Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[I:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47].CCN(C(C)C)C(C)C>CN(C=O)C>[I:43][C:44]1[CH:45]=[C:46]([NH:47][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: O=C(O)c1ccsc1
Reactant: Cc1ccc(N)cc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccsc2)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thiophene-3-carboxylic acid (2.75 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml) were stirred at room temperature for 15 mins. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction stirred at room temperature for 16 hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)thiophene-3-amide. LCMS: retention time 3.69 min, MH+ 344. NMR: δH [2H6]-DMSO 10.06,(1H, b), 8.34,(1H, m), 8.29,(1H, d), 7.70,(1H, dd) 7.66,(1H, dd), 7.62,(1H, dd), 7.30,(1H, d), 2.34,(3H, s).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:39]>COCCOC.C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O-:32])=[O:31])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:39]
Reactant: CCOC(=O)COc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCO
Product: O=C([O-])COc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1

Procedure:
A solution of ethyl [3-[[2-(4,5-diphenyl-2-oxazolyl)-2-cyclohexen-1-yl]methyl]phenoxy]acetate (355 mg) and 1N sodium hydroxide aqueous solution (0.71 ml) in 1,2-dimethoxyethane (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours and evaporated in vacuo. The solid residue was washed with diethyl ether to afford sodium [3-[[2-(4,5-diphenyl-2-oxazolyl)-2-cyclohexen-1-yl]methyl]phenoxy]acetate (308 mg) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.CN(C=O)C.C(Cl)[Cl:27]>S(Cl)(Cl)=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([Cl:27])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: O=C(Cl)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2,6-dichlorophenyl)-3H-benzoimidazole-5-carboxylic acid (5 g) in thionyl chloride (10 mL) containing a catalytic quantity of DMF was stirred at RT for 18 h. Methylene chloride was added and the resulting solid was filtered, washed with methylene chloride and dried under reduced pressure to give the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:8])[CH2:20][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[N:19]=2)=[CH:11][CH:12]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)c1ccc(Br)cc1
Product: O=C(Cc1cccc(Cl)n1)c1ccc(Br)cc1
Yield: 78.9 %

Procedure:
In a similar manner as described in Example 1, from ethyl 4-bromobenzoate (12.8 mL, 78.3 mmol) and 6-chloro-2-picoline (4.3 mL, 39.2 mmol), 1-(4-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (9.6 g, 82%) was obtained as a crystalline solid existing as a keto-enol tautomeric mixture. 1H NMR (CDCl3): for the keto tautomer δ 7.95 (d, 2H), 7.74–7.56 (m, 3H), 7.27 (m, 2H), 4.47 (s, 2H); MS m/z 310 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOC1.Cl[CH2:53][CH2:54][CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>C(OCC)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:53][CH2:54][CH2:55][CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)[N:10]=[CH:9]1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: ClCCCC1CCCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1nc(CCCOCCCC2CCCCC2)c[nH]1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
5 mmol of sodium 3-[1-(triphenylmethyl)imidazol-4-yl]propoxide in 10 ml of toluene containing 0.5 mmol of 15-Crown-5 and 5 mmol of (3-chloropropyl)cyclohexane are mixed and the mixture is stirred for 24 h at 75° C. The suspension is concentrated under vacuum, the product obtained is dissolved in diethyl ether, the solution is filtered and the residue washed with petroleum ether (40°-60° C.). The filtrate obtained is concentrated and maintained for 1 h at the boiling point in a 2N aqueous/alcohol (ethanol/water) hydrochloric acid solution. The ethanol is removed under a low vacuum and the precipitate is filtered under vacuum. The solution is basified, extracted with dichloromethane and the organic phase is concentrated. The title compound obtained is recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:13]([C:14]#[N:15])=[C:12]([F:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:3][CH3:4].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CC(O)C>[F:16][C:12]1[CH:11]=[CH:10][C:8]2[N:9]=[C:5]([C@@H:2]([NH:1][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[CH2:3][CH3:4])[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[C:13]=1[C:14]#[N:15]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
A mixture of 2-((S)-1-amino-propyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carbonitrile (0.260 g, 0.88 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.290 g, 1.24 mmol) and DIPEA (0.28 mL, 1.59 m mol) in IPA (2 mL) was stirred at 90° C. in a sealed tube for 16 h. The resulting mixture was concentrated in vacuo and the residue purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM). The product was dissolved in methanol and treated with HCl/dioxane (4M, 1.1 mL, 0.00450 mol) and stirred for 20 minutes. The mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) to give 244 as a white solid (0.205 g, 57%). LCMS (method K): Rt 3.51 min, [M+H]+ 413. 1H NMR (DMSO-d6): δ 13.20-12.50 (1H, bs), 9.60 (1H, s), 8.00 (1H, s), 7.71 (1H, m), 7.60 (2H, s), 7.51-7.49 (3H, m), 7.11-7.08 (1H, m), 6.86 (1H, m), 5.64 (1H, m), 2.10 (3H, s), 1.50 (3H, d, J=6.81 Hz)
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.C[O-].[Na+].O[N:15]=[C:16](Cl)[C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH:1]1([C:4]2[O:10][N:15]=[C:16]([CH:17]3[CH2:19][CH:18]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: ON=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1c(C2CC2c2ccccc2)noc1C1CC1
Temperature: 25 °C

