Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.BrCCCCCC[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=O.[C:35]([O-:38])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:12][CH2:11][CH2:10][CH2:15][CH2:14][CH2:25][C:26]34[CH:33]=[CH:32][CH:31]=[CH:30][CH:27]3[C:28]([NH:24][C:35]4=[O:38])=[O:29])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:10]1([OH:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccc(OCCN2CCOCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C2(CCCCCCOc3ccc(OCCN4CCOCC4)cc3)C=CC=CC12
Product: Oc1ccccc1
Temperature: 95 °C
Reaction time: 17 h

Procedure:
4-(2-Morpholin-4-yl-ethoxy)-phenol (3.39 g, 15.2 mmol), N-(6-bromohexyl)-phthalimide (4.72 g, 15.2 mmol) and K2CO3 (4.20 g, 30.4 mmol) were suspended in DMF (35 mL) under an atmosphere of argon and stirred at 95° C. for 17 h. The solvent was evaporated under reduced pressure and the residue was partitioned between water (150 mL) and CH2Cl2 (150 mL). The aqueous layer was extracted with CH2Cl2 (2×100 mL), the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (EtOAc) to give the title compound together with some starting phenol (≈2:1). The mixture was used for subsequent reactions without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[C:16]([O:18][CH3:19])=[O:17])=[O:11]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(C=O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 5-liter four-necked round-bottomed flask 1.5 l of methylene chloride was cooled to -78° C. Oxalyl chloride (164 g, 1.29 moles) was added slowly, followed by dropwise addition of 202 g (2.59 moles) of dry dimethylsulfoxide in 125 mL of methylene chloride, keeping the temperature below -70° C. After the addition was complete the reaction mixture was stirred at -78° C. for 30 minutes and 273 g (1.29 moles) of previously prepared methyl 3-hydroxymethyl-4-nitrobenzoate dissolved in 250 mL of methylene chloride was added dropwise. The reaction mixture was stirred an additional 30 minutes. Triethylamine (392 g 3.88 moles) in 125 mL of methylene chloride was added dropwise keeping the temperature below -65° C. The reaction mixture was warmed up slowly to room temperature and stirred overnight. The solvent was removed using a rotary evaporator and the resulting solid treated with a mixture of 2 l of ethyl acetate and 1 l of water. The organic phase was separated, filtered through diatomaceous earth, and washed sequentially with dilute aqueous hydrochloric acid (2×250 mL), water (2×250 mL), saturated aqueous sodium bicarbonate (2×250 mL), water (2×200 mL), brine (1×200 mL) and dried over anhydrous magnesium sultate. The solvent was removed using a rotary evaporator. The crude reaction mixture was triturated with hexane and filtered yielding 234.1 g of the expected methyl 3-formyl-4-nitrobenzoate as a yellow solid. This compound was used as such in the next step.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:20])[CH3:19])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[CH2:21](I)[CH3:22]>CN(C=O)C>[CH2:21]([N:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[CH:6][C:5]([CH:3]=[O:4])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)[C:18](=[O:20])[CH3:19])[CH3:22]
Reactant: CC(=O)NC1CCN(c2ccc(C=O)cc2)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)C1CCN(c2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 63.8 %

Procedure:
A 60% suspension in oil of NaH (0.113 g, 2.8 mmol) was added to a 0° C. solution of N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.700 g, 2.8 mmol) in DMF (10 mL) and stirred for 35 minutes. To this mixture was added EtI (0.23 mL, 2.8 mmol) and the reaction was warmed to room temperature for 2 hours, quenched with H2O, and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 0% to 5% MeOH/CH2Cl2, afforded N-ethyl-N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.490 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]([N:15]=[C:16]=S)([CH3:14])([CH3:13])[CH3:12].C1(N=C=NCCN2CCOCC2)CCCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>N1C=CC=CC=1>[C:11]([NH:15][C:16]1[NH:9][C:5]2[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[CH:3][C:4]=2[N:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)(C)N=C=S
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)(C)Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 80 °C
Yield: 26.8 %

