Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.C[N:42](C)C=O.N>C(Cl)Cl.C(OCC)C.C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:42])=[O:6]
Reactant: CN(C)C=O
Reactant: Cc1ccc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C(=O)O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C(N)=O
Reaction time: 1 h
Yield: 72 %

Procedure:
(R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzoic acid (Example 9-1; 1.026 g, 2.10 mmol) was dissolved in 20 mL CH2Cl2 and treated with oxalyl chloride (0.22 mL, 2.52 mmol) and 10 mL of dimethyl formamide. The mixture was allowed to stir for 1 h until all solids had dissolved. 10 mL of THF saturated with ammonia was added slowly. A thick white precipitate formed. The slurry was stirred for 20 min then diluted with diethyl ether (100 mL), washed with 100 mL of each of H2O, 0.2 N aqueous HCl, saturated aqueous NaHCO3, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 50% ethyl acetate/hexanes to yield 740 mg (72%) of the desired 2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzamide as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:6]/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: O=C1CC(c2cccnc2)Oc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(c2cccnc2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of 6-bromo-2-(pyridine-3-yl)chroman-4-one (1.0 g, 3.3 mmol) in anhydrous DCM (20 mL) was added TiCl4 (1 M solution in DCM, 2.5 g, 13.2 mmol) dropwise within 15 minutes at room temperature in absence of light. It was stirred for another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (1.35 g, 7.26 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was poured into ice-water, extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(6-bromo-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide (687 mg, 64%), which was used for next step without further purification.
Reaction SMILES: Br[Zn][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[C:12]1[C:21]2[C:16](=[C:17]([C:22]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[C:29]([Cl:37])[CH:28]=4)[O:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>C1COCC1.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>[Cl:37][C:29]1[CH:28]=[C:27]([C:25]2[O:24][N:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH:15]=[CH:14][N:13]=[C:12]4[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:26]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]([CH3:36])[CH3:35]
Reactant: CCOC(=O)CCC[Zn]Br
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Br)nccc34)no2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1nccc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12

Procedure:
Bromo[4-(ethyloxy)-4-oxobutyl]zinc (Aldrich; 0.5 M in THF, 2 ml) was added dropwise to a solution of 1-bromo-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D40; 0.15 g) and tetrakis(triphenylphosphine)palladium(0) (50 mg) in THF (5 ml). The resulting solution was heated to reflux for 1 hour. The solvent was evaporated in vacuo and the residue was dissolved in DCM (20 ml). The organic solution was washed with 0.5 M aq. NaOH (8 ml), then dried over anhydrous sodium sulphate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the title compound (0.1 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]=O)[CH:2]=1.[NH2:10][CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([CH3:33])([CH3:32])[C:23]([N:25]3[CH:29]4[CH2:30][CH2:31][CH:26]3[CH2:27][CH2:28]4)=[O:24])[CH:20]=2)[NH:15][C:14]=1[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=1.[C:42]([BH3-])#[N:43].[Na+]>CO.C(O)(=O)C>[CH:26]12[N:25]([C:23](=[O:24])[C:22]([C:19]3[CH:20]=[C:21]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14]([C:34]3[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=3)=[C:13]4[CH2:12][CH2:11][N:10]([CH2:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:7][C:3]3[CH:2]=[N:43][CH:42]=[CH:5][CH:4]=3)([CH3:33])[CH3:32])[CH:29]([CH2:28][CH2:27]1)[CH2:30][CH2:31]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN)c1
Reactant: O=CCc1cccnc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN(CCc2cccnc2)CCc2cccnc2)c1
Reaction time: 15.5 h

