Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].Cl.C[N:15](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[OH-].[NH4+]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc(Cl)cc(Cl)c1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: NC(=O)c1c(N)cc(Cl)cc1Cl
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 2-amino-4,6-dichloro-benzoic acid (0.5 g, 2.43 mmol) in THF (22 mL) under nitrogen atmosphere was added successively N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.51 g, 2.67 mmol), N-hydroxybenzotriazole (0.36 g, 2.67 mmol) and N-methylmorpholine (0.3 mL, 2.67 mmol). The mixture was stirred for 1.5 h before a 50% ammonium hydroxide solution (1.03 mL, 14.58 mmol) was added. The mixture was stirred overnight. The solvent was evaporated under reduced pressure, water (20 mL) was added and the solution was extracted with EtOAc (50 mL×2). The combined organic layers were washed with water, brine, dried over sodium sulfate and evaporated under reduced pressure to provide crude yellow solid (0.45 g). The crude product was triturated with ether to give pure 2-amino-4,6-dichloro-benzamide (0.41 g, 82%). A mixture of 2-amino-4,6-dichloro-benzamide (0.2 g, 0.97 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.3 g, 0.97 mmol), sodium hydrogensulfite (0.11 g, 1.05 mmol) and p-toluenesulfonic acid (0.093 g, 0.48 mmol) in N,N-dimethyl acetamide (8 mL) was stirred at 150° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, then water (70 mL) was added and the precipitate was collected, and washed with water, dried under vacuum and triturated with ether to provide the crude mixture of 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-5,7-dichloro-3H-quinazolin-4-one and 5,7-dichloro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-3H-quinazolin-4-one (0.298 g), which was used as such in the next step. To the above described mixture (0.298 g, 0.59 mmol) in tetrahydrofurane (5 mL) was added tetrabutylammonium fluoride (2.35 mL, 2.35 mmol) under nitrogen atmosphere. The reaction mixture was stirred overnight before the solvent was evaporated under reduced pressure and water was added to obtain a precipitate. The solid was filtered off, washed with water, dried under vacuum and triturated with ether to provide crude yellow solid (0.226 g, 98%). The crude was purified twice by flash column chromatography to give pure 5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.069 g, 19%). Selected data: MS (ES) m/z: 378.92, 380.88, 382.89; MP 260.8-262.6° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]1=2)=[O:19])[CH3:17]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: C[C@H](N)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-R), the title compound was prepared. The product was purified by chromatography (silica, 2.5% MeOH/CHCl3).
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:34][C:35]1[CH:36]=[C:37]([CH:52]=[C:53]([F:66])[C:54]=1[O:55][Si:56]([CH:63]([CH3:65])[CH3:64])([CH:60]([CH3:62])[CH3:61])[CH:57]([CH3:59])[CH3:58])[CH2:38][CH:39]([CH:50]=O)[CH2:40][CH2:41][C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1.[Cl-].[NH4+]>CCCCCC.C1COCC1>[F:34][C:35]1[CH:36]=[C:37]([CH:52]=[C:53]([F:66])[C:54]=1[O:55][Si:56]([CH:57]([CH3:59])[CH3:58])([CH:60]([CH3:62])[CH3:61])[CH:63]([CH3:65])[CH3:64])[CH2:38][CH:39](/[CH:50]=[CH:10]/[C:9]1[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=1[OH:7])[CH2:40][CH2:41][C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1
Reactant: CC(C)[Si](Oc1c(F)cc(CC(C=O)CCc2ccc(C#N)cc2)cc1F)(C(C)C)C(C)C
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](Oc1c(F)cc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1F)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.82 ml (2.91 mmol) of a 1.6 M solution of n-butyllithium in hexane are slowly added to a solution of 579 mg (1.25 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 11.5 ml of THF at 0° C. Then, at this temperature, 490 mg (1.04 mmol) of 4-[3-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)-4-oxobutyl]benzonitrile are slowly metered in. The reaction solution is stirred at 0° C. for 2 h and then mixed with 100 ml of saturated ammonium chloride solution and extracted with diethyl ether. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 379.7 mg (54% of theory) of a colorless solid are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=[CH:11][C:5]=2[CH:4]=[CH:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>[Fe].C(O)(=O)C>[C:16]([NH:12][C:9]1[CH:10]=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([CH3:15])([CH3:1])[O:7][C:6]=2[CH:8]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)C=Cc2ccc([N+](=O)[O-])cc2O1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)OC(C)(C)C=C2
Temperature: 120 °C