Procedure:
4,5-Dichlorophenylene diamine (8.0 g, 45.2 mmol) (Aldrich, Milwaukee, Wis.) was combined with tert-butyl isothiocyanate (6.3 mL, 49.7 mmol) (Aldrich, Milwaukee, Wis.) in anhydrous pyridine (100 mL). The solution was heated at 80° C. for 1 h under nitrogen. 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-ρ-toluene-sulphonate (24.9 g, 58.8 mmol) (Fluka Chemika) was added along with anhydrous pyridine (90 mL). This solution was heated at 90° C. for 2.5 h. The pyridine was removed by rotoevaporation, and the residue was dissolved in ethyl acetate (300 μM) and extracted with water (4×100 mL). The ethyl acetate layer was treated with decolorizing carbon and washed through a silica gel filter pad (4×8 cm, 230-400 mesh) using ethyl acetate. The crude product was purifed on a silica gel column (5×16 cm, 230-400 mesh) using (1:4) ethyl acetate : hexane. Crude fractions were repurified on a second identical column using (1:3) ethyl acetate : hexane. Pure fractions from the two columns were combined to give a tan solid (3.13 g, 12.1 mmol, 27%); m.p. 219-221° C.; MS (API+): m/z (rel. intensity) 258 (100, M+1); 1H NMR (DMSO-d6) d 10.31 (s, 1H, NH), 7.31 (s, 2H, Ar--H), 6.61 (s, 1H, NH), 1.38 (s, 9H, t-butyl).
Reaction SMILES: [I:1]I.[I-].[K+].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[S:22]>O.CO>[IH:1].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[S:22][C:16]1[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:15]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: II
Reactant: S=C1NCCCCN1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Brc1ccc2[nH]cc(SC3=NCCCCN3)c2c1
Product: I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6.35 g of iodine and 11 g of potassium iodide in 50 ml of water is added dropwise to a mixture of 4.9 g of 5-bromoindole in 35 ml methanol and 3.25 g of 4,5,6,7-tetrahydro-1H-1,3-diazepine-2-thione in 50 ml of methanol. The reaction mixture is allowed to be stirred at room temperature for 2 hours. The crystalline precipitate formed is filtered off and recrystallized from a mixture of methanol and ethyl acetate to yield 5-bromo-3-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-ylthio)indole hydriodide which melts at 243°-246° (with decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.C(N(CC)CC)C.[C:23](=[N:26]O)([NH2:25])[CH3:24].CCN=C=NCCCN(C)C.Cl.Cl.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:24][C:23]1[N:26]=[C:10]([CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=2)[O:12][N:25]=1
Reactant: CC(N)=NO
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1noc(COc2ccc([N+](=O)[O-])cc2)n1
Yield: 60.4 %

Procedure:
A mixture of 4-nitrophenoxyacetic acid (12) (2.25 g, 11.4 mmol), acetamide oxime triethylamine hydrochloride salt (11, 5.85 g, 27.62 mmol), EDCl.HCl (4.37 g, 22.79 mmol) and diisopropylethylamine (7.42 g, 10 mL, 57.40 mmol) in anhydrous tetrahydrofuran (THF) (250 mL) was refluxed for 18 hours. The heterogeneous brown reaction mixture was then quenched with water and extracted with EtOAc (3×300 mL). The combined organic layers were washed successively with aqueous sodium bicarbonate (NaHCO3) and brine. The resulting organic phase was dried over anhydrous Na2SO4 and solvent was removed by using rotary evaporator. The resulting residue was purified by silica gel column chromatography to yield 1.62 g (60%) of the desired product, 3-methyl-5-(4-nitrophenoxymethyl)-1,2,4-oxadiazole (13a) as a white solid. 1H NMR (CDCl3, 300 MHz): δ 8.24 (d, 2H, J=8.8 Hz), 7.08 (d, 2H, J=8.8 Hz), 5.36 (s, 2H), 2.44 (s, 3H); LCMS (m/z): 236 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([C:14](=[N:16][OH:17])[CH3:15])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8].[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH3:15])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8]
Reactant: COC(=O)NCc1cc(C(C)=NO)ccc1Cl
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)NCc1cc(C(C)=NOCc2ccc(F)cc2)ccc1Cl
Reaction time: 1 h
Yield: 75.4 %

