Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:30][CH:31]([CH2:34][CH2:35][CH3:36])[CH:32]=O.[H-].[Na+]>C(#N)C.O>[CH3:30][CH:31]([CH2:34][CH2:35][CH3:36])[CH:32]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCCC(C)C=O
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CCCC(C)C=CCCCC(=O)OCC
Yield: 54 %

Procedure:
104.54 g (0.5 mol) of ethyl 5-bromovalerate and 137.5 g (0.525 mol) of triphenyl phosphine were refluxed for 36 hours in 1 l of acetonitrile. After the reaction terminated, 500 ml of acetonitrile was distilled off, then the reaction mixture was dried. Under nitrogen atmosphere, 50.1 g (0.5 mol) of 2-methyl valeraldehyde was added, then the reaction mixture was stirred. Controlling the reaction temperature to within the range of 25°-35° C., 20.0 g (0.5 mol) of oily (60%) sodium hydride was added little by little. After the addition, the reaction mixture was stirred over night at room temperature. After the reaction ended, 250 g of water was added into the reaction mixture, then oil layer was separated and the water layer was extracted three times with 150 ml of hexane. The organic layers were combined and washed with 150 ml of water. After the hexane solution was dried sufficiently with anhydrous Magnesium sulfate, solvent was removed under reduced pressure, and distilled to obtain 57.3 g of ethyl 7-methyl-5-decenoate (Yield: 54%, based upon starting material). The product was gradually added dropwise into 500 ml of dried ethylether solution including 5.12 g (0.135 mol) of aluminum lithium hydride under nitrogen stream. The dropwise addition was done while a reaction vessel was cooled sufficiently by ice water. After the addition was completed, the reaction temperature was returned to room temperature and stirred for 2 hours. Then, 300 ml of water was added gradually into the reaction mixture, and the organic layer was separated. The water layer was returned to pH7 and extracted three times with 100 ml of diethylether. The organic layers were combined and washed with 100 ml of water, and solvent was removed from the reaction mixture under reduced pressure to obtain 44.2g of 7-methyl-5-decen-1-ol (Yield: 52", based upon starting material).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([NH2:23])=[CH:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([NH:23][S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])=[CH:20]2)=[CH:15][CH:14]=1
Reactant: Nc1ccc2ccc(OCc3ccc4ccccc4n3)cc2c1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ccc2ccc(OCc3ccc4ccccc4n3)cc2c1
Yield: 74.9 %

Procedure:
A solution of 5.00 g 7-(2-quinolinylmethoxy)-2-naphthalenamine (17 mmol), prepared according to the procedure of Example 7, 1.7 g triethylamine (17 mmol) and 2.18 g ethanesulfonyl chloride (17 mmol) in 50 mL tetrahydrofuran is refluxed overnight. The solvent is removed and the residue is partitioned between methylene chloride and saturated sodium bicarbonate. After drying over potassium carbonate, the organic layer is freed of solvent to afford 5.00 g of a brown gum. Chromatography on alumina and elution with 9:1 methylene chloride/ethyl acetate affords 1.4 g of a white solid which is recrystallized from ethyl acetate. Rechromatography on HPLC and final recrystallization from ethyl acetate affords 0.6 g (9%) of white crystals, m.p. 166°-167.5° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]#[N:19])[CH:12]=2.[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[C@@H:31]1[CH2:33][O:32]1>CCO>[OH:32][C@H:31]([C:22]1[CH:23]=[CH:24][C:25]2[C:26](=[O:30])[O:27][CH2:28][C:29]=2[C:21]=1[CH3:20])[CH2:33][N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([C:18]#[N:19])[CH:12]=3)[C:2](=[O:1])[CH2:7]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: N#Cc1ccc2cc(N3CCNCC3=O)cnc2c1
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(c3cnc4cc(C#N)ccc4c3)C(=O)C2)ccc2c1COC2=O
Temperature: 140 °C

