Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([NH:8][CH2:9][C:10]1[S:11][C:12]([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:13][CH:14]=1)=[O:7].[CH3:39]CN(C(C)C)C(C)C.C=O.C([BH3-])#N.[Na+]>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([NH:8][CH2:9][C:10]1[S:11][C:12]([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]([CH3:39])[CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=3)[CH2:22][CH2:23]2)(=[O:17])=[O:16])=[CH:13][CH:14]=1)=[O:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cccc(C(=O)NCc2ccc(S(=O)(=O)N3CCC(NCc4ccc(C(F)(F)F)cc4)CC3)s2)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc(C(=O)NCc2ccc(S(=O)(=O)N3CCC(N(C)Cc4ccc(C(F)(F)F)cc4)CC3)s2)c1

Procedure:
A solution of the hydrochloride salt of 1 (50 mg, 0.08 mmol), DIEA (12 ul, 0.08 mmol), formaldehyde solution 37% aq. (32 ul, 0.4 mmol) and Sodiumcyanoborohydride (10 mg, 0.16 mmol) in THF were heated under reflux for 15 h, whereupon complete alkylation took place. The reaction was diluted with DCM and the inorganic salts were extracted with water. The crude was dried over MgSO4, and the solution was evaporated to dryness. The oily residue was taken up in THF, 1N HCl in ether was added slowly upon which colourless crystalls of compound 205 were formed (yield: 51 mg, 97%). Anal. HPLC: R.t=4.39 min (method b). M/Z APCI: 582.1 (M+1), 580.4 (M−1). The following compound was prepared in a similar fashion according to the example 205 described above:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][C:8]1([CH2:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH2:20][CH2:21][C:22](O)=[O:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[O:40]=[S:37]1(=[O:41])[CH2:38][CH2:39][N:34]([C:22](=[O:23])[CH2:21][CH2:20][C:14]2[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=2[C:10]2[CH2:9][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:33])([CH2:25][C:26]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:32])[O:12][N:11]=2)[CH2:35][CH2:36]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)O)=NO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)N2CCS(=O)(=O)CC2)=NO1
Temperature: 25 °C
Reaction time: 7 h
Yield: 35.4 %

Procedure:
A mixture of 3-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoic acid (317 mg), thiomorpholine 1,1-dioxide (92 mg), WSC (106 mg), HOBt (92 mg), and DMF (3 mL) was stirred at room temperature for 7 hours. To the reaction mixture, 0.1 M hydrochloric acid was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (140 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]1[C:13](=O)[C:14](=[O:19])[C:15]=1[O:16]CC)[CH3:10]>C(O)C>[CH2:9]([O:11][C:12]1[C:15](=[O:16])[C:14](=[O:19])[C:13]=1[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1ccc(F)cc1
Solvent: CCO
Product: CCOc1c(Nc2ccc(F)cc2)c(=O)c1=O

Procedure:
A solution of 4-fluoroaniline and 3,4-diethoxy-3-cyclobutene-1,2-dione in ethanol was processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][N:11]=1)=S.[N:15]#[C:16][NH2:17].[Pb]>>[C:16]([NH:17][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][N:11]=1)#[N:15]
Reactant: CNC(=S)NCCSCc1ccon1
Reactant: N#CN
Agent: [Pb]
Product: CNC(=NCCSCc1ccon1)NC#N

Procedure:
Reaction of N-methyl-N'-[2-(3-isoxazolylmethylthio)-ethyl]thiourea with lead cyanamide by the procedure of Example 121 gives N-cyano-N'-methyl-N"-[2(3-isoxazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([C:20]#[N:21])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:22])[CH:10]=2)=[CH:5][CH:4]=1.[OH-:25].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([C:20]([NH2:21])=[O:25])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:22])[CH:10]=2)=[CH:23][CH:24]=1
Reactant: [OH-]
Reactant: COc1ccc(COc2cn(C)c3c(C#N)cccc3c2=O)cc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(COc2cn(C)c3c(C(N)=O)cccc3c2=O)cc1
Yield: 65.5 %

