Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:15])[N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9]2)=[N:4]1.[N+](C1C=C2C(=CC=1)NN=C2)([O-])=O>[Pd].C(OCC)(=O)C>[F:15][CH:2]([F:1])[N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH2:12])=[CH:9]2)=[N:4]1
Reactant: O=[N+]([O-])c1ccc2nn(C(F)F)cc2c1
Agent: [Pd]
Agent: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CCOC(C)=O
Product: Nc1ccc2nn(C(F)F)cc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In accordance with Example 62 (Step 1), ethyl acetate (20 mL) was added to 2-(difluoromethyl)-5-nitro-2H-indazole (429 mg) obtained by using 5-nitro-1H-indazole instead of 5-bromo-7-methyl-1H-indazole. Thereafter, 10% palladium on carbon (300 mg) was added, and the reaction solution was stirred under hydrogen atmosphere at room temperature for 4 hours. The insolubles were filtrated, and then the solvent was evaporated under vacuum to obtain 2-(difluoromethyl)-2H-indazol-5-amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
Into a 1-L 3-necked round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-chloro-4-iodobenzene (10.0 g, 41.9 mmol) in tetrahydrofuran (150 mL). The solution was cooled to −78° C., then n-BuLi (2.4 M) (16.6 mL, 39.8 mmol) was added dropwise and the resulting mixture was stirred for 0.5 h at −78° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (7.60 g, 38.1 mmol) in tetrahydrofuran (50 mL) was added dropwise and the resulting mixture was stirred for 1 h at -78° C. The reaction was then warmed to 0° C., and carefully quenched by the slow addition of water (150 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (150 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:50 to 1:3) to yield the title compound as a light yellow solid (9.3 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:31])[CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17]1>>[CH3:14][N:15]([CH3:31])[CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([NH:30][C:9](=[O:11])[CH:8]=[CH:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=4)[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17]1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Product: COc1ccc(C=CC(=O)Nc2ccc3nc(N4CCC(N(C)C)C4)sc3c2)cc1
Yield: 5.7 %

Procedure:
Prepare according to Method B, using trans-4-methoxycinnamic acid (112 mg, 0.629 mmol) and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (162 mg, 0.618 mmol) to afford the title compound (15 mg, 6%). mass spectrum (m/e): 423.3 [M+H], 421.3 [M−H].
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]([N+:22]([O-:24])=[O:23])=[C:13](F)[C:12]=1[F:26]>>[F:26][C:12]1[C:11]([F:10])=[CH:16][C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:14]([N+:22]([O-:24])=[O:23])[C:13]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: COCCOc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Product: COCCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Yield: 32 %

Procedure:
2-Fluoro-4-iodoaniline (1.6 g, 6.8 mmol) and 1,2,3-trifluoro-5-(2-methoxyethoxy)-4-nitrobenzene (1.7 g, 6.8 mmol) were reacted using the condition described in Example 1 (Step A) to form the title compound (1.02 g, 32%); m/z=467 [M−1].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26].[CH3:36][Zn]C.C1(C)C=CC=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:36])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26]
Reactant: C[Zn]C
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (150 mg, 0.270 mmol) and 2N dimethylzinc in toluene (0.27 mL, 0.540 mmol), the title compound was obtained as a solid (75 mg, 47% yield). MS (ESI): 535 [M+H]+.
Reaction SMILES: CC([O-])(C)C.[K+].[F:7][C:8]([F:27])([F:26])[C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[NH:12][CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:32]Cl>CS(C)=O>[C:15]([C:14]([C:17]#[N:18])=[CH:13][N:12]([CH2:32][C:31]1[CH:34]=[CH:35][C:36]([Cl:37])=[C:29]([Cl:28])[CH:30]=1)[C:11]1[CH:10]=[C:9]([C:8]([F:26])([F:27])[F:7])[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=1)#[N:16]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: N#CC(C#N)=CNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)=CN(Cc1ccc(Cl)c(Cl)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
With stirring, 16.8 g of potassium tert-butylate are added by small amounts to a solution of 45.7 g of 3,5-bis-trifluoromethyl-N-(2,2-dicyanovinyl)-aniline in 200 ml of dimethyl sulphoxide. The solution is kept for 4 hours at 40° C. With further stirring, 20.8 ml of 3,4-dichlorobenzyl chloride in 20 ml of dimethyl sulphoxide are added dropwise and the reaction mixture is then stirred for 12 hours at 40° C. The mixture is then poured onto 2 liters of ice and the precipitated product is extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulphate and the chloroform is distilled off. The crude product is chromatographed over a silica gel column with methyl acetate/hexane (1:3 v/v) as eluant, yielding 15 g of the desired product in the form of yellow crystals with a melting point of 102°-103° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)#[N:2].[N:11]([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2)=[C:12]=[O:13]>C(OCC)C>[CH:19]1[C:20]2[C:15](=[C:14]([NH:11][C:12](=[O:13])[O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: O=C=Nc1cccc2cnccc12
Reactant: N#Cc1ccc(CO)cc1
Solvent: CCOCC
Product: N#Cc1ccc(COC(=O)Nc2cccc3cnccc23)cc1
Reaction time: 2 h
Yield: 44 %