Procedure:
To a solution of pyridin-3-yl-acetaldehyde (120 mg in a mixture of 5 mL methanol and 0.018 mL glacial acetic acid) was added 141 mg of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(7-aza-bicyclo[2.2.1]hept-7-yl)-2-methyl-propan-1-one followed by 20 mg 3Å powdered molecular seives. To this mixture, 68 mg sodium cyanoborohydride was added and the pH adjusted to 5.5 by the addition of 10% methanolic acetic acid. After 15.5 hours, the reaction was quenched by the addition of saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic portion was washed successively with saturated ammonium chloride, sodium bicarbonate and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 92:8) gave the title compound (130 mg). MASS: 640 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[N:11]1([CH2:16][CH:17]([CH3:20])[CH2:18][NH2:19])[CH:15]=[CH:14][N:13]=[CH:12]1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:19][CH2:18][CH:17]([CH3:20])[CH2:16][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(CN)Cn1ccnc1
Product: CC(CNC(=O)c1ccc(Cl)nc1)Cn1ccnc1

Procedure:
When 6-chloronicotinic acid was reacted with 3-(1H-imidazol-1-yl)-2-methylpropanamine by the procedure of Example 20, the compound of the Example was obtained, mp 102°-104° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.CCN(C(C)C)C(C)C.[CH:22]([O:25][C:26]1[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=1)([CH3:24])[CH3:23]>C1COCC1>[Cl:8][C:7]1[C:2]([NH:31][C:28]2[CH:27]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[NH:30][N:29]=2)=[N:3][C:4]([Cl:12])=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(Cl)c([N+](=O)[O-])cc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 18.1 %

Procedure:
To a mixture of 2,3,6-trichloro-5-nitropyridine (2.61 g, 11.4 mmol) and DIEA (1.90 ml, 11.4 mmol) in THF (50 ml) was added 5-isopropoxy-1H-pyrazol-3-amine (1.20 g, 8.50 mmol) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 5 days. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.51 g, 18%). 1H NMR (400 MHz) δ 12.22 & 11.35 (s, 1H), 10.12 & 9.80 (s, 1H), 8.64 & 8.54 (s, 1H), 5.95 & 5.84 (s, 1H), 4.70 & 4.46 (m, 1H), 1.27-1.32 (m, 6H). MS: Calcd.: 331. Found: [M+H]+ 332.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([F:14])[C:5]=1[N:15]1[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[CH:16]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:11])[F:13])[CH:7]=[C:6]([F:14])[C:5]=1[N:15]1[C:20](=[O:21])[C:19]([Br:1])=[C:18]([C:22]([F:24])([F:25])[F:23])[N:17]=[CH:16]1
Reactant: O=c1cc(C(F)(F)F)ncn1-c1c(F)cc(C(F)(F)F)cc1F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1c(Br)c(C(F)(F)F)ncn1-c1c(F)cc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of bromine (146 mg) in acetic acid (1 ml) was added dropwise to a solution of compound 11 (in Table I) (285 mg) and sodium acetate (204 mg) in acetic acid (3 ml). After stirring at the ambient temperature for 16 hours, the solvent was removed by evaporation under reduced pressure and the residue dissolved in agueous sodium bicarbonate solution. After extraction with ethyl acetate, the organic layer was washed with agueous sodium thiosulphate solution, dried and filtered, and concentrated under reduced pressure to give a pale yellow solid. Recrystallization from a mixture of ethyl acetate and petroleum ether (boiling range 60°-80° C.) gave 1-(2,6-difluoro-4-trifluoromethylphenyl)-5-bromo-4-trifluoromethylpyrimidin-6-one;
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].[Cl-].C(N(CC)CC)C.Cl[S:28]([C:31]1[CH:43]=[CH:42][C:34]2[O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:33]=2[CH:32]=1)(=[O:30])=[O:29]>>[CH:32]1[C:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][C:34]=2[CH:42]=[CH:43][C:31]=1[S:28]([NH:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:30])=[O:29]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1N
Reactant: O=S(=O)(Cl)c1ccc2oc3ccccc3c2c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Methyl (Z)-7-[(1S,2R,3R,4R)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (II-1) (251 mg, 1.00 mmol) was dissolved inmethylene chloride (8 ml) and triethylamine (0.238 ml, 2.00 mmol) was added thereto under a nitrogen atmosphere. To the mixture was added 2-chlorosulfonyldibenzofuran (350 mg, 1.31 mmol) under ice-cooling, and the mixture was stirred for 30 min and allowed to warm up to room temperature. The reaction mixture was purified by column chromatography on silica gel (n-hexane/ethyl acetate (1:4)) and recrystallized from n-hexane (10 ml) to yield methyl (Z)-7-[(1S,2R,3R,4R)-3-(2-dibezofuryl)sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (1a-1) (342 mg, 0.710 mmol). Yield 71 %, mp 115-116° C.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:3].[PH2:9]([OH:11])=[O:10]>>[CH3:3][CH:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:1][PH:9](=[O:10])[OH:11]
Reactant: O=[PH2]O
Reactant: C=C(C)CC(C)(C)C
Product: CC(C[PH](=O)O)CC(C)(C)C

