Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[F:30])C1C=CC=CC=1>C(O)C.C1COCC1.C(OCC)(=O)C.[Pd]>[F:30][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][C:9]=1[OH:8])[CH2:13][N:14]([N:23]1[CH:24]=[N:25][N:26]=[CH:27]1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(F)c2)n2cnnc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(O)c(F)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[(4-Benzyloxy-3-fluoro-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03019, 2.83 g, 7.09 mmol) was dissolved in a mixture of ethanol (50 mL), THF (50 mL) and ethyl acetate (50 mL) by heating and palladium on charcoal (150 mg, 5% Pd) was added. The mixture was stirred under hydrogen-atmosphere (balloon) for 18 h, filtered through a 3 cm layer of celite and concentrated under reduced pressure. The residue was suspended in 2-propanol (30 mL), the mixture was heated to reflux for 5 minutes. After cooling room temperature the white precipitate was filtered off and dried under high vacuum. Yield: 2.13 g (97%). 1H-NMR (400, d6-DMSO)=4.93 (s, 2H), 6.75 (d, J=9.0 Hz, 2H), 6.82-6.89 (m, 2H), 7.07-7.12 (m, 1H), 7.76 (d, J=9.0 Hz, 2H), 8.77 (s, 2H), 9.95 (s, 1H, —OH).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:36])([F:19])[F:37])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(OC(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(OC(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.00 min; [M+H]+=461.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[C:12](=[O:22])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:12](=[O:22])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(N2C(=O)CCCC2c2ccc(Cl)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: O=C1CCCC(c2ccc(Cl)cc2)N1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a stirred mixture of 2.95 g of 6-(4-chlorophenyl)-1-(4-methoxyphenyl)-2-piperidone, 3 ml of ethanethiol, and 50 ml of methylene chloride was added, under ice-cooling 5.06 g of anhydrous aluminum chloride. After stirring at room temperature for 1 hour, the mixture was poured into ice-cold water and extracted with chloroform. The extract was washed with an aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried, and concentrated. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 2.75 g of 6-(4-chlorophenyl)-1-(4-hydroxyphenyl)-2-piperidone as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[I:12].[Br:14]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:14])=[C:7]([F:11])[C:6]=1[I:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Nc1cccc(F)c1I
Solvent: CC#N
Product: COC(=O)Nc1ccc(Br)c(F)c1I

Procedure:
(4-Bromo-3-fluoro-2-iodo-phenyl)-carbamic acid methyl ester was prepared from (3-fluoro-2-iodo-phenyl)-carbamic acid methyl ester by reaction with N-bromosuccinimide in acetonitrile in the presence of trifluoromethansulfonic acidm.p.:162-164° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:60]=[CH:61][CH:62]=1)[C:22]([NH:24][C:25]1[C:26]([CH3:59])=[C:27]([C:34]([C:36]2[CH:37]=[CH:38][C:39]([NH:52][C:53](=[O:58])[C:54]([F:57])([F:56])[F:55])=[C:40]([CH:51]=2)[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=[O:35])[N:28]2[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]2)=[O:23])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:60]=[CH:61][CH:62]=1)[C:22]([NH:24][C:25]1[C:26]([CH3:59])=[C:27]([C:34]([C:36]2[CH:37]=[CH:38][C:39]([NH:52][C:53](=[O:58])[C:54]([F:55])([F:56])[F:57])=[C:40]([CH:51]=2)[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=[O:35])[N:28]2[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]2)=[O:23]
Reactant: Cc1c(NC(=O)c2cccc(OCCNC(=O)OC(C)(C)C)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NC(=O)c2cccc(OCCN)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
16 ml (0.20 mol) of trifluoroacetic acid are added to the suspension of 6.28 g (8.28 mmol) of benzyl 5-({1-[(3-{2-[(tert-butoxycarbonyl)amino]ethoxy}benzoyl)-amino]-2-methylindolizin-3-yl}carbonyl)-2-[(trifluoroacetyl)amino]benzoate in 40 ml of dichloromethane. After stirring at ambient temperature for 30 minutes, the reaction medium is poured into 1 l of a saturated aqueous solution of sodium bicarbonate. The precipitate is filtered, washed thoroughly with water and then with diisopropyl ether and dried, so as to obtain 4.5 g (82%) of a yellow powder.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH2:6][C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=4)[CH:8]=2)[CH2:3]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:26]([N:22]1[CH:21]=[C:20]2[C:24]([CH:25]=[C:17]([C:9]3[CH:8]=[C:7]([CH2:6][CH:4]4[CH2:5][N:2]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:3]4)[N:15]4[C:10]=3[C:11]([NH2:16])=[N:12][CH:13]=[N:14]4)[CH:18]=[CH:19]2)=[N:23]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(CC3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 17.7 %

