Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:7][CH:8]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][C:2]([CH3:23])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)CC(CCCCO)CCCc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CC(CCCCOS(C)(=O)=O)CCCc1cccnc1
Reaction time: 1 h

Procedure:
To a solution of 1.28 g (4 mmol) of methyl 2,2-dimethyl-4-[3-(3-pyridyl)propyl]8-hydroxyoctanoate in 20 ml methylene chloride at 0° is added 0.9 ml (6.5 mmol) triethylamine followed by 0.4 ml (5.2 mmol) methylsulfonyl chloride. After 1 h, the reaction mixture is diluted with methylene chloride and washed with saturated sodium bicarbonate, water and brine. The organic phase is dried, filtered and evaporated to give methyl 8-methylsulfonyloxy-2,2-dimethyl-4-[3-(3-pyridyl)propyl]-octanoate as an oil.
Reaction SMILES: O.[O:2]1CCCC1.[CH3:7][C:8](/[CH:15]=[CH:16]/[CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[BH4-].[Na+]>[OH-].[Na+]>[OH:2][C:22]([CH3:23])([CH3:24])[CH2:21][CH2:20][CH2:19][CH:18]([CH3:25])[CH2:17][CH:16]=[CH:15][C:8]([CH3:7])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C=C(C)/C=C/CC(C)CCC=C(C)C
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)(C)O
Reaction time: 0.33 h

Procedure:
To a mixture of 1.9 g. of mercuric acetate, 6 ml. of water and 20 ml. of tetrahydrofuran is added 1.49 g. of trans ethyl 3,7,11-trimethyldodeca-2,4,10-trienoate slowly. After addition is complete, the reaction mixture is stirred for about 20 minutes. The mixture is cooled to about 0° and 6 ml. of aqueous sodium hydroxide (3 molar) is added followed by 0.49 g. of sodium borohydride in aqueous sodium hydroxide (about 3 molar). The mixture is stirred for about 30 minutes. The mixture is then decanted, concentrated, diluted with water and then extracted with ether. The ethereal extract is washed with water, dried over magnesium sulfate and the product chromatographed on silica gives ethyl 11-hydroxy-3,7,11-trimethyldodeca-2,4-dienoate (trans).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[O:4][NH2:5].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13]>N1C=CC=CC=1.ClCCl>[C:15]1([O:14][C:12](=[O:13])[NH:5][O:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=2[Cl:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NOc1cccc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NOc1cccc(Cl)c1Cl)Oc1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
9.10 g (51.1 mmole) of 2,3-dichlorophenoxyamine was dissolved in 7.5 ml of pyridine and 70 ml of dichloromethane, and the solution was cooled to -10° C. Then, 30 ml of a dichloromethane solution containing 7.28 g (46.5 mmole) of phenyl chloroformate was dropwise added thereto over a period of 1 hour, and the mixture was stirred at a temperature of from -10° to 25° C. for 6 hours. The solvent was distilled off under reduced pressure, and 300 ml of ethyl acetate was added. The mixture was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue thereby obtained was recrystallized from toluene/hexane, whereby 11.5 g of the desired product was obtained as light brown crystals (yield: 83%)
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([OH:21])C=CC=CC=1.O.C1(CC2C=CC=CC=2)C=CC=CC=1.SCCCS(O)(=O)=O>>[C:1]1(=[O:21])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: Oc1ccccc1
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)CCCS
Solvent: O
Solvent: c1ccc(Cc2ccccc2)cc1
Product: O=C1C=CC=C2C1=Cc1ccccc12
Temperature: 53 °C