Procedure:
0.70 g of methyl N-[2-chloro-5-(1-hydroxyiminoethyl)benzyl]carbamate was dissolved in 10 ml of N,N-dimethylformamide, and 0.13 g of 60% sodium hydride was added thereto under cooling with ice, followed by stirring for 1 hour. 0.57 g of 4-fluorobenzyl bromide was dissolved in 2 ml of N,N-dimethylformamide, which was dropwise added to the reaction mixture under cooling with ice. After completion of the dropwise addition, the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was poured into water, extraction with ethyl acetate was carried out, followed by washing with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-200, eluent: hexane/ethyl acetate=5/1) to obtain 0.75 g of methyl N-{2-chloro-5-[1-(4-fluorobenzyloxyimino)ethyl]benzyl}carbamate (m.p. 101-103° C.) as colorless crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:21])([F:20])[C:7]([N:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)=[O:8].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>ClCCCl>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([C:18]1[CH:17]=[CH:16][C:13]2[CH2:14][CH2:15][N:9]([C:7](=[O:8])[C:6]([F:5])([F:20])[F:21])[CH2:10][CH2:11][C:12]=2[CH:19]=1)=[O:28]
Reactant: O=C(N1CCc2ccccc2CC1)C(F)(F)F
Reactant: O=C(Cl)CCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCCCCl)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aluminum chloride (17 g, 130 mmol) was added by portions to a solution of 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (15.0 g) and 5-chlorovaleryl chloride (8.8 ml) in 1,2-dichloroethane (40 ml) under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was poured into ice (500 g), extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-diethyl ether to give a pale yellow solid (15.2 g). Further recrystallization from ethanol-diethylether afforded colorless crystals (13.2 g) as the title compound.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:23][C:17]4([CH2:20][CH:19]([C:21]#N)[CH2:18]4)[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:24]([CH2:27][CH3:28])[N:25]=[CH:26][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:29].[K+].Cl.[OH2:32]>C(O)C>[CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:23][C:17]4([CH2:18][CH:19]([C:21]([OH:32])=[O:29])[CH2:20]4)[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:24]([CH2:27][CH3:28])[N:25]=[CH:26][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O
Reactant: [OH-]
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(C3)CC(C#N)C4)cnc21
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(C3)CC(C(=O)O)C4)cnc21

Procedure:
7-[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-carbonitrile (300 mg, 0.00079 mole) (example 9) was dissolved in ethanol (10 ml). Aqueous potassium hydroxide (178 mg, 0.0031 mole) was added and reaction mixture was refluxed for about 3-4 hrs. Ethanol was evaporated off and reaction mixture was diluted with water, acidifed with dilute hydrochloric acid to pH of about 6. It was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to give crude compound. The title compound was purified by preparative thin layer chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[C:10]([C:15](=[O:17])[NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[N:11][CH:12]=[CH:13][N:14]=1)[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1csc(N)n1
Reactant: CC(C)(C)OC(=O)N(c1cccnc1)c1nccnc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)c2nccnc2N(C(=O)OC(C)(C)C)c2cccnc2)n1
Temperature: 25 °C

