Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([NH:14][NH2:15])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:17](N)(=[NH:19])[CH3:18].[OH-].[Na+].O>C1COCC1>[CH3:18][C:17]1[NH:15][N:14]=[C:12]([C:10]2[O:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[N:19]=1
Reactant: NNC(=O)c1ccc(-c2ccccc2)o1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(-c3ccccc3)o2)n[nH]1
Yield: 13.3 %

Procedure:
To a suspension of 5-phenylfuran-2-carbohydrazide (100 mg, 0.5 mmol) and acetamidine hydrochloride (141 mg, 1.49 mmol) in THF (20 mL), NaOH (59 mg, 1.49 mmol) was added. The mixture was refluxed overnight, cooled, then treated with H2O (30 ml) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O (1×10 mL) and brine (1×10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc:Petroleum ether=1:1) to afford 5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazole as a white solid (15 mg, 13%). MS (ES+) C13H11N3O requires: 225. found: 226 [M+H]+.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[CH:20](Br)[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].C(OCC)(=O)C>C(Cl)Cl>[Cl:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[CH:20]([N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:21](=[O:26])[C:22]([F:24])([F:25])[F:23]
Reactant: c1cc2c(s1)CCNC2
Reactant: O=C(C(Br)c1ccccc1Cl)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(C(c1ccccc1Cl)N1CCc2sccc2C1)C(F)(F)F
Temperature: 25 °C
Yield: 39.2 %

Procedure:
10 ml of methylene chloride were added to 0.39 g (2.6 mmole) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and 0.28 g (2.6 mmole) of sodium carbonate, and then a solution of 0.67 g (2.2 mmole) of 2-chloro-α-trifluoroacetylbenzyl bromide in 10 ml of methylene chloride was slowly added to the resulting mixture, whilst stirring at room temperature. The mixture was then stirred at room temperature for 3 hours. At the end of this time, 200 ml of ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, using a 100:4 by volume mixture of toluene and ethyl acetate as the eluent, to give 0.31 g of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:16][NH:17][CH3:18]>C(O)C>[CH3:16][N:17]([CH3:18])[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=CN1CCN(c2ccnc(Cl)n2)CC1
Solvent: CCO
Product: CN(C)c1nccc(N2CCN(C=O)CC2)n1

Procedure:
2-Chloro-4-(4-formylpiperazino)pyrimidine (5.0 g) and dimethylamine (7.8 ml, 33% solution in ethanol) in ethanol (70 ml) were heated under reflux for 8 hours. The solvent was evaporated in vacuo and the residue was partitioned between chloroform and water. The aqueous layer was extracted twice with chloroform and the combined chloroform layers dried (Na2SO4) and evaporated in vacuo. The residue was re-crystallized from ethyl acetate to give 2-dimethylamino-4-(4-formylpiperazino)pyrimidine (2.7 g), m.p. 116° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[O:13][C:12]2[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][C:5]=2[O:4]1.O.Cl[CH2:16][CH:17]=[C:18]([CH3:25])[CH2:19][CH2:20][O:21][CH:22]([CH3:24])[CH3:23]>C1C=CC=CC=1>[CH:22]([O:21][CH2:20][CH2:19][C:18]([CH3:25])=[CH:17][CH2:16][O:9][CH2:8][C:7]1[CH:10]=[CH:11][C:12]2[O:13][CH2:3][O:4][C:5]=2[CH:6]=1)([CH3:24])[CH3:23]
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CC(=CCCl)CCOC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CC(=CCOCc1ccc2c(c1)OCO2)CCOC(C)C