Procedure:
9-Fluorenone (3.65 g, 0.0200 mol, 1.00 equiv.), molten phenol (39.6 g, 0.420 mol, 20.8 equiv.), deionized water (0.055 g, 3.06 mmol, 0.151 equiv.) and diphenylmethane (32.83 g) is added to the reactor (reactor design 2). The reaction mixture is heated to 53° C. with stirring under a pad of nitrogen. 3-Mercaptopropanesulfonic acid (0.170 g, 1.10 mmol, 0.0537 equiv.) is added slowly over approximately 1 minute to the reaction mixture at 53° C. The reaction is monitored throughout the reaction period by collecting samples and analyzing by HPLC. The 9-fluorenone is found to be 49% consumed within 2 hours and 77% consumed within 4.5 hours. HPLC analysis (analytical method 3) gives the following relative area % analysis for the reaction products (fluorenone area not included) at 77% conversion:
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[N:33]2)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:38])=[O:5])(=[O:13])=[O:14])=[C:16]([O:25][CH2:26][CH2:27][C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][CH:32]=[N:33]3)[CH:17]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(OCCc2cccc3ncccc23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
3-[4-Acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (130 mg, 0.24 mmol) was dissolved in 2 mL methylene chloride and 2 mL trifluoroacetic acid. The reaction was stirred at room temperature for 90 minutes. The reaction was concentrated in vacuo, and chased with toluene to yield 110 mg (68%) of the desired product.
Reaction SMILES: [CH2:1]([NH:6][S:7]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[NH2:16])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:17]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[CH2:1]([N:6]1[CH2:17][NH:16][C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[S:7]1(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNS(=O)(=O)c1cnccc1N
Reactant: C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCCCCN1CNc2ccncc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.5 g of N-pentyl-4-aminopyridine-3- sulfonamide (Preparation 9) and 0.5 g of paraformaldehyde in 15 cm3 of isopropanol to which 50 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 48 hours. After this lapse of time, the solvent is removed under partial vacuum. The residue is suspended in 20 cm3 of 0.1N NaOH. After stirring for 1 hour at ambient temperature, the insoluble material is collected on a filter, washed with water and recrystallized twice from a methanol/water (1/2) mixture and then once from CHCl3 /petroleum ether (40°-60° C.) (1/1).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[CH2:6]1)=[N+:2]=[N-:3].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[CH2:35][NH2:36].C(N(CC)C(C)C)(C)C>C(O)CCC>[N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:36][CH2:35][C:28]2[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=2[O:26][CH3:25])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 80 °C

Procedure:
A solution of 9-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-6-chloro-9H-purine (1.29 g, 3.69 mmol) and (2,4-dimethoxyphenyl)methanamine (0.71 mL, 4.7 mmol) in 1-butanol (10 mL) was treated with N,N-diisopropylethylamine (0.93 mL, 5.3 mmol) and heated at 80° C. for 16.5 h; HPLC/LC MS indicated conversion to the desired product. The reaction mixture was allowed to cool to rt and the volatiles were removed under the flow of air to afford a brown-orange paste. Purification by column chromatography (2×8 cm silica; 0-10% acetone/CH2Cl2) afforded the title compound (1.72 g, 97%) as a yellow-orange foam/oil: MS (ESI+) for C22H28N8O4 m/z 481.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[N+:14]([CH3:17])([O-:16])=[O:15].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:11][O:10][C:8](=[O:9])[CH2:7][CH:6]([C:5]1[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:17][N+:14]([O-:16])=[O:15]
Reactant: COC(=O)C=Cc1ccc(C)cc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture to 300 g of p-methylcinnamic acid, methyl ester, 500 g of nitromethane and 39 g of tetramethylguanidine is allowed to stir at room temperature for 72 hours. The solution is diluted with diethyl ether and (1 liter, 1 N) aqueous hydrochloric acid solution added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(4-methylphenyl) butanoic acid methyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]1[N:13]([CH3:26])[C:14](=[O:25])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:16][C:7]2=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:34]([F:39])([F:38])C([O-])=O.[Na+]>CN(C=O)C.O>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:34]([F:39])[F:38])[C:8]1[N:13]([CH3:26])[C:14](=[O:25])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:16][C:7]2=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CC(=O)c1ccc2[nH]c3c(cc(-c4ccc(Cl)cc4Cl)c(=O)n3C)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F
Temperature: 100 °C

Procedure:
460 mg (1.19 mmol) of compound from preparation 1.9A, 6-acetyl-3-(2,4-dichlorophenyl)-1-methyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one, are dissolved in 7 ml of DMF and 2 ml of water. 543 mg (1.67 mmol) of caesium carbonate and 419 mg (2.75 mmol) of sodium chlorodifluoroacetate are added. The mixture is heated at 100° C. for 48 hours. It is allowed to return to ambient temperature. The reaction medium is poured into water, and the precipitate formed is filtered off and washed with water. The product is taken up in an EtOAc/MeOH mixture and adsorbed onto silica. Purification is carried out on a silica column, elution being carried out with a 50/50 EtOAc/cyclohexane mixture and then with EtOAc.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[C:8]1[C:9]2[N:10]([N:27]=[CH:28][N:29]=2)[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[C:50](=[O:54])[NH:49][CH2:48][CH2:47]2>CN(C=O)C.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]([O:5][C:6](=[O:42])[N:7]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)=[CH:32][CH:31]=1)[C:8]1[C:9]2[N:10]([N:27]=[CH:28][N:29]=2)[C:11]([C:44]2[CH:45]=[C:46]3[C:51](=[CH:52][CH:53]=2)[C:50](=[O:54])[NH:49][CH2:48][CH2:47]3)=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2ncnn12
Reactant: O=C1NCCc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2ccc3c(c2)CCNC3=O)n2ncnc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a degassed solution of (4-morpholin-4-yl-phenyl)-(5-tributylstannanyl-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (100 mg, 0.15 mmol) and 6-bromo-3,4-dihydro-2H-isoquinolin-1-one in DMF (1 mL) is added tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) and the reaction mixture is stirred at 90° C. overnight. After removing the solvent in vacuo, the residue is purified by silica gel column chromatography. Elution with 1:1 petroleum ether:ethyl acetate and ethyl acetate affords the target compound as a yellow solid (30 mg, 37%).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([N:22](S(CCC)(=O)=O)[S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.[C-:36]#[N:37].[Na+]>CN(C=O)C.O>[C:36]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:24])=[O:25])[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2)#[N:37]
Reactant: [C-]#N
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(C#N)nc3c2)c1F
Temperature: 100 °C

