Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([S:17](Cl)(=[O:19])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:22][C@H:23]([C@H:26]1[O:30][C:29](=[O:31])[C@H:28]([CH2:32][CH3:33])[CH2:27]1)[CH2:24][OH:25].O1CCCC1>O>[CH2:32]([C@H:28]1[C:29](=[O:31])[O:30][C@H:26]([C@@H:23]([NH:22][S:17]([C:11]2[CH:10]=[CH:9][CH:8]=[CH:13][C:12]=2[N+:14]([O-:16])=[O:15])(=[O:19])=[O:18])[CH2:24][OH:25])[CH2:27]1)[CH3:33]
Reactant: CC[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 2 h
Yield: 59 %

Procedure:
25.6 g of triethylamine (253 mmol) and 28.6 g of O-nitrobenzenesulfonyl chloride (129 mmol) were added to a solution of (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-ethyldihydrofuran-2-one hydrochloride obtained in the above reaction in a mixed solvent of tetrahydrofuran (350 ml) and water (35.0 ml) at 0° C., and the mixture was stirred at the same temperature for two hours. The reaction mixture was concentrated under reduced pressure and 500 ml of water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate). Further, 20 ml of diisopropyl ether and 40 ml of ethyl acetate were added, and the precipitated solid was collected by filtration to obtain 17.0 g of the title compound (total yield over two steps: 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]([F:26])([F:25])[C:12]1[CH:13]=[C:14]([NH:19][CH2:20][CH:21](O)[CH2:22][CH3:23])[CH:15]=[CH:16][C:17]=1[F:18]>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[N:19]([C:14]3[CH:15]=[CH:16][C:17]([F:18])=[C:12]([C:11]([F:26])([F:10])[F:25])[CH:13]=3)[CH2:20][CH:21]([CH2:22][CH3:23])[O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCC(O)CNc1ccc(F)c(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Product: CCC1CN(c2ccc(F)c(C(F)(F)F)c2)C(c2cccc(Cl)c2)O1

Procedure:
Meta-chlorobenzaldehyde (2.3 g, 0.016 mole) was combined with 5 g of 1-(3-trifluoromethyl-4-fluorophenylamino)-2-butanol and 3 drops of methane sulfonic acid was added. The mixture was heated on the steam bath for about one hour and stripped on the rotary evaporator. The product, a sticky, thick liquid, was characterized by IR and NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1>>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([NH2:22])[CH:16]=2)[N:7]=1
Reactant: Nc1cccc(N)c1
Reactant: Clc1nccc(Sc2ccccn2)n1
Product: Nc1cccc(Nc2nccc(Sc3ccccn3)n2)c1
Yield: 30.1 %

Procedure:
In a procedure analogous to Example 6, reaction of 2-chloro-4-(pyridin-2-ylthio)pyrimidine (100 mg, 0.45 mmol) and 1,3-phenylenediamine (193 mg, 1.78 mmol) furnished the product (40 mg, 30%).
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34]>C(Cl)Cl.O>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2C[C@@H]1CCCN1
Solvent: O
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Yield: 69.1 %

Procedure:
A solution of 3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-((S)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.4 g Crude, 3.65 mmol, 1.00 equiv), 2-cyanoacetic acid (0.47 g, 5.48 mmol, 1.50 equiv), HAW (2.08 g, 5.48 mmol, 1.50 equiv), TEA (2.54 ml, 18.25 mmol, 5.00 equiv) in DCM (40 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water, and extracted with DCM. The DCM layers were combined and washed with brine, dried over Na2SO4 and concentrated. The residue was submitted to flash chromatography (SiO2, PE:EtOAc=2:1 to 1:1) to give 1.28 g (69%) of 3-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24]O)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24][O:12][C:11](=[O:13])[CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: COc1ccccc1CCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Yield: 54.6 %

