Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:13](=[O:27])[NH:14][C:15](=[O:26])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[CH:4]1.C[Si](Cl)(C)C.[CH2:33]1[O:36][CH:34]1[CH3:35]>CN(C=O)C.O>[OH:36][CH:34]([CH3:33])[CH2:35][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:13](=[O:27])[NH:14][C:15](=[O:26])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:33][CH:34]([OH:36])[CH3:35])[CH:18]=2)=[CH:4]1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Reactant: CC1CO1
Agent: C[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)Cn1cc(C2=C(c3cn(CC(C)O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
40 mg of a 60% suspension of sodium hydride in mineral oil was added to a solution of 327 mg of 3,4-bis-(3-indolyl)-1H-pyrrole-2,5-dione in 5 ml of DMF at 0° C. under nitrogen. After 0.5 hour the mixture was cooled to -20° C. and 108 mg of trimethylsilyl chloride were added. The mixture was allowed to warm to room temperature, then cooled to 0° C. and then a further 80 mg of sodium hydride were added thereto. After 0.5 hour at 0° C. 116 mg of propylene oxide were added and the mixture was stirred overnight. 5 ml of water were added and the mixture was extracted with dichloromethane. The organic phase was dried and evaporated. The residue was purified on silica gel with ethyl acetate/petroleum ether. Recrystallization from diethyl ether/petroleum ether gave 30 mg of 3,4-bis[1-(2-hydroxypropyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=O)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:30].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][OH:31])[CH2:35][CH2:36]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:30]
Reactant: OCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(Cl)c(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc(Cl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Yield: 94.2 %

Procedure:
In a similar manner to Step 2 of Example 6, 4,5-dichloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (115 mg, 0.258 mmol) was dissolved in acetonitrile (8.1 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (134 mg, 1.03 mmol), acetic acid (0.295 mL, 5.16 mmol) and sodium triacetoxyborohydride (191 mg, 0.903 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4,5-dichloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (136 mg, yield 94%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:7][C:6]=1[O:20][CH3:21].[SH:22][C:23]1[S:24][CH2:25][CH2:26][N:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([O:20][CH3:21])=[CH:7][C:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([N:27]2[CH2:26][CH2:25][S:24][C:23]2=[S:22])=[O:19])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: SC1=NCCS1
Reactant: COCOc1c(OC)cc(CCCCC(=O)O)cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1c(OC)cc(CCCCC(=O)N2CCSC2=S)cc1OC
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 0.88 g of 5-(4-methoxymethoxy-3,5-dimethoxyphenyl)pentanoic acid and 0.42 g of 2-mercaptothiazoline in 30 ml of dichloromethane were added 0.73 g of dicyclohexylcarbodiimide and 36 mg of 4-dimethylaminopyridine at room temperature followed by stirring for 16 hours. The reaction mixture was filtered with suction, and the filtrate washed with a 1N aqueous NaOH solution and then with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent was removed by distillation, and the residue subjected to column chromatography on silica gel. From the fraction eluted with dichloromethane was obtained 1.15 g of N-[5-(4-methoxymethoxy-3,5-dimethoxyphenyl)pentanoyl)-thiazolidine-2-thione.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].Cl[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:22])([CH3:21])[C:19]#[CH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:22][C:18]([CH3:21])([C:19]#[CH:20])[CH2:17][CH2:16][CH2:15][CH2:14][N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: C#CC(C)(O)CCCCCl
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CC(C)(O)CCCCn1cnc2c1c(=O)[nH]c(=O)n2C

