Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)(C)C.C1COCC1.O.C([O-])([O-])=O.[K+].[K+]>CCO>[CH:23]([Si:16]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[O:15][CH2:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][CH:6]=[CH:7]2)([CH3:25])[CH3:24]
Reactant: CC(C)[Si](OCc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc2[nH]ccc2c1)(C(C)C)C(C)C
Temperature: 85 °C

Procedure:
To a suspension of 1-triisopropylsilanyl-5-triisopropylsilanyloxymethyl-1H-indole (2.80 g, 6.09 mmol) in EtOH (30 mL)/THF (10 mL)/water (10 mL) was added K2CO3 (4.21 g, 30.4 mmol), and the reaction mixture was heated at 85° C. for 16 h. The reaction was quenched with 1N HCl at 0° C. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layers were washed with brine, dried (phase separator) and concentrated under reduced pressure. The oily residue was purified by flash column chromatography on silica gel (eluent gradient: c-hexane to c-hexane/EtOAc 9:1) to afford the title compound as a yellow oil. TLC, Rf (c-hexane/EtOAc 9:1)=0.29. tR (HPLC conditions k): 5.02 min. MS (LC/MS): 304 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH:11]1[CH2:14][CH2:13][CH2:12]1>>[N:11]1([C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH2:14][CH2:13][CH2:12]1
Reactant: N#Cc1cccnc1F
Reactant: C1CNC1
Agent: Cl
Product: N#Cc1cccnc1N1CCC1
Yield: 82 %

Procedure:
Prepared in 82% yield from 3-cyano-2-fluoropyridine and azetidine hydrochloride according to the procedure described for Example 178A. MS (ESI+) m/z 160.0 (M+H)+; 1H NMR (DMSO-d6) δ 2.28-2.38 (m, 2H), 4.19-4.25 (m, 4H), 6.73 (Dd, J=7.6, 4.9 HZ, 1H), 7.92 (dd, J=7.7, 1.8 Hz, 1H), 8.30 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([CH2:43][O:44][C:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[O:46])[O:23][C:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:25])=[O:19]>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([O:23][C:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:25])[CH2:43][O:44][C:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[O:46])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)CCCCCCC/C=C\CCCCCCCC
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCCCC

Procedure:
Next, 60% by mass of the olein part of the transesterified oil D obtained was mixed with 40% by mass of the above-mentioned palm medium-melting fraction 45 (PMF45) as the XOX type oil-and-fat B, and acetone of which volume was four times that of the above-mentioned mixture of the olein part of the transesterified oil D and the palm medium-melting fraction 45 (PMF45) was mixed, and a solvent fractionation was further carried out at −2 to 1 degrees C. so as to obtain a stearin part that were adopted as oil-and-fat compositions of Example 9.
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:15])[O:12]CC)[CH2:3]1.CCOC(/[N:21]=N/C(OCC)=O)=O.N=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.C1C=CC=CC=1>[NH2:21][C@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:15])[OH:12])[CH2:3]1
Reactant: CCO[PH](=O)CCCC[C@H]1CC[C@@H](O)C1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: [N-]=[N+]=N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](CCCC[PH](=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
To a solution of (±)-cis-ethyl (3-hydroxycyclopentanyl)butylphosphinate (10) (1.24 g, 5.29 mmol), DEAD (1.7 cm3) and HN3 (5.6 cm3 of a 1.9 M solution of benzene) in anhydrous THF (50 cm3) under an atmosphere of N2 at 0° C. was added triphenylphosphine (5.52 g, 21.1 mmol) in small portions over a period of 1 hour. The reaction mixture was allowed to warm to room temperature and stirring was continued for 12 hours. The reaction mixture was then heated to 50° C. for 3 hours, then water (2 cm3) was added and heating continued for a further 2 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between aqueous HCl (1 M, 30 cm3) and DCM (30 cm3). The organic layer was separated and further extracted with water (3×30 cm3). The combined aqueous fractions were washed with DCM (2×30 cm3) and concentrated in vacuo. The crude amino ester hydrochloride salt was hydrolysed by refluxing in aqueous HCl (6 M) for 30 hours after which time the reaction mixture was cooled to room temperature and the aqueous HCl removed under reduced pressure. The crude product was purified by ion exchange chromatography (Dowex 50, H+), eluting first with water until the eluate was colourless and the pH 7. On further elution with aqueous pyridine (1 M), ninhydrin positive fractions were collected and the solvent was removed in vacuo. The residual traces of pyridine were removed by repeatedly redissolving the compound in water (20 cm3) and re-evaporating (3 times). Recrystallisation from ethanol/acetone followed by drying gave the desired title compound (11) as a pale yellow solid (535 mg, 49%, m.p. (dec.) 145-148° C.): 1H-NMR (300 MHz, D2O) δH 0.78 (3H, t, J=7.2 and 7.2 Hz, PCH2CH2CH2CH3),1.02-2.24 (13H, m, C(1)—H, C(2)—H, C(2)—H′, C(4)—H, C(4)—H′, C(5)—H and C(5)—H′, PCH2CH2CH2CH3, PCH2CH2CH2CH3,PCH2CH2CH2CH3),3.61 (1H, m, C(3)—H); 13C-NMR (75 MHz, D2O) δC 13.45 (s, PCH2CH2CH2CH3), 24.08 and 24.29 (d, 3JPC=15.46 Hz, PCH2CH2CH2CH3), 24.29 and 24.35 (d, 2JPC=5.15 Hz, PCH2CH2CH2CH3), 25.31 (s, C(5)), 27.90 and 29.11 (d, JPC=91.04 Hz, PCH2CH2CH2CH3), 31.38 (s, C(2)), 31.72 and 31.84 (d, 3JPC=9.45 Hz, C(4)), 35.90 and 37.16 (d, JPC=95.05 Hz, C(1)), 52.76 and 52.90 (d, 3JPC=10.59 Hz, C(3)); 31P-NMR (121 MHz, D2O) δP 51.41; MS (ESI) m/z 206.4 (28%) (MH+), 166.9 (100), 102.4 (82), 411.3 (58).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:4]1=N)[CH3:2].C(OC(=O)C)(=[O:33])C.Cl>O>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:4]1=[O:33])[CH3:2]
Reactant: CCn1c(=N)c(-c2ccc3ccccc3c2)cc2cnc(Nc3ccccc3)nc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Product: CCn1c(=O)c(-c2ccc3ccccc3c2)cc2cnc(Nc3ccccc3)nc21

Procedure:
(8-Ethyl-7-imino-6-naphthalen-2-yl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine (150 mg) was added to 1 mL of acetic anhydride and heated at reflux for 2 minutes. The reaction was cooled and concentrated, resulting in an oil which was heated at reflux with 10 mL of 6N HCl for 10 minutes. The reaction was cooled, and 40 mL of water was added causing precipitation. The precipitate was removed by filtration and washed with water. The resulting solid was dried in a vacuum oven to provide 8-ethyl-6-naphthalen-2-yl-2-phenylamino-8H-pyrido[2,3-d]-pyrimidin-7-one; mp 254-256° C.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])([CH3:6])[CH2:3][S:4][CH3:5].[I:19]N1C(=O)CCC1=O>>[CH3:6][C:2]([NH:7][C:8](=[O:18])[C:9]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:11][CH:12]=[CH:13][C:14]=1[I:19])([CH3:1])[CH2:3][S:4][CH3:5]
Reactant: O=C1CCC(=O)N1I
Reactant: CSCC(C)(C)NC(=O)c1ccccc1[N+](=O)[O-]
Product: CSCC(C)(C)NC(=O)c1c(I)cccc1[N+](=O)[O-]
Yield: 43 %

Procedure:
N-(1,1-Dimethyl-2-methylthioethyl)-2-nitrobenzamide was treated in the same manner as in Example 19, except that N-iodosuccinimide was used as the iodinating agent, to obtain N-(1,1-dimethyl-2-methylthioethyl)-2-iodo-6-nitrobenzamide (yield 43%, melting point 114–115° C.). Regioselectivity of iodination into the 2-position was 100%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1.O=[C:24]([CH3:38])[CH2:25][CH2:26][N:27]1C(=O)C2C(=CC=CC=2)C1=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:17]3[CH2:22][CH2:21][N:20]([CH:24]([CH3:38])[CH2:25][CH2:26][NH2:27])[CH2:19][CH2:18]3)[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(C2(c3ccc(Br)cc3)Oc3ccccc3O2)CC1
Yield: 59.3 %

