Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=4)[NH2:22])[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[CH2:37]([O:36][C:34](=[O:35])[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH:8]3[CH2:7][CH2:6][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:10][CH2:9]3)[CH2:18][CH2:17]2)[CH:20]=1)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: Nc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a cooled solution of 1 g (3 mmol) of 3-{4-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]piperazin-1-yl}aniline in 30 mL of dichloromethane and 0.3 g (3 mmol) of triethylamine, is slowly added 0.32 g (3 mmol) of ethyl chloroformate. The mixture is stirred overnight at room temperature then concentrated under reduced pressure. The product is dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The oily residue is purified over 10 g of silica gel (eluant dichloromethane/methanol 95/5) to give 0.35 g (29%) of (3-{4-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]piperazin-1-yl}phenyl)carbamic acid ethyl ester.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14]>C(Cl)Cl>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[CH2:6]1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCC(O)C2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.3 %

Procedure:
4-hydroxypyrrolidine (12 g, 0.14 mol), DCM (300 ml) and 1N aqueous sodium carbonate solution (200 ml) were charged to a flask and cooled to <10° C. A solution of 4-cyanobenzenesulfonyl chloride (26.8 g, 0.133 mol) in DCM (100 ml) was added dropwise, maintaining the temperature below 10° C. (typically addition takes 40-50 min). Cooling was removed and stirring at room temperature continued for 2 h. The layers were separated, the organic layer was washed with water (2×100 ml) and concentrated in vacuo to approximately 100 ml. Hexane (about 300 ml) was added to initialise crystallisation. The precipitate was aged at 0-5° C. for 10-30 min, filtered and washed with hexane (2×100 ml) to yield 30.3 g (86%) of sulfonamide 4-[(3-hydroxy-1-pyrrolidinyl)sulfonyl]benzonitrile 23a as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(Cl)nc1N
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(Nc2ccc(S(N)(=O)=O)cc2)nc1N

Procedure:
A solution of (4-amino-2-chloro-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (120 mg, 0.40 mmol, Example 289) and 4-amino-benzenesulfonamide (260 mg, 1.51 mmol, Aldrich) in isopropyl alcohol (30 mL) was stirred for 2 hours at 150° C. in a sealed pressure bottle. The reaction was cooled and poured into water (˜60 mL) and the resulting precipitate was filtered and air dried. This residue was purified by silica gel chromatography (2% triethylamine/ethyl acetate) to give 4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-benzenesulfonamide as a white solid. MS: M+H; 436
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][OH:30].[H-].[Na+]>CN(C)C=O.O>[F:11][C:8]1[CH:9]=[CH:10][C:2]2[O:30][CH2:29][C@H:25]3[CH2:26][CH2:27][CH2:28][N:24]3[C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: OC[C@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(F)ccc2OC[C@H]2CCCN12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
To a solution of 2,5-difluorobenzoic acid (1.0 g; 6.325 mmol) in dimethylformamide (5 ml) was added 1,1′- carbonyldiimidazole (1.07 g; 6.64 mmol) and the solution stirred at room temperature for 1 h, followed by the addition of (R)-(−)-2-pyrrolidinemethanol (0.655 ml; 6.64 mmol). The reaction was stirred at room temperature overnight whereupon 60% sodium hydride in mineral oil (0.507 g; 12.7 mmol) was carefully added and the mixture was heated to 120° C. for 2 h. The reaction was cautiously diluted with water and extracted with ethyl acetate and the organic layer washed with water then dried (Na2SO4) and evaporated to give the crude product. Trituration with ether and filtration afforded the title compound (0.29 g). M.p.: 85-86° C.; EIMS: m/z=222.2 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[I:10]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.N1C=CC=CC=1>[I:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: Cc1cccc(C)c1N
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cc1cc(I)cc(C)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 2,6-dimethyl aniline (50 gm) in 1,4-dioxane (400 ml) and pyridine (40 ml) was added iodine (157.3 gm) slowly at 0° C. The solution was stirred for 1 hour at 0° C. and the temperature was raised to room temperature. The solution was stirred for 1 hour at room temperature and then added a saturated solution of sodium thiosulfate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to obtain 91.8 gm of 4-iodo-2,6-dimethyl benzenamine.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>ClCCl.CN(C1C=CN=CC=1)C>[O:7]=[C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: NCCc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCC(=O)NCCc1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.5 %

