Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([S:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([S:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cccnc1Cl
Reactant: O=S([O-])c1cccc(Cl)c1
Agent: [Na+]
Product: O=Cc1cccnc1S(=O)(=O)c1cccc(Cl)c1

Procedure:
The title compound was prepared by the method of Preparation 5a using 2-chloropyridine-3-carbaldehyde and 3-chlorobenzenesulfinic acid sodium salt.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH:13]1([N:16]2[C:24]3[C:19](=[CH:20][C:21]([CH2:25][NH:26][S:27]([C:30]4[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:31]=4[CH3:40])(=[O:29])=[O:28])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:15][CH2:14]1>>[Cl:8][C:7]1[C:2]([N:26]([CH2:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[N:16]([CH:13]2[CH2:15][CH2:14]2)[N:17]=[CH:18]3)[S:27]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:31]=2[CH3:40])(=[O:29])=[O:28])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C3CC3)c2)c(C)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C3CC3)c2)c2ncc(C(F)(F)F)cc2Cl)c(C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-cyclopropyl-1H-indazol-5-yl)methyl)sulfamoyl)-3-methylbenzoate (step-2 of Example 33).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:6]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([CH2:2][C@@H:3]([OH:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:6]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(CC)COc1cccc(C[C@H](O)CCl)c1
Agent: [Na+]
Product: CCC(CC)COc1cccc(C[C@H](O)CN=[N+]=[N-])c1

Procedure:
Treatment of (S)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol with sodium azide following the method used in Example 6 gave (S)-1-azido-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol which was used without further purification.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][N:5]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[F:18][C:2]1([F:1])[CH2:3][CH2:4][N:5]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([O:11][C@@H:21]2[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]2)=[O:10])[CH2:6][CH2:7]1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1ccccc1)N1CCC(F)(F)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCC(F)(F)CC1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A mixture of 2-(4,4-difluoropiperidin-1-yl)-2-phenylacetic acid (512 mg, 2.01 mmol), (R)-quinuclidin-3-ol (306 mg, 2.41 mmol), DCC (497 mg, 2.41 mmol) and HOBT (369 mg, 2.41 mmol) in THF (20 ml) was stirred at room temperature over a week-end. THF was evaporated, the crude was taken up with EtOAc and washed twice with 2M K2CO3 and then with brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash-chromatography (DCM/MeOH=9/1) to obtain the title compound (348 mg, 47.6% yield) as a yellow sticky oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[C:9](O)(=[O:11])C>CO.C[O-].[Na+]>[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[C:1](=[NH:2])[O:11][CH3:9]
Reactant: CC(=O)O
Reactant: N#Cc1cnccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cnccn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 910.8 %

Procedure:
Cyanopyrazine (5.26 g, 50 mmol) was dissolved in methanol (40 ml), and sodium methoxide (0.27 g, 5.0 mmol) was added. The reaction mixture was stirred at room temperature for 45 minutes. After the reaction was completed, acetic acid (0.33 g, 5.5 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Dichloromethane (50 ml) and diethyl ether (50 ml) were added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl pyrazinecarboximidate (6.87 g) as colorless powder.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)(O)[O-:13].[Na+].ClCCl.ClC1C=CC=C(C(OO)=O)C=1>O>[O:13]1[CH:6]2[CH:5]1[CH:4]1[CH2:7][CH:1]2[CH:2]([S:8]([NH2:11])(=[O:9])=[O:10])[CH2:3]1
Reactant: NS(=O)(=O)C1CC2C=CC1C2
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)C1CC2CC1C1OC21
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 63.1 %

Procedure:
To a four-necked flask having an inner volume of 500 ml and equipped with an electromagnetic stirring device, a nitrogen inlet tube, and a thermometer, there were charged 10.0 g (57.7 mmol) of 5-norbornene-2-sulfonamide, 15.1 g (180.0 mmol) of sodium bicarbonate, and 200 g of dichloromethane. After cooling the mixture to 5° C., 14.8 g (60.0 mmol) of 70% m-chloroperbenzoic acid was added thereto over a 20 minute period, and the mixture was stirred at 5° C. for 2 hours. To the reaction mixture was added 100 g of distilled water, and the mixture was separated into an organic layer and an aqueous layer. The organic layer was washed with 40 g of distilled water and concentrated under reduced pressure. By recrystallizing the residue obtained from ethyl acetate, there was obtained 6.89 g (36.4 mmol) of 5,6-epoxy-2-norbornanesulfonamide represented by the following formula (yield 63%):
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)[CH2:9][OH:10])(C)(C)C.[ClH:25]>ClCCl.O1CCOCC1>[ClH:25].[NH2:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)[CH2:9][OH:10]
Reactant: CCCC(C)COc1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCC(C)COc1ccc([C@@H](N)CO)cc1