Procedure:
A mixture of diisobutylene (112 g, 1 mol) and hypophosphorous acid (30%, 230 mL) are reacted in the presence of t-butyfperbenzoate. After aqueous work up, 45 g of oily product are obtained. It is characterized by 1H NMR and 31P NMR which shows formation of product (64% pure).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([CH2:8][N:9]1[C:13](=[O:14])[C:12](=[CH:15]OCC)[S:11][C:10]1=[S:19])([OH:7])=[O:6]>C(O)C>[C:5]([CH2:8][N:9]1[C:13](=[O:14])[C:12](=[CH:15][NH:4][CH2:1][CH:2]=[CH2:3])[S:11][C:10]1=[S:19])([OH:7])=[O:6]
Reactant: C=CCN
Reactant: CCOC=C1SC(=S)N(CC(=O)O)C1=O
Solvent: CCO
Product: C=CCNC=C1SC(=S)N(CC(=O)O)C1=O
Yield: 52.6 %

Procedure:
0.3 Gram (0.005 mole) of allylamine was added to a mixture of 1.2 g (0.005 mole) of 3-carboxymethyl-5-ethoxymethylidenerhodanine and 10 ml of ethanol, and the resulting mixture was subjected to reaction at a temperature of 50° to 60° C. for 1 hour. The reaction mixture was cooled and the formed precipitate was separated by filtration and recrystalized from a mixture of methanol and ether (7/3 by volume) to give 0.68 g of 3-carboxymethyl-5-allylaminomethylidenerhodanine in the form of yellow crystal (yield: 52.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:28][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: O=C(Cc1ccc(F)cc1)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(Cc1ccc(F)cc1)NC1CCN(Cc2ccc3ccccc3n2)CC1
Yield: 25.2 %

