Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH:4]([OH:23])[CH2:5][CH2:6]/[C:7](/[CH3:22])=[CH:8]\[CH2:9][CH2:10]/[C:11](/[CH3:21])=[CH:12]\[CH2:13][O:14]C1CCCCO1)=[CH2:3]>C(Cl)CCl.[O-2].[O-2].[Mn+4]>[OH:14][CH2:13]/[CH:12]=[C:11](/[CH3:21])\[CH2:10][CH2:9]/[CH:8]=[C:7](/[CH3:22])\[CH2:6][CH2:5][C:4](=[O:23])[C:2]([CH3:3])=[CH2:1]
Reactant: C=C(C)C(O)CC/C(C)=C\CC/C(C)=C\COC1CCCCO1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Product: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C\CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.5 g (0.0016 mol) of (6Z,10Z)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol dissolved in 15 ml of ethylene chloride is treated with 10 g of manganese dioxide. The suspension is stirred at room temperature for 18 hours under argon. After filtration and removal of the solvent the residue is chromatographed on silica gel with ether-hexane 10:1. The product, containing (6Z,10Z)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-one, is dissolved in 10 ml of tetrahydrofuran and 2.6 ml of water and treated with 118 mg of pyridinium p-toluenesulfonate. The solution is boiled at reflux for 17 hours. After cooling 100 ml of water and 200 ml of ether are added thereto. The organic phase is neutralized with sodium bicarbonate solution. After drying and removing the solvent the residue is chromatographed on silica gel with ether-hexane 1:1. There is obtained (6Z,10Z)-12-hydroxy-2,6,10-trimethyl- 1,6,10-dodecatrien-3-one which exhibits the following absorption bands in the IR spectrum: 3387 cm-1, 1677 cm-1, 1629 cm-1, 1417 cm-1, 1389 cm-1, 997 cm-1, 950 cm-1.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21](Cl)([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22]>O1CCCC1>[C:21]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22]
Reactant: CC(C)Nc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)N(c1ccccc1[N+](=O)[O-])C(C)C
Temperature: 0 °C

Procedure:
To a stirred ice-cooled solution of 2-isopropylamino-nitrobenzene (19.5 g, 0.1 mole) and triethylamine (15 ml, 0.11 mole) in tetrahydrofurane (THF, 200 ml) was dropwise added ethoxalyl chloride. The ice bath was removed and the mixture was heated to reflux for 3 hours. The precipitated triethylammonium chloride was filtered off and the filtrate was evaporated in vacuo to give the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][OH:18])=[CH:6]1.FC1C=C(F)C=CC=1CN1C2=CN=C(C(OCC)=O)C=C2C(CO)=C1.C(OCC1C2C(=CN=C([C:67]([NH:69][OH:70])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.Cl.CNO>>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:69]([OH:70])[CH3:67])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][OH:18])=[CH:6]1
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: O=C(O)c1cc2c(CO)cn(Cc3ccc(F)cc3F)c2cn1
Agent: CCOC(=O)c1cc2c(CO)cn(Cc3ccc(F)cc3F)c2cn1
Agent: CNO
Agent: Cl
Product: CN(O)C(=O)c1cc2c(CO)cn(Cc3ccc(F)cc3F)c2cn1

Procedure:
1-(2,4-Difluorobenzyl)-3-hydroxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound was prepared by hydrolysis of ethyl 1-(2,4-difluoro-benzyl)-3-hydroxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylate in a manner similar to step (b) of example 1. 1H NMR (DMSO-d6). δ: 8.96 (s, 1H), 8.41 (s, 1H), 7.69 (s, 1H), 7.29-7.32 (m, 2H), 7.08 (m, 1H), 5.61 (s, 2H), 5.09 (s, 1H), 4.66 (s, 2H). LCMS (API-ES, M+H+): 319.1. (b) 1-(2,4-Difluorobenzyl)-N-hydroxy-3-hydroxymethyl-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. The title compound was prepared by coupling of 1-(2,4-difluoro-benzyl)-3-hydroxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and N-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (CD3OD) δ: 8.80 (s, 1H), 8.29 (s, 1H), 7.67 (s, 1H), 7.29-7.32 (m, 1H), 6.93-7.04 (m, 2H), 5.57 (s, 2H), 4.81 (s, 2H), 3.43 (s, 3H). LCMS (APCI, M+H+): 348.0. HRMS (M+H): 348.1175; cal: 348.1160 with C17H16F2N3O3. HPLC: 96.15% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH:15]=[C:14]1[C:23]([O:25]CC)=[O:24])(=[O:12])=[O:11].[OH-].[Li+].Cl>O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:22][CH2:21][C:16]2([O:17][CH2:18][CH2:19][O:20]2)[CH:15]=[C:14]1[C:23]([OH:25])=[O:24])(=[O:12])=[O:11]
Reactant: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCCO2
Temperature: 50 °C
Reaction time: 7 h
Yield: 85.1 %