Procedure:
4-Cyanobenzyl alcohol (150 mg, 1.13 mmol) in diethyl ether (10 mL) was treated with the product from Example 61A as an ethereal solution. The mixture was stirred for 2 hours, filtered, and the filter cake was washed with diethyl ether to provide the title compound as an off-white solid (150 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.32 (d, J=1.0 Hz, 1H), 8.52 (d, J=6.1 Hz, 1H), 7.88-7.99 (m, 5H), 7.65-7.70 (m, 3H), 5.31 (s, 2H); MS (ESI+) m/z 304 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][NH2:17])=[CH:12][CH:13]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[Br:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][CH:27]=O)[CH:22]=[CH:23][CH:24]=1>>[C:2]([O:6][C:7]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][NH:17][CH2:27][CH2:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[CH:20]=2)=[CH:12][CH:13]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=CCCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCN)s1
Agent: Cl
Product: CC(C)(C)OC(=O)c1ccc(CCCNCCCc2cccc(Br)c2)s1

Procedure:
The title compound was prepared from 5-(3-amino-propyl)-thiophene-2-carboxylic acid tert-butyl ester hydrochloride and 3-(3-bromo-phenyl)-propionaldehyde following the method described in Step A of Example 141. 1H NMR (400 MHz, CDCl3) δ7.50 (d, 1H), 7.28-7.30 (m, 2H), 7.06-7.14 (m, 2H), 6.75 (d, 1H), 2.85 (t, 2H), 2.65-2.78 (m, 4H), 2.60 (t, 2H), 1.92-2.04 (m, 4H), 1.52-1.54 (m, 9H); MS 438 (M+).
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:20][O:21][CH2:22][C:23]([OH:25])=O.CCN=C=NCCCN(C)C.[NH2:37][C@@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][C@H:39]1[NH:47][C:48]([C:50]1[NH:54][C:53]2[C:55]([Cl:59])=[C:56]([Cl:58])[S:57][C:52]=2[CH:51]=1)=[O:49]>C(Cl)Cl>[Cl:58][C:56]1[S:57][C:52]2[CH:51]=[C:50]([C:48]([NH:47][C@@H:39]3[CH2:40][C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[C@H:38]3[NH:37][C:23](=[O:25])[CH2:22][O:21][CH3:20])=[O:49])[NH:54][C:53]=2[C:55]=1[Cl:59]
Reactant: COCC(=O)O
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
DIPEA (180 μL, 1.05 mmol), HOBT (68 mg, 0.5 mmol), methoxyacetic acid (0.5 mmol, 38 μL) and EDAC (120 mg, 0.63 mmol) were added to a suspension of N-[(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 8, 240 mg, 0.5 mmol) in anhydrous DCM (7 mL). The reaction was stirred at ambient temperature for approximately 16 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (10 mL), washed with water (2×10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue was purified by flash column chromatography on SiO2 (1:1 EtOAc:isohexane); the solvent removed by evaporation under reduced presssure and dried to give the title compound (44 mg, 20%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11]O.Cl>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:11])=[O:5]
Reactant: CO
Reactant: Cc1ccccc1C(=O)O
Agent: Cl
Product: COC(=O)c1ccccc1C
Yield: 82 %

