Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][CH3:16])[CH:11]=[C:10]([O:17][CH3:18])[C:9]=1[C:19]1[N:20]2[N:26]=[C:25]([O:27][CH3:28])[C:24]([NH:29][C:30]([C:32]3([OH:35])[CH2:34][CH2:33]3)=O)=[C:21]2[S:22][CH:23]=1.B#B.Cl>CCCCCCC.C(OCC)(=O)C.O>[CH3:18][O:17][C:10]1[CH:11]=[C:12]([CH2:14][O:15][CH3:16])[CH:13]=[C:8]([O:7][CH3:6])[C:9]=1[C:19]1[N:20]2[N:26]=[C:25]([O:27][CH3:28])[C:24]([NH:29][CH2:30][C:32]3([OH:35])[CH2:33][CH2:34]3)=[C:21]2[S:22][CH:23]=1
Reactant: COCc1cc(OC)c(-c2csc3c(NC(=O)C4(O)CC4)c(OC)nn23)c(OC)c1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cc(OC)c(-c2csc3c(NCC4(O)CC4)c(OC)nn23)c(OC)c1
Temperature: 55 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a tetrahydrofuran (4 mL) solution of N-{3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl}-1-hydroxycyclopropanecarboxamide (162 mg, 0.374 mmol) was added 0.99 M diborane (0.944 mL, 0.935 mmol), and the mixture was stirred at 55° C. for two hours. The temperature was made to be room temperature, and a 2N aqueous solution of hydrochloric acid (0.374 mL, 0.748 mmol) was added, and the mixture was stirred at 50° C. for one hour. Water was added to the reaction mixture at room temperature, and the reaction mixture was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column (NI-1) chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=1/1) to obtain the title compound (94.5 mg, 0.225 mmol).
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[NH:8][C:7]=1[NH2:19])=[O:5])C.[CH3:20][N:21](C=O)C.C(N)=O>C(O)=O>[OH:5][C:4]1[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=3)[NH:8][C:7]=2[N:19]=[CH:20][N:21]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C#N)cc2)[nH]c1N
Reactant: CN(C)C=O
Solvent: NC=O
Solvent: O=CO
Product: N#Cc1ccc(-c2cc3c(O)ncnc3[nH]2)cc1
Temperature: 150 °C

Procedure:
A mixture of 36.6 g (0.143 mol) 2-amino-5-(4-cyano-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester, 140 ml DMF, 305 ml formamide and 14.6 ml 85% formic acid is heated for 16 h at 150° C. The resulting yellow suspension is cooled to 10° C. and filtered. The solid is washed with methanol (120 ml) and ether (150 ml) and dried. The title compound is obtained as yellowish crystals; m.p.>410° C.; MS-ES+: (M+H)+=254.
Reaction SMILES: [C:1]1([C:7]2[C:8]([OH:32])=[C:9]([C:24]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:25])[C:10]([CH:19]([O:22]C)[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.B(Br)(Br)Br>O>[C:1]1([C:7]2[C:8]([OH:32])=[C:9]([C:24]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:25])[C:10]([CH:19]([OH:22])[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(OC)c1nc(-c2ccccc2)c(-c2ccccc2)c(O)c1C(=O)Nc1nccs1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCC(O)c1nc(-c2ccccc2)c(-c2ccccc2)c(O)c1C(=O)Nc1nccs1
Reaction time: 24 h
Yield: 47.7 %

