Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Cl:30][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][C@@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:32]3[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=3)[C:19](=[O:31])[NH:20]2)=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28]
Reactant: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C

Procedure:
To a solution of (S)-2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (35 mg in 2 mL dry methylene chloride) was added 2 drops of anisole followed by 2 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 30 minutes the solvents were removed in vacuo. The residue was azeotroped in vacuo successively from 2 mL carbon tetrachloride, 2 mL chloroform and 2 mL methylene chloride and the final concentrate purified by preparative tlc on silica gel (chloroform: 10% ammonium hydroxide in methanol, 90:10) to give the title compound, 17 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]=[CH2:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[Cl:19].[OH-:20].[Na+].OO>C1COCC1.O>[Cl:19][C:13]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=1[C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[C:5]([CH2:10][CH2:11][OH:20])[CH:4]=1
Reactant: [OH-]
Reactant: C=Cc1cc(-c2cc(Cl)ccc2Cl)c(Cl)cc1OC
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1CCO
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a stirring solution of 2,2′,5′-trichloro-4-methoxy-5-vinyl-1,1′-biphenyl (310 mg, 1 mmol) in THF (15 mL) under nitrogen at room temperature, BH3 (2 mL, 1N) was added. After stirring for 8 h, a mixture of NaOH (160 mg, 4 mmol) in water (3 mL) and H2O2 (30% in H2O, 0.3 g, 4 mmol) was added and the resulting mixture was stirred for 6 h. The reaction was quenched with NaHCO3 aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=4:1) to afford the desired product (180 mg, 54% yield) as a colorless oil.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>ClCCl.N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)O[C@H]1CS[C@H](COC(=O)c2ccccc2)O1
Yield: 61.8 %

Procedure:
A mixture of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane (8.9 g, 39.6 mmol) (as prepared in example 1) was reacted with 14.6 mL (118.8 mmol) of trimethylacetylchloride in dichloromethane (35 mL) and pyridine (9.6 mL) as described in example 2 to yield 7.94 g of the desired compound in 1:1 ratio.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15](=[O:17])[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15](=[O:17])[NH2:16])[CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NCC(N)=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N(CC(N)=O)Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(carbamoylmethyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g, 2.03 mmol) in dichloroethane (5.0 mL) was added 4-chlorobenzaldehyde 0.34 g, 2.44 mmol), sodium triacetoxy borohydride (0.86 g, 4.06 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using ethyl acetate. 1H-NMR (CDCl3) δ: 1.50 (9H, s), 1.60–1.80 (2H, m), 2.10 (1H, m), 3.10–3.60 (8H, m), 5.65 (1H, br, s), 6.90 (1H, br, s) 7.20–7.40 (4H, m). ESI-MS m/z: 367(M+1), UV retention time: 1.94 min.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH2:12][CH2:13][O:14][CH3:15]>C([O-])(O)=O.[Na+].CCOCC.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>[CH3:6][C:3]1[CH:4]=[CH:12][C:13]2[O:14][C:15]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])=[CH:8][C:9]=2[CH:2]=1
Reactant: N#Cc1ccccc1Br
Reactant: COCCOC
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: CCOCC
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 25 °C

Procedure:
Intermediate 1 (20 g) was added to a stirred solution of 2-bromobenzonitrile (10.34 g) and tetrakis(triphenylphosphine)palladium (0) (1.5 g) in DME (200 ml) and 8% NaHCO3 (50 ml) at reflux under nitrogen. Further catalyst (1.5 g) was added and the reaction continued overnight. The reaction was cooled to room temperature and diluted with ether (200 ml). The organic layer was separated, washed with water (3×100 ml) and dried. Filtration and evaporation gave a white solid which was purified by chromatography eluting with System A (1:9) to give the title compound (10.58 g) as a white solid. T.l.c. System A (1:9), Rf 0.45.
Reaction SMILES: [F:1][C:2]([C:11]1[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=O)[CH3:20].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.N1C=CC=CC=1>[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]1[NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:2]([F:1])([C:7]([F:8])([F:9])[F:10])[C:3]([F:6])([F:5])[F:4])=[CH:12][C:13]=2[N:18]=1)[CH3:20]
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1N
Reactant: CCSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ccccc1-c1nc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 11.5 %