Procedure:
2-(4-Fluorophenyl)-N-(4-piperidinyl)acetamide (WO97/36871; 0.05 g), 2-quinolinecarbaldehyde (0.033 g) and sodium triacetoxyborohydride (0.067 g) in dichloroethane (3 ml) were stirred under nitrogen for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure, triturated with diethyl ether/ethyl acetate and filtered to leave 2-(4-fluorophenyl)-N-[1-(2-quinolinylmethyl)-4-piperidinyl]acetamide (0.020 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(OCC)(=O)C.O.[OH-].[Li+]>CS(C)=O>[CH2:11]([O:10][C:8]([C:3]1[N:4]=[C:5]([CH3:7])[S:6][C:2]=1[NH:1][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])=[O:9])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1nc(C)sc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1nc(C)sc1Nc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Add a solution of ethyl 5-amino-2-methylthiazole-4-carboxylate (120 g; 645 mmol) and 2-fluoronitrobenzene (68 mL; 645 mmol) in dimethylsulphoxide (1L) to a 2L 3-necked RB flask equipped with reflux condenser, thermometer, mechanical stirrer. Add lithium hydroxide monohydrate (54 g; 1290 mmol) to the solution and heat at 50° C. for 3 hours under nitrogen. Cool the purple solution and pour onto ice/water, allow to stir for one hour, filter and wash with water, dry at 50° C. under reduced pressure to give 190 g (96%) as an orange solid: mass spectrum (m/e): 308(M+1); 1HNMR(300 MHz, DMSO-d6, ppm): δ 1.25(tr, 3H), 2.56(s, 3H), 4.25(q, 2H), 7.20(m, 1H), 7.78(m, 2H), 8.20(d, 1H), 11.42(s, 1H, NH). 13CNMR(75 MHz, DMSO, ppm): δ 24.4, 29.2, 71.2, 127.8, 132.5, 132.8, 137.8, 146.5, 147.0, 147.5, 160.2, 161.5, 173.7. Formula: C13H13N3O4S.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18]([OH:20])=O)=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[CH3:15])=[C:4]([F:21])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34]1([CH2:40][S:41]([NH2:44])(=[O:43])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O.Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18]([NH:44][S:41]([CH2:40][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)(=[O:42])=[O:43])=[O:20])=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[CH3:15])=[C:4]([F:21])[CH:3]=1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)O)cn(C)c1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NS(=O)(=O)Cc2ccccc2)cn(C)c1=O
Reaction time: 2 h
Yield: 68 %

Procedure:
N-[4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonyl]-C-phenyl-methanesulfonamide was prepared from 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid as follows. To a solution of 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.040 mg, 0.113 mmol) in DMF (1.5 mL) was added 1,1′-carbonyldiimidazole (0.074 mg, 0.456 mmol). After stirring for two hours, α-toluenesulfonamide (0.079 mg, 0.461 mmol) was added, followed by DBU (0.070 mL, 0.459 mmol). After stirring for 16 hours at room temperature, the reaction mixture was diluted with EtOAc and 1N HCl solution. The organic layer was separated and washed with brine. The aqueous layer was extracted with EtOAc (2×) and washed with brine. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (2% MeOH in methylene chloride) gave 0.039 g (68%) clean desired product; MS APCI (−) m/z 506, 508 (M−, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.27 (m, 3H), 7.18 (d, 1H), 7.11 (m, 3H), 6.56 (t, 1H), 4.44 (s, 2H), 3.54 (s, 3H), 1.62 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH:11]=[CH2:12])[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([Mg]Br)[CH3:20].C1C=CC=CC=1.Cl.CC[O:32]CC>>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH:11]=[CH2:12])[C:8](=[O:32])[CH2:19][CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: C=CCC(C#N)(c1ccccc1)c1ccccc1
Reactant: CC[Mg]Br
Agent: Cl
Solvent: c1ccccc1
Product: C=CCC(C(=O)CC)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2,2-diphenyl-4-pentenenitrile (2.33 g), 3.0M ethylmagnesium bromide in ether (10 ml), and benzene (30 ml) was heated at reflux for 3 hours, with stirring. After cooling to room temperature, the crude intermediate was stirred with 1N hydrochloric acid for 3 hours. The hydrolysate was partitioned between water and ethyl acetate (3×). The combined extracts were washed with water and brine, dried (MgSO4), and rotary evaporated to give a crude material which was flash-chromatographed over silica gel. Elution with hexane/ethyl acetate (5:1) yielded 1.0 g of 4,4-diphenyl-6-hepten-3-one, as a colorless oil.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][C:28](=[O:30])[O:27][N:26]=2)=[C:21]([O:31][CH3:32])[CH:20]=1)C1C=CC=CC=1.I[Si](C)(C)C.CO.C(=O)(O)[O-].[Na+]>ClCCl>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][C:28](=[O:30])[O:27][N:26]=2)=[C:21]([O:31][CH3:32])[CH:20]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1-c1noc(=O)[nH]1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCO)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 39.9 %