Procedure:
8.0 g (0.2 mol) of sodium hydroxide are added to a solution of 30.4 g (0.2 mol) of 3,4-methylendioxy-benzylalcohol in 300 cc of benzene. The mixture is heated while stirring vigorously and kept at reflux temperature whereby the water condensing in a refrigerator is separated by means of a water separator. After 24 hours 35.3 g (0.2 mol) of 1-chloro-5-isopropoxy-3-methyl-2-pentene are added dropwise during the course of 1 hour and the mixture is stirred under reflux for a further 16 hours.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH3:36])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:24]([O:28][C:29](=[O:30])[NH:31][C@H:32]([C:33](=[O:34])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=1)[CH3:36])([CH3:25])([CH3:26])[CH3:27]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1cccc(Nc2ccccc2N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1Nc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
Triethylamine (0.35 mL, 2.59 mmol) was added to a mixture of 3-(2-aminophenylamino)benzonitrile (177 mg, 0.85 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (190 mg, 1.02 mmol), HOAt (140 mg, 1.02 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (190 mg, 1.02 mmol) in anhydrous DCM (10 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min then slowly warmed to RT. Stirring at RT was continued for 16 h. The reaction mixture was then partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-2% 2M NH3/MeOH in DCM) to afford the title compound as a yellow oil (290 mg, 90%). Material still impure, taken forward in the next step without further purification. LCMS (Method J): RT 3.54 min [M+H]+ 380.8
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH:22]3[CH2:24][CH2:23]3)[CH2:20][CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[CH:22]1([N:21]2[C:14]3[N:15]([C:16](=[O:18])[N:17]=[C:12]([O:10][CH2:9][C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[CH:13]=3)[CH2:19][CH2:20]2)[CH2:24][CH2:23]1
Reactant: O=c1nc(Cl)cc2n1CCN2C1CC1
Reactant: OCc1ccc(F)c(F)c1
Product: O=c1nc(OCc2ccc(F)c(F)c2)cc2n1CCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,4-difluorophenyl)methanol and 7-chloro-1-cyclopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8](O[Si](C(C)(C)C)(C)C)=[O:9])([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:30])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([Cl:30])=[O:9])([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC(=O)[C@H](Cc1ccccc1)O[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 21.0 g (53 mmol) of (1,1-dimethylethyl)-dimethylsilyl (2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)-3-phenylpropanoate (3) and five drops of N,N-dimethylformamide in methylene chloride at 0° C. was added 29.3 mL (59 mmol) of a 2.0M solution of oxalyl chloride in methylene chloride over a 30 min period. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 18 hours. The solvent and excess oxalyl chloride were removed by rotary evaporation resulting in a yellow liquid. Purification by vacuum distillation afforded 12.7 g (80%) of (2S)-2-((1,1-dimethylethyl)-dimethylsilyloxy)-3-phenylpropanoyl chloride (4) as a clear liquid: bp 88°-90° C. (0.2 mm Hg); 1H NMR (CDCl3) δ-0.215 (s, 3 H), -0.0339 (s, 3 H), 0.840 (s, 9 H), 2.94-3.01 (m, 1 H), 3.23-3.29 (m, 1 H), 4.52-4.56 (m, 1 H), 7.25-7.35 (m, 5 H); 13C NMR (CDCl3) δ175.7, 135.9, 129.8, 128.4, 127.1, 81.1, 40.8, 25.5, 18.0, -5.40, -5.76.
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1)(OCC)=O.[CH3:22][NH:23][C:24](=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:27].C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:22][N:23]1[C:24](=[O:32])[C:25]2[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:27]=[C:1]1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:20][CH:21]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: CCOC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in any of Examples 16-22 (100 g, 0.32 M), N-methyl anthranilamide (58.7 g, 0.39 M), xylene (100 ml) and p-toluenesulfonic acid (˜200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155° C., oil bath temperature 170-180° C.) for a period of 45-55 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (62 g, =48%, P=98%).
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[CH2:3][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18](O)(=O)C>Cl>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:2]2[CH2:3][CH2:4][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[O:1]2)=[CH:13][CH:14]=1
Reactant: CC(=O)O
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Agent: Cl
Product: Cc1ccc(C2CCc3ccccc3O2)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
The crude flavanone was dissolved in a mixture of acetic acid (200 ml.) and concentrated hydrochloric acid (45 ml.), warmed to 50° C., and added to wet zinc amalgam (prepared from 60 g. zinc powder and 6 g. mercuric acetate). The mixture was swirled for 15 mins., allowed to stand for 30 mins., then heated on the steam bath for 15 mins. The residual zinc was filtered off and the filtrate diluted with water. The crude product was extracted into toluene and the extract washed with water and saturated sodium bicarbonate solution. Evaporation gave a residue which was chromatographed on alkaline, alumina, eluting with toluene. The first fraction obtained on evaporation of the solvent was recrystallised from ethanol to yield 4'-methylflavan (1.4 g.). m.p. 94° C.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[C:10]=1[Cl:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][C:20]#[N:21].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]#[N:21])=[C:11]([Cl:16])[C:10]=1[Cl:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCl
Reactant: O=C(c1ccccc1)c1ccc(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(C(=O)c2ccccc2)c(Cl)c1Cl