Procedure:
A mixture of N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 0.1 mmol, 1.0 eq.) and NaCN (9.8 mg, 0.002 mol, 2.0 eq.) in DMF (10 mL) was heated at 100° C. for 10 h under N2 protection. The mixture was cooled, diluted with water and extracted with EA (20 mL×3). The combined organic layers were washed with water, saline and dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford N-(3-(3-cyanoquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)propane-1-sulfonamide. LRMS (MAT) m/z calculated 435.1, found 435.0. 1H NMR (DMSO-d6, 400 MHz) δ 10.11 (brs, 1 H), 9.52 (s, 1 H), 8.75 (s, 1 H), 8.52 (d, 1 H), 8.41 (d, 1 H), 7.79 (m, 1 H), 3.22 (t, 2 H), 1.72 (m, 2 H), 0.95 (t, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:5][C:4]=1[C:23]([F:26])([F:25])[F:24])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:5][C:4]=1[C:23]([F:26])([F:24])[F:25])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of tert-butyl 4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate (150 mg, 0.41 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 ml). The solution was stirred for 2 hours at room temperature and then concentrated under vacuum. The crude material was diluted with 100 ml of EtOAc and washed with sodium bicarbonate (saturated aqueous) and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude solids were recrystallized from EtOAc/PE to afford N-[4-cyano-3-(trifluoromethyl)phenyl]piperidin-4-amine as a yellow powder (93.1 mg, 85% yield); (ES, m/z): [M+H]+ 270.1; 1H NMR (300 MHz, CDCl3): δ 7.69 (d, J=8.7 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.03 (d, J=1.2 Hz, 1H), 6.85 (dd, J=2.1, 8.7 Hz, 1H), 3.42 (m, 1H), 2.94 (m, 2H), 2.53 (m, 2H), 1.82 (d, J=10.2 Hz, 2H), 1.27 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C@H:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.C(N(CC)CC)C.N#N.[C:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])#[CH:31]>C1(C)C=CC=CC=1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C@@H:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:31]#[C:30][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:3]=1)[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: C[C@H](Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@H](Oc1cc(C#C[Si](C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
The compound (S)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (12.58 g, 33.11 mmol) was dispersed in toluene (100 mL), and triethylamine (14.05 g, 139.06 mmol) and copper iodide (126 mg, 0.66 mmol) were added successively. Under the protection of N2 atmosphere, PdCl2(PPh3)2 (465 mg, 0.66 mmol) was added. The reaction mixture was heated to 30° C., stirred for 0.5 h. Ethynyltrimethylsilane (9.11 g, 92.71 mmol) was added dropwise, gradually warmed to 90° C., and stirred overnight. Through HPLC test, it was found that the raw materials were completely reacted. The reaction liquid was cooled down, washed with water, and the toluene layers were combined. The toluene layer was dried over anhydrous Na2SO4, concentrated; the residue was purified via silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to yield the target product as yellow solid (10.6 g, yield: 80%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C@H:14]([CH3:17])[C@H:13]([OH:18])[C@@H:12]([CH3:19])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:24]O)(C)(C)C>C1C=CC=CC=1.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[C:1]1([S:7]([C:10]2[C@H:16]3[C@H:15]([O:24]3)[C@H:14]([CH3:17])[C@H:13]([OH:18])[C@@H:12]([CH3:19])[CH:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OO
Reactant: C[C@H]1C=CC(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: c1ccccc1
Product: C[C@@H]1[C@H](O)[C@@H](C)C=C(S(=O)(=O)c2ccccc2)[C@@H]2O[C@H]12
Temperature: 80 °C
Yield: 88 %