Procedure:
118 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one were dissolved in 14 mL of dichloromethane by heating and allowing to cool down to room temperature. To the resulting solution was added 144 μL of iodotrimethylsilane. The resulting mixture was stirred at room temperature for 6.5 h and 6 mL of methanol were added followed by a saturated aqueous solution of sodium bicarbonate. The mixture was stirred for 1 h, filtered and concentrated under reduced pressure. Dichloromethane/water were added to the residue. The organic layer was separated and the aqueous layer extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane 90/methanol 10) to give 40 mg of 3-{4-[4-(3-hydroxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [S:1]([O:21][CH2:22][CH3:23])([O:3][CH2:4][C:5]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:6])=[O:2].[OH2:24]>CC#N.C(Cl)Cl>[S:1]([O:21][CH2:22][CH3:23])([O:3][CH2:4][C:5]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:6])(=[O:24])=[O:2]
Reactant: CCCCCCOC(C)(COS(=O)OCC)OCCCCCC
Reactant: O
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCOC(C)(COS(=O)(=O)OCC)OCCCCCC
Temperature: 23 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
To a solution of sulfite 6 (24.5 g, 69.5 mmol) in MeCN (200 mL), CH2Cl2 (200 mL) and water (300 mL) is added NaIO4 (29.7 g, 139.0 mmol) and RuCl3 (10 mg, 0.05 mmol). The mixture is stirred at 23° C. for 5 hours. The mixture is filtered through Celite and extracted with CH2Cl2 (2×200 mL). The combined organic layers are washed with saturated NaHCO3 (100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give 2,2-bis(hexyloxy)propanyl ethyl sulfate 7 (23.3 g, 91%) as a colorless oil: Rf (15% EtOAc/hexane)=0.41; IR (thin film, cm−1) 2931, 2860, 1737, 1467, 1403, 1380, 1196, 1179, 1012, 925, 858; 1H NMR (600 MHz, CDCl3) δ 4.34 (q, J=7.2 Hz, 2H), 4.09 (s, 2H), 3.43 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 3.38 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 1.51 (m, 4H), 1.40 (t, J=7.2 Hz, 3H), 1.37 (s, 3H), 1.34-1.24 (m, 12H), 0.86 (t, J=7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 98.2, 72.4, 69.7, 60.9, 31.6, 29.8, 25.9, 22.6, 20.8, 14.5, 14.0.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:15]1[C:16]([O:30][CH2:31][CH3:32])=[C:17]([CH:25]2[CH2:27][CH:26]2[CH2:28][OH:29])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([C:15]1[C:16]([O:30][CH2:31][CH3:32])=[C:17]([CH:25]2[CH2:27][CH:26]2[CH:28]=[O:29])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CCOc1c(C2CC2CO)cc(C(C)(C)C)cc1C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOc1c(C2CC2C=O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
1.02 g of oxalyl chloride were dissolved in 37 ml of CH2Cl2 and treated with 0.86 ml of dimethyl sulfoxide at −60° C. After shortly warming to −35° C., the reaction mixture was recooled to −60° C. and treated with a solution of 1.2 g of (1RS,2SR)-[2-(3,5-di-tert.butyl-2-ethoxy-phenyl)-cyclopropyl]-methanol in 20 ml of CH2Cl2. After 15 minutes of stirring at −50° C., 1.7 ml of triethylamine were dropped in. The reaction mixture was stirred for 2 hours at room temperature, poured on icewater, extracted with ether, washed (H2O), dried (Na2SO4) and evaporated. The crude material was purified by flash chromatography (silica gel, hexane:ethyl acetate=9:1) and recrystallized from hexane to give 1.01 g of (1RS,2RS)-2-(3,5- di-tert.butyl-2-ethoxy-phenyl)-cyclopropanecarbaldehyde as white crystals, m.p. 96-97° C.