Procedure:
To a solution of {(R)-2-Hydroxy-1-[4-(2-methyl-pentyloxy)-phenyl]-ethyl}-carbamic acid t-butyl ester (0.70 g 2.08 mmol), in dichloromethane (10 ml) in an ice bath was added 4 M HCl in 1,4-dioxane (10 ml). The final mixture was then stirred at room temperature for 1.5 hrs. The excessive solvent was removed in vacuum to give a white solid, which was used directly for next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:32])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([Cl:32])(=[O:17])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccccc1-c1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccccc1-c1ccc(Br)cc1

Procedure:
4′-Bromo-biphenyl sulfonic acid (5 g) was refluxed in thionyl chloride (30 mL) with a catalytic quantity of DMF (0.5 mL) for 4 hours. Toluene was added and the solvents evaporated under vacuum. The residue collected was recrystallised from petrol/ethyl acetate to give the title compound as large colourless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH3:26])=[O:24])=[N:11][N:12]2[CH:17]([C:18](O)=[O:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH3:26])=[O:24])=[N:11][N:12]2[CH:17]([C:18]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)O
Reactant: C1CCNCC1
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)N1CCCCC1
Reaction time: 18 h

Procedure:
The title compound was prepared from 3-benzyloxy-2-methoxycarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-7-carboxylic acid using a procedure similar to that described in Example 2, Step 5 except that piperidine was used in place of 4-fluorobenzylamine, and the reaction time totaled 18 hours. 1H NMR (400 MHz, d6-DMSO) δ 7.50-7.48 (m, 2H), 7.40-7.31 (m, 3H), 5.88 (d, J=2.4 Hz, 1H), 5.19 (dd, J=11.2, 25.6 Hz, 2H), 4.14 (dd, J=5.2, 13.6 Hz, 1H), 3.78 (s, 3H), 3.68-3.52 (m, 4H), 3.34-3.33 (m, 1H), 2.98 (s, 3H), 1.62 (br s, 4H), 1.47 (br s, 2H); ES MS (M+H)=427.
Reaction SMILES: [CH3:1][C@@:2]([S:25]([CH3:28])(=[O:27])=[O:26])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[N:11]1)[C:3]([O:5]CC)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C@@:2]([S:25]([CH3:28])(=[O:27])=[O:26])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[N:11]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(-c2cnc3ccccc3n2)cn1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@](CCn1cc(-c2cnc3ccccc3n2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(quinoxalin-2-yl)-1H-pyrazol-1-yl]butanoate (0.078 g, 0.19 mmol) in THF-H2O (20 mL:10 mL) was added LiOH (0.047 g, 1.94 mmol, 10 eq). The mixture was allowed to stir at room temperature overnight. The mixture was acidified with 1M HCl and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(quinoxalin-2-yl)-1H-pyrazol-1-yl]butanoic acid (0.072 g, 99% yield) as a white solid. LC-MS M+H+375.1.
Reaction SMILES: [CH2:1]([CH:3]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[O:5][CH2:4]1)[CH3:2].O.[F:17][C:18]([F:22])([F:21])[CH:19]=O.[BH3-]C#N.[Na+]>>[CH2:1]([CH:3]1[N:8]([CH2:19][C:18]([F:22])([F:21])[F:17])[C:7]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1COc2cc([N+](=O)[O-])ccc2N1
Reactant: O=CC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CCC1COc2cc([N+](=O)[O-])ccc2N1CC(F)(F)F
Yield: 35.9 %

