Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[NH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:18][CH2:19][CH2:20]Br>C(O)C.Cl>[NH:5]1[CH2:20][CH2:19][CH2:18][C:6]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrCCCBr
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCCN1
Temperature: 25 °C

Procedure:
To a solution of sodium ethoxide (5.14 g) in absolute ethanol (75 mL) at 0° C. under a nitrogen atmosphere, a solution of diethyl aminomalonate (hydrochloride salt, 8 g) in absolute ethanol (75 mL) was slowly added. A yellow suspension was obtained at the end of the addition. 1,3-dibromo propane (7.7 mL) was then added and the resulting mixture was stirred at reflux temperature for 5 hours. The mixture was allowed to cool down to rt, then ethanol was removed in vacuo to give a yellow solid. This was dissolved in HCl (1M solution, 20 mL) and then washed with ethyl ether (2×50 mL). Phases were separated and the aqueous phase was brought to pH=9 by adding NaOH (1M solution). It was then extracted with ethyl ether (3×50 mL) and washed with brine (20 mL). The organic phase was dried and concentrated in vacuo to give the desired compound (2.35 g) as yellow oil.
Reaction SMILES: OS(O)(=O)=O.O[C:7]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[C:8]=1[CH2:14][C:15](=[O:17])[CH3:16].[CH2:18](Cl)Cl.O1C=CCC1=O>C1COCC1>[CH3:16][C:15]1[O:17][C:7]2[CH2:12][CH2:11][C:10](=[CH2:18])[C:9](=[O:13])[C:8]=2[CH:14]=1
Reactant: CC(=O)CC1=C(O)CCCC1=O
Reactant: ClCCl
Agent: O=C1CC=CO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C=C1CCc2oc(C)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of conc. H2SO4 (300 ml) cooled in an ice-bath was added a solution of 3-hydroxy-2-(2-oxopropyl)-2-cyclohexen-1-one (190 g in 300 ml CH2Cl2). Upon completion of addition, the mixture was stirred at ambient temperature for about 1 hour. The mixture was then slowly poured into 3 liters ice water, and then about 1 liter of CH2Cl2 was added. The layers are separated and the aqueous layer extracted thrice with CH2Cl2 and the combined CH2Cl2 layers again extracted thrice with water. The CH2Cl2 layer was washed thrice with dilute aqueous NaHCo3, then once with water and dried (MgSO4). Concentration in vacuo afforded an orange oil. Step B. To a solution of the furanone of Step A (164.5 g, 1.10 mole) in about 400 ml THF was added, in four separate portions, N-methylanilinium trifluoroacetate (TAMA) (243 g) and trioxymethylene (99 g) over 3-1/2 hours, and the mixture refluxed for 20 hours. The mixture was cooled and partitioned between Et2O and water, the layers separated and the aqueous layer was extracted twice with Et2O. The combined Et2O layers were washed exhaustively with water, with NaHCO3 and then with brine, dried over MgSO4 and conc. in vacuo to yield an amber oil. This oil was flash chromatographed on silica gel using CH2Cl2 as solvent in several runs of 10-20 g per run. Fractions containing the fast moving material were combined, concentrated in vacuo to obtain the desired product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][N+:10]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>CO.O1CCCC1.[Zn]>[NH2:10][CH2:9][CH:8]([C:7]1[C:2]([CH3:1])=[C:3]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:4]=[CH:5][CH:6]=1)[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:20]=2)[NH:15][CH:14]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2ccc(N3CCOCC3)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2ccc(N3CCOCC3)cc12
Yield: 85.9 %

Procedure:
A solution of benzyl 2-methyl-3-(1-(5-morpholino-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate (0.8011 g, 1.557 mmol), ammonium chloride (1.249 g, 23.35 mmol) and zinc (1.527 g, 23.35 mmol) in methanol (32.4 mL) and tetrahydrofuran (32.4 mL) was stirred for 2 hr. The reaction was filtered through a pad of CELITE® and rinsed with methanol. The filtrate was concentrated in vacuo, dissolved in EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (6×). The aqueous layer was basified by NaHCO3 (s) and extracted with EtOAc (3×). The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give the desired product (0.7121 g, 1.337 mmol, 86% yield) as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cn(-c2cccc([N+](=O)[O-])c2)cn1
Temperature: 150 °C
Yield: 66.6 %