Procedure:
A solution of 8.65 g of the product of Step F and 86 ml of methylene chloride was cooled to -70° C. to -60° C. and while maintaining this temperature, 116 ml of a solution of boron tribromide were added. After stirring for 24 hours, the temperature was allowed to return to ambient. The solution was poured into 180 ml of iced water and extracted with methylene chloride. The extracts were washed with water, dried and concentrated under reduced pressure. After chromatography under pressure (methylene-chloride - ethyl acetate 8-2), 4 g of the expected product were obtained which after crystallization from ethyl acetate melted at 232° to 234° C.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CC1N=CNC=1.C([S:15][CH2:16][CH:17]([CH2:32][C:33]([O:35]C)=O)[C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=N)[NH2:27])=[O:19])(=O)C>>[SH:15][CH2:16][CH:17]([CH2:32][C:33](=[O:35])[NH2:1])[C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)=[O:19]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: NC(=O)CC(CS)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
By substituting Nα -[3-(acetylthio)-2-methoxycarbonylmethyl)propanoyl]-L-histidine for the Nα -[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-L-arginine in the procedure of Example 19, Nα -[3-mercapto-2-(carbamoylmethyl)-propanoyl]-L-histidine is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C(Cl)Cl>[CH3:18][S:19]([O:6][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])(=[O:21])=[O:20]
Reactant: Cc1ccccc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccccc1CCOS(C)(=O)=O
Temperature: 5 °C
Yield: 92.2 %

Procedure:
10 g (0.0734 mol) of 2-methylphenethyl alcohol were dissolved in 200 mL of dry CH2Cl2 under a nitrogen atmosphere; the solution was cooled to 5° C., 16.4 mL (0.1175 mol) of triethylamine were added, followed by a solution of 9.1 mL (0.1175 mol) of methanesulphonyl chloride in 100 mL of dry CH2Cl2, keeping the temperature below 15° C. The reaction mixture was allowed to warm to room temperate in 2 h, then 250 mL of water were added, the organic phase was collected and the solvent was removed in vacuo. The resulting oil was taken up in Et2O, the organic phase was washed with 1N HCl and with saturated NaHCO3 solution, then it was dried and the solvent was removed in vacuo, yielding 14.5 g of the title product which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1.[BH4-].[Na+].O>CC(C)=O.CO>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccncc2)cc1
Reactant: O=S1(=O)CCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(O)CCCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of 4-phenylpyridine (15.5 g, 0.1 mol) in acetone (100 mL) was added 1,3-propane sultone (12.2 g, 0.1 mol) at room temperature. The mixture was then heated at reflux temperature overnight. The resultant suspension was cooled to room temperature. The solid was collected by filtration and washed with acetone. To a solution of the solid (31 g) in methanol (500 mL) was added sodium borohydride (10 g, 260 mmol) portionwise, and the mixture was stirred at room temperature for 2 h. Distilled water (50 mL) was added to destroy the excess of sodium borohydride. The mixture was diluted with methanol (200 ml), and neutralized with Amberlite IR-120 ion-exchange resin (H+ form, 300 g). A white precipitate was formed. The precipitate and the resin were removed by filtration and treated with distilled water (400 mL) at ˜100° C. The mixture was filtered and the residual resin was washed with hot distilled water (2×200 mL). The filtrates and washings were combined and concentrated to dryness. The residue was co-evaporated with methanol (3×200 mL), and then recrystallized from ethanol-water {8:2 (v/v)} to afford 4-phenyl-1-(3′-sulfopropyl)-1,2,3,6-tetrahydropyridine as white crystals (26 g, 93%). The 1H and 13C NMR spectra were in agreement with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1.[Cl:14][C:15]1[S:16][C:17]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][C:19]=1[Cl:20]>>[Cl:20][C:19]1[CH:18]=[C:17]([S:21]([NH:13][C:10]2[S:11][CH:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:9]=2)(=[O:23])=[O:22])[S:16][C:15]=1[Cl:14]
Reactant: Nc1nc(-c2ccccc2Cl)cs1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Product: O=S(=O)(Nc1nc(-c2ccccc2Cl)cs1)c1cc(Cl)c(Cl)s1