Procedure:
This compound was prepared by General Method 7 (EXAMPLE 5) from (±)-3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (200 mg, 0.96 mmol), 2,2,2-trifluoroacetaldehyde monohydrate (1.12 g, 9.6 mmol) and NaBH3CN (292 mg, 4.6 mmol) to afford 100 mg (36%) of 3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine, a yellow solid. Data for (±)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: Rf 0.69 (2:3 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 7.80 (dd, 1H, J=8.9, 2.6), 7.71 (d, 1H, J=2.6), 6.72 (d, 1H, J=9.0), 4.34 (dd, 1H, J=10.9, 1.4), 4.19-4.05 (m, 1H), 4.02 (dd, 1H, J=11.0, 2.3), 3.87-3.72 (m, 1H), 1.72-1.62 (m, 2H), 1.00 (t, 34H, J=7.4).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:20]2[CH:19]([C:21]([OH:23])=O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:24][NH:25][C@@H:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[N:28]12[CH2:33][CH2:32][CH:31]([CH2:30][CH2:29]1)[C@@H:26]([N:25]([CH3:24])[C:21]([CH:19]1[C:20]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:23])[CH2:27]2
Reactant: CN[C@H]1CN2CCC1CC2
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN(C(=O)C1c2ccccc2Oc2ccccc21)[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
Oxalyl chloride (0.540 ml, 0.0062 mol) was added to a solution of 9H-xanthene-9-carboxylic acid (1.16 g, 0.0051 mol) and dimethylformamide (two drops) in 20 ml of CHCl3 (ethanol free) at 0° C. The mixture was allowed to warm to room temperature under stirring and maintained 1 h at this temperature. After this time, the reaction mixture was concentrated to dryness in vacuo and the obtained residue was dissolved in CHCl3 (15 ml) and concentrated again. This procedure was repeated two times. The obtained residue was dissolved in CHCl3 and the solution cooled to 0° C. A solution of 0.865 g (0.0062 mol) of (3R)-N-methylquinuclidin-3-amine (Intermediate I-4) in 10 ml of CHCl3 was added. The mixture was allowed to warm to room temperature under stirring. After 4 hours at this temperature, the reaction mixture was treated with K2CO3 (saturated solution) and the aqueous phase was extracted with CHCl3. The organic solutions were combined and washed with K2CO3 (saturated solution) and water, dried over Na2SO4 filtered and concentrated to dryness. The obtained residue was purified by column chromatography (silica gel, CHCl3: NH4OH 99:1→CHCl3: MeOH:NH4OH 98:2:1 as eluent) to yield 900 mg (50%) of the title product.
Reaction SMILES: [CH3:1]I.[F:3][C:4]1[CH:5]=[C:6]([C:11]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]2=[S:17])[CH:7]=[CH:8][C:9]=1[F:10]>C(#N)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]([C:11]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][N:13]=[C:12]2[S:17][CH3:1])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCNC1=S
Reactant: CI
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCN=C1SC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Methyl iodide (0.520 ml,) was added to a mixture of ethyl 3-(3,4-difluorophenyl)-2-thioxopiperidine-3-carboxylate (500 mg) in acetonitrile (5 mL) at room temperature, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (530 mg).
Reaction SMILES: [CH3:1][CH2:2][O-].[Na+].[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.C=O>CN(C=O)C>[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:8][C:9]2[C:1]3[C:2](=[CH:13][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH:10]=2)=[CH:6]1
Reactant: C1=Cc2ccccc2C1
Reactant: CC[O-]
Agent: C=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(CC2=CCc3ccccc32)c2ccccc2C1
Yield: 254.1 %

Procedure:
1.05 g of EtONa (15.4 mmol) dissolved in 200 mL of DMF and 10.0 ml of indene (90%, 77.5 mmol) were introduced, at room temperature, in this order in a three-neck, 500 mL flask with stirring bar. 3.15 mL of aqueous formalin (37% solution, 38.8 mmol) dissolved in 10 mL of DMF were added dropwise, in 15 minutes: a mildly exothermic reaction was observed and the solution turned dark brown, with shades of violet. At the end of the addition, the reaction mixture was maintained under stirring for 20 hours, at room temperature. The reaction was quenched by pouring the mixture on ice and NH4Cl. The organic product was extracted with Et2O and the water layer was washed with Et2O; the organic layers were combined, dried over MgSO4, filtered and finally concentrated, thus obtaining an orange-brown oil. Said oil was further concentrated to eliminate the remaining indene, thus yielding 9.56 g of bis-(3-indenyl)methane, as an orange-brown oil (53.2% yield by GC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].O[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:28])[CH2:25][CH2:26][CH3:27])=[CH:20][CH:19]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([OH:28])[CH2:25][CH2:26][CH3:27])=[CH:20][CH:19]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Reactant: CCCC(O)c1ccc(CO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCC(O)c1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.5 %

Procedure:
A solution of ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (2.12 g, 10.0 mmol), 1-[4-(hydroxymethyl)phenyl]-butane-1-ol (1.80 g, 10.0 mmol) and tributylphosphine (4.04 mL, 20.0 mmol) in toluene (150 mL) was stirred under ice-cooling and 1,1′-(azodicarbonyl)dipiperidine (5.04 g, 20.0 mmol) was added by small portions. The mixture was warmed to room temperature and stirred for 22 hr. Hexane (75 mL) was added to the reaction mixture, and precipitated insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-30:70) to give the title compound as a colorless oil (1.93 g, yield 52%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[OH:12].Cl.[NH2:15][OH:16].CO.C[O-].[Na+].CO>O>[OH:16][NH:15][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[OH:12]
Reactant: NO
Reactant: COC(=O)c1ccc(CO)cc1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(NO)c1ccc(CO)cc1O
Reaction time: 3 h
Yield: 82.7 %