Procedure:
Using general procedure B with the above amine (400 mg, 1.11 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (482 mg, 2.22 mmol) and then using general procedure D gave 3-{4-[2-(4-bromophenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (284 mg, 59% over 2 steps) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].C1C(=O)N([Br:28])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:28][C:18]1[N:4]2[CH:5]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]2=[N:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc2c1Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (1.5 g, 4.65 mmol, prepared according to Example 23, Step 12.2) in DMF (19 mL) was treated with NBS (910 mg, 5.12 mmol) at RT and stirred for 1 h. The reaction mixture was diluted in AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated to yield the crude title compound (1.92 g, 4.65 mmol, quant.), which was used in the next step without further purification. MS: 400 [M+1]+; HPLC: AtRet=2.67.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[NH:22][CH3:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:22]([C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[Cl:19])[CH3:23])=[O:17])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1
Reactant: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: CNc1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl

Procedure:
Following Example 10 and General Procedure C, 150 is prepared from 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid 11 and 2-chloro-N-methylaniline. MS: (ESI+) 449.9.
Reaction SMILES: C(O)(=O)/C=C\C(O)=[O:5].C(O)(=O)/C=C\C(O)=O.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[S:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]([NH:38][C:39]2[C:40]([S:48][CH3:49])=[N:41][C:42]([CH3:47])=[CH:43][C:44]=2[S:45][CH3:46])=[O:37])[CH2:31][CH2:30]1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl.CO>[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[S:26][CH2:27][CH2:28][N:29]1[CH2:30][CH2:31][N:32]([CH2:35][C:36]([NH:38][C:39]2[C:40]([S:48]([CH3:49])=[O:5])=[N:41][C:42]([CH3:47])=[CH:43][C:44]=2[S:45][CH3:46])=[O:37])[CH2:33][CH2:34]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Reactant: O=C(O)/C=C\C(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CSc1cc(C)nc(S(C)=O)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 26 h
Yield: 40.1 %

Procedure:
To a mixed solution of this amide (500 mg, 0.664 mmol) in chloroform (10 ml) and methanol (2 ml) was added m-chloroperbenzoic acid (213 mg, 1.23 mmol) with ice-cooling, and stirred at room temperature for 26 hours. The reaction solution was diluted with chloroform. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol=10:1) to provide 138 mg (yield 40%) of the desired compound as colorless amorphous. IR (neat) cm−1: 3424, 3155, 1695, 1571, 1481. 1H-NMR (d6-DMSO, 120° C.) δ: 2.51 (3H, s), 2.56 (3H, s), 2.73,(3H, s), 2.59-2.68 (6H, m), 2.77 (2H, t, J=7.1 Hz), 2.81-2.92 (2H, br s), 3.11 (1H, d, J=15.8 Hz), 3.17 (1H, d, J=15.8 Hz), 3.41 (2H, t, J=7.1 Hz), 7.07-7.13 (2H, m), 7.30 (1H, S), 7.38-7.44 (2H, m), 9.26 (1H, br s).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH2:6][CH:5]2[CH3:12].N1C=CC=CC=1.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>C(Cl)Cl>[C:20]([N:7]1[C:8]2[C:4](=[C:3]([CH3:13])[C:2]([OH:1])=[C:10]([CH3:11])[CH:9]=2)[CH:5]([CH3:12])[CH2:6]1)(=[O:24])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cc2c(c(C)c1O)C(C)CN2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1O)C(C)CN2C(=O)C(C)C
Temperature: 0 °C
Reaction time: 17 h
Yield: 73.2 %