Procedure:
A mixture of 26.70 g. (0.10 mole) of 4-benzoyl-2,3-dichlorophenol, 7.40 g. (0.10 mole) of chloroaceto nitrile, 10.40 g. (0.15 mole) of anhydrous K2CO3 and catalytic amount of KI in 200 ml. of acetone was refluxed overnight. The residue was triturated with ether and the product was collected by filtration and dried to yield 22.80 g. (75%); m.p. 110°-112°. This product was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][C:23]4[S:24][C:25]5[C:26]([N:31]=4)=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][C:16]=3[O:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+].Cl>CC(O)C>[S:24]1[C:25]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:31]=[C:23]1[O:22][C:20]1[CH:19]=[CH:18][C:17]2[C:13]([CH2:12][N:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[CH:14][O:15][C:16]=2[CH:21]=1
Reactant: CCOC(=O)C1CCN(Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(O)C1CCN(Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution 1-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (77 mg, 0.18 mmol) in IPA (1.7 mL) was added 2 M KOH (0.9 mL, 1.8 mmol) and stirred (rt, 2 h). The pH of the reaction mixture was adjusted to pH 8 with 1 M HCl (1.7 mL) and partitioned with DCM (30 mL). The aqueous phase was extracted with DCM (3×30 mL). The organic layers were combined, dried, filtered and concentrated in vacuo to provide the title compound as a yellow solid (28 mg, 39%). MS (ESI): mass calcd. for C21H19N3O4S, 409.1; m/z found, 410.0 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.49 (dd, J=4.8, 1.4, 1H), 8.31 (dd, J=8.0, 1.5, 1H), 7.98 (5, 1H), 7.89 (d, J=8.6, 1H), 7.75-7.70 (m, 1H), 7.44-7.29 (m, 2H), 4.06 (5, 2H), 3.28-3.08 (m, 2H), 2.72-2.47 (m, 2H), 2.34-2.22 (m, 1H), 2.09-1.95 (m, 2H), 1.93-1.72 (m, 2H). The remaining proton was not detected (COOH).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][N:5]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([N:6]1[N:5]=[C:4]([Cl:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2c(Cl)nn1Cc1ccccc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 0.92 g, 22.8 mmol) was added in one portion to a stirred suspension of 4-chloro-2H-phthalazin-1-one (3.74 g, 20.7 mmol) in anhydrous DMF (80 mL). The reaction was stirred for 15 min and then cooled to 10° C. Benzyl bromide (4.25 g, 24.8 mmol) was added drop wise and the reaction mixture was then stirred for 21 h at rt. After that time the reaction was diluted with ethyl acetate (200 mL), washed with water (5×80 mL) then brine (80 mL), dried over MgSO4 and concentrated under reduced pressure. The resulting pale yellow solid was suspended in hexanes (80 mL) and stirred for 3 h. After that time, the precipitate was collected by filtration, washed with hexanes and dried to give 2-benzyl-4-chloro-2H-phthalazin-1-one (5.05 g, 90%) as white solid: 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=7.6 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.97-7.83 (m, 2H), 7.50 (d, J=6.8 Hz, 2H), 7.36-7.7.29 (m, 3H), 5.37 (s, 2H).
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:49]=[CH:48][C:47]([C:50](=[O:55])[C:51]([F:54])([F:53])[F:52])=[CH:46][CH:45]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:44]2[CH:49]=[CH:48][C:47]([C:50](=[O:55])[C:51]([F:53])([F:54])[F:52])=[CH:46][CH:45]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:14][CH2:13]1)=[O:17]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Product: COc1ccc(-c2ccc(C(=O)C(F)(F)F)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (250 mg, 0.40 mmol) is coupled to 4′-bromo-2,2,2-trifluoroacetophenone (120 mg, 0.48 mmol) using Method B to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH:15]([OH:32])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[O:30][CH3:31])[CH2:19][CH2:18]2)[N:8]=1)=[O:6].Cl[C:34]1[N:39]=[C:38]([C:40]([NH2:42])=[O:41])[CH:37]=[CH:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:42][C:40]([C:38]1[CH:37]=[CH:36][N:35]=[C:34]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH:15]([OH:32])[CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=4[O:30][CH3:31])[CH2:19][CH2:18]3)[N:8]=2)=[O:6])[N:39]=1)=[O:41]
Reactant: COc1ccc(Cl)cc1N1CCN(CC(O)CNc2nccc(C(=O)NCCN)n2)CC1
Reactant: NC(=O)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cl)cc1N1CCN(CC(O)CNc2nccc(C(=O)NCCNc3nccc(C(N)=O)n3)n2)CC1

Procedure:
2.32 g (4.96 mmol) of (±)-N-(2-aminoethyl)-2-[[3-[4-(5-chloro-2-methoxyphenyl) piperazin-1-yl]-2-hydroxypropyl]amino]pyrimidine-4-carboxamide, 0.8 g (5.1mmol) of 2-chloropyrimidine-4-carboxamide and 1 g (7.2 mmol) of potassium carbonate are introduced, under an argon atmosphere, into 150 ml of acetonitrile in a 0.5 l round-bottomed flask and the mixture is heated at reflux for 17 h.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide to yield an off-white solid (2.8%). LCMS: m/z=493.22 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.48 (d, 1H, J=8.3 Hz), 8.06 (s, 1H), 7.72 (d, 1H, J=1.8 Hz), 7.52 (d, 1H, J=7.6 Hz), 7.17 (m, 5H), 3.56 (m, 2H), 3.37 (s, 2H), 2.98 (m, 3H), 2.29 (m, 2H), 2.01 (m, 2H), 1.30 (m, 6H), 1.06 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16](SC)[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][C:30]=4[F:32])[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1
Reactant: CSc1nncc(-c2ccc(F)c(-c3ccc(F)cc3C#N)c2)n1
Reactant: OB(O)c1ccc(F)cc1F
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnnc(-c3ccc(F)cc3F)n2)ccc1F
Yield: 69.4 %