Procedure:
1H-Imidazole-4-carboxylic acid methyl ester (1 g, 7.9 mmol) was dissolved in MeOH and NaH (348 mg, 8.7 mmol) was added slowly. When the gas evolution had ceased 1-fluoro-3-nitro benzene (926 uL, 8.7 mmol) was added, and the mixture was heated to 150° C. under N2 for 16 h. After cooling to room temperature the precipitation was isolated by suction filtration, washed with MeOH, and dried under vacuum to afford 1.3 g (67%) of 1. HRMS (ESI+): m/z=247.2091 [M+H]
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[CH3:23][NH:24][O:25][CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:24]([O:25][CH3:26])[CH3:23])=[O:10])[CH:5]=[N:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cncc(Cl)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
To a 100 ml round bottom flask, 6-chloropyrazine-2-carboxylic acid (1 g, 6.31 mmol) was suspended in dry CH2Cl2 (30 ml). Oxalyl chloride (3.78 ml, 7.57 mmol) was added along with a few drop of DMF, the mixture was stirred at room temperature for 12 hrs, N,O-Dimethylhydroxylamine hydrochloride (0.800 g, 8.20 mmol) was added, the resulting mixture was cooled down to 5° C., TEA (2.64 ml, 18.92 mmol) was added via a dropping funnel, the reaction mixture was stirred at room temperature for 30 minutes, filtered and the filter cake was washed with EtOAc, the combined filtrate was washed with saturated sodium bicarbonate and brine, concentrated to an oil, purified on silica gel with Hexanes/EtOAc solvents to give product (1.06 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]1[C:12]2=[CH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7]1.CN([CH:30]=[O:31])C>>[CH:30]([C:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[N:11]2[CH2:10][CH2:9][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7][CH2:6][C:12]=12)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCc2cc3ccccc3n2CC1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2c(C=O)c3ccccc3n2CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of DMF (10 mL) cooled to 0° C. is treated with phosphorus oxychloride (0.30 mL, 3.3 mmol) and stirred for 10 min. This clear colorless solution of the cloroiminium salt is slowly treated with a solution of tert-butyl 1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate in DMF (9 mL) followed by warming to rt. After 18 hr, the reaction is quenched with 5N sodium hydroxide (40 mL), stirred 5 min, and extracted twice with dichloromethane (40 mL). The combined organics are washed twice with water (25 mL), once with brine (25 mL), dried over MgSO4, filtered, and concentrated to give 942 mg of a crude yellow solid. This material is purified by LC (biotage 40 g column) eluting with 35% ethyl acetate/heptane to afford 677 mg of tert-butyl 11-formyl-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate as a pale yellow solid, mp 167-168° C. IR (drift) 1684, 1654, 1469, 1424, 1396, 1370, 1350, 1304, 1248, 1197, 1170, 1121, 762, 757, 752 cm−1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.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.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][N:14]=4)[CH2:21][CH2:22]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(N3CCN(c4cnccn4)CC3)ccc12
Yield: 16.7 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (145 mg, 0.559 mmol), 1-(2-pyrazinyl)piperazine (104 mg, 0.633 mmol), Pd2(dba)3 (43 mg, 0.047 mmol), rac-BINAP (116 mg, 0.186 mmol) and NaOtBu (167 mg, 1.738 mmol) in DMA (5 mL) was heated at 85° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Preparatory HPLC afforded 4-chloro-6-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-2H-phthalazin-1-one (32 mg) as a yellow solid, 1H (400 MHz, d6-DMSO) δ: 3.62 (m, 4H), 3.78 (m, 4H), 7.12 (d, 1H), 7.60 (dd, 1H), 7.87 (d, 1H), 8.07 (d, 1H), 8.11 (m, 1H), 8.37 (s, 1H), 12.51 (s, 1H) ppm. m/z (M+1) 342.98.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10](O)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
Indole-6-carboxylic acid (1.0 g, 6.2 mmol) was dissolved into anhydrous THF (20 mL) under argon. Lithium aluminum hydride (494 mg, 13 mmol) was added portionwise and the mixture was stirred overnight. The mixture was cooled to 0° C. and ethyl acetate (10 mL) was carefully added, followed by methanol (5 mL) and water (5 mL). The mixture was stirred for 30 min. and filtered through celite. The solution was concentrated and dissolved into ethyl acetate (200 mL) and washed with brine (2×20 mL), dried over MgSO4 and concentrated to afford the title compound as a brown oil (880 mg, 96%). 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.23 (d, J=1.1 Hz, 1H), 7.13-7.05 (m, 2H), 6.51-6.49 (m, 1H), 4.70 (s, 2H).
Reaction SMILES: [Na].[F:2][C:3]([F:23])([S:19]([OH:22])(=[O:21])=[O:20])[C:4]([O:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([OH:18])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[Cl-].[C:25]1([S+:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[OH:18][C:10]12[CH2:16][CH:14]3[CH2:13][CH:12]([CH2:17][C:8]([CH2:7][O:6][C:4]([C:3]([F:23])([F:2])[S:19]([O-:22])(=[O:20])=[O:21])=[O:5])([CH2:15]3)[CH2:9]1)[CH2:11]2.[C:38]1([S+:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(OCC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)S(=O)(=O)O
Agent: [Cl-]
Agent: [Na]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(OCC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)S(=O)(=O)[O-]
Reaction time: 15 h

