Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[CH2:8][C:9](=[O:11])[CH:10]=1)=[O:4].S(Cl)([Cl:25])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[CH2:8][C:9](=[O:11])[C:10]=1[Cl:25])=[O:4]
Reactant: COC(=O)C1=CC(=O)CC(c2ccc(Cl)c(OC)c2F)N1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1=C(Cl)C(=O)CC(c2ccc(Cl)c(OC)c2F)N1
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
6-(4-Chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (16; 483 mg, 1.54 mmol) was slurried in CH2Cl2 (10 mL) and cooled in an ice bath. A solution of SO2Cl2 (209 mg, 1.55 mmol) in CH2Cl2 (5 mL) was added dropwise. After 30 min, the reaction solution was quenched with 10% aqueous sodium bisulfite solution. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, H2O and brine and then dried (MgSO4). The solution was evaporated to a yellow oil which was crystallized from cold methanol to give 3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (33; 0.437 g, 81%) as a light yellow solid: mp 127-129° C.; 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, JF-H=1.5 Hz, JH-H=8.1 Hz, 1H, aromatic), 7.10 (dd, JF-H=6.9 Hz, JH-H=8.1 Hz, 1H, aromatic), 5.82 (br s, 1H, NH), 5.10 (t, J=9.3 Hz, 1H, H6), 3.98 (d, JF-H=1.5 Hz, 3H, OCH3), 3.97 (s, 3H, CO2CH3), 2.88 (d, J=9 Hz, 2H, H5); ESIMS m/z 347.9 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[CH3:30][CH:31]([CH3:35])[C:32](Cl)=[O:33]>CN(C)C(=O)C>[F:28][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]3[N:6]([CH:29]=[C:3]([NH:2][C:32](=[O:33])[CH:31]([CH3:35])[CH3:30])[N:4]=3)[N:7]=2)=[CH:17][C:16]=1[NH:18][C:19]([C:21]1[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=1)=[O:20]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C(C)C)cn4n3)ccc2F)n(C)n1
Yield: 45.2 %

Procedure:
Using N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol), 2-methylpropanoyl chloride (53 mg, 0.50 mmol) and N,N-dimethylacetamide (5.0 mL), and by a reaction in the same manner as in Example 148, the title compound (98 mg, 45%) was obtained as pale-blue crystals.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[H][H]>CO.[Rh]>[CH3:1][C:2]1([C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1(c2ccc(O)cc2)CCCCC1
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: CC1([C@H]2CC[C@@H](O)CC2)CCCCC1

Procedure:
56.1 g (0.29 mol) of 4-(1-methylcyclohexyl)phenol (from 1-methylcyclohexene and phenol in accordance with Chem. Ber. 57 (1924) 857) in 200 ml of methanol to which 1 ml of concentrated hydrochloric acid had been added were hydrogenated at 50° C. with 150 bar of hydrogen in the presence of 5 g of rhodium (5% on charcoal). After removal of the catalyst by filtration with suction, and concentration, 56.1 g (98.5% of theory) remained of an almost pure cis alcohol as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:19]([O:26][CH3:27])(=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][CH:10]([CH:20]([C:19]([O:26][CH3:27])=[O:25])[C:21]([O:23][CH3:24])=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccc(Br)cc1
Product: COC(=O)C(C(=O)OC)C(CC(=O)c1ccc(Br)cc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-bromophenyl)-3-(4-chlorophenyl)prop-2-en-1-one and dimethyl malonate, dimethyl 2-(3-(4-bromophenyl)-1-(4-chlorophenyl)-3-oxopropyl)malonate was obtained as colourless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2=[N:8][C:9]([CH2:11][CH3:12])=[CH:10][C:5]2=[C:4]([Cl:13])[N:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([Cl:13])[C:5]2[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[N:7]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(C)[nH]c-2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)nc(C)nc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
A solution of 500 mg (2.55 mmol) of 2-methyl-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine in 5.0 mL of tetrahydrofuran (THF) was added to a 2° C. slurry of 437 mg (2.55 mmol) of benzylbromide and 60 mg (2.55 mmol) of sodium hydride in 4.0 mL of THF. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was quenched by the addition of 7 mL of 2 M sodium hydrogen sulfate and then extracted with 7 mL of ethyl acetate. The organic phase was dried with sodium sulfate and concentrated to 500 mg. The residue was purified by flash chromatography (50 g of silica gel, methylene chloride) to provide 490 mg (67%) of 2-methyl-4-chloro-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine as a solid. nmr (500 MHz, CDCl3) δ1.29 (t, J=7.5 Hz, 3H), 2.61 (q, J=7.5 Hz, 2H), 2.74 (s, 3H), 5.45 (s, 2H), 6.33 (s, 1H), 7.03 (d, J=7.0 Hz, 2H), 7.28 (m, 3H)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29]/[C:30](=[N:33]/[H])/[NH:31]O)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]>CS(C)=O>[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[N:31]=[C:6]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)[O:8][N:33]=2)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3ccc(O)cc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 4.4 %