Procedure:
2,2-Dimethyl-7-nitro-2H-benzo[b]pyran (40.00 g, the preparation of which is disclosed in British Patent No. 1,548,222), glacial acetic acid (200 ml), acetic anhydride (120 ml) and electrolytic iron powder (88 g) were stirred and heated at 120° C. for 16 hours. Dilution with water, extraction via chloroform followed by washing of the organic layer with water and sodium bicarbonate solution, drying evaporation etc., gave a crude gum which was chromatographed on a silica gel column using ethyl acetate -60°-80° petroleum ether mixtures in a gradient elution technique. Fractions homogeneous by TLC were combined and recrystallised from 60°-80° petroleum ether to give 7-acetamido-2-,2-dimethyl-2H-benzo[b]pyran (5.27 g) as white needles of mp 80°-81° C.; nmr (CDCl3) 1.39 (6H), 2.12 (3H), 5.48 (1H, d, J=10), 6.21 (1H, d, J=10), 6.76-7.34 (3H, m), 8.95 (1H). Anal. Calcd for C13H15NO2 ; C, 71.87; H, 696; N, 6.45. Found: C, 72.00; H, 7.11; N, 6.23%.
Reaction SMILES: [C:1](=[O:7])([O-:6])[O:2][CH:3](Cl)[CH3:4].[CH3:8][CH2:9][O:10][C:11]1[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:32]([C:33]4[N:37]([C:38]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:36]=[N:35][N:34]=4)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:57]([OH:59])=[O:58])[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O.O.C1(C)C=CC=CC=1>[CH3:8][CH2:9][O:10][C:11]1[N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[C:32]([C:33]4[N:37]([C:38]([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)([C:51]5[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:36]=[N:35][N:34]=4)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:57]([O:59][CH:3]([O:2][C:1]([O:6][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:7])[CH3:4])=[O:58])[N:12]=1
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Cl)OC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 62.5 °C

Procedure:
Carbohexyl 1-chloroethyl carbonate (36 g) is added to a suspension of trityl candesartan (100 g), potassium carbonate (24 g) and potassium iodide (12 g) in DMSO (500 ml) at temperature of 60-65° C. over 30 min. Reaction mass is maintained at 60-65° C. for 2 hrs, added toluene (300 ml) and water (300 ml). Reaction mass is mixed for 15 min., allowed to settle, the layers are separated at 60-65° C. and aqueous layer is extracted with toluene (200 ml). Water (200 ml) washings are given to the combined organic layer and toluene extractions twice at temperature of 60-65° C. Toluene is distilled off from water washed organic layer at temperature below 60° C. under vacuum, ethanol (100 ml) is added, mixed for about 30 min and distilled off solvents under vacuum at temperature below 60° C. under vacuum. Residue is cooled to 30-35° C., ethanol (300 ml) is added, mixed for 2 hrs at 25-30° C. and filtered the product. Wet cake is washed with ethanol (100 ml) and suck dried. Wet weight of Cilexetil trityl candesartan is 180 g
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl>NC(CC)CC>[CH2:7]([CH:6]([N:5]1[C:2]2[C:11]3[N:10]=[CH:9][CH:8]=[C:7]([C:12]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=4[CH3:20])[C:6]=3[N:5]=[C:4]([CH3:21])[C:3]=2[CH2:22][CH2:23]1)[CH2:11][CH3:2])[CH3:8]
Reactant: Cc1cc(C)c(-c2ccnc3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Agent: CCC(N)CC
Product: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)ccnc3c21
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A solution of 4-chloro-3-(2-chloroethyl)-8-mesityl-2-methyl[1,5]naphthyridine (150 mg, 0.42 mmol) in 3-aminopentane (7.5 mL) was stirred at 200° C. for four hours in a sealed tube. After overnight, the residue was purified by silica gel column chromatography (30-50% ethyl acetate/hexane), to give the title compound (50 mg) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[C:13]=2[CH3:14])=[O:17])[CH:20]=[CH:21][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][OH:35])[CH2:31][CH2:32]1)#[N:25]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1F
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCO)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.8 %