Procedure:
To a obtained solution of the sodium salt of 3-hydroxy-1-adamantylmethyl difluorosulfoacetate, 17.2 parts of chloroform, and 2.9 parts of a 14.8 mass % aqueous triphenyl sulfonium chloride solution were added, and the mixture was stirred for 15 hours, and then an organic layer was separated from the resultant solution, and an aqueous layer was subjected to extraction with 6.5 parts of chloroform. Organic layers were combined and washed with an ion-exchanged water, and the obtained organic layer was concentrated. To the concentrated solution, 5.0 parts of tert-butyl methyl ether was added, and the resultant mixture was stirred and filtered to obtain, as a white solid, 0.2 parts of triphenylsulfonium 1-((3-hydroxy-1-adamantyl)methoxycarbonyl)difluoromethane sulfonate (B1-2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1)[CH3:11].N1CCC[C@H]1C(O)=O>C(O)C>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][CH:16]1[CH2:17][C:18]2=[N:1][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=[C:19]2[CH2:20][CH2:21]1)[CH3:11]
Reactant: Nc1ncccc1C=O
Reactant: CCOC(=O)CCC1CCCC(=O)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CCC1CCc2cc3cccnc3nc2C1
Temperature: 25 °C

Procedure:
A solution of 2-amino-pyridine-3-carbaldehyde (1-3)(0.244 g, 2.0 mmol) and 3-(3-oxo-cyclohexyl)-propionic acid ethyl ester (14-1) (0.245 g, 2.00 mmol; for prep., see J. R. Wiseman et.al., J. Am. Chem. Soc., 1970, 92, 956-962) in ethanol (10 mL) was treated with L-proline (0.230 g, 2.00 mmol) and heated at reflux for 12 h. The solution was cooled to ambient temperature and concentrated. The residue was purified by flash chromatography (10% acetone in CH2Cl2) to give 14-2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19]Cl>>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: ClSc1cc(Cl)c(Cl)cc1Cl
Product: COC(=O)c1c[nH]c(Sc2cc(Cl)c(Cl)cc2Cl)c1
Yield: 32.7 %

Procedure:
By the procedure of Example 23, methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was reacted with 2,4,5-trichlorobenzenesulfenyl chloride (4.95 g., 20 mmoles) to yield crude product (6.0 g.) as a foam. The crude was chromatographed on 300 g. of silica gel with 200 ml. fractions of the ethyl acetate-1/hexane-7 eluant collected. Fractions 6 to 12 were combined and evaporated to yield methyl 5-(2,4,5-trichlorophenylthio)pyrrole-3-carboxylate (2.2 g., m.p. 165°-175° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:14]=[CH:15][C:16]4[C:17]([CH:29]=3)=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[O:19][N:20]=4)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1>C1COCC1.[Pd]>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:18]([C:17]2[CH:29]=[C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[O:12][CH2:11][CH2:10][O:9]3)[CH:14]=[CH:15][C:16]=2[NH2:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(-c2onc3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2N)c1
Yield: 103.5 %

Procedure:
Interm. (5-b) (30 g) in THF (250 ml) was hydrogenated with palladium on carbon (3 g) as a catalyst at room temperature for 12 hours under a 2.6 105 Pa pressure in a Parr apparatus. After uptake of H2(1 equivalent), the catalyst was filtered through celite and the filtrate was evaporated till dryness. The product was used without further purification, yielding 31.2 g (100%) of (3-methoxyphenyl)[2-amino-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]phenyl]methanone (interm. 5-c).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)[CH3:14]>>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cncc(Br)c1
Product: CCOC(=O)c1cncc(-c2ccc(CC)cc2)c1