Procedure:
1.8 g (4.29 mmol) of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 1 was dissolved in 60 ml of a water-tetrahydrofuran (1:1) solution, and 900 mg (21.45 mmol) of lithium hydroxide was added thereto, followed by stirring for 7 hours at 50° C. The reaction solution was cooled with ice, it was then made acidic by addition of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was washed with hexane to give 1.43 g of the title compound as a pale brown powder (yield: 85%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C@@H:23]([CH3:37])[C@@H:24]([CH3:36])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].[N+:44]([C:47]1[NH:48][CH:49]=[CH:50][N:51]=1)([O-:46])=[O:45]>>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH2:25][C@H:24]([CH3:36])[C@H:23]([CH3:37])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:48]3[CH:49]=[CH:50][N:51]=[C:47]3[N+:44]([O-:46])=[O:45])[CH:15]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCOCCOCCOCCBr)c2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCOCCOCCOCCn3ccnc3[N+](=O)[O-])c2)cc1OC
Yield: 85.1 %

Procedure:
The Standard Procedure 2 was followed by use of 5b (135.1 mg, 0.2315 mmol, 1.0 equiv), potassium carbonate (67.5 mg, 0.488 mmol, 2.1 equiv), and 2-nitroimidazole (6b, 54.3 mg, 0.485 mmol, 2.0 equiv). After workup and purification with column chromatography (80% EtOAc in hexanes as eluant), 7d (121.2 mg, 0.1970 mmol) was obtained in 85% yield as a yellow gummy oil: 1H NMR (CDCl3, 400 MHz) δ 0.81 (d, J=6.4 Hz, 6H, 2×CH3), 1.73 (m, 2H, 2×CH), 2.23-2.29 (m, 2H, 2×ArCH), 2.69-2.74 (m, 2H, 2×ArCH), 3.56-3.86 (m, 21H, 3×OCH3+6×OCH2), 4.12 (t, J=5.0 Hz, 2H, CH2N), 4.56 (t, J=4.8 Hz, 2H, CH2O), 6.62 (s, 1H, ArH), 6.67-6.69 (m, 3H, 3×ArH), 6.75-6.78 (m, 2H, 2×ArH), 7.08 (s, 1H, nitroimidazole C5-H), 7.23 (s, 1H, nitroimidazole C4-H); 13C NMR (CDCl3, 100 MHz) δ 16.05, 16.07, 38.63, 38.68, 39.09, 39.12, 49.71, 55.66, 55.76, 55.82, 68.30, 69.22, 69.58, 70.37, 70.46, 70.47, 70.61, 110.89, 111.56, 112.10, 114.58, 120.82, 121.56, 127.30, 127.86, 134.34, 134.40, 144.57, 146.88, 147.41, 147.77, 148.54; IR (neat) 2925 (s), 2873 (s), 1590 (w), 1538 (m), 1516 (s), 1456 (w), 1361 (s), 1260 (s), 1236 (s), 1029 (s) cm−1; HRMS (FAB) m/z calcd for C32H46N3O9 (M+H)+: 616.3234. found: 616.3231.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:17](Br)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(Nc2ccccc2)n1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nccc(N(CCc2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
2-Chloro-4-anilinopyrimidine (Reference Example A-9, 600 mg, 2.9 mmol) was dissolved in anhydrous DMF (8 ml) and sodium hydride (140 mg, 3.5 mmol, 60% in oil) was added portion wise. 10 min later phenethylbromide (478 μl, 3.5 mmol) was added and the mixture was stirred at ambient temperature for 5 hours. More sodium hydride (140 mg, 3.5 mmol, 60% in oil) and phenethylbromide (478 μl, 3.5 mnmol) were added and stirring was maintained overnight. The solvent was evaporated off and the residue partitioned between water and DCM. The organic phase was dried (MgSO4) the solvent evaporated. The crude product was purified by flash chromatography using first DCM then EtOAc/petroleum ether (25/75). The solvent was evaporated to give the title product as a white solid (530 mg, 59%). NMR (400 MHz, 353K): 2.90 (t, 2H), 4.10 (t, 2H), 6.15 (d, 1H), 7.25 (m, 7H), 7.45 (t, 1H), 7.65 (t, 2H), 8.00 (d, 1H); m/z: (ES+) 310 and 312 (MH+).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:7][C:8]=1[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[CH2:19][C@H:18]2[C:20](O)=[O:21])=[CH:13][CH:12]=1)([CH3:3])[CH3:2].CN(C(ON1N=[N:48][C:43]2[CH:44]=CC=N[C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>ClCCl.CN(C=O)C>[CH:43]([NH:48][C:20]([C@@H:18]1[CH2:19][C@H:17]1[C:14]1[CH:15]=[CH:16][C:11]([NH:10][CH2:9][C:8]2[S:7][C:6]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=3)=[N:5][C:4]=2[CH:1]([CH3:2])[CH3:3])=[CH:12][CH:13]=1)=[O:21])([CH3:44])[CH3:42]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(C)N
Product: CC(C)NC(=O)[C@@H]1C[C@H]1c1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1
Reaction time: 0.25 h
Yield: 18.1 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[({4-isopropyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid (I-2n) (0.05 g, 0.11 mmol) in dichloromethane (3 mL) and DMF (1 mL) was added HATU (0.06 g, 0.16 mmol). The mixture was stirred for 15 min followed by addition of isopropylamine (0.01 g, 0.16 mmol). The solution stirred for 3 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a white ppt which was filtered and dried under high vacuum to give the title compound as a white powder (0.01 g, 22%). 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 8.3 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.60 (d, J=8.5 Hz, 2H), 5.37 (d, J=7.9 Hz, 1H), 4.45 (s, 2H), 4.10-4.08 (m, 1H), 3.93 (s, 1H), 3.16-3.13 (m, 1H), 2.39-2.37 (m, 1H), 1.54-1.50 (m, 1H), 1.42-1.39 (m, 1H), 1.35 (d, J=6.8 Hz, 6H), 1.15-1.09 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:18]([C:20]([CH2:27][CH3:28])([C:24](Cl)=[O:25])[C:21](Cl)=[O:22])[CH3:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([N:8]2[C:21](=[O:22])[C:20]([CH2:27][CH3:28])([CH2:18][CH3:19])[C:24](=[O:25])[O:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NO)c1ccc(Cl)cc1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(Cl)cc2)C1=O
Yield: 16.4 %