Procedure:
350 g of 2-hydroxy-4-(hydroxymethyl)benzoic acid methyl ester and 160 g of hydroxylamine hydrochloride were added to 700 mL of methanol. Under heating reflux, 1.11 kg of 28% sodium methoxide/methanol solution was added dropwise, and this was stirred for 3 hours. To this, 2.1 L of water was added and 850 mL of solvent was distilled off under atmospheric pressure. Then, 196 mL of hydrochloric acid was added at 40-50° C. The result was stirred for 30 minutes at the same temperature, and 116 mL of hydrochloric acid was added dropwise. After filtering solids, 291 g of N,2-dihydroxy-4-(hydroxymethyl)benzamide was obtained in the form of a pale yellowish-white solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][C@@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1)[C@@H:9]1[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:28][C:24]1[C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)=[C:22]([C@@H:8]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
(R)-tert-butyl 2-((S)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (202 mg, 0.42 mmol) was dissolved in 20% TFA in CH2Cl2 (8 mL) and stirred for about 1 h at rt. The mixture was neutralized with satd aq NaHCO3 and the product was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give N-(2-((S)-(6-fluoro-3′-methylbiphenyl-2-yl)((R)-morpholin-2-yl)methoxy)ethyl)acetamide (130 mg, 82%). 1H NMR (300 MHz, CDCl3): δ=1.98 (s, 3 H), 2.39 (s, 3 H), 2.90˜3.3 (m, 6 H), 3.31˜3.41 (m, 2 H), 3.6˜4.0 (m, 3 H), 4.33 (d, 1 H), 6.56˜6.57 (s, 1 H), 6.97˜7.14 (m, 3 H), 7.27˜7.40 (m, 4 H), 9.40˜9.55 (s, 1H). MS (E/Z): 387 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)[S:27]([CH3:26])(=[O:29])=[O:28])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1CNc1ccc(Oc2ccc(C)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ncc(Br)cc1CN(c1ccc(Oc2ccc(C)cc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-bromo-2-methoxy-pyridin-3-ylmethyl)-(4-p-tolyloxy-phenyl)-amine (0.73 g, 1.82 mmol) from Step A in CH2Cl2/pyridine (6 mL/3 mL) was dropwise added methylsulfonyl chloride (0.17 mL, 2.2 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction was then diluted with CH2Cl2 and washed with aqueous HCl (3N) to remove pyridine. The organic layer was then brought to the usual work-up. The crude product was purified by chromatography (silica gel, 30% EtOAc/hexanes). MS (EI) 477, 479 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[CH2:8][S:9][C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:2]([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([NH:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[CH2:8][S:9]([C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:31])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CNc1ccccc1CSc1nc2ncccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)CNc1ccccc1CS(=O)c1nc2ncccc2[nH]1
Temperature: 0 °C

Procedure:
In 20 ml of chloroform was dissolved 900 mg of 2-[2-(isobutylamino)benzylthio]imidazo[4,5-b]pyridine. To the resulting solution was portionwise added under chilling with ice 618 mg of m-chloroperbenzoic acid (purity: 80%) over a period of 30 min. To the mixture was added a saturated NaHCO3 solution, and the resulting mixture was then stirred. The organic phase was separated and extracted successively with 20 ml of 0.1N NaOH and 10 ml of 0.1N NaOH. The alkaline extracts were combined and neutralized by NH4Cl, and the deposited oil was extracted with chloroform. The chloroform extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and placed under reduced pressure to distill off the solvent. The residue was crystallized by addition of diethyl ether. The crystalline product was washed with diethyl ether to give 195 mg of 2-[2-(isobutylamino)benzylsulfinyl]imidazo[4,5-b]pyridine as a pale yellow crystalline powder. m.p.: 116° C. (decompn.)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18](O)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]([N:46]1[C:42](=[O:52])[C:43]2[C:44](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:45]1=[O:47])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(c1cc2cc(Cl)ccc2n1Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-ol (0.6 mmol), Ph3P, (1 mmol), phthalimide (1.8 mmol) in 5 mL of dry THF at 0° C., was added DIAD (1 mmol) drop wise. The mixture was warmed up to room temperature gradually and stirred overnight. The solution was poured into water, and extracted with EtOAc (×3). The organic layers were combined, washed with H2O (×3), brine (×3), dried (Na2SO4), filtered, and the filtrate was concentrated. The material was purified by flash chromatography (10% EtOAc:hexane) to yield 170 mg of title compound.