Procedure:
To an ice-cold solution of indoline 10 (160 mg, 0.9 mmol) dissolved in methylene chloride (4 mL) and kept under an argon atmosphere were added sequentially pyridine (1 mL) and isobutyryl chloride (0.I mL, 9 mmol); the mixture was stirred over the range of 0° C. to room temperature for some 17 h. The mixture was diluted with methylene chloride, washed with brine and dried (MgSO4). Removal of solvents followed by purification of the residue using 1:9 ethyl acetate:hexanes as eluent afforded the desired N-isobutyryl-5-hydroxy-3,4,6-trimethylindoline (11b, 163 mg, 73% yield) as a colorless solid, mp 123°-125° C. Spectral data: 1H NMR: δ1.1-1.25 (m, 9H), 2.17 (s, 3H), 2.20 (s, 3H), 2.72 (quintet, 1H, J=6.5 Hz), 3.35 (t, 1H, J=6.5 Hz), 3.78 (dd, 1H, J=10.1, 1.0 Hz), 4.13 (t, 1H, J=9.1 Hz), 7.95 (s, 1H); 13C NMR: δ 11.9, 16.5, 18.8, 19.3, 20.7, 33.1, 34.0, 56.3, 116.8, 119.5, 122.1, 134.1, 135.0, 148.8, 175.0; HRMS: calcd. for C15H21NO2 247.1523, fnd. 247.1573. Anal: calcd. for C15H21NO2C, 72.85, H, 8.55, N, 5.66, fnd. C, 72.63, H, 8.59, N, 5.60.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]([CH3:26])[C:23](=[O:25])[CH3:24]>>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH:22]([CH3:26])[C:23](=[O:25])[CH3:24])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)Cl
Reactant: O=C(c1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)C(C)N1CCN(C(=O)c2ccccc2)CC1

Procedure:
0.05 g (73%) target compound as yellow syrup was yielded on the same method as manufacturing example 10 using 0.05 g (0.26 mmol) 1-benzoylpiperazine, 0.11 g (0.79 mmol, 3.0 eq.) potassium carbonate, 0.03 g (0.26 mmol, 1.0 eq.) 3-chloro-2-butanon.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].O1CCCC1.C([Li])CCC.[CH2:17]([CH:24]([CH2:27]Br)[CH2:25]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C(Cl)Cl.CCCCCC>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:27][CH:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25]1
Reactant: BrCC(CBr)Cc1ccccc1
Reactant: CSCS(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CSC1(S(C)=O)CC(Cc2ccccc2)C1
Temperature: -10 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (1.010 g) was dissolved in 15 ml. of tetrahydrofuran, and at -10° C., 6.0 ml of an n-hexane solution (1.4 millimols/milliliter) of n-butyl lithium was added. The mixture was stirred at -10° C. for 1 hour, and then 1.030 g of 2-benzyl-1,3-dibromopropane was added. The mixture was stirred for 100 minutes at -10° C., and then for 3 hours at room temperature. Methylene chloride (100 ml) and 30 ml. of water were added and the organic phase was separated. The aqueous phase was extracted twice with 50 ml. of methylene chloride each time. The extract and the organic phase were combined, dried with anhydrous sodium sulfate, and concentrated at reduced pressure. The residue was separated by column chromatography (silica gel, eluted with methylene chloride and ethyl acetate) to afford 686 mg of 3-benzylcyclobutanone dimethyl mercaptal S-oxide as a light yellow oil in a yield of 77%.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30](COC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@@H:9]([O:10]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@@H]2F)[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1.[C:60]([OH:66])([C:62](F)(F)[F:63])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30]([CH2:9][OH:10])[C@H:62]([F:63])[C@H:60]2[OH:66])[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1
Reactant: F[C@H]1[C@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1c(Cl)nc2cc(Cl)c(Cl)cc21
Reactant: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@H]1F