Procedure:
A solution of 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-8-carbonitrile (1.75 g, 5.46 mmol) and 25% aqueous sodium hydroxide (20 mL) in methanol (100 mL) was stirred at reflux for 3 h. After complete consumption of the nitrile, the mixture was concentrated to remove ˜75% of the methanol. The mixture was acidified to pH 3 with 1 M HCl (aq), and partitioned between EtOAc and brine. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The crude product was absorbed onto silica gel and purified by automatic silica gel column chromatography (Combiflash RF), eluting with methanol/dichloromethane (0-30%) to afford 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-8-carboxamide (1.21 g, 3.58 mmol, 65.5% yield) as light brown solid. LCMS (M+H)+: 339.3.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[C@@H:4]1NC(=O)C1C=CC=C([Cl:19])C=1>Cl>[ClH:19].[ClH:1].[NH2:2][C@H:3]1[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1
Reactant: NC1C2CCN(CC2)[C@@H]1NC(=O)c1cccc(Cl)c1
Agent: Cl
Product: N[C@@H]1CN2CCC1CC2
Yield: 97.8 %

Procedure:
To 11.2 g of (S)-(-)-N-(3-aminoquinuclidinyl)-3-chlorobenzamide hydrochloride was added 40 ml of concentrated hydrochloric acid and the mixture was refluxed for 6 hours. The reaction mixture was cooled and filtered to remove insolubles and the filtrate was concentrated and dried. To the residue was added ethanol and the resulting crystals were recovered by filtration to provide 6.9 g of (S)-(-)-3-aminoquinuclidine dihydrochloride. m.p. not lower than 260° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([N:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[O:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH3:25][N:26]([CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[Al+3].[Cl-].[Cl-].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>ClCC(Cl)(Cl)Cl.[OH-].[Na+]>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([C:10]2([C:30]3[CH:31]=[CH:32][C:27]([N:26]([CH3:33])[CH3:25])=[CH:28][CH:29]=3)[C:19]3[C:14](=[CH:15][C:16]([N:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[O:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:24]
Reactant: CCN(CC)c1cccc(C2OC(=O)c3cc(N(C)C)ccc32)c1
Reactant: CN(C)c1ccccc1
Agent: ClCC(Cl)(Cl)Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Al+3]
Product: CCN(CC)c1cccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)c1
Temperature: 50 °C
Yield: 68.7 %

Procedure:
33 g of 3-(m-diethylaminophenyl)-6-dimethylaminophthalide and 13 g of dimethylaniline were dissolved in 300 cc of tetrachloroethane. 14 g of anhydrous aluminum chloride was added to the solution, and then the mixture was heated at 50° C. for 3 hours with stirring. After the termination of reaction, 30% aqueous solution of caustic soda was added to the mixture to dissolve aluminum chloride while cooling with ice. Tetrachloroethane phase was steam distilled to remove unreacted dimethylaniline and tetrachloroethane. The remaining aqueous phase was neutralized with acetic acid to obtain a white solid. This solid was dissolved in 600 cc of 2.5% aqueous solution of caustic soda, and then heated at 50° C. 600 cc of 5% aqueous solution of potassium persulfate was added dropwise to the above solution, and then the mixture was heated at 60° C. for 3 hours. After the termination of reaction, the resultant precipitates were filtered and recrystallized from methanol to obtain 31 g of 3-(m-diethylaminophenyl)-3-(p-dimethylaminophenyl)- 6-dimethylaminophthalide having the following structure whose m.p. was 177°-178° C. in the form of colourless crystals. This compound become green on contact with silica gel. ##STR73##
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[Cl:8][CH2:9][NH2:10]>C1(C)C=CC=CC=1>[Cl:8][CH2:9][NH:10][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4]
Reactant: COCC(Cl)C=O
Reactant: NCCl
Solvent: Cc1ccccc1
Product: COCC(C=O)NCCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Chloromethylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-chloromethylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCc1cccnc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCc1cccnc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 3-(2-aminoethyl)pyridine (39 mg, 0.32 mmol). The title compound was obtained as a solid (75 mg, 49% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.91 (1H, m), 8.40 (2H, m), 8.38 (1H, s), 7.62 (1H, m), 7.30 (1H, m), 3.48 (2H, m), 2.81 (2H, m). MS m/z: 455.01, 457.00 [M+H]+.
Reaction SMILES: [Br:1]Br.[OH-].[Na+].[C:5]([C:7]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)([CH2:14][CH:15]=[CH2:16])[CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:6].O>O1CCOCC1>[C:5]([C:7]([C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][Br:1])=[CH:21][CH:22]=1)([CH2:14][CH:15]=[CH2:16])[CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:6]
Reactant: C#Cc1ccc(C(C#N)(CC=C)Cn2cncn2)cc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCC(C#N)(Cn1cncn1)c1ccc(C#CBr)cc1