Procedure:
4,2′-Difluoro-5′-(3-methylsulfanyl-[1,2,4]triazin-5-yl)biphenyl-2-carbonitrile (0.15 g, 0.44 mmol) was coupled to 2,4-difluorobenzeneboronic acid (0.135 g, 0.97 mmol) by the method of Example 2 to give the title product as a pale yellow solid (124 mg): δH (400 MHz, CDCl3) 6.99-7.11 (2H, m), 7.44-7.48 (2H, m), 7.54-7.59 (2H, m), 8.32-8.39 (3H, m) 9.65 (1H, s); m/z (ES+) 407 (M++H).
Reaction SMILES: [C:1]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(O)C.[OH-].[Na+:26]>O>[C:1]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[CH:13][CH:12]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Na+:26]
Reactant: CC(C(=O)O)c1ccc(NC(=O)c2ccccc2O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)[O-])c1ccc(NC(=O)c2ccccc2O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A solution of 53.05 g (0.186 mol) of 2-(4-(N-salicyloyl)aminophenyl-)propionic acid and 300 ml of ethanol is treated with 7.59 g (0.190 mol) of NaOH dissolved in 22 ml of water. The reaction mixture is stirred for 30 min at 25° C. and for 30 min at 0° C. The resulting pale yellow solid is isolated by filtration to give 52.61 g of sodium 2-(4-(N-salicyloyl)aminophenyl)propionate. Properties. Solubility: 200 mg/ml clear solution, pH=6.85. Analysis C, 60.45; H, 5.45; N, 3.92; Na, 6.43. Melting point 236–238° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[NH:7]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1>O1CCCC1>[O:3]=[C:2]1[C:15]2=[C:16]3[C:11](=[CH:12][C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[CH2:10][CH2:9][CH2:8][N:7]3[C:1]1=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)Cc1ccc2c(c1)CCCN2
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc2c3c(c1)C(=O)C(=O)N3CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the refluxing mixture of oxalyl chloride (0.3 ml) in dry tetrahydrofuran (THF; 15 ml) was added ethyl 1,2,3,4-tetrahydroquinolin-6-ylacetate (500 mg) in dry THF (5 ml) dropwise. The mixture was refluxed for 4 hours after addition was completed, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in carbon disulfide (20 ml) and added aluminum chloride (610 mg) portionwise. The mixture was refluxed for 4 hours and allowed to stand for overnight at room temperature. After decantation of the solvent, ice water (20 ml) was added to the residue. The mixture was extracted with chloroform and dried over anhydrous sodium sulfate. Evaporation of chloroform afforded the title compound. The compound was recrystallized from acetonitrile to give 490 mg (75%) of dark red needles, mp 124°-125° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:25])=[C:8](C(OC(C)(C)C)=O)[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH:26]([N:29]=[C:30]=[O:31])([CH3:28])[CH3:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:25][C:30]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:31])=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(F)c2)c(C(=O)OC(C)(C)C)c1N
Reactant: CC(C)N=C=O
Product: CCOC(=O)c1cn(-c2cccc(F)c2)cc1NC(=O)NC(C)C
Yield: 55 %

Procedure:
Following general method 4, employing 3-amino-1-(3-fluorophenyl)-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester and isopropyl isocyanate, afforded the title compound as an off-white solid (0.150 g, 55%); LCMS (method B): RT=3.77 min, M+H+=334; 1H NMR (CDCl3, 300 MHz): 8.35 (s, 1H), 7.62 (d, J=2.7 Hz, 1H), 7.45 (d, J=2.7 Hz, 1H), 7.38 (dt, J=8.2, 6.2 Hz, 1H), 7.22 (ddd, J=8.2, 2.3, 0.9 Hz, 1H), 7.15 (dt, J=9.9, 2.3 Hz, 1H), 6.98 (tdd, J=8.2, 2.3, 0.9 Hz, 1H), 4.52 (br. s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.94 (br. s, 1H), 1.37 (t, J=7.1 Hz, 3H), 1.22 (d, J=6.5 Hz, 6H).