Procedure:
To a mixture of 4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzene-1,2-diamine (552 mg), 2-ethylsulfanylbenzoic acid (401 mg), and pyridine (27 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (422 mg) and 1-hydroxybenzotriazole (27 mg) were added at room temperature. The reaction mixture was stirred at room temperature for 5 hours, diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in a mixed solution of DMF (7.5 mL) and toluene (30 mL), and then p-toluenesulfonic acid (837 mg) was added at room temperature. The mixture was stirred with heating at 130° C. for 8 hours, and allowed to stand to cool to room temperature. Into the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 97 mg of 2-(2-ethylsulfanyl-phenyl)-5-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-1H-benzimidazole (hereinafter, Present Compound 346).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:2]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Temperature: 92.5 °C
Yield: 82.1 %

Procedure:
A mixture of methyl 2-chloro-4-nitrobenzoate (44.2 g, 205 mmol), phenylboronic acid (27.5 g, 226 mmol), sodium carbonate (2.0 M in water, 123 mL, 246 mmol), and bis(triphenylphosphine)palladium(II) chloride (2.8 g, 4 mmol) in dioxane (300 mL) was degassed by nitrogen, and heated at 90-95° C. for 20 hours. The reaction mixture was diluted with ether (500 mL) and ethyl actate (500 mL), washed with water (2 times, 200 mL each) and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystalized from hexane-ethyl acetate (1/1) to give 2-phenyl-4-nitrobenzoic acid methyl ester as a white solid (43.3 g). The mother liquid from the recrystalization was concentrated in vacuo, and the residue was purified by column chromataography (80:15:5 hexane-chloroform-ethyl acetate) to yield an additional 5.2 g of the desired compound (total yield 48.5 g, 92%). 1H NMR (300 MHz, CDCl3) δ 8.25 (d, 1H), 8.24 (dd, 1H), 7.94 (dd, 1H), 7.44 (m, 3H), 7.35 (m, 2H), 3.67 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18]CC3C=CC=CC=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: [H][H]
Reactant: Fc1cnccc1Nn1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc2c(ccn2Nc2ccncc2F)c1
Yield: 137.1 %

Procedure:
In a 500 ml Parr hydrogenation bottle, 10% Pd/C (1.0 g) was suspended in 50 ml ethanol, and to this was added a solution of 1-(3-fluoro-4-pyridinylamino)-5-phenylmethoxy-1H-indole (5.0 g) in 200 ml ethanol. The mixture was shaken at 50° C. under 50 psi hydrogen gas for two hours. After cooling, the mixture was filtered, and the filtrate was concentrated to give an oil (5.0 g) which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:1) via HPLC. The desired fractions were combined and concentrated to give a crystalline solid, 3.5 g, m.p. 70°-73° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1.O>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:15])=[O:16])=[C:10]([C:18]([F:21])([F:19])[F:20])[CH:9]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccc(Br)cc1C(F)(F)F)N1CCOCC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Morpholine (1.1 ml) was added to a solution of [4-bromo-2-(trifluoromethyl)phenyl]sulfonyl chloride (2.03 g) in DCM (7 ml) at 0° C. and stirred at 20° C. for 16 h. Water was added and the mixture was extracted with DCM. The organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol-ether as eluent) to give the sub-title compound 2.10 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH3:15]>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:15])[C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: CI
Reactant: Clc1cc2[nH]ccc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2c(Cl)nc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine (270 mg, 1.44 mmol) in tetrahydrofuran (4 mL) at 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (69.3 mg, 2.89 mmol) followed by iodomethane (225 mg, 1.59 mmol). After stirring at 0° C. for 0.5 h, the reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 5 h. At this time, the resulting mixture was quenched with a saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (30% ethyl acetate/hexanes) afforded 4,6-dichloro-1-methyl-1H-pyrrolo[3,2-c]pyridine (278 mg, 95.8%). LC-MS calcd. for C8H6Cl2N2 [(M+H)+] 201, obsd. 200.8.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1>>[CH2:2]1[CH:1]2[CH:7]3[C:6](=[O:12])[O:11][C:9](=[O:10])[CH:8]3[CH:3]1[CH:4]=[CH:5]2
Reactant: C1=CCC=C1
Reactant: O=C1C=CC(=O)O1
Product: O=C1OC(=O)C2C3C=CC(C3)C12
Yield: 25 %