Procedure:
0.8 g of bromine are added, at 0°, to 5 ml of 10% NaOH while stirring vigorously. After the solution has become colourless a solution of 1 g 2-cyano-2-(4-ethinylphenyl)-1-(1H-1,2,4-triazol-1-yl)-4-pentene in 3 ml of dioxane are added dropwise, at 0°, within a few minutes. The reaction mixture is then stirred for 3 hours at room temperature, poured into 100 ml of water, extracted with diethylether, the ether extract washed with water (3 times), dried and the ether evaporated. The residue is heated for 3 hours at high vacuum and a temperature of 50°-60° C. The thus obtained title compound has a Rf value of 0.75, employing CH2Cl2 /CH3OH 9:1 as eluant (Compound 4).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][CH:13]([F:31])[C:14]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:19]=[CH:18][C:15]=1[CH:16]=O>>[F:31][CH:13]([F:12])[C:14]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:19]=[CH:18][C:15]=1[C:16]1[NH:1][C:2]2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1C(F)F
Reactant: Nc1cccc(C(=O)O)c1N
Product: O=C(O)c1cccc2nc(-c3ccc(OCCN4CCOCC4)cc3C(F)F)[nH]c12
Yield: 48 %

Procedure:
2,3-Diaminobenzoic acid (1; 222 mg, 1.5 mmol) and the corresponding 2-(difluoromethyl)-4-(2-morpholinoethoxy)benzaldehyde 124 were subjected to the same general procedure detailed above to afford 2-(2-(difluoromethyl)-4-(2-morpholinoethoxy)phenyl)-1H-benzo[d]imidazole-7-carboxylic acid 125 (300 mg, 48%).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:34](O)=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CN(C=O)C>[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:34]([O:14][CH2:13][C@H:12]1[O:15][C@@H:7]([N:6]2[CH:16]=[C:2]([F:1])[C:3](=[O:18])[NH:4][C:5]2=[O:17])[C@H:8]([OH:9])[C@@H:10]1[OH:11])=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of 5-fluorouridine (5-FU, 521 mg, 1.98 mmol) in 6 mL of anhydrous THF-DMF (1:1 under nitrogen was added N-(benzyioxycarbonyl)-L-valine (500 mg, 1.99 mmol), triphenylphosphine (521 mg, 1.98 mmol), and diisopropyl azodicarboxylate (402 mg, 1.98 mmol). The mixture was stirred overnight at 25 °C. The volatile components were removed under reduced pressure and the residue chromatographed over silica gel eluting with methyl alcohol:chloroform (1:5 ) to provide 5'-O-[N-(benzyloxycarbonyl)-L-valinyl]-5-fluorouridine (413 mg., 40% yield) as a white solid melting at about 64° C.-67° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.ClCCl.[OH:15][CH2:16][C:17]1[O:22][C:21]([CH3:24])([CH3:23])[O:20][C:19](=[O:25])[C:18]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCOCC>[CH:16]([C:17]1[O:22][C:21]([CH3:24])([CH3:23])[O:20][C:19](=[O:25])[C:18]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:15]
Reactant: CC1(C)OC(=O)C(c2ccccc2)=C(CO)O1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)OC(=O)C(c2ccccc2)=C(C=O)O1
Reaction time: 5 h
Yield: 62 %