Procedure:
While the desired 3',5'-di-O-trityl derivative, compound 2, was only obtained in 10% yield from compound 1, the isomeric 2',5'-ditrityl derivative, compound 3, was obtained in a 30% yield. The fluorination of compound 3 using DAST and pyridine in CH2Cl2 gave 2,5,6-trichloro-1-(2,5-di-O-trityl-3-deoxy-3-fluoro-β-D-xylofuranosyl)benzimidazole (compound 5) in a 71% yield. The fluorination of compound 2 using the same conditions gave 2,5,6-trichloro-1-(3,5-di-O-trityl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)benzimidazole (compound 4) in a 63% yield. Both compounds 4 and 5 were deprotected using 10% CF3COOH in CHCl3 to give good yields of the deprotected nucleosides 2,5,6-trichloro-1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)benzimidazole (compound 6) and 2,5,6-trichloro-1-(3-deoxy-3-fluoro-β-D-xylofuranosyl)benzimidazole (compound 7), respectively.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH:7]1([Mg]Cl)[CH:11]=[CH:10][CH:9]=[CH:8]1>>[CH2:2]=[CH:3][CH2:4][CH:5]([C:8]1[CH2:7][CH:11]=[CH:10][CH:9]=1)[CH3:6]
Reactant: C=CCCCBr
Reactant: Cl[Mg]C1C=CC=C1
Product: C=CCC(C)C1=CC=CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-1-pentene (100 g of 95 wt %, 0.637 mol) was added cyclopentadienyl magnesium chloride (700 mL of 1 M solution in THF, 0.7 mol) at 0° C. in an hour. After stirring for an additional 30 minutes at 0° C., the mixture was warmed to room temperature. After stifling overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a yellow-brown liquid (98 g, crude penten-4-ylcyclopentadiene). To the crude penten-4-yl-cyclopentadiene (89 g, ca. 0.579 mol, theoretical number=(89/98)*0.637) dissolved in THF (500 mL) was added n-BuLi (60 mL of 10 M in hexanes, 0.6 mol) at −78° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (110 g, 0.604 mol) dissolved in THF (500 mL) at 0° C. in 25 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 40° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (145 g, 84% yield based on 5-bromo-1-pentene) as a dark red viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH3:11].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([Br:9])[C:3]=1[O:10][CH3:11]
Reactant: COc1c(Br)cc(F)cc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1c(Br)cc(F)c([N+](=O)[O-])c1Br
Temperature: 4 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a stirred solution of c.H2SO4 (740 mL) at 0 to 5° C. was added 1,3-dibromo-5-fluoro-2-methoxybenzene (223.3 g, 0.786 mol). A solution of fuming nitric acid (90%, 38 mL, 0.815 mol) in c.H2SO4 (740 mL) was added dropwise, maintaining the temperature between 0 and 5° C. The reaction mixture was stirred at 3 to 5° C. for 2 hours, quenched into ice (2.2 kg) and extracted with dichloromethane (3×2 L). The combined dichloromethane extracts were washed with saturated aqueous NaHCO3 solution (2×2 L), dried over Na2SO4, filtered and the filter cake washed with DCM (3×400 mL). The filtrate was concentrated in vacuo at 40° C. to give 1,3-Dibromo-5-fluoro-2-methoxy-4-nitrobenzene as a pale orange crystalline solid (244.9 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[CH3:41][C@@H:42]1[C@@H:47]([NH2:48])[CH2:46][C@H:45]2[CH2:49][C@@H:43]1[C:44]2([CH3:51])[CH3:50]>>[CH3:41][C@@H:42]1[C@@H:47]([NH:48][C:30]([C@H:29]2[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]2[CH2:24][C:23]2[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=3[F:38])[C@H:10]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:22]=2)=[O:31])[CH2:46][C@H:45]2[CH2:49][C@@H:43]1[C:44]2([CH3:50])[CH3:51]
Reactant: C[C@@H]1[C@@H](N)C[C@H]2C[C@@H]1C2(C)C
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3[C@@H](C(=O)N[C@H]4C[C@H]5C[C@@H]([C@@H]4C)C5(C)C)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 56.7 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7 (Epimer 2), 0.075 g, 0.125 mmol) was reacted with (1S,2S,3S,5R)-2,6,6-Trimethyl-bicyclo[3.1.1]hept-3-ylamine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 26 μL, 0.154 mmol) to form (R)-2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (Epimer 2) (0.052 g, 57%). m/z=733 (M+1); HRMS: calcd for C39H59ClFN4O4S. Calc [M+H+] 1733.3924. found 733.3925.