Procedure:
A solution of methyl 3-cyclopropyl-3-oxopropanoate (0.36 mL, 2.9 mmol) in methanol (8 mL) was cooled to 0°C. and treated with sodium methoxide (0.76 mL of a 25% wt. solution in MeOH). After stirring fo(20 minutes, trans-N-hydroxy-2-phenylcyclopropanecarbimidoyl chloride rac-I-6D (0.57 g, 2.9 mmol) in methanol (0.5 mL) was added dropwise. The reaction mixture was warmed to rt and stirred fo(1 h. The reaction was concentrated in vacuo, diluted with water and extracted with dichloromethane. The aqueous was acidified with 6N HCl to pH=5 and extracted again with dichloromethane. The organics were washed with brine dried over Na2SO4, filtered, concentrated to yield 5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazole-4-carboxylic acid as clear oil which was directly used in the next step without further purification. MS m/z 270.1 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH:19]1[CH:20]=[CH:21][C:16]([S:22]([NH2:6])(=[O:24])=[O:23])=[CH:17][CH:18]=1.[I:1][C:2]1[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Ic1ccccc1
Product: NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
A mixture of 4-iodoaniline (10.00 g, 45.7 mmol, 1.0 equiv), triethylamine (6.36 ml, 45.7 mmol, 1.0 equiv) and CH2Cl2 (200 ml) was cooled to 0° C. Benzenesulfonyl chloride (5.85 ml, 45.7 mmol, 1.0 equiv) was added drop wise. The reaction mixture was stirred at rt for 3 h and then concentrated under vacuum to give a white solid (8.45 g, 51.5%) which was dried and used as such in the next step.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[NH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>>[C:10]([CH2:9][NH:8][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: C=CC(=O)OCC
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNCC(=O)OCc1ccccc1
Yield: 73 %

Procedure:
Ethyl acrylate (24.4 mL, 225 mmol) and glycine, benzyl ester, p-toluenesulfonate (50.0 g, 148 mmol) were combined in a 250 mL round bottom flask. With stirring, triethylamine (24.8 mL, 178 mmol) was added via syringe and the reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate (660 mL) and 10% aqueous Na2CO3 (300 mL). The organics were washed with water (100 mL) and saturated NaCl (100 mL). The organics were dried over MgSO4, filtered and concentrated in vacuo followed by pumping under high vacuum to yield N-(carbobenzyloxymethyl)-3-aminopropionic acid, ethyl ester (39.3 g, 73% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH3:3].P(Br)(Br)[Br:16]>C(OCC)C>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][Br:16])=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH3:3]
Reactant: CCCOc1ccc(CO)cc1OC
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCCOc1ccc(CBr)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 195.3 %