Procedure:
Pyridinium chlorochromate (1.29 g) was suspended into dichloromethane (8 ml), then a dichloromethane suspension (3 ml) of 6-hydroxymethyl-2,2-dimethyl-5-phenyl-2H,4H-1,3-dioxin-4-one (Compound No. 236, 0.70 g) was added thereto at room temperature. After stirring for 5 hours, a large amount of ether was added and extracted by decantation. The organic layer was dried with magnesium sulfate, the solvent was removed by evaporation, and the crude product was purified by silica gel chromatography to afford the captioned compound (0.43 g, yield 67%).
Reaction SMILES: [C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[N+:25]([O-:27])=[O:26])[O:18][CH2:19][CH2:20][OH:21])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[N+:25]([O-:27])=[O:26])[O:18][CH2:19][CH2:20][O:21][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1CS(=O)(=O)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1

Procedure:
A solution of 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-ethanol (14.3 g, 36.9 mmol), p-toluenesulfonylchloride (14.9 g, 78.2 mmol) and triethylamine (23 mL, 170 mmol) in methylene chloride (400 mL) was stirred under nitrogen at ambient temperature for 2 hours, 45 minutes. The reaction mixture was then concentrated and partitioned in methylene chloride and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 25-75% ethyl acetate in hexane and 100% ethyl acetate. Drying for 25 minutes in vacuo at 80° C. yielded toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-ethyl ester as a rust-colored solid (15.7 g, 78.5%). Mass Spectrum (+EI, [M+H]+) m/z 542. 1HNMR (500 MHz, DMSO-d6): 88.53 (dd, 1H, J=8.18 Hz and 1.10 Hz), 8.31 (d, 1H, J=8.30 Hz), 8.09-8.11 (m, 1H), 7.94-7.99 (m, 2H), 7.62-7.75 (m, 5H), 7.42 (d, 2H, J=7.93 Hz), 6.98 (dd, 1H, J=9.15 Hz and 2.93 Hz), 6.80 (d, 1H, J=2.81 Hz), 5.20 (s, 2H), 4.28-4.30 (m, 2H), 4.10-4.12 (m, 2H), 2.37 ppm (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([NH:6][CH2:7][C:8]([F:17])([C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)[CH3:9])(=[O:5])=[O:4].[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O>O>[NH2:19][C:20]1[CH:25]=[C:24]([C:13]2[CH:14]=[CH:15][C:10]([C:8]([F:17])([CH3:9])[CH2:7][NH:6][S:3]([N:2]([CH3:18])[CH3:1])(=[O:5])=[O:4])=[CH:11][CH:12]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Temperature: 70 °C

Procedure:
[(Dimethylamino)sulfonyl][2-fluoro-2-(4-iodophenyl)propyl]amine (386, 1.0 mmol, prepared in example 36), 3-aminobenzeneboronic acid (201 mg, 1.3 mmol), potassium carbonate (179 mg, 1.3 mmol), tetrakis(triphenyl phosphine)palladium(0) (58 mg, 0.05 mmol), and dioxane/water (60 mL, 3:1) are mixed together in a 100 mL single neck flask and stirred at 70° C. over night. In the morning, the reaction is cooled to room temperature and poured into H2O, and the desired product is extracted with ethyl acetate. The organic layer is backwashed once with H2O, dried over K2CO3, filtered, and concentrated under reduced pressure. The crude material is purified via silica gel chromatography employing the Chromatotron and using a 2000 micron rotor with hexane/ethyl acetate eluent to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6]2)[CH2:4][CH:3]=1.CCCCCCCCCCCC.NC(N)=[O:25].C(=O)(O)[O-].[Na+].OO>O.C(#N)C.S([O-])([O-])(=O)=O.[Mn+2]>[CH3:9][C:8]1([CH3:10])[CH:7]2[C:2]3([CH3:1])[O:25][CH:3]3[CH2:4][CH:5]1[CH2:6]2
Reactant: CC1=CCC2CC1C2(C)C
Reactant: NC(N)=O
Agent: [Mn+2]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: CCCCCCCCCCCC
Product: CC1(C)C2CC3OC3(C)C1C2
Yield: 85 %