Procedure:
A solution of 2-methylbenzoic acid (18a) (5 g, 36.8 mmol) in MeOH.HCl (2.4M, 50 mL) was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure to give compound 18b (4.5 g, 82% yield), which was used without purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C(=[N:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1.[C:27]([NH:35][CH:36]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37][CH2:38][CH:39]=[O:40])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1>[NH2:20][CH:21]([CH:39]([OH:40])[CH2:38][CH2:37][CH:36]([NH:35][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(CCC=O)NC(=O)c1ccccc1
Reactant: CCOC(=O)CN=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(O)C(N)C(=O)OCC)NC(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
Diisopropylamine (2.34 ml, 16.7 mmoles) is added to anhydrous THF (75 ml) and cooled to -10° C. At this point 2.24M n-BuLi (6.8 ml, 15.2 mmoles) is added slowly. After complete addition the reaction mixture is stirred for 10 minutes before being cooled to -78° C. At that temperature ethyl N-benzylideneglycinate (4) (2.9 g, 15.2 mmoles) is added and stirring is allowed to proceed for 15 minutes before aldehyde (8) (4.0 g, 15.2 mmoles), dissolved in anhydrous THF (25 ml), is added dropwise to the yellow anion. After complete addition the reaction is stirred another 11/2 hours before being poured into cold 5% aqueous NH4Cl. This mixture is extracted with CHCl3 (3×100 ml). The combined extracts are washed with saturated aqueous NaCl, dried over MgSO4, filtered and evaporated to dryness. The oily residue is taken up in THF (300 ml) and shaken with 5% aqueous HCl (200 ml) in a separatory funnel. This mixture is washed with Et2O (3×100 ml), basified with solid NaHCO3 and extracted with CHCl3 (3×150 ml). The combined extracts are washed with saturated aqueous NaCl (1×150 ml), dried over MgSO4, filtered and evaporated to dryness in vacuo to yield 4.0 g (72% yield) of the desired compound as a yellow glass. 'H-N.M.R. (CHCl3 /TMS): δ=1.20 (t, 3H, --CH2CH3); 1.28 (t, 3H, --CH2CH3 ); 1.45-2.20 (m, 4H, --CH2CH2 --); 2.46 (broad s, 2H, --NH2); 3.18-4.00 (m, 2H, >CH--NH2, CHOH); 4.19 (q, 2H, --CH2CH3); 4.25 (q, 2H, --CH2CH3); 4.53-5.08 (m, 1H, >CH--NH--); 7.05-7.97 ppm (m, 5H, Ph).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9]>>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9]
Reactant: C[C@H](O)C(=O)O
Agent: O=C(O)CO
Product: CC(O)C(=O)O
Yield: 70.5 %