Procedure:
1-(2,4-Difluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.4 g), 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.4 g), 1-hydroxybenzotriazole (1.6 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.3 g) were added to dimethylformamide (25 ml) and the mixture was stirred at room temperature for 5 h. The reaction mixture was treated with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase:chloroform:methanol=100:1). Diisopropyl ether was added to the obtained oily substance to allow crystallization. The crystals were recrystallized from isopropyl alcohol to give the title compound (2.4 g), melting point: 193–194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[CH2:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.Br[CH2:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:9]([N:8]1[C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH:12]=[CH:13][C:17]2[N:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=2[CH2:15]1)(=[O:11])[CH3:10]
Reactant: C=Cc1ccc(Cl)cc1NC(C)=O
Reactant: Clc1ccc(CBr)c(Cl)n1
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2ccc(Cl)nc2C=Cc2ccc(Cl)cc21

Procedure:
The title compound was prepared from 6C and 13B by a route analogous to that used for the preparation of 1D. HPLC Rt=2.769 min; LCMS Found: (M+H)+=319.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:21])[C:15]2[CH:34]=[CH:35][CH:36]=[CH:37][C:14]=2[N:13]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[C:12]1=[O:44]>C(Cl)Cl>[O:18]=[C:17]1[N:16]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:21])[C:15]2[CH:34]=[CH:35][CH:36]=[CH:37][C:14]=2[N:13]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[C:12](=[O:44])[CH:11]1[NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)Nc3ccccc3)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1

Procedure:
A solution of phenyl isocyanate (36.6 mg, 0.295 mmol) in methylene chloride (1 ml) was added to a solution of 2-(3-Amino-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide (140 mg, 0.295 mmol) in methylene chloride (1 ml) and the resultant solution stirred at rt for 16 h. The solvent was removed in vacuo and the residue recrystalised from 5% methanol in ethyl acetate to afford the title compound product (49 mg) as a white powder. 1H NMR (300 MHz, CDCl-3). s 8.72 (s, 1H), 8.56 (d, 1H, J=8.0), 7.92 (d, 1H, J=8.0), 6.91-7.43 (m, 16H), 6.43 (d, 1H, J=8.3), 5.43 (d, 1H, J=8.3), 4.95 (sept, 1H, J=6.8), 4.60 (d, 1H, J=11.8), 4.18 (d, 1H, J=11.8), 3.88 (s, 3H), 1.06 (m, 6H). Low resolution MS (FAB) m/e 593 (m+).
Reaction SMILES: ClN1C(=O)CCC1=O.[OH:9][N:10]=[CH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:13]=1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])[CH:30]=[C:29]([Cl:39])[CH:28]=1.BrC(C(F)(F)F)=C.FF.C(N(CC)CC)C>CN(C)C=O.O>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]2([C:35]([F:38])([F:36])[F:37])[O:9][N:10]=[C:11]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]([C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:13]=3)[CH2:34]2)[CH:30]=[C:29]([Cl:39])[CH:28]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(C=NO)c2ccccc12
Agent: C=C(Br)C(F)(F)F
Agent: FF
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-Chlorosuccinimide (1.16 g, 8.72 mmol) was added to a stirred solution of methyl 4-[(hydroxyimino)methyl]-1-naphthalenecarboxylate (i.e. the product of Step A, 1.0 g, 4.36 mmol) in N,N-dimethylformamide (5.0 mL). This mixture was stirred for 1.5 h at room temperature, and then a solution of 1,3-dichloro-5-[1-(trifluoromethyl)ethenyl]benzene (3.20 g, 13.1 mmol, prepared from commercially available 2-bromo-3,3,3-trifluoropropene by the method described in J. Fluorine Chem. 1999, 95, 167-170) and triethylamine (6.1 mL, 43.6 mmol) in N,N-dimethylformamide (4.0 mL) was added. After stirring for an additional 2 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate/hexanes to afford the title compound as a pale yellow oil (700 mg). 1H NMR (CDCl3): δ 8.88 (d, 1H), 8.80 (d, 1H), 8.10 (d, 1H), 7.68 (m, 2H), 7.55 (m, 3H), 7.46 (dd, 1H), 4.27 (d, 1H), 4.03 (s, 3H), 3.91 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:6]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:6]=1)(=[O:26])=[O:25]
Reactant: COc1cc(-c2cc(CCCO)ccn2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cc(CCCOS(C)(=O)=O)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(3-Hydroxypropyl)-2-(3,4,5-Trimethoxyphenyl)-pyridine (486 mg) was dissolved in chloroform (10 mL), and to the solution methanesulfonyl chloride (186 μL) and triethylamine (400 μL) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with chloroform, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: [F:1][C@@:2]([C:10]([F:13])([F:12])[F:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](Cl)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>CCOCC>[F:1][C@@:2]([C:10]([F:11])([F:12])[F:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][OH:4]
Reactant: CCCC[C@](F)(C(=O)Cl)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCC[C@](F)(CO)C(F)(F)F
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
In 80 ml of anhydrous ether was dissolved 7.30 g of (R)-(-)-2-fluoro-2-(trifluoromethyl)hexanoylchloride, and then 0.83 g of lithium aluminum hydride was portionwise added to the above-obtained solution while the solution was being cooled with ice. The resulting mixture was stirred for 30 minutes. Thereafter, 1N hydrochloric acid was portionwise added to the resulting reaction mixture while the mixture was being cooled with ice, and then a reaction product was extracted with ether. The resulting organic layer was dried with magnesium sulfate, the solvent was removed under reduced pressure, and then the residual product was distilled. Thus, 4.6 g of (S)-(+)-2-fluoro-2-(trifluoromethyl)-1-hexanol was obtained which had the physical properties as mentioned hereinbefore.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])=[CH:19][CH:18]=[C:17]([Cl:28])[C:13]=1[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:23])=[O:24])=[CH:19][CH:18]=[C:17]([Cl:28])[C:13]=1[C:14]([NH:10][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)=[O:15]
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1Cl
Reactant: Nc1cnc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1Cl
Temperature: 60 °C
Reaction time: 24 h
Yield: 1.7 %