Procedure:
A mixture of 3-(2-oxopiperazin-1-yl)quinoline-7-carbonitrile [I-4] (17 mg, 0.067 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (19 mg, 0.10 mmol) in EtOH (1.5 mL) in a 5 mL microwave tube was heated to 140° C. for 1 hour. LC showed formation of the title product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 443 [M+1]+.
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:26]#[N:27])=[N:13][N:14]2[CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=1.CO>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:26](=[NH:6])[NH2:27])=[N:13][N:14]2[CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])=[CH:10][CH:9]=1
Reactant: [NH4+]
Reactant: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2cc(Cl)ccc12
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: N=C(N)c1nn(CCC(F)(F)C(F)(F)F)c2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Trimethylaluminum (2.0M in toluene, 23.17 mL, 46.3 mmol) was added dropwise to a suspension of ammonium chloride (2.49 g, 46.5 mmol) in 69 mL toluene cooled to 0° C. The solution was then stirred at room temperature for 3 hours. This solution was then added to the intermediate from Step D (3.0 g, 9.27 mmol) and then heated at 110° C. for 6 hours. The solution was then cooled to room temperature and carefully poured to silica gel (ca 150 mL) and methanol (ca 250 mL). After stirring for 1.5 hours the suspension was filtered and the filtrate concentrated to give the indicated product which was used in the next step without further purification. 1H NMR (400 MHz, CH3 CN-d3): selected peaks δ 8.26 (d, J=8.7 Hz, 1H); 7.70 (d, J=1.7 Hz, 1H); 7.24 (dd, J=8.7, 1.8 Hz, 1H); 4.67 (t, J=7.1 Hz, 2H); 3.01-2.78 (m, 2H). m/z=341.1 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:17]=[C:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[N:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(COC)OC>[CH2:1]([NH:4][C:5]1[N:17]=[C:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[N:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CC(=O)Nc1nc2n(n1)CCc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: CCNc1nc2n(n1)CCc1ccccc1-2
Yield: 53 %

Procedure:
2-Acetamido-5,6-dihydro-s-triazolo[5,1-a]isoquinoline is reduced with lithium aluminum hydride at 0°-10° C. in dimethoxyethane. Yield 53%, m.p. 100°-101° C.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[C:11]([O:15][C:16](=[O:20])[CH2:17][CH2:18]Br)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16](=[O:20])[CH:17]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)[CH3:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)OC(C)(C)C)n1ccc([N+](=O)[O-])n1
Yield: 53.9 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 2.00 g, 17.70 mmol) in anhydrous N,N-dimethylformamide (30 mL), a 60% dispersion of sodium hydride in mineral oil (778 mg, 19.50 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, 3-bromo-propionic acid tert-butyl ester (3.25 mL, 19.50 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) to afford (3-nitro-pyrazol-1-yl)-propionic acid tert-butyl ester (2.30 g, 57%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:27])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH2:23][CH2:24][O:25][CH3:26])[CH:22]=3)[S:17][C:10]=12.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([N:39]=[C:40]=[S:41])=[O:38]>>[F:1][C:2]1[CH:3]=[C:4]([NH:27][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])=[S:41])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH2:23][CH2:24][O:25][CH3:26])[CH:22]=3)[S:17][C:10]=12
Reactant: COCCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1CC(=O)N=C=S
Product: COCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1

Procedure:
Following the procedure described above for the compound 90 (scheme 17) but replacing the amine 89 with the amine 95 and using 2-(2-methoxyphenyl)acetyl isothiocyanate instead of 2-phenylacetyl isothiocyanate, title compound 96 was obtained as a beige solid (6 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.57 (1H, s), 11.77 (1H, s), 8.53 (1H, d, J=5.48 Hz), 8.08 (1H, d, J=12.03 Hz), 8.02 (1H, s), 7.91 (1H, s), 7.76 (1H, s), 7.59-7.52 (2H, m), 7.28-7.21 (2H, m), 6.98 (1H, d, J=8.22 Hz), 6.91 (1H, d, J=7.44 Hz), 6.71 (1H, d, J=5.67 Hz), 4.21 (2H, t, J=4.89 Hz), 3.80 (2H, s), 3.77 (3H, s), 3.65 (2H, t, J=4.89 Hz), 3.26 (3H, s). MS (m/z) 592.1 (M+H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[NH:6][N:5]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:1][NH:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[CH:11]=2)[NH:6][N:5]=1
Reactant: O=CNc1n[nH]c2ccc(C(F)(F)F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CNc1n[nH]c2ccc(C(F)(F)F)cc12

Procedure:
An ether solution of 3-formylamino-5-trifluoromethylindazole is added to 2.0 g. of lithium aluminum hydride in ether. The resulting mixture is refluxed for 16 hours. Ether is added, followed by water. The mixture is filtered and the filtrate is concentrated. The residue is recrystallized from benzene to give 3-methylamino-5-trifluoromethylindazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3Cl)=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[S:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:25]2[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=2)[C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1csc(B(O)O)c1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1csc(-c2ccc(-n3nc(-c4c(F)cccc4-c4cc(C)cs4)[nH]c3=O)cc2)c1
Yield: 22 %