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-1,3-thiazol-2-amine (57 mg) and 2,3-dichlorothiophene-5-sulfonyl chloride (68 mg) as described in the synthetic METHOD B to give a white solid (56.6 mg) with purity >90%: MS (pos) m/z 425.3, 427.3; HRMS m/z 423.8737 (calc. of monoisotopic mass for C13 H7 Cl3 N2 O2 S3 gives 423.8735).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]3[NH:30][CH:31]=[N:32][C:28]=3[CH:27]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=O)[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:35].P(Cl)(Cl)(Cl)=O>>[NH2:1][C:2]1[C:3]([Cl:35])=[CH:4][C:5]([S:9]([NH:12][CH:13]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]3[NH:30][CH:31]=[N:32][C:28]=3[CH:27]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]#[N:24])[CH2:18][CH2:17]2)=[O:15])(=[O:10])=[O:11])=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1

Procedure:
Prepared from 4-amino-N-[1-(1H-benzimidazol-5-ylmethyl)-2-(4-aminocarbonyl-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide by reacting with phosphorusoxychloride at ambient temperature.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>C1COCC1>[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:19][CH2:18]1
Reactant: CN1CCC(=O)CC1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(C)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
Methyl diethylphosphonoacetate (88.69 g, 0.422 mol) was added dropwise to a stirred suspension of sodium hydride (18.56 g, 60% dispersion in oil, 0.464 mol) in THF (300 ml) under nitrogen, at such a rate as to maintain the temperature below 30° C. The mixture was stirred for 1 h and a solution of N-methyl-4-piperidinone (47.71 g, 0.422 mol) in THF (150 ml) was added dropwise. The mixture was heated at 60° C. for 4.5 h before removing the solvent under vacuum and redissolving the residue in dichloromethane (300 ml) and water (200 ml). The dichloromethane phase was separated, washed successively with water (200 ml) and saturated sodium bisulphite solution (2×70 ml) and dried (MgSO4). The crude product was chromategraphed on silica gel, eluting with methanol/ether (5:95) to give the title-product (19.75 g, 28%). 1H NMR (250 MHz, CDCl3) δ (3H, s, N-CH3), 2.35 (2H, t, J=6 Hz, CH2), 2.40-2.50 (4H, m, 2 of CH2), 3.00 (2H, t, J=6 Hz, CH2), 3.70 (3H, s, CO2CH3), 5.65 (1H, s, vinyl CH).
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(C[NH:26][C:27](=[O:52])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH2:38][C:37]([C:43]3[CH:48]=[C:47]([Cl:49])[CH:46]=[C:45]([Cl:50])[CH:44]=3)([C:39]([F:42])([F:41])[F:40])[O:36][N:35]=2)=[CH:30][C:29]=1[CH3:51])(=O)N.O.Cl.[C:55](#[N:57])C.O>>[ClH:49].[NH2:57][CH2:55][NH:26][C:27](=[O:52])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH2:38][C:37]([C:43]3[CH:48]=[C:47]([Cl:49])[CH:46]=[C:45]([Cl:50])[CH:44]=3)([C:39]([F:40])([F:41])[F:42])[O:36][N:35]=2)=[CH:30][C:29]=1[CH3:51]
Reactant: CC#N
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(N)=O
Agent: Cl
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCN
Temperature: 25 °C

Procedure:
In a solution of 0.47 g of [bis(trifluoroacetoxy)iodo]benzene in 12 ml of acetonitrile-water (1:1), a solution of 0.47 g of N-carbamoylmethyl-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide synthesized in Synthetic Example 31 was added with stirring at room temperature, and stirred at room temperature for 5 hours. After the completion of the reaction, 75 ml of water was added in the reaction mixture, 8 ml of concentrated hydrochloric acid was added, then washed with 100 ml of diethyl ether, and the organic phase was subjected to back extraction with 2N hydrochloric acid aqueous solution (20 ml×2). The aqueous phase was combined with the organic phase, water was distilled off, and the residual solid was washed with ethyl acetate to obtain 0.21 g of the aimed product as white crystal. Melting point 155.0 to 157.0° C.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22].O>CN(C=O)C.CCOCC.CCCCCC>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CCC(C)Oc1ccc(OC(C)C(=O)OC)cc1
Reaction time: 60 h