Procedure:
To a solution of 4-(propyloxy)-3-methoxybenzyl alcohol (2.28 g, 11.62 mmol) in anhydrous diethyl ether (30 mL) was slowly added PBr3 (0.55 mL, 5.81 mmol) via syringe, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with diethyl ether (150 mL) and washed with saturated aqueous NaHCO3 (2×75 mL) and brine (2×75 mL). The organic layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford 4-(propyloxy)-3-methoxybenzyl bromide (2.94 g, 98%) as a white solid. n-Butyllithium (2.5 M solution in hexanes, 0.56 mL, 1.40 mmol) was added to a solution of diisopropylamine (0.20 mL, 1.42 mmol) in dry THF (4 mL) at −78° C. The mixture was stirred at −78° C. for one hour, then HMPA (0.33 mL, 1.91 mmol) was added, followed by adding a solution of compound 21 (0.30 g, 1.27 mmol) in THF (3 mL). After 1 hour, a solution of 4-(propyloxy)-3-methoxybenzyl bromide (0.658 g, 2.54 mmol) in THF (3 μL) was added in one portion to the reaction, and the resulting mixture was stirred at −78° C. for an additional 4 hours. The excess base was quenched with saturated aqueous NH4Cl (15 mL), and the resulting solution was extracted with EtOAc (3×25 mL). The combined organic layer was washed with saturated NaCl (2×30 mL), dried over MgSO4, filtered and the filtrate evaporated to dryness. The residue was purified by column chromatography on silica gel (hexanes/EtOAc, 2:1) to give compound 137 (0.302 g, 57%) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[C:9]2=[O:16])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[O:46][C:47]1[CH:52]=[CH:51][N:50]=[C:49]2[CH:53]=[CH:54][S:55][C:48]=12)[NH2:42].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[F:38][C:39]1[CH:40]=[C:41]([NH:42][C:13]([CH:10]2[CH2:11][CH2:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]2=[O:16])=[O:15])[CH:43]=[CH:44][C:45]=1[O:46][C:47]1[CH:52]=[CH:51][N:50]=[C:49]2[CH:53]=[CH:54][S:55][C:48]=12
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)C1CCN(c2ccc(F)cc2)C1=O
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (38 mg, 0.169 mmol), EDCI (88 mg, 0.461 mmol), and HOBt (62 mg, 0.461 mmol) in DMF (3 ml) was stirred at room temperature for 1 hour. 3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (Example 1, Step B; 40 mg, 0.154 mmol) was added followed by Et3N (0.064 mL, 0.461 mmol). After stirring for 2 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (3:1=Et2O:EtOAc to 1:3=Et2O:EtOAc) to afford 38 mg (53%) of the desired product. 1H NMR (400 MHz, CD3OD/CDCl3) δ 8.45 (d, 1H), 7.92 (d, 1H), 7.85 (dd, 1H), 7.61 (m, 2H), 7.54 (d, 1H), 7.44 (m, 1H), 7.30 (t, 1H), 7.12 (m, 2H), 6.59 (d, 1H), 3.99 (m, 2H), 3.80 (dd, 1H), 2.67 (m, 1H), 2.52 (m, 1H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −117.6, −128.3. LRMS (ESI pos) m/e 466.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([Mg]Cl)[CH:15]=[CH:16][CH:17]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[C:7]([CH2:8][CH:9]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[CH:17]=2)[OH:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=CCc1cccnc1Br
Reactant: Cl[Mg]c1cccc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(Cc1cccnc1Br)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.4 %

Procedure:
To 2-(2-bromopyridin-3-yl)acetaldehyde (864 mg, 4.7 mmol) in THF (10 mL) at 0° C. was added (3-chlorophenyl)magnesium chloride (0.5M in THF, 14 mL, 7.04 mmol). The mixture was stirred at room temperature for 4 hours then treated with ammonium chloride (sat) at 0° C., extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel gave 2-(2-bromopyridin-3-yl)-1-(3-chlorophenyl)ethanol (490 mg, 35% yield) as white solid.
Reaction SMILES: C([O:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=1)(C)(C)C.C1CCC([N:25]=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[OH-].[NH4+]>CN(C=O)C>[C:14]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[OH:13])[C:6]([NH2:25])=[O:5])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)c1ccc(O)c(C(C)(C)C)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(N)=O)ccc1O
Yield: 88.4 %