Procedure:
To a solution of 5.0 g (50 mmol) of succinic anhydride in 50 mL of dichloromethane was added 550 mg of DMAP and 6.1 g (50 mmol) of 2-(2'-aminoethyl)pyridine. An exothermic reaction resulted. The reaction was refluxed for 1 h and cooled to room temperature and stirred for 48 h. The reaction is worked up by concentrated in vacuo; the resulting solid was dissolved in pH 4 buffer and extracted three times with 4:1 ethyl acetate/tetrahydrofuran after the aqueous solution had been saturated with ammonium sulfate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was recrystallized from ethyl acetate/methanol to give 5.5 g (50%) of 4-oxo-4-[[2-(2-pyridinyl)ethyl]amino]butanoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].Br[C:14]1[CH:15]=[C:16]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:23]([CH3:34])[CH2:22]2)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[CH:14][CH:15]=[C:16]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:23]([CH3:34])[CH2:22]3)[CH:17]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: C[C@H]1CN(Cc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C[C@H]1CN(Cc2cccc(-c3ccc(F)c(C#N)c3)c2)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of (3-cyano-4-fluorophenyl)boronic acid (0.983 g, 5.96 mmol) in DME (40 mL) was added 1,1-dimethylethyl (2S)-4-[(3-bromophenyl)methyl]-2-methyl-1-piperazinecarboxylate (2.20 g, 5.96 mmol) followed by Na2CO3 (17 mL, 2M in H2O, 34.0 mmol). The reaction vessel was flushed with Ar, and tetrakis(triphenylphosphine)palladium(0) (2.06 g, 1.78 mmol) was added. The reaction mixture was placed in an oil bath at 78° C. under Ar for overnight. The reaction was diluted with EtOAc (600 mL) and washed with H2O (250 mL). The water layer was extracted with EtOAc (1×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. Purification of the crude residue by flash chromatography (20% EtOAc/80% hexane) on silica gel gave the title compound (1.77 g, 73.1%). EI-MS m/z 410 (M−H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][CH:9]=1)[CH3:6].CN(C=O)C>C(Cl)Cl>[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Cl:3])=[CH:10][CH:9]=1)[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(CCl)cc1
Reaction time: 0.12 h

Procedure:
Thionyl chloride (10.4 g, 87.7 mmol) was added dropwise to a 0° C. solution of 4-ethoxybenzyl alcohol (11.0 g, 72.4 mmol) in dry CH2Cl2 (150 mL) with a catalytic amount of DMF (1 mL). Upon addition, reaction was allowed to stir for 5-10 minutes, while monitoring through TLC (CH2Cl2) for completion. Reaction mixture was concentrated under reduced pressure and the residue dissolved in minimal THF and then precipitated in cold H2O to yield a white precipitate. The solid was collected, taken up in CH2Cl2, dried and concentrated. The resulting oil was solidified by cooling with CO2/acetone. The compound as a white solid, which decomposes upon melting 11.3 g(92%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2Cl)([O-:3])=[O:2].[CH3:22][NH:23][CH3:24].O>CN1C(=O)CCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2[N:23]([CH3:24])[CH3:22])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2nc(-c3cccc(F)c3)cc(Cl)c2c1
Reactant: CNC
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C)c1cc(-c2cccc(F)c2)nc2ccc([N+](=O)[O-])cc12
Temperature: 60 °C