Procedure:
To a solution of 4-(1-methylpropoxy)phenol (1.58 g, 9.5 mmol) in 10 ml of DMF at 50° is added potassium carbonate (3.90 g, 28.0 mmol). To this is added dropwise methyl 2-bromopropionate (3.2 ml, 30.0 mmol) in 10 ml of DMF. The mixture is stirred at 70° for 60 hours. The cooled reaction is worked up by addition of water and extraction with a mixture of ether/hexane (3X). The combined organic extracts are washed with 10% sulfuric acid, with water and with brine, dried and the solvent removed to give methyl 2-[4-(1-methylpropoxy)phenoxy]-propanate.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[N:11](C(OC(C)(C)C)=O)[C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C(B(CC)[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)C.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].B>C1(C)C=CC=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]([C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])([CH3:2])[CH3:3]
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1c(OS(=O)(=O)C(F)(F)F)cccc1n2C(=O)OC(C)(C)C
Reactant: CCB(CC)c1cccnc1
Agent: [Pd]
Agent: B
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(-c4cccnc4)c3c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
532 mg of 5-trifluoromethanesulfonyloxy-4-methoxymethyl-9- tert.butoxycarbonyl-β-carboline-3-carboxylic acid isopropyl ester is mixed in 20 ml of toluene in succession with 164 mg of diethyl-3-pyridylborane, 36 mg of tetrakis (triphenylphosphine) palladium (O), 84 mg of lithium chloride, 4 ml of ethanol as well as 2 ml of a 2-m aqueous sodium carbonate solution and refluxed for 3.5 hours. Then borane, palladium catalyst, ethanol, lithium chloride as well as soda solution are added again and heated for 3.5 hours to 120° C. solution temperature. Then it is mixed with 30 ml of water and extracted three times with 30 ml of ethyl acetate. The organic phase is dried, filtered and concentrated by evaporation. The residue is stirred with 13 ml of trifluoroacetate acid for 1 hour at room temperature. After concentration by evaporation it is taken up in 50 ml of dilute sodium carbonate solution and extracted three times with 30 ml of ethyl acetate. The organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed successively twice on silica gel, first with eluant methylene chloride:ethanol=10:1 and then the corresponding fractions on a second column with toluene: glacial acetic acid: water=10:1:1. The corresponding combined fractions are concentrated by evaporation and the residue is refluxed for 1.5 hours with 10 ml of isopropanol and 45 mg of titanium (IV) isopropylate. After concentration by evaporation it is taken up in 15 ml of 1-N hydrochloric acid and extracted three times with 30 ml of ethyl acetate each. The combined organic phase is discarded. The aqueous phase is made alkaline with ammonia and extracted three times with ethyl acetate. The organic phase is dried, filtered and concentrated by evaporation and 45 mg (12% of theory) of 5-(3-pyridyl)-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester with a melting point of 187°-188° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1.ClC1C(C(OO)=[O:21])=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:4][N+:3]=1[O-:21]
Reactant: CC(=O)OCc1ccc(C)nc1
Reactant: O=C(OO)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1ccc(C)[n+]([O-])c1

Procedure:
2-Methyl-5-acetoxymethylpyridine (0.05 mole) is stirred in 50 ml. of chloroform at 15° C. while chloroperbenzoic acid (0.06 mole) is added over 10 min. The solution is extracted with saturated sodium bicarbonate solution (3×20 ml.) and 2×20 ml. of water. The chloroform is dried over magnesium sulfate, and concentrated to dryness to give 2-methyl-5-acetoxymethylpyridine-N-oxide.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[C:14]#[C:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:6]([O:8]CC)=[O:7].[Cl-].[NH+]1C=CC=CC=1.Cl>CN(C=O)C>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[O:2][C:3]3[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:11]=[CH:12][C:13]=3[CH:14]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C)cc2)c(OC)c1
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc3ccc(C(=O)O)cc3o2)cc1
Temperature: 200 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
A mixture of ethyl 3-methoxy-4-(4-methylphenyl)ethynylbenzoate (1.5 g) and pyridinium chloride (9.0 g) was stirred at 200° C. for 2 hours, and then cooled to 100° C. To the mixture was added DMF (20 ml), and the mixture was cooled to room temperature. To the mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the precipitated crystals were collected by filtration, which were washed with diethylether and hexane to give pale yellow crystals of 2-(4-methylphenyl)benzofuran-6-carboxylic acid (0.84 g).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][O:27][CH2:26]4)[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O>C1COCC1>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][O:27][CH2:26]4)[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@H]2CCOC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@H]2CCOC2)c1
Yield: 86.1 %