Procedure:
33.2 g (0.2 mol) of 3-methylxanthine in 350 ml of dimethylformamide were stirred with 32.1 g (0.2 mol) of 1-chloro-5-hydroxy-5-methyl-6-heptyne from Example 1B1) in the presence of 13.8 g (0.1 mol) of potassium carbonate at 120° C. for 6 hours. The hot mixture was then filtered, evaporated to dryness under reduced pressure and taken up in ethanol and, at the boiling point, diisopropyl ether was added to cloudiness, and the mixture was left to crystallize with cooling.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1.ClC1C=CC=C(C(OO)=[O:28])C=1.C(=O)([O-])O.[Na+].N([O-])=O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N+:14]([O-:28])=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc[n+]([O-])c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
In benzene (15 ml) was dissolved 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.09 g), and to the solution was added m-chloroperbenzoic acid (0.963 g). The mixture was stirred at room temperature for 1 hour, and to the mixture were added ethyl acetate (150 ml), saturated sodium hydrogen carbonate solution (200 ml) and sodium nitrite(200 mg). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was washed with a mixture of isopropylether and ethyl acetate (2:1) to give 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-1-oxide (1.04 g) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[N:21]=4)[S:16][C:17]=3[CH3:18])[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C-:29]#[N:30].[Na+]>C(#N)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.[Cu]I>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[N:21]=[C:22]([C:29]#[N:30])[CH:23]=[CH:24][CH:25]=4)[S:16][C:17]=3[CH3:18])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4cccc(Br)n4)sc3C)cn2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(-c3nc(Nc4cccc(C#N)n4)sc3C)cn2)cc1
Yield: 73.4 %

Procedure:
According to Scheme 4 Step 1: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-yl)-6-bromopyridin-2-amine (0.94 mmol, 430 mg), NaCN (3.54 mmol, 174 mg), Pd(PPh3)4 (0.42 mmol, 487 mg) and CuI (0.18 mmol, 34 mg) in acetonitrile (22 mL) was microwaved at 180° C. for 6 hours under nitrogen. After evaporation of the solvent, the resulting crude product was purified by flash chromatography over silica gel using DCM/MeOH (80:20) as eluent to afford 6-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-ylamino)picolinonitrile (0.69 mmol, 277 mg, 73%).
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23]C(=O)C2C=CC=CC=2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]1[C:44]([CH3:46])([CH3:45])[C:43]2[CH:47]=[CH:48][CH:49]=[C:50]([N+:51]([O-:53])=[O:52])[C:42]=2[Se:41]1)(=O)C.[OH-].[Na+].Cl>C1COCC1.CO>[OH:23][C:16]1[CH:17]=[CH:18][C:19]2[C@@H:20]3[C@H:11]([C@H:8]4[C@@:6]([CH2:22][CH2:21]3)([CH3:7])[C@@H:5]([OH:4])[CH2:10][CH2:9]4)[C@H:12]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:44]([CH3:45])([CH3:46])[C:43]4[CH:47]=[CH:48][CH:49]=[C:50]([N+:51]([O-:53])=[O:52])[C:42]=4[Se:41]3)[CH2:13][C:14]=2[CH:15]=1
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCCCCN4[Se]c5c([N+](=O)[O-])cccc5C4(C)C)Cc4cc(OC(=O)c5ccccc5)ccc4[C@H]3CC[C@]12C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)c2cccc([N+](=O)[O-])c2[Se]N1CCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 22 h
Yield: 99 %

Procedure:
N-{8-[17β-acetoxy-3-benzoyloxyoestra-1,3,5(10)-trien-7α-yl]octyl}-3,3-dimethyl-7-nitrobenzisoselenazoline (115 mg, 0.15 mmol) is dissolved in 2 ml of THF and 1 ml of methanol. To the obtained mixture is then added an aqueous solution of NaOH (1 ml, 1N, 1.0 mmol). The reaction medium is stirred at room temperature for 22 hours, then neutralized with an aqueous solution of HCl (1N). The mixture is extracted with ethyl acetate. The combined organic phases are washed with a saturated aqueous solution of NaCl, dried over MgSO4 and evaporated. The residue is purified by silica gel column chromatography (eluent: EtOAc:cyclohexane, 1:3) to provide the expected product (95 mg, 94%) as a deep red solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.[Cl:35][C:36]1[S:37][C:38]([CH2:41]Cl)=[CH:39][CH:40]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:41][C:38]2[S:37][C:36]([Cl:35])=[CH:40][CH:39]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1ccc(Cl)s1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(Cl)s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-chloro-5-(chloromethyl)thiophene (2.39 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 45%).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:19]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CN(C)C=O.O>[OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][S:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:29])=[O:28])=[CH:15][CH:16]=3)[C:7](=[O:18])[C:6]=2[CH:19]=1
Reactant: Nc1ccc(-c2coc3cc(O)c(O)cc3c2=O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)coc2cc(O)c(O)cc12