Procedure:
A mixture consisting of 2.70 g (0.0157 mol) of 4-chlorobenzohydroxamic acid, mp 170-171° C. (dec). (lit. mp 168° C. dec., Bielstein Handbook of Organic Chemistry, series H, vol 9. p. 341), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 3.097 g (0.0157 mol) of diethylmalonyl chloride was added dropwise over a 15 minutes period with stirring. The reaction mixture was stirred for 4 hours at room temperature after which time all the hydroxamic acid had dissolved. The solution was extracted two times with 50 ml portions of water, three times with 50 ml portions of 5% hydrochloric acid, and two times with 50 ml portions for 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 0.76 g (16.4%) of crude 2-(4-chlorobenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a solid residue. Recrystallization of the solid from methanol gave pure 2-(4-chlorobenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a white solid: mp 98-100° C.; IR (Nujol) 1812 (s, C=0) 1745 (s C=0) 1700 cm-1 (s, C=0); 1H NMR (400 MHz, CDCl3) 7.77-7.80 (m, 2H), 7.49-7.52 (m, 2H), 1.99 (q/ 4H), 1.04 (t, 6H); High resolution MS, calc'd for: C14H14NO4 -Cl: 295.0612. Found: 295.0615. Anal. Calc'd for: C14H14NO4Cl: C, 56.86; H, 4.77; N, 4.74; Cl, 11.99. Found: C, 57.04; H, 4.63; N, 4.58; Cl, 11.88.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:18](Br)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1)[CH:19]=[CH2:18]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 101 %