Procedure:
The compound of Example 47E (800 mg, 4.1 mmol), DCC (856 mg, 5.4 mmol), and HOBt (540 mg, 5.4 mmol) were mixed in DMF (10 mL). Ammonium hydroxide (28%, 22 mL) was added to the mixture at 0° C. The reaction was stirred over night and purified by silica gel chromatography (70% -90% EtOAc/Hexane) to provide the title compound (700 mg, 87.5%). MS (DCI) m/z 194 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[O:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([CH:21]=[O:22])[C:14]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[O:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([C:21]([OH:25])=[O:22])[C:14]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)N1CCc2oc3c(OC)ccc(C=O)c3c2C1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)N1CCc2oc3c(OC)ccc(C(=O)O)c3c2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
2-ethoxycarbonyl-6-methoxy-1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine-9-carbaldehyde (from step 8) (170 mg, 0.559 mmol) was dissolved in acetone (10 ml): water (2.5 ml). To this solution sulfamic acid (81.0 mg, 0.838 mmol) was added and then reaction was cooled to 0° C. Then sodium chlorite (85 mg, 0.950 mmol) in water (2.5 ml) was added drop wise to maintain temperature below 10° C. and reaction was further stirred for 2 h. Reaction was quenched with water (20 ml) and precipitate was filtered on and dried to give 120 mg of white solid as the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1cc(-c2cc(CN(c3ccc(C)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-methylphenyl)amino]piperidine (581 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reaction time: 8 h

Procedure:
At room temperature, 22.67 ml (294.3 mmol) of trifluoroacetic acid were added slowly to a solution of 6.6 g (14.7 mmol) of tert-butyl cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetate in 90 ml of dichloromethane, and the mixture was stirred overnight. The solvent was then removed under reduced pressure and the residue was taken up in 100 ml of ethyl acetate and extracted with 50 ml of water. The organic phase was dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure. This gave 4.8 g (12.23 mmol, 83% of theory) of a colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=NC=[N:2]1.[H-].[Na+].[CH3:8][CH:9]([CH2:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:13]Cl)[CH3:10].O.[CH3:23][N:24](C=O)C>>[CH3:8][CH:9]([CH2:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:13][N:24]1[CH:23]=[CH:5][N:1]=[N:2]1)[CH3:10]
Reactant: CC(C)CC(O)(CCl)c1ccccc1
Reactant: CN(C)C=O
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)CC(O)(Cn1ccnn1)c1ccccc1
Temperature: 25 °C

Procedure:
1,2,4-Triazole (0.03 mol, 2.07 g) was added portionwise to 100% sodium hydride (0.03 mol, 0.72 g) in dry DMF (30 ml) and stirred at room temperature until the effervescence ceased. 2-Methyl-4-phenyl-5-chloropentan-4-ol (0.01 mol, 2.1 g) in dry DMF (10 ml) was added dropwise at room temperature and then the solution was stirred at 100° for 6 hours. On cooling to room temperature the solution was poured into water to precipitate out a solid which was recrystallised from petroleum (60°-80°)/chloroform giving the title compound (60%) as a white crystalline solid, m.p. 94°-95°.
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])[C:13]=1[NH2:29]>>[F:19][C:15]1[C:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:13]([NH:29][S:7]([C:4]2([CH2:1][CH:2]=[CH2:3])[CH2:6][CH2:5]2)(=[O:9])=[O:8])[C:12]([F:11])=[CH:17][C:16]=1[F:18]
Reactant: Nc1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Product: C=CCC1(S(=O)(=O)Nc2c(F)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1

Procedure:
According to the general procedure B, 1-allyl-cyclopropanesulfonyl chloride was reacted with 3,5,6-trifluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine to obtain the title product. 1H NMR (CDCl3, 300 MHz): δ 7.41 (dd, 1H), 7.38 (dd, 1H), 7.09 (s, 1H), 6.78 (m, 1H), 6.49 (m, 1H), 5.96 (s, 1H), 5.86 (m, 1H), 5.18 (d, 2H), 2.76 (d, 2H), 1.23 (m, 2H), 0.872 (m, 2H).