Procedure:
6-Nitro-4-chloro-2-(3-fluoro-phenyl)-quinoline, 20 g (59.4 mmoles), was placed in a 500 mL three-neck round-bottom flask equipped with magnetic stirrer, nitrogen inlet, gas outlet, condenser and heating bath. The material was dissolved in 150 mL of N-methyl pyrrolidinone, stirred and 250 mL of a 40% aq. solution of dimethylamine was added. The mixture was then warmed to 60° C. for 48 hrs. At the end of this time the reaction was cooled, poured into 3 L of water in a 4 L Erlenmeyer flask and the mixture stirred until solids formed. The solids were collected by vacuum filtration and dried in a vacuum oven. The product was recrystallised from-ethanol in a −20° C. freezer to give 19.6 g (95%) yield of the desired product.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:22]([NH:24][CH2:25][CH3:26])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:34][CH2:35]1)[C:22]([NH:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 105 °C
Yield: 35.3 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide hydrochloride (139 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (5:1, 6 mL) and dried in vacuum to afford (S)-3-chloro-N-ethyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (75.6 mg, 0.161 mmol, 35.3% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.20 Hz, 3 H) 1.76-1.93 (m, 3 H) 2.06-2.17 (m, 1 H) 2.44-2.51 (m, 4 H) 2.96 (br. s., 4 H) 3.14-3.23 (m, 2 H) 3.28-3.38 (m, 3 H) 3.46-3.58 (m, 1 H) 3.88-3.97 (m, 1 H) 6.92 (d, J=2.02 Hz, 1 H) 7.10 (d, J=8.34 Hz, 1 H) 7.56 (d, J=1.77 Hz, 1 H) 7.70 (dd, J=8.34, 2.02 Hz, 1 H) 7.81 (d, J=2.27 Hz, 1 H) 8.37 (t, J=5.43 Hz, 1 H) 10.38 (s, 1 H). [M+H] calc'd for C24H29ClN6O2, 469; found, 469.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:7]([N+:22]([O-:24])=[O:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:31](C(OC(C)(C)C)=O)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=O>CN(C=O)C>[CH3:36][C:35]([O:34][C:32](=[O:31])[N:11]([C:8]1[N:7]([N+:22]([O-:24])=[O:23])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[N:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1)([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1cccc2c1nc(Nc1cccc(C(F)(F)F)c1)n2[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(N(C(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1)n2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.7 %

Procedure:
(Methyl-nitro-1H-benzoimidazol-2-yl)-(3-trifluoromethyl-phenyl)-amine (2.34 g) and cesium carbonate (5.61 g, 17.2 mmol) was stirred in DMF for 15 min., then (BOC)2O (2.81 g, 12.9 mmol) was added. The resulting mixture was stirred at room temperature for 4 days, the reaction mixture was then concentrated and the residual was taken into EtOAc and washed by water, then brine, drying and concentration, silica flash, which gave 1.45 g of the title compound as a yellow foam: LC/MS(m/e) 437 [M+H]+, Rt at 2.34 min.
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH3:15])[C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)=O.C([O-])(=O)C.[NH4+:22].CC(O)=O.[OH-].[Na+]>O>[CH3:15][N:5]1[CH:4]=[CH:3][N:22]=[C:6]1[C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1
Reactant: COC(CN(C)C(=O)[C@H]1CC[C@H](O)CC1)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cn1ccnc1[C@H]1CC[C@H](O)CC1
Temperature: 125 °C

Procedure:
A mixture of trans-N-(2,2-Dimethoxyethyl)-4-hydroxy-N-methylcyclohexanecarboxamide (265 mg, 1.08 mmol) and Ammonium acetate (2.2 g, 29 mmol) in AcOH (3.0 mL, 53 mmol) was heated to reflux (oil bath temperature 125° C.) for 16.5 h. To the cooled solution were added 10 N NaOH (≈10 mL) and water (≈10 mL), and the mixture was extracted with DCM (3×20 mL). The combined DCM extracts were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound as light orange solid. Additional material was obtained by saturating the aqueous layer from the previous extractions with NaCl and extracting with more DCM (4×25 mL). The light orange solid was chromatographed on silica gel [Isco Combiflash, 2.5 g loading column/4 g Gold column, eluting with DCM→10% 7N NH3 in MeOH] to give the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): δ=6.92 (d, J=1.4 Hz, 1H), 6.77 (d, J=1.4 Hz, 1H), 3.73 (tt, J=10.8, 4.2 Hz, 1H), 3.60 (s, 3H), 2.60 (tt, J=12.0, 3.6 Hz, 1H), 2.18-2.08 (m, 2H), 1.99-1.91 (m, 2H), 1.88 (brs, 1H), 1.83-1.71 (m, 2H), 1.46-1.35 (m, 2H). MS (ES+): m/z=181.13 (100) [MH+]. HPLC: tR=0.69 min (very polar—5 min, ZQ3). UV: λmax=216 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:22]=[CH:21][C:20]4[C:16](=[C:17]([CH3:26])[N:18]([CH2:23][CH2:24][OH:25])[N:19]=4)[CH:15]=3)[C:10](=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:33][CH2:34][O:35][CH3:36].O>CN(C)C=O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:22]=[CH:21][C:20]4[C:16](=[C:17]([CH3:26])[N:18]([CH2:23][CH2:24][O:25][CH2:33][CH2:34][O:35][CH3:36])[N:19]=4)[CH:15]=3)[C:10](=[O:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1c2cc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)ccc2nn1CCO
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCn1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 4-[(4-chlorobenzyl)oxy]-1-[2-(2-hydroxyethyl)-3-methyl-2H-indazol-5-yl]pyridin-2(1H)-one (30 mg) in N,N-dimethylformamide (2 ml) was added 60% sodium hydride (3.51 mg) at 0° C., and the mixture was stirred at room temperature for 30 min. To the obtained reaction mixture was added (2-bromoethyl)methyl ether (15.3 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (28.1 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=2)[O:3]1.CC[N:22]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:22])=[O:17])=[CH:11][CH:10]=2)[O:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(CC(N)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a solution of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (500 mg) and HOBt ammonium salt (435 mg) in DMF (5 mL) was added EDCI hydrochloride (539 mg), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (420 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([NH2:19])(=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>CC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:11](=[S:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(=S)c1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(NC(=S)c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 22.7 %

