Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13]([NH:15][NH:16]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:12][C:11](=O)[CH2:10]1.C(=O)([O-])[O-].[K+].[K+].CO.Br[CH2:37][C:38](=O)[CH3:39]>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13]2[N:15]=[N:16][CH:37]=[C:38]([CH3:39])[C:12]=2[CH2:11][CH2:10]1
Reactant: CC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(C)ccc3Cl)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cc1ccc(Cl)c(C2CCc3c(C)cnnc3C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(2-chloro-5-methylphenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (2.03 g), anhydrous potassium carbonate (1.73 g) and methanol (20 ml) was stirred at room temperature for 30 minutes, and to the mixture were added 1,2-dimethoxyethane (10 ml) and bromoacetone (0.891 g). The mixture was stirred at 80° C. for 4.5 hours. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate (200 ml) and water (30 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(2-chloro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin,-5-one (0.804 g) as brown crystals.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27](OC)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27]([NH:12][C:9]2[CH:8]=[N:7][C:6]([CH3:5])=[CH:11][N:10]=2)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Cc1cnc(N)cn1
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)[C@@H](O)CN2CC(O[Si](C)(C)C(C)(C)C)C2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
Trimethylaluminum (6.22 mL, 12.44 mmol) was added to 5-methylpyrazin-2-amine (1.357 g, 12.44 mmol) in anhydrous toluene (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (2 g, 6.91 mmol) in anhydrous toluene (10 mL) was added and the resulting solution was allowed to warm to room temperature and then heated at 80° C. overnight. The reaction was allowed to cool to room temperature and a solution of Rochelle salt in water (20%, 75 ml) was added. The mixture diluted with water (25 mL) and ethyl acetate (75 mL) and allowed to stir for 2 hours. The organic layer was separated and the aqueous was extracted with ethyl acetate (75 mL). The combined organics were washed with brine (75 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 20 to 50% ethyl acetate in isohexane. This was further purified by flash silica chromatography, eluting with 0 to 10% methanol in dichloromethane, to afford the product (1.50 g, 59.2%). 1H NMR (400 MHz, CDCl3) δ 0.03 (3H, d), 0.04 (3H, s), 0.87 (9H, q), 2.54 (3H, s), 2.93 (2H, d), 3.09 (2H, q), 3.71-3.77 (2H, m), 4.04 (1H, t), 4.46 (1H, t), 8.13 (1H, d), 9.39 (1H, d), 9.81 (1H, s); m/z (ES+) (M+H)+=367.34; HPLC tR=1.76 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:12]3[CH2:13][NH:14][CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]=[C:34]=[O:35])=[CH:28][CH:27]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:12]3[CH2:13][N:14]([C:34]([NH:33][CH2:32][C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)=[O:35])[CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCCN12
Reactant: O=C=NCc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)N1CCN2C(=O)OC(c3cccc(F)c3)(c3cccc(F)c3)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
1,1-Bis(3-fluorophenyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.18 g, 0.55 mmol) was dissolved in tetrahydrofuran (5 mL). (4-Fluorophenyl)methyl isocyanate (0.15 g, 1.0 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=50:1 to ethyl acetate) to obtain the title compound (0.25 g, yield 96%).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:15]>>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:15])=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: CCCCc1ccc(C(N)=O)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred solution of 200 ml of aqueous ammonium hydroxide was added dropwise 35 ml of 4-butylbenzoyl chloride. The resulting mixture was stirred at room temperature for several hours. The white solid was collected by filtration, washed with water, then hexane, and dried in vacuo at 60° C. to give 33.4 g (99% yield) of the desired product, mp 135°-136° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([Cl:10])[CH:3]=1.Br.[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:14]2[CH2:15][CH2:16][CH2:17][C@H:13]2[CH3:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: C[C@@H]1CCCN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1Cc1ccc(Br)cc1Cl
Reaction time: 8 h
Yield: 77.2 %

Procedure:
Intermediate 3, 4-bromo-1-(bromomethyl)-2-chlorobenzene (15.4 g, 55 mmol) was added to a mixture of (2R)-2-methylpyrrolidine HBr (9.0 g, 55 mmol), potassium carbonate (18 g, 130 mmol), and 150 mL of dimethylformamide under ice cooling. The mixture was allowed to reach room temperature, and the stirring was continued overnight. The mixture was evaporated. Water (400 mL) was added followed by addition of 5M NaHSO4 to attain pH˜2. The organic layer was separated. The aqueous phase was extracted with Et2O (2×200 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜12 and subjected to extraction with Et2O (2×300 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 (100 g), and evaporated in vacuo. The residue was distilled at 1 mmHg, bp 95° C. to give the title compound (12.25 g, 79%). LC/MS data: 289.9 and 287.9 (M)+ (calculated for C12H15BrClN 288.6). 1H NMR data (DMSO-d6): δ 7.66 (d, 1H, J=1.9 Hz, Ar—H); 7.52 (dd, 1H, J1=1.9 Hz, J2=8.0 Hz, Ar—H), 7.43 (d, 1H, J=8.1 Hz, Ar—H), 3.91 (d, 1H, J=14.4 Hz), 2.28 (d, 2H, J=8.5 Hz); 2.78-2.85 (m, 1H); 2.42-2.49 (m, 1H); 2.11 (dd, 1H, J1=8.8 Hz, J2=17.6 Hz); 1.87-1.97 (m, 1H); 1.57-1.67 (m, 2H); 1.27-1.39 (m, 1H); 1.08 (d, 3H, J=5.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].O>O1CCOCC1>[C:18]([NH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:8][S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)NC1=NS(=O)(=O)c2cc(N)ccc2N1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(NC(C)C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-amino-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.18 g) and acetic anhydride (0.6 mL) in dioxane (2 mL) was stirred for 1 h at room temperature. The medium was then mixed with water (5 mL) and stirred for 1 h. The solvents were removed by distillation under reduced pressure and the residue of the crude title compound was recrystallized from methanol-water to give the title compound (yield: 0.16 g); m.p. 260-262° C.; IR (KBr): 3353, 3316, 3240, 3101, 3069, 2974, 1672, 1624, 1608, 1581, 1546, 1497, 1467, 1391, 1279, 1159, 1142, 1123, 1104 cm−1; 1H-NMR (DMSO-d6, HMDS; d ppm): 1.10 (d, 6H, 2×CH3), 2.00 (s, 3H, COCH3), 3.90 (m, 1H, NH—CH), 6.85 (bd, 1H, NH—CH), 7.05 (d, 1H, 5-H), 7.60 (bd, 1H, 6-H), 8.00 (bs, 1H, 8-H), 10.00 (bs, 1H, CONH), 10.10 (bs, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:14].Cl[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C.ClC(O)CCCCC>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:14]
Reactant: OCCCCCCCl
Reactant: COc1cc(N)c2nccc(C)c2c1
Agent: CCCCCC(O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(NCCCCCCO)c2nccc(C)c2c1
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a stirred mixture of 1.9 g (0.01 mole) of 6-methoxy-4-methyl-8-quinolinamine and 1.4 g (0.01 mole) of 6-chlorohexanol at 150° was added portionwise over one hr 1.4 ml (0.01 mole) of triethylamine. The mixture was stirred for 1 hr at the same temperature, and then 0.8 g (0.0056 mole) of 1-chlorohexanol was added, followed by the portionwise addition of 0.8 (0.0056 mole) of triethylamine. The mixture was stirred for 1 hr and the procedure was repeated with 0.5 g (0.0037 mole) of 1-chlorohexanol and 0.5 ml of triethylamine. After the mixture was stirred an additional hr, the mixture was allowed to cool, diluted with acetone, filtered, and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane and chromatographed over 70 g of silica gel first with 500 ml of dichloromethane and then with the following solutions of ethyl acetate in dichloromethane: 5% (500 ml), 10% (1 liter), 15% (500 ml), and finally 20% (500 ml). Fractions of the 20% eluant containing the product, Rf(silica--ethyl acetate)=0.3, were combined and concentrated to dryness in vacuo. Recrystallization from 2-propanol afforded 1.6 g (55%) of the title compound, mp 97°-99°.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>>[C:3]1([N:8]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:11]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: O=C(Nc1ccccc1)c1cccnc1
Product: c1ccc(-n2c(-c3cccnc3)nc3ccccc32)cc1
Yield: 50.1 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and nicotinanilide (119 mg, 0.6 mmol) yielded the title compound as brown solid (68 mg, 50%). mp 110-112° C. 1H NMR (DMSO) δ 7.26 (d, J=7.3Hz, 1H), 7.32-7.63 (m, 8H), 7.86 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.8Hz, 1H), 8.62 (d, J=3.0Hz, 1H), 8.72 (br s, 1H); 13C NMR δ 111.0, 118.7, 123.8, 124.0, 124.4, 125.4, 127.6, 129.5, 130.2, 135.2, 136.4, 137.7, 140.3, 148.6, 149.6, 158.3. HRMS (FAB): cal. for C18H14N3 [M+H+]: 272.1188; found: 272.1180.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13]C(C#N)=[CH:15][C:3]1=2.S(=O)(=O)(O)O.[C:23]([OH:26])(=[O:25])[CH3:24].[OH-].[Na+]>O>[O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][C:24]([C:23]([OH:26])=[O:25])=[CH:15][C:3]1=2