Procedure:
A 90 wt % aqueous solution of L-lactic acid (50 g) and 50 g of glycolic acid were put into a reaction vessel equipped with a stirrer and a nitrogen-introducing tube. After substitution of nitrogen gas was carried out three times, the mixture was concentrated at 150° C. for 5 hours with stirring in a stream of nitrogen to give 65 g of lactic acid-glycolic acid oligomer. To the obtained oligomer was added 1.3 g of Baylith 5A with which sodium elution (381 ppm) had been observed. Then, the temperature was raised to 210° C., and the pressure was reduced gradually to 20 mmHg over 30 minutes. The mixture was stirred at 210±10° C. for 3 hours. After the pressure was reduced gradually to 1 mmHg over 30 minutes, the mixture was stirred at 210±10° C. for 7 hours to give lactic acid-glycolic acid copolymer in the molten state. The product was cooled to room temperature to give 23.50 g of lactic acid-glycolic acid copolymer as a light brown solid. The weight-average molecular weight of this copolymer was 65,000.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][O:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>C(#N)CC.CO>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][O:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:44][CH2:43]2)=[CH:40][CH:41]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCOCC12
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CO
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCOCC12
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-(hydroxymethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-6(5H)-one (73.2 mg, 0.311 mmol) in propiononitrile (778 μl) was added (cyanomethyl)trimethylphosphonium iodide (91 mg, 0.373 mmol) and DIPEA (163 μl, 0.934 mmol) and finally 1-(4-chlorophenyl)piperazine (61.2 mg, 0.311 mmol). The mixture was heated to 90° C. for 4 hours. The crude product was cooled to RT and left to sit 16 hours, then treated with MeOH (5 mL). The precipitate was collected and refluxed in EtOH (15 mL) 2 hours. The suspension was cooled to room temperature and filtered to retrieve the title compound (75.6 mg, 58.7%) as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 7.82 (d, J=1.8 Hz, 1H), 7.72 (br. s., 1H), 7.16-7.24 (m, 2H), 6.99 (br. s., 1H), 6.77-6.89 (m, 2H), 4.41 (dd, J=11.5, 3.7 Hz, 1H), 4.26 (dd, J=13.3, 1.6 Hz, 1H), 3.95-4.12 (m, 2H), 3.59-3.75 (m, 2H), 3.46 (br. s., 2H), 3.16 (br. s., 4H), 2.94-3.06 (m, 1H), 2.60 (br. s., 4H). [M+H] calc'd for C21H24ClN5O2, 414; found, 414.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9](OS(C)(=O)=O)[CH2:8][N:7]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].[C:29]([SH:32])(=[O:31])[CH3:30].CC(C)([O-])C.[K+]>CN(C)C=O>[C:29]([S:32][C@@H:9]1[CH2:8][N:7]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[O:17])[C@H:6]([CH2:5][O:4][CH2:3][CH2:2][F:1])[CH2:10]1)(=[O:31])[CH3:30]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCF)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](COCCF)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C

Procedure:
A solution of (2S,4R)-2-(2-fluoroethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.95 g) in dimethylformamide (5 ml) was added to a mixture of thioacetic S-acid (1.26 ml) and potassium tert-butoxide (1.98 g) in dimethylformamide (25 ml) in a nitrogen stream, and the mixture was heated at 75°-80° C. for 2 hours. The mixture was poured into ice-water (100 ml) and extracted with ethyl acetate (100 ml). The extract was washed with water (100 ml×2) and brine (100 ml), in turn, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (80 g) and eluted with chloroform to give (2S,4S)-4-acetylthio-2-(2-fluoroethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.75 g).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][CH:7]([OH:16])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH:7]2[CH2:6][NH:5][C:3](=[O:4])[CH2:2][O:16]2)=[CH:10][CH:11]=1
Reactant: O=C(CBr)NCC(O)Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1COC(Cc2ccc(F)cc2)CN1
Yield: 13.9 %