Procedure:
The title compound was prepared according to the procedure described in Example-2 using 2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-1, 0.100 g, 0.271 mmol), (4-methylthiophen-2-yl)boronic acid (0.059 g, 0.407 mmol), K2CO3 (0.112 g, 0.81 mmol), tetrakistriphenyl phosphine palladium (0) (0.062 g, 0.054 mmol) and DMSO (3.0 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 6.86 (s, 1H), 6.91 (s, 2H), 7.13 (s, 1H), 7.21 (d, J=9.3 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.48-7.55 (m, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.92 (d, J=9.0 Hz, 2H), 9.27 (br s, 1H). MS (m/z): 384.88 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4](I)=[C:5]([CH3:9])[C:6]=1[CH2:7][OH:8].[Na].[CH3:12][OH:13]>>[CH3:1][C:2]1[S:3][C:4]([O:13][CH3:12])=[C:5]([CH3:9])[C:6]=1[CH2:7][OH:8]
Reactant: CO
Reactant: Cc1sc(I)c(C)c1CO
Agent: [Na]
Product: COc1sc(C)c(CO)c1C

Procedure:
12.0 G. (0.151 mol) of cupric oxide and 12.5 g. (0.0466 mol) of 2,4-dimethyl-3-hydroxymethyl-5-iodothiophene were added to a solution of 12.5 g. (0.543 mol) of sodium in 100 ml. of dry methanol. The reaction mixture was heated to 80°-82° C. (internal temperature) for 20 hrs. with vigorous stirring, then cooled. The cold solution was diluted with 150 ml. of methanol, filtered, poured into ice water and extracted with ether/hexane (ratio 4:1). The organic layers were washed with 5% sodium carbonate solution, dried and evaporated. The residue which resulted was recrystallized from hexane to yield 2,4-dimethyl-3-hydroxymethyl-5-methoxythiophene, m.p. 55°-60° C. This product contained about 10% of 2,4-dimethyl-3-hydroxymethylthiophene which is formed in this reaction by reduction of the iodide. Fraction recrystallization of a sample from hexane yielded pure 2,4-dimethyl-3-hydroxymethyl-5-methylthiophene, m.p. 64°-65° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[N:22]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:23]=[CH:24][CH:25]=1>>[N:21]1[N:22]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])[N:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cccc(-n2nccn2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-n2nccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(2H-1,2,3-triazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 393.05 g/mol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([CH3:28])[CH:3]=1.C([Li])CCC.[CH3:34][S:35]SC>O1CCCC1.[Cl-].[NH4+]>[Cl:22][C:21]1[C:16]2[N:15]=[C:14]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([S:35][CH3:34])=[CH:3][C:4]=4[CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17]=2[C:18]([CH:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:19][CH:20]=1
Reactant: CSSC
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Br)cc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(SC)cc1C
Reaction time: 0.33 h
Yield: 53.7 %

Procedure:
To a solution of 1-(4-bromo-2-methylphenyl)-10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (572 mg, 1.24 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (1.60 M solution in n-hexane, 0.85 mL, 1.36 mmol) at −78° C., and the mixture was stirred for 20 min. To the mixture was added dimethyl disulfide (0.34 mL, 3.72 mmol), and the mixture was stirred at −78° C. for 30 min, at 0° C. for 1 hr. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-25% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound as a colorless powder (285 mg, 0.666 mmol, 54%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[CH2:8]([NH2:11])[C:9]#[CH:10]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH:11][CH2:8][C:9]#[CH:10])[CH3:2]
Reactant: C#CCN
Reactant: CCOC(=O)CBr
Solvent: CCOCC
Product: C#CCNCC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a cooled solution of ethylbromoacetate (37.6 g) in diethyl ether (75 mL), was added propargylamine (25 g). The mixture was stirred for 3 hour at 0°-5° C. The reaction temperature was raised to ambient temperature, and the stirring continued for 18 hours. A solid formed. The solid was filtered and discarded. The filtrate was evaporated to dryness to give crude ethyl-N-propargylaminoacetate (30.1 g). The crude product was used without further purification.
Reaction SMILES: C[O-].[Na+].C1(C)C=CC=CC=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]#[N:20].Cl.[C:22](=O)([O:25]C)[O:23][CH3:24]>O>[C:19]([CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])[C:22]([O:23][CH3:24])=[O:25])#[N:20]
Reactant: N#CCc1ccccc1F
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(C#N)c1ccccc1F
Temperature: 75 °C
Yield: 97.1 %