Procedure:
6,7-Dihydroxy-3-(4-aminophenyl)-4H-1-benzopyran-4-one [see Example 51a] (538 mg) is dissolved in a mixture of dimethylformamide and water 15:85 (5 ml) and the solution is heated to 90° in the presence of benzenesulfonyl chloride (210 mg). After 15 minutes the pH has dropped to 3 and it is adjusted to 9 by addition of a 25% sodium hydroxide solution. Benzenesulfonyl chloride (additional 143 mg) and 25% sodium hydroxide solution (total amount used: 1 ml) are added in the same way until the pH does not vary any more. Aqueous hydrochloric acid is then added to lower the pH to 3 and the solution is cooled until precipitation occurs. The precipitate is filtered, washed with water and dried to give 6,7-dihydroxy-3-(4-phenylsulfonylaminophenyl)-4H-1-benzopyran-4-one, m.p. 285°-286°.
Reaction SMILES: CN(C)N=[C:4]([CH2:6][CH:7]([OH:28])[CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH3:5].I([O-])(=O)(=O)=[O:31].[Na+]>CO.P([O-])([O-])([O-])=O.O>[OH:28][CH:7]([CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH2:6][C:4](=[O:31])[CH3:5]
Reactant: CC(CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)=NN(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h

Procedure:
4-Hydroxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone N,N-dimethylhydrazone (1 mmol) is dissolved in methanol (15 ml) and 1.0 N pH 7 phosphate buffer (3 ml), and a solution of sodium periodate (2.2 mmol) in water (5 ml) is added at 25° with stirring. After about 3 hours, the reaction mixture is filtered, poured into water and extracted with methylene chloride. The extract is dried and concentrated in vacuo to give 4-hydroxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone (cpd. 1, Table B).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:19][N:20]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][N:22]=[CH:21]1>C1(C)C=CC=CC=1.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.[Pd]>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:24]3[N:20]([CH3:19])[CH:21]=[N:22][CH:23]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: Cn1ccc2ccc(Br)cc21
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1cncc1-c1ccc2ccn(C)c2c1
Yield: 83.6 %

Procedure:
A solution of 6-bromo-1-methyl-1H-indole (6.2 g, 29.5 mmol) in toluene was degassed by bubbling argon through the solution for 10-20 min. Et3N (8.2 mL, 59 mmol), tetrakis(triphenylphosphine)palladium (0) (681 mg, 0.59 mmol) and 1-methyl-5-(tributylstannyl)imidazole (Gaare, K.; Repstad, T.; Benneche, T.; Undheim, K. Acta Chem. Scan. 1993, 47, 57.) (11.6 g, 31.2 mmol) in toluene (30 mL) were added and the mixture was heated to 120° C. for 18 h until Pd black appeared. The mixture was cooled, filtered through a pad of silica gel and the pad was washed well with EtOAc. The filtrate was evaporated and chromatography of the residue over silica gel using 0.5-1% methanol in EtOAc gave 1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indole (5.21 g, 84%) as an off white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][N:12](C=O)C>[C-]#N.[C-]#N.[Zn+2].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(OCC)(=O)C>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[C:11]#[N:12]
Reactant: COc1cc(C)cc(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C#N)c1
Temperature: 90 °C
Yield: 83 %

Procedure:
In a 100 mL round bottom flask, 1-bromo-3-methoxy-5-methyl-benzene (2.17 g, 10.79 mmol), Zn(CN)2 (1.9 g, 16.19 mmol, 1.5 eq.) and Pd(PPh3)4 (1.24 g, 1.08 mmol, 0.1 eq.) was charged with DMF (20 mL). The reaction mixture was heated at 90° C. under Ar for 7 hours. Ethyl acetate was added, followed by washing with brine. The organic layer was concentrated and purified (silica gel, 0-50% EtOAC/hexane) to give a white solid (1.31 g, 83%). 1H NMR (300 MHz, CDCl3): δ 7.05 (s, 1H), 6.97 (s, 2H), 3.81 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][O:14][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: OCC1(c2ccc(Br)cc2)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred of [1-(4-bromophenyl)-cyclopentyl]-methanol (226) (47.0 g, 184.19 mmol) in dichloromethane (300 mL) was added Et3N (51.3 mL, 368.39 mmol) followed by dropwise addition of mesyl chloride (17.1 mL, 221.03 mmol) at 0° C., and the reaction mixture stirred at room temperature for 1 h. The reaction was quenched by the addition of water, extracted with dichloromethane, washed with water, dried over Na2SO4 and concentrated. The crude product was purified by 100-200 silica column chromatography using 5% ethyl acetate in hexane as the eluent to give methanesulfonic acid 1-(4-bromophenyl)-cyclopentylmethyl ester (227) (52.8 g, 86%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1.FC(F)(F)S(O[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=1[CH3:32])(=O)=O>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH3:32])=[CH:8][CH:9]=1
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)CCCC1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COC(=O)c1ccc(C2=C(C)CCCC2)cc1