Procedure:
Methyl 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (7.02 mmol) was dissolved in THF (50 mL), 1N sodium hydroxide (7.0 mL) was added followed by water (50 mL) and the resultant solution stirred at RT for 4 hours. The organics were removed in vacuo, the aqueous solution filtered and extracted with ethyl acetate (30 mL). The aqueous layer was acidified with 2N hydrochloric acid, extracted with ethyl acetate (3×50 mL), and the organic extracts washed with water (10 mL), brine (10 mL) then evaporated to dryness to give the desired material as a white foam (2.33 g). 1H NMR δ (CDCl3): 2.14-2.30 (m, 2H), 2.34-2.42 (m, 2H), 3.89-3.94 (m, 2H), 3.97-4.02 (m, 2H), 4.28 (t, 2H), 4.69 (t, 2H), 4.97-5.00 (m, 1H), 6.94 (t, 1H), 7.48 (t, 2H), 8.34 (d, 1H), 8.85 (d, 1H); m/z 386 (M+H)+, 384 (M−H)−
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]=[O:25])=[CH:21][CH:22]=2)[CH:17]=[N:16]1>>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=[O:25])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: COc1ccc(CBr)c(C(F)(F)F)c1
Product: COc1ccc(Cn2ncc3cc(C=O)ccc32)c(C(F)(F)F)c1

Procedure:
1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1-bromomethyl-4-methoxy-2-trifluoromethyl-benzene and 1H-indazole-5-carbaldehyde following General Procedure A.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[C:3]=1[Br:12].[CH3:13][Mg+].[Br-]>C1COCC1>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]([OH:7])[CH3:13])=[C:4]([F:11])[C:3]=1[Br:12]
Reactant: C[Mg+]
Reactant: Nc1c(F)cc(C=O)c(F)c1Br
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1cc(F)c(N)c(Br)c1F
Reaction time: 0.25 h

Procedure:
To a stirred solution of 20 g of 4-amino-3-bromo-2,5-difluorobenzaldehyde and 400 mL of THF under an N2 atmosphere and cooled in ice is added 60 mL of an 2.85M ethereal solution of MeMgBr. The addition is carried out over 15 minutes at a temperature of 10°-16° C. 80 minutes later another 40 mL of MeMgBr is added and the ice bath is removed. 2 hours later the mixture is poured into 1 L of ice/H2O and 10% HCl is added to pH 4. The mixture is extracted with 3×300 mL of CH2Cl2. The extracts are washed with 2×150 mL of H2O, dried with Na2SO4 and stripped in vacuo to give 21.76 g of crude 4-amino-3-bromo-2,5-difluoro-α-methylbenzyl alcohol with M+1 ions at 252 and 254 in the mass spectrum.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Temperature: 40 °C

Procedure:
A mixture of 5-methyl-1H-pyrazol-3-amine (3.00 g, 30.9 mmol), 2,4,5-trichloropyrimidine (5.67 g, 30.9 mmol, 1 equiv.) and Na2CO3 (3.60 g, 34.0 mmol, 1.1 equiv.) in EtOH (100 mL) was heated at 40° C. for 24 h. The solvent was removed in vacuo. The resulting residue was partitioned between EtOAc (350 mL) and water (100 mL). The EtOAc layer was washed with water (3×), saturated aqueous NaCl (1×) and dried over Na2SO4. The resulting EtOAc solution was concentrated in vacuo, providing the product 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine; SMS m/z 244.0 (M+H+).