ncc(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)cc2c1
Yield: 67.8 %

Procedure:
Beginning with 0.175 gm (0.83 mMol) 3-chloropropyl indol-4-yl ether and 0.177 gm (0.83 mMol) 4-(quinolin-3-yl)piperidine, 0.217 gm (68%) of the title compound were recovered as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(C)(C)CNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1

Procedure:
Reaction of 3-cyclopentylamino-2,2-dimethyl-propionic acid ethyl ester with 2,4-dichloro-5-nitropyrimidine and K2CO3 in acetone gave 3-[(2-Chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propionic acid ethyl ester
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
4-Bromobenzaldehyde (5.0 g, 27 mmol) was slowly added to concentrated sulfuric acid (25 mL) at 0 IC followed by dropwise addition of fuiming nitric acid (1.7 mL, 40.5 mmol) in concentrated sulfuric acid (8 mL). The reaction mixture was stirred at room temperature overnight, then poured onto ice water to provide 5.7 g of the title compound.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]>>[C:17]([O:10][C:8]1[CH:7]=[CH:6][NH:5][C:4](=[O:3])[CH:9]=1)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)Oc1cc[nH]c(=O)c1
Yield: 41 %

Procedure:
The general procedure of Example 31 was followed using 1.00 g of 2,4-bis(trimethylsilyloxy)-pyridine and 1.02 ml of n-pentanoyl chloride, thereby giving 310 mg of the title compound in a yield of 41%.