Procedure:
To a solution of 4-fluorobenzoylchloride (1.3 g, 8.5 mmol) in acetone (7.0 ml) was added a solution of thiobenzamide (1.16 g, 8.5 mmol) and pyridine (0.66 g, 8.5 mmol) in acetone (7.0 ml). The mixture was refluxed for 6 h. and cooled to room temperature. The reaction mixture was poured into water/ice and extracted with chloroform. Flash chromatography on silica gel afforded 0.5 g of the title compound as a red solid.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].O1CCCC1.[CH2:20]([S:24]([CH2:27][Li])(=[O:26])=[O:25])[CH2:21][CH2:22][CH3:23].[Cl-].[NH4+]>[Hg].CCCCCC.O1CCCC1>[CH2:20]([S:24]([CH2:27][Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:26])=[O:25])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: [Li]CS(=O)(=O)CCCC
Agent: [Cl-]
Agent: [Hg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCS(=O)(=O)C[Sn](CCCC)(CCCC)CCCC

Procedure:
A 250-ml, three-necked flask fitted with a stirrer, a dropping funnel, and a thermometer was swept thoroughly with argon and maintained in an air-free condition by a mercury-filled trap. The flask was charged with 27 ml. of tri-n-butyltin chloride dissolved in 50 ml. of tetrahydrofuran (THF). To the solution of tributyltin chloride was added dropwise with stirring 100 ml. of an approximately one-molar solution of (butylsulfonyl-methyl)lithium in a hexane-THF mixture. The temperature was held at -10° C to 10° C during the addition which required 15 minutes. The reaction mixture was then agitated by stirring at room temperature for 2 hours. The reaction mixture was hydrolyzed by pouring into aqueous one-molar ammonium chloride. Extraction from the hydrolyzate with ether solvent and purification by distillation yielded the desired product (butylsulfonylmethyl)-tributyltin. The product, a colorless liquid, had a boiling point of 161°-165° C/0.1 mm. Hg. Analysis gave 48.4% Carbon and 9.2% Hydrogen compared to the calculated values, respectively, of 48.0% and 9.0%. Infrared and proton nuclear magnetic resonance spectral analyses confirmed the assigned structure.
Reaction SMILES: O.[OH-].[Na+].[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.Cl.[CH3:14][C:15]([CH3:17])=[O:16]>>[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:15](=[O:16])[CH3:17])=[CH:7][CH:6]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.6 %

Procedure:
Water (20 ml) and 10% NaOH aqueous solution (4 ml) were added under stirring to the solution of 4-methylbenzaldehyde (10.2 g, 10 mmol) in acetone (10 ml). The reaction mixture was stirred for 14 hr at room temperature, then the pH value was adjusted to pH=7.0 with 10% hydrochloric acid, extracted with methylene chloride. The combined methylene chloride extract was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give 0.73 g of a yellow viscous oil, yield: 45.6%.