Reactant: N#Cc1ccc2oc3ncccc3c(=O)c2c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A mixture of 3 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbonitrile, 30 ml of sulfuric acid, 30 ml of acetic acid and 30 ml of water is heated under reflux for 3 hours. The reaction mixture is poured on ice, and adjusted to pH 3 by addition of 10% sodium hydroxide. The crystalline precipitate is filtered off and recrystallized from a mixture of dioxane and dimethylformamide to give 1.5 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylic acid melting at 293°-294°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][N:24]2[CH3:29].C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][N:24]2[CH3:29])#[N:18]
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Reactant: Cn1ccc2c(N)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2cccc3c2ccn3C)n1)C(N)=O
Reaction time: 20 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (80 mg, 0.299 mmol), 4-amino-N-methyl-indole (62 mg, 0.424 mmol), K2CO3 (65 mg, 0.471 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-cyano-6-(1-methyl-1H-indol-4-ylamino)pyrazin-2-ylamino)-4-methylpentanamide as a crude residue (151 mg).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[N:13]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH:17]=[CH:16][N:15]=[CH:14]1>O1CCOCC1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:21][CH2:20][CH2:19][CH2:18][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[O:4]
Reactant: NCCCn1ccnc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: C1COCCO1
Product: Nc1ccccc1C(=O)NCCCn1ccnc1
Reaction time: 0.67 h

Procedure:
Isatoic anhydride (22.0 g) was added in portions to a stirred solution of 3-imidazol-1-ylpropylamine (17.2 g) in dioxan (100 ml) over a period of 15 minutes. Stirring was continued for 40 minutes before the solution was evaporated in vacuo to give 2-amino-N-(3-imidazol-1-ylpropyl)benzamide as a buff coloured solid, used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[K+]>CCO.O>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][CH2:7][CH2:6][C:5]2([C:3]([OH:4])=[O:2])[CH3:17])=[CH:10][CH:11]=1
Reactant: COC(=O)C1(C)CCCc2ccc(OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)C(C)(C(=O)O)CCC2
Reaction time: 8 h

Procedure:
A mixture of 7-methoxy-1-methyltetralin-1-yl-carboxylic acid, methyl ester (0.67 g; 2.9 mmol; from step (ii) above) and KOH (4 g) in EtOH:H20 (1:1; 50 mL) was stirred overnight. The resultant mixture was diluted with water and extracted with ether. The aqueous layer was acidified (HCl) and extracted 3 times with ether. The combined organic layer was washed with water, dried (Na2SO4), and concentrated. Yield 0.58 g (81%).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1([CH:16]=[CH:15][C:13]([OH:14])=[CH:12][CH:11]=1)[OH:10]>>[C:3]1([CH:2]([C:11]2[CH:12]=[C:13]([OH:14])[CH:15]=[CH:16][C:9]=2[OH:10])[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: Oc1ccc(O)cc1
Product: CC(c1ccccc1)c1cc(O)ccc1O

Procedure:
Styrene and hydroquinone are reacted to produce (1-phenylethyl) hydroquinone, i.e., ##STR1##
Reaction SMILES: N(OC(C)(C)C)=O.ON1C(=O)C2=CC=CC=C2C1=O.[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([CH:25]=[N:26]O)=[CH:23][CH:22]=1.CC1C=CC(C=O)=CC=1>C(O)(=O)C.CC1C=CC(C)=CC=1>[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C=NO)cc1
Agent: CC(C)(C)ON=O
Agent: Cc1ccc(C=O)cc1
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: Cc1ccc(C)cc1
Solvent: CC(=O)O
Product: Cc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
In a flask p-xylene (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.1 mmol), and acetic acid (1 ml) were placed and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that p-methylbenzaldehyde oxime, p-methylbenzaldehyde, and p-methylbenzonitrile were formed in yields of 55%, 4%, and 5%, respectively.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](Br)[CH:7]=1.[C:11]([C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[C:23]=2[CH3:37])=[O:20])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>COCCOC.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>[NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([C:24]2[C:23]([CH3:37])=[C:22]([NH:21][C:19](=[O:20])[C:18]3[CH:17]=[CH:16][C:15]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:39][CH:38]=3)[CH:27]=[CH:26][CH:25]=2)[CH:7]=1
Reactant: Cn1cc(Br)cc(N)c1=O
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
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: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(N)c(=O)n(C)c1
Temperature: 95 °C
Yield: 71.9 %

Procedure:
A 48-mL sealed tube equipped with a magnetic stirring bar was charged with 3-amino-5-bromo-1-methyl-1H-pyridin-2-one (4) (0.10 g, 0.50 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (0.24 g, 0.70 mmol), and Pd(PPh3)4 (0.030 g, 0.025 mmol) in DME (10 mL) and 1N Na2CO3 (5 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane and the phases were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10% MeOH in dichloromethane/ether (1/1), to afford 0.14 g (68%) of N-[3-(5-amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (5) as a solid.