Procedure:
The Diels-Alder adduct from cyclopentadiene and maleic anhydride, endo-cis-5-norbornene-2,3-dicarboxylic anhydride, m.p. 165° C, was heated at 220° C. for 4 hours. On cooling, the product solidified with a melting point of 101° C. The crude reaction product was recrystallized from benzene three times to isolate exo-cis-5-norbornene-2,3-dicarboxylic anhydride, m.p. 141° C., in 25% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:6]([Cl:22])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:57]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=[CH:59][C:58]=1[C:67](O)=[O:68].O>CN(C=O)C>[Cl:22][C:6]1[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:23])=[C:10]([N:11]([CH3:12])[CH3:13])[N:9]=[C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:67]([C:58]3[CH:59]=[CH:60][C:61]4[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=4)[CH:57]=3)=[O:68])=[CH:19][CH:20]=2)[N:7]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1N(C)C
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C

Procedure:
To a mixture of methyl[2-(4-aminobenzyl)-4-chloro-6-(dimethylamino)pyrimidin-5-yl]acetate (0.090 g, 0.30 mmol) and PyBOP (0.187 g, 0.36 mmol) in anhydrous DMF (1 mL) at room temperature was added 2-naphthoic acid (0.062 g, 0.36 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours at which time water was added and the resulting aqueous phase was extracted with EtOAc. The combined organic extracts was sequentially washed with 0.5N HCl, saturated NaHCO3, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give methyl {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]4[NH:23][N:22]=[N:21][N:20]=4)[CH:16]=[C:15]([F:24])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.[N+](=[CH2:27])=[N-]>O1CCCC1>[F:24][C:15]1[CH:14]=[C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[N:12]=2)[CH:18]=[C:17]([C:19]2[N:23]([CH3:27])[N:22]=[N:21][N:20]=2)[CH:16]=1
Reactant: Fc1ccc(-c2noc(-c3cc(F)cc(-c4nnn[nH]4)c3)n2)nc1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: Cn1nnnc1-c1cc(F)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Yield: 21.3 %

Procedure:
To a solution of 3-(5-fluoro-pyrid-2-yl)-5-[3-fluoro-5-(1H-tetraazol -5-yl)-phenyl]-1,2,4-oxadiazole (30mg, 0.092 mmol) in tetrahydrofuran (1 mL), 0.5 M diazomethane (1 mL, 0.5 mmol, ether) was added. The reaction was quenched with water and extracted with dichloromethane. The product was purified by column chromatography with 20% ethyl acetate in hexanes to give 6.7 mg (21.4%) of 5-[3-fluoro -5-(1-methyl-1H-tetraazol-5-yl)-phenyl]-3-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.87 (s, 1H), 8.70 (d, 1H), 8.29 (dd, 1H), 8.10 (m, 2H), 7.62 (dt, 1H), 4.46 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)(=[O:3])[CH3:2].[CH2:11]([OH:14])[C:12]#[CH:13]>C(N(CC)CC)C.O.[Cu]I.Cl[Pd]Cl>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:13][C:12]#[C:11][OH:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: C#CCO
Reactant: CC(=O)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(CC#CO)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A suspension of 3 g (15.1 mmol) of 2-acetyl-6-bromopyridine, 0.89 g (15.9 mmol) of propargyl alcohol, 0.078 g of CuI, 300 mg of PdCl2 (P (Ph)3)2 in 60 ml of triethylamine was stirred under nitrogen at room temperature for 6 h. The mixture was diluted with water, extracted with ether, and the organic layer was washed with water (2×), brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo and the residue was purified by MPLC (silica gel 60, hexane/ethyl acetate, 1:1) to afford 1.3 g (50%) of 2-acetyl-6-(3-hydroxy-2-propynyl)pyridine, as a solid product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)=[O:4].C([Mg]Br)C.[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24](Cl)=[O:25]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[C:10]2[C:24]([CH:20]1[C:21]([CH3:23])([CH3:22])[C:19]1([CH3:27])[CH3:18])=[O:25])=[O:4]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: COC(=O)c1cccc2cc[nH]c12
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)c1cccc2c(C(=O)C3C(C)(C)C3(C)C)c[nH]c12
Yield: 63.2 %