Procedure:
4-Hydroxybenzoic acid (35 mg, 0.25 mmol) and CDl (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The mixture was purified by MDAP to give the title compound as a white solid (5 mg, 4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14]S(C2C=CC(C)=CC=2)(=O)=O)[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28]([CH2:32][C:33]([OH:35])=[O:34])(C)[CH:27]=1.O.[OH-].[Li+].Cl.[CH3:40]O>O.C(OCC)(=O)C>[OH:14][C:5]1[C:4]([CH2:25][C:26]2[CH2:30][CH2:29][CH:28]([CH2:32][C:33]([OH:35])=[O:34])[C:27]=2[CH3:40])=[C:3]([O:2][CH3:1])[C:11]([CH3:12])=[C:10]2[C:6]=1[C:7](=[O:13])[O:8][CH2:9]2
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=CC(C)(CC(=O)O)CC1)C(=O)OC2
Reactant: CO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C)c2c(c(O)c1CC1=C(C)C(CC(=O)O)CC1)C(=O)OC2
Reaction time: 4 h

Procedure:
The 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy -5-isobenzofuranylmethyl)-1-methylcyclopent-2-en-1-ylacetic acid obtained in Example ZC-1G was dissolved in a mixture of methanol (8 mL) and water (2 mL) and treated with lithium hydroxide monohydrate (0.15 g). After 4 hours, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the product was washed out of the combined organic layers with 2M NaOH. Acidification of the basic layers with 5% hydrochloric acid and extraction of the product into ethyl acetate was followed by drying the organic layer with magnesium sulfate. Filtration and solvent removal was followed by two flash chromatographies (hexanes/ethyl acetate, 4/1 with 1% HOAc; then methylene chloride/methanol 25/1) to provide 3-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetic acid (0.010 g) m.p. 153°-159° C.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[CH:11]1[CH2:12][NH:8][CH2:9][CH:10]1[CH:21]([OH:23])[CH3:22]
Reactant: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(F)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1CNCC1c1ccc(F)cc1F
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To a solution of 1-[(3RS,4SR)-1-benzyl-4-(2,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanone (IV-4) (1.87 g, 5.92 mmol) in THF (30 mL) at 0° C. were added portion wise LiAlH4 (0.19 g, 5.21 mol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (RS)-1-[(3RS,4SR)-4-(2,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol (V-B-4) 0.72 g (38%) as a white solid ES-MS m/e: 318.1 (M+H+) and (SR)-1-[(3RS,4SR)-4-(2,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol (V-A-4) 0.374 g (19%) as a white solid ES-MS m/e: 318.1 (M+H+).
Reaction SMILES: ClCCl.[Cl:4][C:5]1[C:6]([CH:13]([S:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:7][C:8]([CH2:11]O)=[N:9][CH:10]=1.C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCC>[Br:31][CH2:11][C:8]1[CH:7]=[C:6]([CH:13]([S:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[C:5]([Cl:4])=[CH:10][N:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(CBr)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.3 %

Procedure:
To a dichloromethane (15 ml) solution of the [5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol (582 mg, 1.41 mmol) obtained in Example 256 were sequentially added carbon tetrabromide (936 mg, 2.82 mmol) and triphenylphosphine (407 mg, 1.55 mmol) at 0° C. The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=20:1 eluate was concentrated under reduced pressure to give the title compound (518 mg, 1.09 mmol, 77%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[C:25](#[N:31])[CH2:26][CH2:27][CH2:28][C:29]#[CH:30]>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][C:25]#[N:31])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCCCC#N
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: N#CCCCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 8 h

Procedure:
To a solution of the title compound of Example 5 (0.35 g), CuI (0.042 g), and Pd(PPh3)2Cl2 (0.012 g) in 10 mL diethylamine is added 5-hexynenitrile (0.085 mL). The reaction is stirred overnight. The reaction is then partitioned between ethyl acetate and water. The organic layer is washed twice with water, dried over MgSO4, filtered, and adsorbed onto silica. A Biotage Flash 40S (eluent 3% MeOH:CH2Cl2) affords the desired product. The product is recrystallized from CH2Cl2 --MeOH/hexanes. A second crop of crystals is obtained by concentration of the filtrate. The total yield of the title compound is 0.21 g.
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][C:9](OC)=O)[O:7][CH2:6][CH2:5][O:4]1)C.C(=O)([O-])[O-:14].[K+].[K+].O1CCCC1>O>[CH2:8]([C:3]1([CH2:1][OH:14])[O:4][CH2:5][CH2:6][O:7]1)[CH3:9]
Reactant: CCC1(CC(=O)OC)OCCO1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CO)OCCO1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 71.5 %