Procedure:
A mixture of 3-(2-methoxyphenyl)propionic acid (5.0 g, 27.8 mmol), 2-(p-toluenesulfonyl)ethanol (5.5 g, 27.8 mmol), and p-toluenesulfonic acid hydrate (p-TsOH.H2O) (0.5 g) in 100 mL of toluene was refluxed with Dean-Stark trap for 5 h. Then water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution (2×), dried over MgSO4, and concentrated to give 3-(2-methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 59, 5.5 g, 88%) as a light brown liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([NH2:19])[N:18]=3)[N:15]=2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([N:27]=[C:28]=[O:29])[CH:24]=[CH:23][C:22]=1[F:30].[N-]=C=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([NH:19][C:28]([NH:27][C:25]4[CH:24]=[CH:23][C:22]([F:30])=[C:21]([Cl:20])[CH:26]=4)=[O:29])[N:18]=3)[N:15]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: Nc1ccc(C#Cc2ccc3nc(N)cn3n2)cc1
Agent: [N-]=C=O
Product: Nc1ccc(C#Cc2ccc3nc(NC(=O)Nc4ccc(F)c(Cl)c4)cn3n2)cc1

Procedure:
The compound of Example 14 was made by preparing 6-[(4-aminophenyl)ethynyl]imidazo[1,2-b]pyridazin-2-amine as in Example 20, followed by a procedure similar to Example 3 using 2-chloro-1-fluoro-4-isocyanatobenzene as the isocyanate (see also Schemes 1, 2, and 9).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([OH:13])[CH:3]=1.C1C(=O)N([Cl:21])C(=O)C1.Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.O>[Cl:21][C:3]1[C:4]([OH:13])=[N:5][CH:6]=[C:7]([C:2]=1[OH:1])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1cnc(O)cc1O
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(O)c(Cl)c1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
To a solution of ethyl 4,6-dihydroxynicotinate (1.0 g, 5.43 mmol) in DMF (10 mL) was added NCS (797 mg, 5.96 mmol) and conc. HCl (0.05 mL). After stirring at room temperature for 2.5 h, it was added water and Na2S2O3, the precipitate was collected by filtration, washed with 1N HCl and dried to give ethyl 5-chloro-4,6-dihydroxynicotinate (920 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][N:5]=[CH:4][N:3]=1.[NH2:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:9][CH:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:7]=1
Reactant: Clc1cncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ncn2)C1
Yield: 51.5 %

Procedure:
A solution of 4,5-dichloropyrimidine (0.6 g, 4.02 mmol), 3-amino-Boc-pyrrolidine (0.5 g, 2.6 mmol) and DIPEA (1.73 g, 13.3 mmol) in n-butanol (5.0 mL) was heated in a pressure tube (120° C., 12 h). It was cooled, quenched with water (10 mL) and was extracted with EtOAc (2×25 mL). The combined EtOAc extract was washed with water (5 mL), brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure to afford tert-butyl 3-(6-chloropyrimidin-4-ylamino)pyrrolidine-1-carboxylate (0.4 g, 50%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:16]1[CH2:20][CH2:19][CH:18]([C:21](=O)[CH2:22][F:23])[C:17]1=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:9]([N:16]1[CH2:20][CH2:19][CH:18]([CH:21]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:22][F:23])[C:17]1=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CF)C1CCN(Cc2ccccc2)C1=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1C(C(CF)NCc2ccccc2)CCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Benzylamine (3.9 mL, 35.7 mmol) was added to a solution of 1-benzyl-3-(2-fluoro-acetyl)pyrrolidin-2-one (7.00 g, 29.8 mmol, Example 15) in dichloroethane (150 mL). The solution was cooled to 0° C. and sodium triacetoxyborohydride (8.20 g, 38.7 mmol) added. The reaction mixture was warmed to room temperature and stirred overnight, then washed with aqueous sodium bicarbonate solution and brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (99:1 to 97:3 dichloromethane/methanol) to afford the title compound (7.2 g) as a mixture of diastereomers. MSCI: m/z 327 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>CN(C)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][N:12]([C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)[C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=C1CC(CCOC2CCCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Solvent: CN(C)c1ccccc1
Product: COc1cc(C(=O)N2CC(CCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Combine 4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)ethyl]-pyrrolidin-2-one (as prepared in example 11.3) (5 mmol) and 3,4,5-trimethoxy-benzoyl chloride (5.0 mmol) in N,N-dimethylaniline (20 mL). Heat to 90° C. and stir for 24 h. Concentrate in vacuo . Partition the reaction mixture between dichloromethane and H2O. Separate the organic layer, dry over MgSO4, filter, and concentrate in vacuo to obtain a residue. Purify to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH:14]([CH2:21][C:22]2([CH3:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]3=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C1(C)C=CC=CC=1.OS(O)(=O)=O>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14]([CH2:21][C:22]2([CH3:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:15]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(CC2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(CC2=Cc3cccc(-c4ccc(C(C)(C)C)cc4)c3C2)CCCCC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 96.8 %