Procedure:
1H-Pyrrolo[2,3-b]pyridin-5-amine (192 mg, 1.44 mmol) in N,N-dimethylformamide (7.2 mL) was sequentially treated with 2,6-dichloro-3-(propylsulfonamido)benzoic acid (690.5 mg, 2.212 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (466.4 mg, 2.433 mmol), and 1-hydroxybenzotriazole (328.8 mg, 2.433 mmol) and heated to 60° C. After 24 hours, the reaction mixture was allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate, washed with water (4×), sodium bicarbonate (2×), and brine (1×), dried over sodium sulfate, and concentrated. The crude product was applied directly to a silica gel column and eluted with a gradient (30% to 100%) of ethyl acetate-hexanes to provide 2,6-dichloro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (10.5 mg, 0.0246 mmol, 3.41% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 11.70-11.59 (s, 1H), 10.77-10.68 (s, 1H), 9.88-9.75 (s, 1H), 8.39-8.30 (m, 2H), 7.56-7.47 (m, 3H), 6.49-6.45 (d, 1H), 3.21-3.04 (m, 2H), 1.82-1.70 (m, 2H), 1.03-0.95 (t, 3H); MS (APCI-neg) m/z=425.1 (M-H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]Br.CCCCCCC>COC>[Br:26][C:10]1[C:11]([CH3:25])=[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Reactant: BrBr
Agent: COC
Solvent: CCCCCCC
Product: Cc1c(C)c(OCc2ccccc2)c(Br)c(C)c1OCc1ccccc1
Reaction time: 8 h

Procedure:
In 100 mL dimethyl ether (DME) was dissolved 1,4-bis(benzyloxy)-3,5,6-trimethylbenzene prepared as in step 1 (5 g, 15.0 mmol) which was treated with a solution of Br2 (0.85 mL, 16.5 mmol, 1.1 equiv.) in 10 mL DME (1.6 M) over ten minutes via a dropping funnel. The reaction was judged incomplete by HPLC. Additional Br2 in DME (0.42 mL, 1.31 g, 8.19 mmol, 0.55 equiv.) was added and stirred overnight. A white solid precipitated from the solution during the night. The reaction was treated with 200 mL EtOAc, which dissolved the solid, and washed with H2O until the aqueous washings were colorless (3×100 mL) The combined aqueous layers were back extracted with EtOAc (3×50 mL) and the combined organics washed 2×100 mL saturated NaCl, dried over Na2SO4 and concentrated to a brown solid. The solid was adsorbed onto silica and purified by flash chromatography (gradient elution 2-20% EtOAc/heptane) to give a yellow solid. The solid was suspended into heptane, stirred overnight, filtered and the filter cake rinsed with heptane. The resulting white powder was dried in vacuo and yielded 3.31 g of 2-bromo-1,4-bis(benzyloxy)-3,5,6-trimethylbenzene as a white powder. HPLC 97.8% at 215 nm, did not ionize; 1H NMR (400 MHz, CDCl3) d=7.57 (d, 2H), 7.48 (d, 2H), 7.44-7.36 (m, 6H), 4.87 (s, 2H), 4.74 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H) ppm.