Procedure:
To a solution 7-(azetidin-3-ylmethyl)-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.22 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (19 μL, 0.25 mmol) and N,N-diisopropylethylamine (117 μL, 0.67 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 19 mg (17%) of the desired product. 1H NMR (400 MHz, DMSO-da) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.25-7.37 (m, 5 H), 7.13 (dd, 1 H), 6.66 (s, 1 H), 5.64 (s, 2 H), 3.97 (t, 2 H), 3.69 (dd, 2 H), 3.14-3.19 (m, 2 H), 2.97-3.98 (m, 1 H), 2.96 (s, 3 H); ES-MS m/z 5488.38 [M+H]+, HPLC RT (min) 2.98.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[OH-].[NH4+:13]>O>[Br:1][C:2]1[C:3]([F:11])=[C:4]([C:5]([F:9])=[C:6]([F:8])[CH:7]=1)[NH2:13]
Reactant: Fc1cc(Br)c(F)c(F)c1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1c(F)c(F)cc(Br)c1F
Temperature: 150 °C

Procedure:
To a microwave tube was added 1-bromo-2,3,4,5-tetrafluorobenzene (1.0 g) and 28% aqueous ammonium hydroxide (5 mL). The mixture was heated under microwave irradiation at 150° C. for 2 hrs, then the mixture was poured into water and extracted with hexane. The organic layer was separated, dried with MgSO4, then concentrated. The residue was purified by silica gel flash chromatography (9:1 hexanes/ethyl acetate eluant) afford the title compound as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 6.75 (m, 1H), 3.95 (br s, 2H) ppm; MS m/z: 226, 228 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure of Example 3 was followed for the reaction of 67g (0.5 mole) of tert-butylbenzene with 53.3g (0.5 mole) of isobutyryl chloride. Obtained after high vacuum concentration was 88g of a clear liquid; ir (film) 3.4 (m), 5.95 (s), 8.2 (s), 10.2 (s) microns; nmr (CDCl3) 7.65 (4H, d of d) 3.50 (1H, quintet), 1.28 (9H, s) 1.15(6H, d) ppm. A VPC analysis indicated one pure product.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=O)=[C:9]([C:21]#[N:22])[C:8]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30]O.[OH-].[Na+]>C(O)C.O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:22][C:21](=[O:30])[C:9]3=[C:8]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1NC(=O)Cc1ccccc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1nc(Cc2ccccc2)nc2n(C3CCCC3)[nH]c(Cc3ccccc3)c1-2
Temperature: 0 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To an ice-cooled solution of 1-cyclopentyl-3-phenylmethyl-4-cyano-5-(phenylmethylcarbonylamino)-1H-pyrazole (1.1 g, 2.8 mmol) in ethanol (30 ml) was added 30% H2O2 (2.5 ml), followed by NaOH (100 mg) dissolved in water (5 ml). The reaction mixture was stirred a such for 1 hour, then at room temperature for 1 hour, then it was heated on a steam bath for 3.5 hours and finally it was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, and partitioned between water (25 ml) and CHCl3 (50 ml). The organic layer was separated, and concentrated in vacuo and the oily residue was crystallized from isopropanol to afford 234 mg (22%) of 1-cyclopentyl-3-phenylmethyl-6-(phenylmethyl)-pyrazolo[3,4-d]pyrimidin-4-one, as a white solid, m.p. 204°-206° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)C=O.[CH:11]([O:14][N:15]=[C:16]([C:20]1[N:21]=[C:22]([NH:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:23][CH:24]=1)[C:17]([OH:19])=O)([CH3:13])[CH3:12].[NH2:45][CH:46]1[C:71](=[O:72])[N:48]2[C:49]([C:55]([O:57][CH:58]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])=[C:50]([CH2:53][Cl:54])[CH2:51][S:52][C@H:47]12.[OH-].[Na+]>O.C(OCC)(=O)C.C(Cl)Cl>[Cl:54][CH2:53][C:50]1[CH2:51][S:52][C@@H:47]2[CH:46]([NH:45][C:17](=[O:19])[C:16](=[N:15][O:14][CH:11]([CH3:12])[CH3:13])[C:20]3[N:21]=[C:22]([NH:25][C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[S:23][CH:24]=3)[C:71](=[O:72])[N:48]2[C:49]=1[C:55]([O:57][CH:58]([C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56]
Reactant: CC(C)ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
0.41 ml (4.4 mmol) of phosphorus oxychloride was added to 5 ml of ethyl acetate, and 0.35 ml (4.5 mmol) of N,N-dimethylformamide was dropwise added thereto under cooling with ice. Then, the mixture was stirred at room temperature for 15 minutes. To the solution, 20 ml of a methylene chloride solution containing 1.59 g (3.38 mmol) of 2-isopropoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (syn-isomer) was added, and the mixture was stirred for 30 minutes. To the reaction solution, 1.4 g (3.37 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate was added under cooling with ice, and the mixture was stirred for 2 hours. To the reaction solution, 50 ml of ethyl acetate and 20 ml of water were added, and the mixture was adjusted to pH 7.0 with a 5N sodium hydroxide aqueous solution. The organic layer was separated and washed sequentially with a 5% sodium hydrogen carbonate aqueous solution, water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The oily residue was purified by silica gel column chromatography to obtain 1.94 g (yield: 66%) of benzhydryl 3-chloromethyl-7-[2-isopropoxyimino-2-(2-tritylaminothiazol-4-yl) acetamido]-3-cephem-4-carboxylate (syn-isomer).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].B1([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[CH3:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1-c1cccnc1
Yield: 103.1 %