Procedure:
A mixture of methyl (2-ethyl-1,3-dioxolan-2-yl)acetate (1.39 g, 7.94 mmol), potassium carbonate (2.19 g, 15.9 mmol), tetrahydrofuran (20 ml) and water (10 ml) was stirred at room temperature for 6 hours and 50 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, which was subjected to NH silica gel pad filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (0.75 g, 71.5%) as colorless oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]>O>[OH2:3].[OH2:3].[OH2:3].[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A mixture of the protected compound obtained according to Example 38 (0.26 g, 0.5 mmol) and L(+)-tartaric acid (0.23 g, 1.5 mmol) in water (2.5 ml) was heated under reflux for one hour and allowed to cool to room temperature. The separated precipitate was collected to give the ditartrate-trihydrate of the title compound which was identical with the salt obtained according to Method A) above, yield: 65.8%, mp 169°-175° C.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[Se:8][C:7]=1[C:15]([O-:17])=[O:16])[CH3:3].[OH-].[Na+]>CO.O>[CH3:3][N:2]([N:4]=[N:5][C:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[Se:8][C:7]=1[C:15]([OH:17])=[O:16])[CH3:1]
Reactant: CN(C)N=Nc1c(C(=O)[O-])[se]c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)N=Nc1c(C(=O)O)[se]c2c1CCCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
To a solution of ethyl and methyl esters of 3-[(dimethylamino)diazenyl]-4,5,6,7-tetrahydrobenzo[2,1-d]selenophene-2-carboxylate (1.0 g, 3.1 mmol) prepared as described in Example 5 step c) in methanol (10 mL) was added a solution of sodium hydroxide (500 mg, 12.6 mmol) in water (2 mL) and stirred at rt for 5 h. The mixture was diluted with ice cold water and extracted with chloroform (2×50 mL) to remove impurities. The aqueous layer was acidified with dil. HCl and stirred for 30 min. The solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent (550 mg, 57%). The crude product was recrystallized from chloroform-diethyl ether to give the product as a dark brown color solid (330 mg), mp 100-102° C. IR (Neat) νmax 3429, 2927, 2855, 1701, 1350, 1110, 1050, 1023, 880 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.71 (1H, br s, —COOH), 3.59 (3H, s, —NCH3), 3.20 (3H, s, —NCH3), 2.83 (2H, t, J=5.4 Hz, H-4), 2.73 (2H, t, J=5.6 Hz, H-7), 1.75-1.81 (4H, m, H-5,6); 13C NMR (100 MHz, CDCl3): δ 164.5, 151.3, 148.9, 131.5, 124.0, 44.1, 36.5, 28.8 (2C), 22.8, 22.4; LC-MS (positive ion mode): m/z 300, 302 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27](O)[CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][CH2:27][O:8][C:7](=[O:9])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1
Reactant: OCCCO
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(OCCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 9 h
Yield: 77 %