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Step A (2 g, 7.63 mmol) and a mixture of 2-methyl-cyclohex-1-en-1-yl trifluoromethanesulfonate and 6-methyl cyclohex-1-en-1-yl trifluoromethanesulfonate (2.24 g, 9.16 mmol, approximately 5:1 ratio) were reacted according to the procedure of Example 1, Step F. Purification by preparative HPLC (Primesphere 5 silica, 5% methyl tert-butyl ether in hexane) afforded the title compound as an amorphous white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21]([CH:22]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[O:26].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:17][CH2:18]3)[N:12]3[N:19]=[CH:20][C:21]([CH:22]=[C:30]4[NH:24][C:25](=[O:26])[NH:27][C:28]4=[O:29])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Nc3cccc(Cl)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To 5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (26 mg, 0.08 mmol) in EtOH was added hydantoin (8 mg, 0.08 mmol) and piperidine (8 μl, 0.08 mmol). The mixture was stirred at 70° C. for 3 days. Insolubles were filtered off, and filtrate was concentrated under reduced pressure. Filtrate was then dissolved in methanol and purified by HPLC to yield 5-((5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=410)
Reaction SMILES: [CH2:1](Cl)[C:2](=[CH2:4])[CH3:3].[CH2:6]([NH:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:6]([N:13]([CH2:3][C:2]([CH3:4])=[CH2:1])[CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCNCc1ccccc1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=C(C)CN(CCO)Cc1ccccc1
Temperature: 62 °C
Yield: 96.2 %

Procedure:
Add methallyl chloride (68.8 g, 0.760 mol, Aldrich) to a mixture of N-benzylethanolamine (100 g, 0.663 mol) and potassium carbonate (139 g, 1.00 mol) in water (600 mL). Heat the mixture to 62° C. for 23 h and then transfer to a separatory funnel. Extract the product with tert-butyl methyl ether (500 mL). Dry, filter, and concentrate the organic solution to give the title compound (131 g, 96%) as a colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.20-7.33 (5H, m), 4.92 (1H, br s), 4.83 (1H, br s), 4.35 (1H, t), 3.53 (2H, s), 3.44-3.50 (2H, m), 2.94 (1H, s), 2.42 (2H, t), 1.69 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[C:17](=[C:18]2[CH2:22][CH:21]([CH2:23]I)[O:20][C:19]2=[O:25])[O:16][C@H:15]2[N:12]1[C:13](=[O:26])[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]([CH:11]1[C:17](=[C:18]2[CH2:22][CH:21]([CH2:23][N:27]=[N+:28]=[N-:29])[O:20][C:19]2=[O:25])[O:16][C@H:15]2[N:12]1[C:13](=[O:26])[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(CI)CC1=C1O[C@@H]2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: [N-]=[N+]=NCC1CC(=C2O[C@@H]3CC(=O)N3C2C(=O)OCc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the compound of Example 41 (500 mg), 50 ml of tetrahydrofuran and tetrabutylammonium azide (364 mg) is stirred at room temperature for 30 minutes. The mixture is partitioned between ethyl acetate and brine. The organic phase is separated, washed with brine, dried (MgSO4) and stripped of the solvents. The residue is subjected to chromatography over an SiO2 column using toluene/t-butyl methyl ether (12/1). The title compound is obtained as an oil, having characterization data as indicated below.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)C(O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
10 g of 3-(4-hydroxyphenyl)pyruvic acid and 50 ml of methanol were charged to a pressure reactor to form a solution, and 0.5 g of 5% palladium on charcoal was added thereto. The atmosphere was displaced with hydrogen, and the mixture was stirred at 25° C. under a hydrogen pressure of 5 kg/cm2 for 2 hours. After completion of the reaction, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to give 10.1 g of 3-(4-hydroxyphenyl)lactic acid as colorless crystals.