Procedure:
To a solution of benzyl 4-hydroxybenzoate (15.00 g, 65.1 mmol) in 130 mL acetone cooled in an ice water bath was added allyl bromide (11.4 mL, 130.1 mmol), followed by portionwise addition of potassium carbonate (45.00 g, 325.3 mmol). The ice bath was removed and the reaction mixture was warmed to rt. The mixture was stirred for 19 h. The precipitates were removed by filtration and the filtrate was concentrated to yield a colorless oil (17.65 g, 100%). LC/MS m/z 269 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.00-8.04 (m, 2H), 7.31-7.45 (m, 5H), 6.91-6.94 (m, 2H), 6.00-6.91 (m, 1H), 5.30-5.45 (m, 4H), 4.58-4.61 (m, 2H).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[CH:4]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=[O:5].[ClH:14]>CCOCC>[ClH:14].[CH2:1]([O:3][C:9](=[NH:10])[C:8]1[CH:11]=[CH:12][CH:13]=[C:6]([CH:4]=[O:5])[CH:7]=1)[CH3:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)c1cccc(C=O)c1
Reaction time: 144 h

Procedure:
59.7 ml (1.025 mol) of absolute ethanol are added to a solution of 86.7 g (0.662 mol) of 3-formylbenzonitrile in 530 ml of absolute ether and the whole is cooled to 0°. The reaction solution is saturated with dry hydrochloric acid gas and then left to stand for six days at 0°. After filtering off a fine precipitate, 1 liter of ether is added to the reaction solution, whereupon the title compound crystallises out; m.p. 126°-128° (with foaming).
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H:5]([OH:6])[C@H:3]1[OH:4].Cl.BrBr>O>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: BrBr
Agent: Cl
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Temperature: 35 °C

Procedure:
To a solution of 50 g whey lactose in 150 ml of water there is added 1 ml of concentrated hydrochloric acid and 1/2 g of bromine. The mixture is heated to about 35° C. on a water bath. After a reaction period of about 1 hour under stirring, the solution becomes completely clear. The D-galactose is separated by evaporation in vacuo and is precipitated in the form of white crystals.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]#[N:17])=[CH:10][C:9]=1[Cl:18])(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:18][C:9]1[CH:10]=[C:11]([C:16]#[N:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=1[CH:7]=[CH2:6]
Reactant: COc1cc(CCOS(C)(=O)=O)c(Cl)cc1C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=Cc1cc(OC)c(C#N)cc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 2-(2-chloro-4-cyano-5-methoxyphenyl)ethyl methanesulfonate (274 mg, 0.945 mmol) in DCM (4 mL) was treated with DBU (0.712 mL, 4.73 mmol) and stirred for 3 hours at 50° C., then at RT for 12 hours. TLC (50% ethyl acetate/hexanes) showed complete conversion to a faster intense UV band for the product. The reaction was then diluted with DCM and aq. citric acid and the mixture was extracted twice with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (10-20% ethyl acetate/hexanes) afforded the title intermediate.
Reaction SMILES: Cl.O1CCOC[CH2:3]1.[Cl:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>CO>[CH3:3][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:9]=1[Cl:8]
Reactant: C1COCCO1
Reactant: Cc1ccc(C(=O)O)c(Cl)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C)cc1Cl
Temperature: 25 °C
Yield: 87 %

Procedure:
Add 4N hydrogen chloride in 1,4-dioxane (20 mL, 80 mmol) to 2-chloro-4-methylbenzoic acid (5.0 g, 29.3 mmol) in methanol (60 mL). Stir the reaction mixture at room temperature over the weekend. Concentrate the reaction mixture and partition the residue between ethyl acetate and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract the aqueous with ethyl acetate (2×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to provide the title compound as a brownish oil (4.7 g, 25.5 mmol).
Reaction SMILES: [F-].[Cs+].Br[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:13][CH:12]=[N:11]2)=[CH:6][CH:5]=1.C([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)#N>COCCOC.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[C:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:13][CH:12]=[N:11]2)=[CH:6][CH:5]=1
Reactant: N#Cc1ccccc1B(O)O
Reactant: CC(C)S(=O)(=O)Nc1ccnn1-c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1ccnn1-c1ccc(-c2ccccc2)cc1
Temperature: 85 °C
Reaction time: 30 h
Yield: 36.4 %