Procedure:
A mixture of 2-bromo-4-nitrotoluene (3 g, 13.0 mmol) and pyridine-3-boronic acid-1,3-propanediol cyclic ester (2.72 g, 16.7 mmol) in EtOH (30 ml) and toluene (30 ml) together with 2N Na2CO3 solution (13.9 ml) was degassed with a stream of N2 for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.3 g, 0.26 mmol) was added and the reaction heated at reflux for 4 h. The mixture was concentrated under reduced pressure to remove the organic solvents and water (100 ml) was added. The organics were extracted with EtOAc (200 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under reduced pressure while dry loading onto silica. The resulting crude residue was purified by column chromatography on silica, using 60% diethyl ether in hexane as the eluent, to yield 3-(2-methyl-5-nitrophenyl)pyridine (2.87 g, 99%): δH (360 MHz, CDCl3) 2.38 (3H, s), 7.36-7.50 (2H, m), 7.67 (1H, dt, J 7.9 and 1.9), 8.10 (1H, d, J 2.4), 8.61 (1H, d, J 1.8), 8.67 (1H, dd, J 4.8 and 1.5).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OC)cc2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2ccc(O)cc2)c1C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
1.0M Solution of borone tribromide in dichloromethane (35 ml) was added to a solution of 1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.0 g) in dichloromethane (12 ml) under ice cooling, and the mixture was stirred at the same temperature for three hours. After completion of the reaction, the reaction mixture was added to a saturated aqueous solution of sodium bicarbonate under ice cooling, a saturated aqueous solution of sodium bicarbonate was further added until the mixture was neutralized to pH 7 and extracted with chloroform three times. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (chloroform/methanol) to give 1-(4-hydroxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.33 g) as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: COc1cc(OC)cc(B(O)O)c1
Product: COc1cc(OC)cc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 59.7 %

Procedure:
6-(3,5-Dimethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (55 mg, 60%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,5-dimethoxyphenylboronic acid (62.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>>[Cl:14][C:6]1[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc2occc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2occc2c(Cl)n1
Temperature: 100 °C
Yield: 96 %