Procedure:
29 g (126 mmol) of ethyl 5-bromonicotinate and 23 g (152 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted according to the General Method 1A. Yield: 32 g (82% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.CC[O-].[Na+].[Na].[F:16][C:17]([F:24])([CH3:23])[C:18](OCC)=O>C(O)C>[F:16][C:17]([C:23]1[N:1]=[C:2]2[N:3]=[C:4]([CH3:10])[CH:5]=[C:6]([OH:9])[N:7]2[N:8]=1)([F:24])[CH3:18]
Reactant: Cc1cc(=O)n(N)c(N)n1
Reactant: CCOC(=O)C(C)(F)F
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1cc(O)n2nc(C(C)(F)F)nc2n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Intermediate 1 was added to a stirring solution of NaOEt prepared from sodium (FLUKA, 3.28 g, 143 mmol) and ethanol (150 ml) and the mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled down to room temperature and ethyl 2,2-difluoropropanoate (FLUOROCHEM, 11.83 g, 86 mmol) was added. The mixture was stirred at room temperature for 30 min before being heated to 80° C. for 1.5 h. The reaction mixture was concentrated to dryness and water (200 mL) was added. The reaction mixture pH was adjusted to 4 by addition of 2N HCl solution while a white solid precipitated. The solid was filtered, washed with water and dried under vacuum to afford Intermediate 2. The mother liquors were extracted with DCM (5×35 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give more Intermediate 2 as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:47][C:48]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:49]=1[NH2:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:50][C:49]4[CH:51]=[C:52]([CH3:55])[CH:53]=[CH:54][C:48]=4[Cl:47])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1ccc(Cl)c(N)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cc(C)ccc2Cl)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-chloro-5-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 788 [(M+H)+].
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:21]=1[C:22](Cl)=[O:23].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:21]=1[C:22]([N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:23]
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(=O)n2ccnc2-c2ccccc2)c(C)c1
Yield: 78.3 %

Procedure:
144.2 g (1.00 mole) of 2-phenylimidazole are dissolved at 90° C. in 900 ml of toluene. 104.2 g (1.03 moles) of triethylamine are added to this solution, and a solution of 182.6 g (1.00 mole) of 2,4,6-trimethylbenzoyl chloride in 300 ml of toluene is added dropwise at 90° C. in the course of 2 hours, triethylamine hydrochloride being precipitated. The latter is filtered off with suction at room temperature and extracted by washing with toluene. Concentrating the filtrate gives 296 g of crude product, recrystallisation of which from 580 ml of acetonitrile gives a total of 227.3 g of 1-(2,4,6-trimethylbenzoyl)-2-phenylimidazole (78.3% of theory).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:23]1[C:22]2[C:26](=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[NH:25][C:24]1=[O:28])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1ccc2c(c1)NC(=O)C2=Cc1cc(C(C)C)c(OC)c(C(C)C)c1

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-methoxy-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-6-methoxy-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17]=2[Cl:25])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7]>[OH-].[Na+]>[Cl:25][C:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[S:20][C:16]=1[CH2:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:26])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(OCc2sc3ccccc3c2Cl)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(OCc2sc3ccccc3c2Cl)c1C(=O)O
Yield: 91.9 %

Procedure:
A solution of 3-(3-chloro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid dimethyl ester (1.9 g, 4.8 mmol) in reagent alcohol (120 mL) and 3 N sodium hydroxide (60 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (100 mL) and washed with methylene chloride (3×100 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers was washed with water (2×100 mL), dried and concentrated to give 3-(3-chloro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid as an off-white solid (1.6 g, 92% yield). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>O1CCCC1.O>[Cl:1][C:2]1[N:11]=[C:10]([N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CNc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2nc(Cl)nc(N(C)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 192 h
Yield: 62.4 %

Procedure:
A mixture of 2,4-dichloro-6-methoxyquinazoline, (38.3 g, 0.19M assuming 100% yield from previous step), N-methylaniline (19.26 g, 0.18M), sodium acetate (16.4 g, 0.2M) in tetrahydrofuran (2 liters) and water (1 liter) was stirred at room temperature for 8 days. Reaction was then concentrated to low volume (about 500 ml) and an oil separated out which solidified. The solid was filtered off and extracted with dichloromethane. Silica gel column chromatography followed by evaporation to dryness gave a residue which was washed with 40-60° petroleum ether (to remove trace impurity) to yield title compound (31.25 g) m.p. 133°-134°.