Procedure:
A mixture of methyl-indole-7-carboxylate (Maybridge, 1.0 g, 5.7 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.9 mL, 6.9 mmol), zinc chloride (1.0 M solution in Et2O, 6.9 mL, 6.9 mmol) and the product of Example 1A (7.4 mmol) in 25 mL of dichloromethane was processed as described in Example 1B to provide the title compound (1.1 g, 3.6 mmol, 63% yield). MS (DCI/NH3) m/z 300 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18].[OH-:19].[Na+].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:11][C:10]([OH:18])=[O:19]
Reactant: [OH-]
Reactant: O=C1Cc2ccccc2N1c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 90 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a stirred solution of 1-(2,6-Dichloro-phenyl)-1,3-dihydro-indol-2-one 1 (10 g, 0.03 mol) in toluene (340 mL) was added aq. NaOH (2N, 34 mL)) at rt. The resulting mixture was stirred at 90° C. for 16 h. After completion, clear solution was cooled in an ice bath and acidified with con. HCl. The precipitated solid was filtered, washed with ethanol and dried under reduced pressure to get 9.0 g (84.4% yield) of Compound 2 as an off white solid. Used in the next step without any further purification; Mass: 294.1 (M−H); 1H-NMR (400 MHz, DMSO): 12.70 (s, 1H), 7.53-7.51 (d, J=8.0 Hz, 2H), 7.24-7.16 (m, 3H), 7.08-7.03 (m, 1H), 6.87-6.83 (m, 1H), 6.28-6.26 (d, J=7.8 Hz, 1H), 3.69 (s, 2H); 13C-NMR (400 MHz; DMSO): 173.86, 142.66, 137.11, 130.89, 130.04, 129.17, 127.51, 125.56, 123.89, 120.76, 115.95, 37.74.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[O:21][CH3:22].Cl>O1CCOCC1>[F:10][C:5]1[C:6]([NH:8][CH3:9])=[N:7][C:2]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[O:21][CH3:22])=[N:3][CH:4]=1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CNc1nc(Cl)ncc1F
Agent: Cl
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(C(=O)O)cc2OC)ncc1F
Temperature: 120 °C
Yield: 88.4 %

Procedure:
A mixture of 50 mg 2-chloro-5-fluoro-N-methylpyrimidin-4-amine, 57 mg 4-Amino-3-methoxybenzoic acid, 0.1 mL 4N HCl in 1,4-dioxane and 1 mL N-butanol was placed in a 10 mL snap-top microwave vial (CEM Corp.) and heated to 120° C. microwave for 40 min. The reaction was monitored by LC/MS. The precipitated solid was filtered to yield 80 mg of 4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO>[F:21][C:18]1([F:22])[CH2:17][CH2:16][CH:15]([CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:10][OH:11])[CH2:20][CH2:19]1
Reactant: COC(=O)[C@H](CC1CCC(F)(F)CC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CCC(F)(F)CC1
Temperature: 2.5 °C
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propanoate (28.6 g, 0.089 mol) in EtOH (600 mL) at 0° C. was added NaBH4 (27.1 g, 0.713 mol) in portions while the temperature was maintained at 0-5° C. The mixture was stirred for 2-3 hr at rt and then evaporated. The residue was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated to give (S)-tert-butyl 1-(4,4-difluorocyclohexyl)-3-hydroxypropan-2-ylcarbamate (25.7 g, 99%), which was used in the next step without purification. 1H NMR (CDCl3, 400 MHz) δ 4.61 (d, J=7.6 Hz, 1H), 3.70 (m, 1H), 3.50 (m, 1H), 2.45-1.10 (m, 11H), 1.44 (s, 9H). MS ESI +ve m/z 295 (M+1).