Procedure:
Add cesium fluoride (0.221 g, 1.45 mmol) and dichloro[1,1′bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.024 g, 0.029 mmol) to a mixture of propane-2-sulfonic acid [2-(4-bromo-phenyl)-2H-pyrazol-3-yl]-amide (0.100 g, 0.290 mmol) and 2-cyanophenylboronic acid (0.043 g, 0.290 mmol) in anhydrous 1,2-dimethoxyethane (5.0 mL). Deoxygenate the mixture three times, immerse into a pre-heated (85° C.) oil bath, and stir for 30 h. Dilute the mixture with water and dichloromethane, filter through Celite®, and wash through with dichloromethane. Concentrate the mixture, re-dissolve in dichloromethane, adsorb onto silica gel, and subject to silica gel flash column chromatography (12 g column, eluting with a gradient of 0-10% methanol/dichloromethane for 40 min., followed by (20% 2.0M NH3 in methanol/dichloromethane) to yield the title product as a light brown solid (0.036 g, 34%): mass spectrum (m/e): 367.0 (M+1), 365.0 (M−1).
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[CH2:9]([CH:16]([CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.CN(C)C=O>[NH2:7][C:6]([NH2:8])=[NH:5].[S:23](=[CH:22][CH:16]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:25])=[O:24]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Agent: N=C(N)N
Agent: O=C(O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C=S(=O)=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
5.06 g (28 mmol) of guanidine carbonate are added at -10° to a solution of 4.73 g (16.2 mmol) of crude ethyl 2-benzyl-3-chlorosulphonyl-propionate, prepared according to the procedure described in EPA 0236734, in 150 ml of methylene chloride and 40 ml of dimethylformamide. The reaction mixture is stirred at room temperature overnight and thereafter evaporated. The residue is partitioned between methylene chloride and water, the aqueous phase is separated, evaporated under reduced pressure and the residue obtained is chromatographed on 50 g of silica gel using a 9:1 to 1:1 mixture of water and methanol as the eluent. The product obtained is recrystallized from a mixture of methanol and ether. There are obtained 3.29 g of ethyl (RS)-α-(sulphonylmethyl)hydrocinnamate guanidine salt as colourless crystals.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:22])[CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14])[CH3:10].[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH2:9]([O:11][C:12](=[O:22])[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])[CH:35]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:38][CH:37]=1)[OH:36])[CH3:10]
Reactant: CCOC(=O)C(C)Oc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(Oc1ccccc1)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
A solution of lithium diisopropylamide (LDA) (26 mL, 52 mmol, 2 M in tetrahydrofuran) was cooled to −78° C. and then added to a solution of 2-Phenoxypropionic acid ethyl ester (10 g, 51 mmol) in anhydrous tetrahydrofuran (THF) (80 mL) also cooled to −78° C. under an atmosphere of nitrogen. After 30 min, 4-benzyloxybenzaldehyde (10 g, 47 mmol) was added in one portion. After stirring over night, the reaction mixture was quenched with saturated solution of aqueous NH4Cl (10 mL) and the mixture allowed to warm to ambient temperature. The biphasic mixture was diluted with dichloromethane and partitioned, and the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified in silica to provide colorless oil (8.9 g, 47%), Rf=0.30 in 10:1 ethyl acetate: petroleum ether.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][CH:7]=2)[N:3]=[N:2]1.[Li+].[OH-]>O1CCOCC1.CCOC(C)=O>[S:1]1[CH:5]=[C:4]([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][CH:7]=2)[N:3]=[N:2]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(-c4csnn4)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(-c4csnn4)cc3)cc21
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(7-(4-(1,2,3-thiadiazol-4-yl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (42.7 mg, 0.030 mmol) in dioxane was added 1M LiOH (0.394 mL, 0.394 mmol). The reaction was stirred overnight. The reaction mixture was taken up in EtOAc and washed with 1 M HCl. The EtOAc extract was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a solid. LCMS m/z=406.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03-2.12 (m, 1H), 2.36 (dd, J=16.04, 8.97 Hz, 1H), 2.58-2.79 (m, 4H), 3.41-3.51 (m, 1H), 5.16 (s, 2H), 6.74 (dd, J=8.78, 2.46 Hz, 1H), 6.95 (d, J=2.40 Hz, 1H), 7.21 (d, J=8.72 Hz, 1H), 7.63 (d, J=8.21 Hz, 2H), 8.15 (d, J=8.21 Hz, 2H), 9.61 (s, 1H), 10.46 (s, 1H), 12.19 (bs, 1H).