Procedure:
Sodium methoxide (51.84 g) was added to dry toluene (815 mL) in a 1 L reactor under a nitrogen atmosphere. The reaction mixture was heated to 75° C., and then a mixture of 2-fluorobenzeneacetonitrile (100 g) in dimethyl carbonate (131.64 g) was added at 70-74° C. over a period of 45 minutes. The reaction mixture was further maintained at this temperature (70-75° C.) for an additional 4.5 hours. The reaction mixture was then cooled to 25-30° C. and added to a mixture of HCl (110 g, 35.2 wt %) diluted with water (300 mL) at 10-15° C. using an addition funnel. The resulting layers were separated, and the aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (2×200 mL), dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound as a brown oily liquid (138.8 g, 94.8% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=S.O[Li].O.OO>O1CCCC1>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([NH:19][C:20]2[O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=2)=[C:12]([F:11])[CH:17]=1
Reactant: Cc1cc(C)c(O)c(N)c1
Reactant: Fc1cc(Br)ccc1N=C=S
Agent: OO
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2oc(Nc3ccc(Br)cc3F)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ambient solution of 2-amino-4,6-dimethylphenol (0.85 g, 6.2 mmol) and 2-fluoro-4-bromophenyl isothiocyanate (1.44 g, 6.20 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the dropwise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 335[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1>C1(C)C=CC=CC=1.C(O)C.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2nccs2)cc1
Temperature: 95 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
To a stirred solution of (4-fluorophenyl)boronic acid (10 g, 60.9 mmol) in toluene (70 mL) and ethanol (200 mL) was added 2-bromothiazole (12.7 g, 91.4 mmol), followed by Pd(PPh3)4 (3.5 g, 3.04 mmol). The reaction mixture was purged with argon for 20 min, Na2CO3 solution (2M, 100 mL, 19.39 g) added, and the reaction mixture stirred at 95° C. for 5 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (2×100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with ice-cold water (2×100 mL) followed by brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtained crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in hexane to obtain 2-(4-fluorophenyl)thiazole as white solid (9.0 g, 82% yield). 1H NMR (400 MHz, DMSO): 7.98 (dd, 2H, J=6.8 & 14.0 Hz), 7.88 (d, 1H, J=4.8 Hz), 7.91 (d, 1H, J=2.8 Hz), 7.88 (d, 1H, J=4.8 Hz), 7.31 (t, 2H, J=8.8 & 17.2 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[O-:27][CH2:28][CH3:29].[Na+]>>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][O:27][CH2:28][CH3:29])=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Reactant: CC[O-]
Agent: [Na+]
Product: CCOCc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (50 mg) was added to a freshly prepared sodium ethoxide solution (0.087M, 2 ml), and the reaction stirred at room temperature for 72 hours. The reaction was partitioned between ethyl acetate and water, the organic phase dried (sodium sulphate) and reduced to dryness under vacuum. The residue was purified by HPLC to give, after evaporation of the solvent, N-cyclopropyl-4′-[5-(ethoxymethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(N(CC)CC)C.[I-]>C(#N)C.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.[Cu]>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:23])([F:22])[F:13])=[CH:16][CH:17]=2)=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#Cc1ccc(N)c(C#N)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C#Cc2ccc(C(F)(F)F)cc2)ccc(N)c1C#N
Yield: 72.7 %

Procedure:
A solution of 3.5 grams (0.022 mole) of 2-amino-5-ethynyl-6-methylbenzonitrile, 8.4 grams (0.031 mole) of 4-trifluoromethylphenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper(l) iodide in 100 mL of acetonitrile was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The two-layered mixture was filtered to remove a solid. The aqueous layer and the organic layer were separated, and the aqueous layer was washed with ethyl acetate. The ethyl acetate wash was combined with the organic layer, and the combination was washed with an aqueous solution of 10% lithium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was triturated with methylene chloride and filtered. The filtrate was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.8 grams of 2-amino-6-methyl-5-[(4-trifluoromethylphenyl)ethynyl]benzonitrile, mp 136°-138° C. The NMR spectrum was consistent with the proposed structure.