Procedure:
To an ethanol solution (16 mL) of 2-bromo-N-[3-(4-fluorophenyl)-2-hydroxypropyl]acetamide (1.00 g, 3.45 mmol) synthesized in Reference Synthesis Example 42, potassium carbonate (715 mg, 5.17 mmol) was added and the resultant solution was stirred at 80° C. for 2.5 hours. After completion of the reaction, the reaction solution was filtered with Celite and the filtered residue was washed with ethanol. The filtrate was concentrated under reduced pressure and chloroform was added to the concentrated filtrate, followed by concentrating the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/20→ethyl acetate/methanol=20/1 (v/v)) to obtain the title compound (100 mg, yield 14%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[Br:34])=[O:28].CCOCC.CCCCCCC>O1CCCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[Br:34])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1sccc1Br
Reactant: c1ccc(COCn2cnc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1sccc1Br)c1nc2ccccc2n1COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
To a stirred solution of 1-benzyloxymethyl-1H-benzimidazole (648 mg, 2.72 mmol, Example 1B) in tetrahydrofuran (15 mL) at −78° C. under nitrogen is added n-butyllithium (1.30 mL of a 2.5 M solution in hexanes, 3.25 mmol) over 5 minutes and the resulting yellow solution is stirred at −78° C. After 25 minutes, a solution of 3-bromo-thiophene-2-carboxylic acid methoxy-methyl-amide (680 mg, 2.72 mmol, Example 1A) in tetrahydrofuran (10 mL) is added over 15 minutes and the reaction stirred at −78° C. After 1 hour the reaction is warmed to ambient temperature and stirred for an additional 2 hours. The reaction is quenched with saturated ammonium chloride and the mixture extracted with ethyl acetate. The organic layer is washed with water and brine successively, dried over magnesium sulfate, and concentrated under reduced pressure to a yellow oil. The crude material is chromatographed on silica, eluting with 40% ethyl acetate/heptane, to give the product. Trituration with ether/heptane affords (1-benzyloxymethyl-1H-benzimidazol-2-yl)-(3-bromothiophen-2-yl)methanone as an off-white powder; TLC Rf 0.52 (silica, 1:1 ethyl acetate/heptane); LC/MS: (M+H 427.0, RT=3.84 minutes); 1H NMR [(CD3)2SO), 300 MHz]: δ 8.18 (d, 1H, 5.2 Hz), 7.90-7.82 (m, 2H), 7.55-7.50 (m, 1H), 7.45-7.38 (m, 2H), 7.25-7.17 (m, 5H), 6.13 (s, 2H), 4.58 (s, 2H).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1F)[CH2:13][Br:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C)C=CC=1[Cl:34])(=O)C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:34])[CH2:13][Br:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(OC(=O)c2ccccc2)c1
Reactant: O=C(Oc1cc(CBr)ccc1F)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Oc1cc(CBr)ccc1Cl)c1ccccc1
Yield: 62 %

Procedure:
The title compound was prepared by adapting the method for 3-benzoyloxy-4-fluorobenzyl bromide using 3-benzoyloxy-4-chlorotoluene (2.47 g, 10.0 mmol), NBS (1.96 g, 11.0 mmol) and benzoyl peroxide (10 mg) in carbon tetrachloride (25 mL). The residue was purified by flash column chromatography [SiO2, EtOAc/n-hexane (1:40)] to give 3-benzoyloxy-4-chlorobenzyl bromide as a colourless oil (2.012 g, 62%) which solidified on standing and was used without further purification; δH (400 MHz, CDCl3) 4.48 (s, 2H), 7.27 (dd, J=8.2, 2.0, 1H), 7.36 (d, J=2.0, 1H), 7.46 (d, J=8.2, 1H), 7.50-7.58 (m, 2H), 7.64-7.71 (m, 1H), 8.22-8.28 (m, 2H). LRMS (FAB+) m/z (rel. intensity) 325.0 (81, [M+H]+), 327.0 (100, [M+H]+);
Reaction SMILES: [BrH:1].C1C2C(=CC=CC=2)CCC1.BrBr.[CH3:14][C:15]([CH3:22])([CH:20]=[CH2:21])[CH2:16][C:17]([OH:19])=[O:18].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:1][CH2:21][CH2:20][C:15]([CH3:22])([CH3:14])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: C=CC(C)(C)CC(=O)O
Reactant: Br
Agent: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccc2c(c1)CCCC2
Product: CC(C)(CCBr)CC(=O)O
Temperature: -10 °C

Procedure:
A stream of dry hydrogen bromide gas (made from 83.3 m) of tetralin and 71 ml of bromine) was bubbled through a stirred solution of 3,3-dimethylpent-4-enoic acid (80 g, 0.625 mol) in dry light petroleum b.p. 40°-60° C. (940 ml) together with benzoyl peroxide (6.4 g, 0.025 mol) until it was saturated (about 2 hours) whilst the reaction mixture was maintained at the temperature between 10°-20° C. by occasional cooling. After completion of the reaction, the mixture was cooled down to -10° C. and the solid product was collected (near quantitative yield). The product was sufficiently pure by NMR spectroscopy to be used directly in the next step synthesis. However, a pure product was obtained after recrystallised from light petroleum spirit m.p. 53°-55° C. 1H NMR δ3.43 (2H, t), 2.27 (2H, s), 2.10 (2H, t), and 1.08 (6H, s).