Procedure:
A mixture of 6-methylfuro[3,2-c]pyridin-4(5H)-one (11.9 g, 0.08 mol) and phosphorus oxychloride (15.2 ml, 0.163 mol) was heated, under a nitrogen atmosphere, at 100° C. for 1.5 hours. The cooled blackish liquid was poured onto crushed ice and the solution made basic with sodium hydroxide solution. The precipitated product was extracted into methylene chloride. This solution was dried over anhydrous sodium sulfate, filtered through a pad of charcoal and evaporated. Pure product was collected by filtration after the residue was triturated with hexane to give 12.9 g (96% yield), mp: 64.5°-66° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C:10]([C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([C@:31]2([CH3:37])[CH2:35][O:34][C:33](=[O:36])[NH:32]2)[CH:25]=[CH:24]3)[CH2:16][CH2:15]1)([CH3:13])[CH2:11][CH3:12]>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH3:13][C:10]([C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[C:22]([I:1])=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([C@:31]2([CH3:37])[CH2:35][O:34][C:33](=[O:36])[NH:32]2)[CH:25]=[CH:24]3)[CH2:16][CH2:15]1)([CH3:9])[CH2:11][CH3:12]
Reactant: CCC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reactant: O=C1CCC(=O)N1I
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2I)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-iodosuccinimide (204.77 mg, 0.91016 mmol), (R)-4-{6-[trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-naphthalen-2-yl}-4-methyl-oxazolidin-2-one (300.00 mg, 0.75847 mmol) and zirconium tetrachloride (35.3 mg, 0.152 mmol) in methylene chloride (10.00 mL) was stirred RT for 2.5 hrs. LCMS showed the reaction was completed. The solution was purified with 4 g of silica gel column eluted with ethyl acetate in hexanes from 10 to 50% to give 100 mg of white precipitate, (R)-4-{6-[trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-5-iodo-naphthalen-2-yl}-4-methyl-oxazolidin-2-one. (20% yield). MS: m/z=522.20 M+H.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([CH3:13])[C:5]=1[O:14][CH3:15])([O-])=O.C(O)C.[H][H].[ClH:21]>[Pd].O>[ClH:21].[ClH:21].[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([CH3:13])[C:5]=1[O:14][CH3:15]
Reactant: COc1c(C)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1c(C)cc(N)cc1N

Procedure:
105 g of 2,4-dinitro-6-methylanisole, 1.35 l of ethanol, 150 ml of water and 1 g of Pd/C (5% strength) were initially introduced into the autoclave and hydrogenated at 50° C. with a hydrogen pressure of 50 bar for 12 h. Subsequently, the mixture was cooled and then poured into 1.0 l of semiconcentrated HCl. The catalyst was filtered off, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was extracted by boiling with 2×150 ml of ethanol, filtered off and dried overnight under reduced pressure.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:20](O)[CH2:21][OH:22].COC(OC)OC.C([O-])(O)=O.[Na+]>ClCCl>[C:14]1([C:7]2([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[O:22][CH2:21][CH2:20][O:6]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCO
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCl
Product: O=C(O)CCCC1(c2ccccc2)OCCO1
Reaction time: 16 h
Yield: 17.3 %

Procedure:
Step AAH (1): Concentrated sulfuric acid (0.200 mL, 3.75 mmol) was added to a mixture of 5-oxo-5-phenylpentanoic acid (4.0 g, 20.81 mmol), ethylene glycol (6.96 mL, 125 mmol), and trimethylorthoformate (6.90 mL, 62.4 mmol) in dichloromethane (40 mL) at it under nitrogen. The mixture was stirred at it for 16 h. Solid NaHCO3 (2.0 g) was carefully added. The resulting mixture was concentrated in vacuo. The residue was taken up in methanol (50 mL) and the vessel was placed in a it water bath. Aqueous 50% NaOH (5 mL) was slowly added and the mixture was stirred at for 16 h. The mixture was concentrated in vacuo (to remove methanol) and the resulting aqueous layer was neutralized to pH 2. The aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was crystallized from diethyl ether to afford 4-(2-phenyl-1,3-dioxolan-2-yl)butanoic acid (850 mg, 17% yield) which was contained with a significant portion of 5-oxo-5-phenylpentanoic acid. LC-MS (M+H)+ 235.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:7].[CH2:17]([Mg]Br)[CH:18]=[CH2:19].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH2:19][CH:18]=[CH2:17])[CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1
Reactant: C=CC[Mg]Br
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.9 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)benzaldehyde (10 g, 41 mmol) in THF (100 mL) was drop wise added allylmagnesium bromide (50 mL, 1 M in THF, 50 mmol) at −40° C. The reaction mixture was stirred at room temperature for 5 h and then poured into saturated aqueous NH4Cl solution and extracted with EtOAc (2×100 mL). The organic layers were dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (800 mg, yield: 7%).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>C(O)C>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[CH:18]=1
Reactant: COCCCOc1ccnc(CCl)c1
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1
Yield: 99.3 %

Procedure:
A mixture comprising 1.50 g (0.01 mol) of 2-mercapto-1H-benzimidazole, 3.20 g (0.015 mol) of 2-chloromethyl-4-(3-methoxypropoxy)pyridine, 0.51 g (0.012 mol) of 95% sodium hydroxide and 60 ml of ethanol was stirred at 40° C. for 0.5 hour and filtered. The filtrate was concentrated under a reduced pressure and purified by silica gel column chromatography (ethyl acetate/n-hexane) to obtain 3.27 g of the title compound as a colorless crystal.