Reaction SMILES: [ClH:1].[N:2]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:22]=3[C:23]([F:26])([F:25])[F:24])=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:33][C:34]1([CH3:41])[CH2:39][C:38](=[O:40])[O:37][C:35]1=[O:36]>C(Cl)Cl>[ClH:1].[CH3:33][C:34]([CH3:41])([CH2:39][C:38](=[O:40])[N:5]1[CH2:6][CH2:7][CH2:8][N:2]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:22]=3[C:23]([F:26])([F:24])[F:25])=[O:17])=[CH:11][CH:10]=2)[CH2:3][CH2:4]1)[C:35]([OH:37])=[O:36]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: O=C(Nc1ccc(N2CCCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CC(C)(CC(=O)N1CCCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1)C(=O)O
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-[1,4]diazepan-1-yl-phenyl)-amide hydrochloride (35 mg, 0.075 mmol), methylene chloride (5 mL), and TEA (40 mg, 0.39 mmol) was stirred at room temperature. 2,2-Dimethylsuccinic anhydride (20 mg, 0.15 mmol) was added slowly. The reaction was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in ethyl acetate (50 mL) and washed with saturated ammonium chloride (50 mL), water (50 mL), and brine (20 mL). The solvent was removed and the residue was treated with hydrogen chloride in ether (1 N, 4 mL). The solid was filtered and washed with dry ether to afford 2,2-dimethyl-4-oxo-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepan-1-yl)-butyric acid hydrochloride salt (35 mg, 85% yield). LCMS calcd for C28H29F3N4O5 (m/e) 558, observed 559 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:22])[C:12]=2[NH:13][C:14](=[O:21])[O:15][C@@H:16]([CH:18]([CH3:20])[CH3:19])[CH3:17])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([C:37]3([C:40]([O:42][CH3:43])=[O:41])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:43][O:42][C:40]([C:37]1([C:34]2[CH:35]=[CH:36][C:31]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[N:9]=[N:10][N:11]([CH3:22])[C:12]=4[NH:13][C:14]([O:15][C@H:16]([CH3:17])[CH:18]([CH3:20])[CH3:19])=[O:21])=[CH:4][CH:3]=3)=[CH:32][CH:33]=2)[CH2:39][CH2:38]1)=[O:41]
Reactant: COC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(C)[C@@H](C)OC(=O)Nc1c(-c2ccc(Br)cc2)nnn1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ccc(-c3ccc(-c4nnn(C)c4NC(=O)O[C@H](C)C(C)C)cc3)cc2)CC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
(R)-3-Methylbutan-2-yl 4-(4-bromophenyl)-1-methyl-1H-1,2,3-triazol-5-ylcarbamate (101.4 mg. 0.28 mmol), methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate (108 mg, 0.36 mmol), X-Phos (39.5 mg, 0.083 mmol), palladium acetate (9.3 mg, 0.041 mmol), and potassium phosphate tribasic (176 mg, 0.83 mmol) were combined in toluene (6 mL). To this mixture was added degassed water (1.5 mL) and the mixture was stirred at 95° C. for 2 hrs until it became black. LC/MS indicated no more starting material. The mixture was extracted with ethyl acetate and water. The organic layer was washed with brine and dried. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (12 g silica gel, 5% to 65% ethyl acetate in hexanes) to give a pale yellow solid as 1-{4′-[5-((R)-1,2-dimethyl-propoxycarbonylamino)-1-methyl-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester (97.8 mg, 76.6% yield). LC/MS calcd for C26H30N4O4 (m/e) 462, obsd 463.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:25]([O:27]CC)=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)[C:25]([OH:27])=[O:26])[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C(c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1)C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetate (400 mg, 0.78 mmol) and lithium hydroxide monohydrate (0.330 g, 7.87 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic acid (0.08 g). 1H-NMR (CDCl3, 400 MHz): 12.5 (s, 1H), 7.84 (d, 2H); 7.70 (d, 2H), 7.55 (s, 1H); 7.35 (s, 1H); 4.22 (q, 2H); 3.3.35 (d, 1H); 1.82 (m, 1H); 1.18-1.68 (m, 7H); 1.08 (m, 1H).