Procedure:
A suspension of dienyl sulfone 32 (67 mg, 0.24 mmol), molybdenum hexacarbonyl (3 mg, 0.01 mmol), and tert-butylhydroperoxide (74 μL of 5M solution in decane) in benzene (3 mL) was heated at 80° C. for 10 h. The reaction mixture was concentrated via rotary evaporation, purified by flash column chromatography (ethyl acetate/hexanes; 50:50) to afford 62 mg (88% yield) of epoxide α36 as a light yellow solid. mp 137.0-139.0° C.; [α]20D=+59.3 (c=0.51, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.93-7.96 (m, 2H), 7.58-7.70 (m, 3H), 7.39 (d, J=7.2 Hz, 1H), 3.90 (dd, J=4.5 Hz, 1.5 Hz, 1H), 3.64 (br s, 1H), 3.42 (m, 1H), 3.05-3.15 (m, 2H), 2.55 (tq, J=2.1 Hz, 7.2 Hz, 1H), 1.39 (d J=7.2 Hz, 3H), 1.18 (d, J=7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 147.9, 139.7, 136.5, 133.9, 129.7, 128.2, 78.3, 65.5, 52.5, 41.5, 32.2, 17.4, 17.2; Analytical. Calculated for C15H18O4S: C, 61.20; H, 6.16. Found: C, 60.95; H, 6.07.
Reaction SMILES: Br[C:2]1([F:20])[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH2:3]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].O>COCCOC>[F:20][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1Cc2ccccc2C1)C1=CCC(F)(Br)C=C1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: O=C(NC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2C1)c1ccc(F)cc1
Yield: 44.5 %

Procedure:
150 mg (0.45 mmoles) 4-bromo-N-indan-2-yl-4-fluoro-benzamide, 102 mg (0.54 mmoles 3-trifluoromethylbenzeneboronic acid, 211 mg (0.67 mmoles) barium hydroxide octahydrate and 20 mg tetrakis-triphenylphosphine-palladium were suspended in 10 ml 1,2-dimethoxyethane and 10 ml water and heated to reflux for 7 h. Subsequently, the reaction mixture was evaporated to dryness, the residue taken up in methylenchloride and extracted twice with water. The oil remaining after evaporation of the organic phase was purified using prep. HPLC chromatography. (RP18, acetonitrile/water, 1% trifluoroacetic acid). 80 mg (45%) of the title compound were obtained.
Reaction SMILES: [S:1]([C:5]1[S:9][C:8]([C:10]#[N:11])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[OH:14][NH:13][C:10]([C:8]1[S:9][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=1)=[NH:11]
Reactant: N#Cc1ccc(S(N)(=O)=O)s1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc(S(N)(=O)=O)s1
Yield: 57.5 %

Procedure:
A stirred mixture of 5-sulfamoyl-thiophene-2-carbonitrile [CAS-No. 519055-65-3] (0.31 g, 1.65 mmol), hydroxylamine hydrochloride (0.23 g, 3.31 mmol) and sodium carbonate (0.175 g, 1.65 mmol) in water (4.6 ml) and ethanol (1 ml) was heated under reflux conditions for 1.5 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/MeOH/hexane) to yield the title compound (0.21 g, 58%) as a white solid. MS (ISN) 220.1 [(M−H)−]; mp 189° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][CH3:25])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([N:24]([CH3:25])[C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CNC1CCCN(Cc2ccccc2)C1
Product: CN(c1ccnc2[nH]ccc12)C1CCCN(Cc2ccccc2)C1
Temperature: 200 °C
Yield: 130 %

Procedure:
A sealed melted mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.18 g, 0.0012 mol) in 1-benzyl-N-methylpiperidin-3-amine (0.50 g, 0.0024 mol) was heated to 200° C. overnight. The reaction mixture was partitioned between ethyl acetate (30 mL) and sat. NaHCO3 (20 mL), and the organic phase was washed with sat. NaCl, then dried and was reduced under vacuum to give 500 mg of orange oil. The product was chromatographed with 7% MeOH/DCM, 0.7% NH4OH to give 192 mg of an orange oil (48.8% yield).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6].[Br:28][CH2:29][C:30](Br)=[O:31].O>ClCCl>[Br:28][CH2:29][C:30]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:5][CH3:6])=[C:9]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=3[N:19]=2)[CH:10]=1)=[O:31]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(C(=O)CBr)ccc3OCC)nc12
Reaction time: 18 h
Yield: 78.4 %

Procedure:
Aluminium trichloride (12.8 g, 0.096 mol) was added portionwise over 1 hour to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (10.0 g, 0.032 mol) and bromoacetyl bromide (5.6 ml, 0.064 mol) in dichloromethane (150 ml) at 0° C. After 18 hours at room temperature, the reaction mixture was poured into ice and water (400 g) and the resulting mixture stirred vigorously. The organic phase was separated and the aqueous phase further extracted with dichloromethane (2×100 ml). The organic solutions were combined, dried (Na2SO4) and evaporated under vacuum to give an off-white solid, trituration of which from ether gave the title compound as a white solid (10.87 g, 78%), m.p. 159°-160° C. Found: C,52.54; H,4.88; N,12.78. C19H21BrN4O3 requires C,52.67; H,4,88; N,12.93%.