Procedure:
27.9 g of crude 4-(4-tert-butyl-phenyl)-2-[(1-methylcyclohexyl)methyl]-indan-1-one (˜83% purity), 2.82 g (74.5 mmol) of NaBH4 and 70.5 ml of toluene are charged in a flask equipped with reflux condenser, dropping funnel and magnetic stirring bar. The mixture is warmed to 50° C. and 14 ml of methanol are slowly added with stirring and stirring is continued for 2.5 h to ensure a complete reaction. Excess NaBH4 is carefully hydrolyzed with approx. 40 ml of 2n H2SO4. The organic phase is separated and the water phase is washed with another 35 ml of toluene. The combined organic phases are twice extracted with 2n H2SO4 and dried over anhydrous MgSO4. Most of the solvent is removed in a vacuum and replaced by fresh toluene up to a total volume of 100 ml and 0.3 g of p-toluenesulfonic acid are added. The reaction flask is fitted with a water separator and the reaction mixture is heated to reflux for 1.5 h. The conversion can be monitored by TLC. Once the dehydration is complete, the solution is washed with a saturated NaHCO3 solution and dried over anhydrous MgSO4. The solvent is thoroughly removed in a vacuum and 25.85 g of a brown oil is obtained. Purification of the indene is carried out via a column chromatography. Yield: 18.85 g (˜85%) of 7-(4-tert-Butyl-phenyl)-2-[(1-methylcyclohexyl)methyl]-1H-indene.
Reaction SMILES: C(OC(=O)[N:10]([CH2:18][CH2:19][O:20]CC1C=CC=CC=1)[C@@H:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:20][CH2:19][CH2:18][NH:10][C@@H:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13]
Reactant: [H][H]
Reactant: C[C@@H](C(=O)N(C)C)N(CCOCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NCCO)C(=O)N(C)C
Temperature: 45 °C
Reaction time: 24 h
Yield: 64.1 %

Procedure:
Under nitrogen atmosphere, to a solution of 2.75 g of the compound obtained in Step 79-2 in EtOH (30 ml) was added palladium-activated carbon (10% Pd, 0.30 g), and the inside of the reaction system was displaced with hydrogen gas. The solution was stirred for 24 hours at 45° C., then, the reaction solution was filtered, and the solvent was filtered out under reduced pressure. To a solution of the obtained residue in EtOH (30 ml) solution was added palladium-activated carbon (10% Pd, 0.30 g), and the reaction system was displaced with hydrogen gas, again. The solution was stirred for one day at 45° C., then, the reaction solution was filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=9/1 to 4/1; v/v) to obtain 734 mg of the title compound (colorless oil).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[N+:31]([O-])([OH:33])=[O:32].O>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:30])=[N:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:19][CH:18]=2)=[C:10]([N+:31]([O-:33])=[O:32])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OCOCCOC)cc2)[nH]c(=O)c1C(=O)OCC
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(O)nc(-c2ccc(OCOCCOC)cc2)c([N+](=O)[O-])c1C(=O)OCC
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In 3 ml of acetic anhydride was dissolved 1.0 g of 3,4-diethoxycarbonyl-6-(4-methoxyethoxymethoxyphenyl)-2-pyridone, and the mixture was cooled to -20° C. and thereafter 0.2 ml of fuming nitric acid was added dropwise. After the mixture was stirred for 1 hour, water was added. After 2 hours' stirring at room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride, and dried. After the solvent was distilled off the resulting crystals were collected by filtration with diethyl ether.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]4[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([O:32][CH3:33])[CH:25]=4)[N:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.CO>O>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]3[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([O:32][CH3:33])[CH:25]=3)[N:20]=2)=[CH:11]1
Reactant: COc1cc2nc(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)cc(C(=O)O)c2cc1OC
Solvent: CO
Solvent: O
Product: COc1cc2nc(-c3c[nH]c4ccccc34)cc(C(=O)O)c2cc1OC