Procedure:
A mixture of 30 g 3,5-dinitrobenzoic acid, 0.8 g p-toluenesulfonic acid and 100 ml 1,3-propanediol was stirred 9 hours at 110° C. After cooling, a white product crystallized and was separated from solution by filtration after adding a large quantity of water. The product was recrystallized from methanol to provide 77% white crystals with m.p. 76° C. IR: 1712 cm-1 (carbozyl) 1535 cm-1 (nitro asymmetric), 1341 cm-1 (nitro symmetric). 1H-NMR (DMSOd6): 9.05 ppm (C4), 8.93 ppm (C2, C6), 4.47 ppm (CH2OCO, triplet) 3.62 ppm (CH2O, triplet), 1.94 ppm (CH2 multiplet).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:24])=[O:5])[CH3:2].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:24][Br:25])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)cc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)cc2)nc1CBr
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A mixture of 4-methyl-2-(4-phenoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.40 g, 4.14 mmole), N-bromosuccinimide (760 mg, 4.27 mole) and benzoyl peroxide (50 mg, 0.21 mmole) in carbon tetrachloride (18 ml) was refluxed for 8 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil (1.69 g). MS: (+) m/z 417.87, 419.87 (M+1, 79Br/81Br).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([OH:9])([CH3:8])[CH2:4][C:5]([OH:7])=[O:6].[CH3:12][Si](C=[N+]=[N-])(C)C>CO>[CH3:12][O:6][C:5](=[O:7])[CH2:4][C:3]([C:2]([F:10])([F:11])[F:1])([OH:9])[CH3:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(O)(CC(=O)O)C(F)(F)F
Solvent: CO
Product: COC(=O)CC(C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 4,4,4-trifluoro-3-hydroxy-3-methylbutyric acid (1.81 g, 10.0 mmol) in methanol (10 ml) was added (trimethylsilyl)diazomethane (10 ml), dropwise. The reaction was then stirred at room temperature for 4 h. Removal of the solvent afforded the crude 3-(trifluoromethyl)-3-hydroxybutyric acid methyl ester as a yellow oil (1.92 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]3([CH3:14])[CH2:13][CH2:12]3)[NH:8][C:5]2=[CH:6][N:7]=1.[NH3:15]>CCO>[CH3:14][C:11]1([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([NH2:15])[CH:3]=[C:4]3[CH:10]=2)[CH2:13][CH2:12]1
Reactant: N
Reactant: CC1(c2cc3cc(Cl)ncc3[nH]2)CC1
Solvent: CCO
Product: CC1(c2cc3cc(N)ncc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
In a 100 mL autoclave, a solution of 5-chloro-2-(1-methylcyclopropyl)-1H-pyrrolo[2,3-c]pyridine (1.0 g, 4.9 mmol) and CuSO4′5H2O (100 mg, 0.4 mmol) in aqueous ammonia (60 mL) and EtOH (20 mL) was heated to 200° C. and stirred at this temperature for 8 hours. The mixture was allowed to cool down to room temperature. The alcohol was removed under vacuum. The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and purified by chromatography on silica gel (2% CH3OH in dichloromethane as eluant) to afford 2-(1-methylcyclopropyl)-1H-pyrrolo[2,3-c]pyridin-5-amine (250 mg, 27%). 1H-NMR (DMSO, 300 MHz) δ 7.96 (s, 1H), 6.37 (s, 1H), 5.88 (d, J=1.2, 1H), 5.01 (br s, 2H), 1.41 (s, 3H), 0.98 (t, J=2.1, 2H), 0.80 (t, J=2.1, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[NH2:26][CH2:27][C:28]1[C:29]([OH:36])=[N:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34]>ClCCl>[OH:36][C:29]1[C:28]([CH2:27][NH:26][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:2]=2[CH3:1])=[C:33]([CH3:34])[CH:32]=[C:31]([CH3:35])[N:30]=1
Reactant: Cc1cc(COc2ccccc2)ccc1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(COc3ccccc3)cc2C)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.1 %

Procedure:
2-Methyl-4-(phenoxymethyl)benzoic acid (42 mg, 0.17 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyfluoroniumhexafluorophosphate (99 mg, 0.26 mmol), triethylamine (0.1 mL) and dichloromethane (15 mL) were stirred at 25° C. for half hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.17 mmol) was added to the mixture. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (20 mL), dried over sodium, filtered, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-(phenoxymethyl)benzamide as a white solid (50 mg, 78%). LRMS (M+H+) m/z: calcd 376.18. found 376. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.11 (t, J=4.8 Hz, 1H), 7.28-7.20 (m, 5H), 7.00-6.84 (m, 3H), 5.86 (s, 1H), 5.07 (s, 2H), 4.27 (d, J=4.8 Hz, 2H), 2.31 (s, 3H), 2.19 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccsc1
Reactant: Clc1cncc(Cl)n1
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: COCCOC
Product: Clc1cncc(-c2ccsc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,2-Dimethoxyethane (120 mL) was added to a mixture of tetrakis(triphenylphosphine)palladium (0) (0.87 g, 0.75 mmol) and 2,6-dichloropyrazine (2.43 g, 16.3 mmol). After 15 min of stirring at room temperature, thiophene-3-boronic acid (2.09 g, 16.3 mmol) followed by aqueous Na2CO3 (2 M; 25 mL) were added. The mixture was heated at reflux for 2 h [TLC monitoring by SiO2/n-hexane/ethyl acetate (85:15)]. The layers were separated and the light brownish water layer was extracted with ether (2×100 mL). The combined organic layers were dried (K2CO3), filtered and concentrated in vacuo. The brownish oil obtained was purified by silica gel chromatography (18×5 cm) eluting with n-hexane/ethyl acetate (85:15). This furnished 1.46 g (45%) of the title compound as an off-white solid. HRMS m/z calcd for C8H5ClN2S (M)+ 195.9862, found 195.9868. Anal. (C8H5ClN2S) C, H, N.