Procedure:
To a mechanically stirred solution of α-pinene (0.01 mol), dodecane (0.001 mol), urea (0.208 mol), sodium bicarbonate (0.003 mol) and manganese sulphate (0.1 mmol) in 10.0 ml of water and 30 ml acetonitrile at 25° C. is added 30% aqueous hydrogen peroxide (0.4 mol) in three equal portions over a period of 3 hours. After 6 hours the reaction mixture was extracted with 4×5 ml diethyl ether. The combined organic layer was dried over anhydrous sodium sulphate. Removal of solvent yielded α-pinene oxide in 85% yield with selectivity 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1F
Reaction time: 1 h
Yield: 92 %

Procedure:
To a suspension of 5-chloro-2-fluoro-benzoic acid (2.0 g, 11.5 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 6.5 ml, 13 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 1 hour, methanol (10 ml) was added. After stirring for 20 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to provide methyl 5-chloro-2-fluoro-benzoate (2.0 g, 92% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:14]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:36])([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[CH3:28])=[C:23]([F:37])[CH:22]=3)[CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[CH:16]1([CH2:15][CH:14]([C:12]2[NH:11][C:8]3=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]3[CH:13]=2)[C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH3:36])([O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[CH3:28])=[C:23]([F:37])[CH:22]=2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(C(C)(C)OC4CCCCO4)c(F)c3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(OC1CCCCO1)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1F
Yield: 85.7 %

Procedure:
A mixture of 2-(2-cyclopentyl-1-{3-fluoro-4-[1-methyl-1-(tetrahydro-pyran-2-yloxy)-ethyl]-phenyl}-ethyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (1.8 g, 3.54 mmol) in tetrahydrofuran (8 mL) and a 10% aqueous sodium hydroxide solution (13 mL) was heated at 70° C. for 10 h. The mixture was neutralized with a 3N aqueous hydrochloric acid solution, diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(2-cyclopentyl-1-{3-fluoro-4-[1-methyl-1-(tetrahydro-pyran-2-yloxy)-ethyl]-phenyl}-ethyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (1.5 g, 85.8%) as a light yellow solid: LC/MS m/e calcd for C29H35FN2O4 [M+H]+ 495.61, observed 494.9.
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[CH2:10][CH2:11][OH:12])C(=O)[O-])(C)C.[ClH:21].O1CCOCC1>>[ClH:21].[NH2:5][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=1)[CH2:10][CH2:11][OH:12]
Reactant: CC(C)(C)N(C(=O)[O-])[C@H](CCO)Cc1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](CCO)Cc1ccc(Br)cc1
Reaction time: 2 h
Yield: 94 %

Procedure:
1,1-Dimethylethyl{(1S)-1-[(4-bromophenyl)methyl]-3-hydroxypropyl}carbamate (4.4 g, 12.8 mmol) was dissolved in 4N HCl/dioxane (20 mL). After 2 h, the reaction mixture was concentrated in vacuo to give 3.69 g (94%) of the title compound as a white solid. LC/MS (ES) m/e 244.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.N>O>[O:22]=[C:19]1[CH:20]=[CH:21][N:2]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=3)=[CH:5][CH:4]=2)[CH:17]=[CH:18]1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=c1ccocc1
Agent: Cl
Agent: N
Solvent: O
Product: O=C1CCC(c2ccc(-n3ccc(=O)cc3)cc2)=NN1

Procedure:
A stirred mixture of 6-(4-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone hydrochloride (1.5 g), 4H-pyran-4-one (0.7 g), and water (20 ml), was heated under reflux for 41/2 hours. The resultant solid was dissolved in the minimum of hot water and the solution was neutralised with ammonia to give the crude product. Recrystallisation from water gave the title compound, 0.73 g, m.p. 270°-272° C.