Procedure:
A stirred solution of (0.547 g) of 2-(N-phenylsulfonylindol-3-yl)-4-carboxy-6,7-dimethoxyquinoline, K2 CO3 (0.380 g), MeOH (40 ml) and H2O (10 ml) are heated to reflux. The MeOH is evaporated in vacuo, and the aqueous residue diluted with more H2O, and acidified with 0.1N HCl to pH between 6-7 while contained in an ice-bath. An orange solid precipitates. This is collected, washed with ether then dried under vacuum (0.1 mm at 22° C.) for a few hours to obtain 2-(indol-3-yl)-4-carboxy-6,7-dimethoxyquinoline m.p. 286° C. dec).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([CH2:15][N:16]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:17]2[C:18]([S:36][CH3:37])=[N:19][N:20]3[C:25]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])=[CH:24][CH:23]=[CH:22][C:21]=23)[CH2:14][CH2:13]1.O.C(OCC)(=O)C>ClCCl>[CH:12]1([CH2:15][N:16]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:17]2[C:18]([S:36]([CH3:37])=[O:9])=[N:19][N:20]3[C:25]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])=[CH:24][CH:23]=[CH:22][C:21]=23)[CH2:13][CH2:14]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(S(C)=O)nn12
Reaction time: 2 h
Yield: 78 %

Procedure:
m-Chloroperbenzoic acid (234 mg) was added to a solution of N,N-dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (200 mg) in dichloromethane (10 mL) at 0° C., and the mixture was stirred for 2 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (162 mg) was obtained from the n-hexane:ethyl acetate (1:1) fraction as a light yellow oil.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:32]([NH2:34])=[O:33])[CH:17]=[C:18]([C:21]4[CH:29]=[C:28]([CH:30]=O)[C:24]5[CH2:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:35][NH:36][CH3:37].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:35][N:36]([CH2:30][C:28]1[C:24]2[CH2:25][CH2:26][O:27][C:23]=2[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:32]([NH2:34])=[O:33])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]2)[CH:29]=1)[CH3:37]
Reactant: CNC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)c5c(c4)OCC5)cc23)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CN(C)C)c5c(c4)OCC5)cc23)CC1
Yield: 28 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2,3-dihydro-1-benzofuran-6-yl)-1H-indole-7-carboxamide (20 mg, 0.042 mmol) in methanol (2 mL) was added dimethylamine (3 μL 0.050 mmol), zinc chloride (3 mg, 0.021 mmol) and sodium cyanoborohydride (4 mg, 0.062 mmol). This mixture was reacted in the microwave at 100° C. for 1 h and then removed all solvent. The residue was washed with EtOAc and water. All solvent was removed and purified by Gilson Preparatory HPLC to give 6.0 mg of the title compound (19.6%).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:14]=[CH:15][CH:16]=2)=[C:8]([N+:26]([O-:28])=[O:27])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([N+:26]([O-:28])=[O:27])=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH:14]=[CH:15][CH:16]=3)[CH:24]=[CH:25][C:6]=2[N:5]=1
Reactant: Nc1ccc(Oc2cccc(NC(=O)C(F)(F)F)c2)c([N+](=O)[O-])c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3cccc(NC(=O)C(F)(F)F)c3)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.6 %

Procedure:
Potassium thiocyanate (4.3 g, 44.2 mmol) was suspended in acetic acid (40 mL), and the mixture was stirred at room temperature for 10 min. N-[3-(4-Amino-2-nitrophenoxy)phenyl]-2,2,2-trifluoroacetamide (3.02 g, 8.85 mmol) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (1.98 g, 12.4 mmol) in acetic acid (10 mL) was slowly added dropwise to the obtained solution, and the mixture was stirred at room temperature for 16 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (400 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (400 mL). The aqueous layer was extracted with ethyl acetate (200 mL), and the combined organic layer was washed with saturated brine (400 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (1.29 g, 37%) as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[Na+]>CN(C)C=O>[O:27]([CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1)[Si:28]([C:41]([CH3:43])([CH3:42])[CH3:44])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1)(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
200 mg (corresponding to 0.595 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine was dissolved in 3.0 mL of dimethylformamide, and 247 mg (corresponding to 1.79 mmol) of potassium carbonate was added thereto. Then, 259 mg (corresponding to 0.714 mmol) of 1-bromo-2-(t-butyldiphenylsiloxy)ethane was added thereto. After the reaction mixture was stirred at 90° C. for 2 hours, a saturated sodium chloride solution was added, and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 368 mg (corresponding to 0.595 mmol) of 2-[4′-(2″-t-butyldiphenylsiloxyethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 2-1, Step 4).