Procedure:
3-(tert-Butoxycarbonyl-pyridin-3-yl-amino)-pyrazine-2-carboxylic acid (405 mg, 80%, 1.02 mmol), 2-amino-4-methylthiazole (129 mg, 1.12 mmol), N,N-diisopropylethylamine (0.23 ml, 1.33 mmol) and TBTU (430 mg, 1.33 mmol) were dissolved in 1 ml DMF and stirred over night at room temperature. The reaction mixture was quenched with water and extracted two times with ethyl acetate. The organic extracts were washed with 2N NaOH-solution, water and brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->40:60 gradient). The desired compound was obtained as a yellow foam (195 mg, 46%), MS: m/e=413.3 (M+H+).
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.C[O-:13].[Na+].[N:15](OCC(C)C)=[O:16].Cl>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:15][OH:16])[C:3](=[O:13])[O:2]1
Reactant: CC(C)CON=O
Reactant: O=C1OCCc2ccccc21
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1OCc2ccccc2C1=NO
Temperature: 15 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To a suspension of isochromanone (99% pure, 149.7 g, 1.00 mol) in methanol (280 mL) was added dropwise over a period of 90 min at 14-16° C. sodium methanolate (30% in methanol, 270.0 g, 1.50 mol) and the resulting mixture was stirred for 90 min at 15° C. To this mixture was added dropwise over a period of 6.5 h at 9-13° C. iso-butyl nitrite (94% pure, 137.1 g, 1.25 mol) and the mixture was stirred at 8° C. overnight. The conversion was monitored by HPLC. After completion of the reaction, 4 M hydrochloric acid was added to adjust a pH<1 before the resulting suspension was stirred for overnight at 4° C. The crude product was collected by filtration, washed with cold dist. water (2×500 mL) and dried in vacuo at max. 45° C. Isochroman-3,4-dione-4-oxime was obtained as a colorless solid (145.9 g, 90.4 HPLC-area %, 74% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.CS(C)=O.[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15][CH2:14]1>C(OCC)(=O)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:20][CH2:19][CH:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: NCC1CCOCC1
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Clc1cncc(NCC2CCOCC2)n1
Temperature: 75 °C
Reaction time: 6 h
Yield: 81.6 %

Procedure:
A mixture of 2,6-dichloropyrazine (950 mg, 6.38 mmol), DMSO (14 ml), TEA (1.067 ml, 7.65 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (771 mg, 6.70 mmol) was stirred at 75° C. for 6 hours, and the reaction progress was followed by LCMS. The crude reaction mixture was cooled to ambient temperature, diluted with 300 ml of ethyl acetate, washed with 1M NaOH soln.(1×), water (1×), saturated salt soln. (1×), dried with sodium sulfate, filtered, and concentrated to constant mass, giving 1185 mg of titled compound as free base, used without further purification. LCMS (m/z): 228.0 (MH+), retention time=0.73 min.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH2:38][NH2:39])[CH:35]=[CH:36][CH:37]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:39][CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=2)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)NCc2cccc(C(F)(F)F)c2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 1-[3-(trifluoromethyl)phenyl]methanamine (45.58 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol) and DMAP (27 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 75 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.06 (s, 9H), 3.56 (s, 2H), 4.61 (s, 2H), 7.16 (t, J=75.3 Hz, 1H), 7.18-7.25 (m, 1H), 7.36-7.51 (m, 2H), 7.57-7.65 (m, 3H), 7.71-7.77 (m, 2H), 7.83 (d, J=15.6 Hz, 1H), 8.02-8.08 (m, 1H), 8.82-8.88 (m, 1H); APCI-MS (m/z) 580.29 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:38])([CH3:37])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:37][C:3]([CH3:38])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:9][CH:10]=1)[CH:2]=[O:1]
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of 4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.01 g) in methylene chloride (10 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.26 g), and the mixture was stirred for 1 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.79 g, 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:5]=[CH:4][N:3]=1.[NH3:13]>CO>[N:8]1([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:13])[CH:7]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Clc1cc(-n2ccnc2)ncn1
Reactant: N
Solvent: CO
Product: Nc1cc(-n2ccnc2)ncn1
Temperature: 65 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
4-Chloro-6-(1H-imidazol-1-yl)pyrimidine (4.0 g, 22.1 mmol) was split into two equal portions and separately placed into two sealed tubes with a solution of 7 N ammonia in methanol (40 mL). The tubes were sealed and heated at 65° C. for 20 h, then allowed to stand at room temperature for 3 days. The reactions were combined, concentrated and purified by flash chromatography on a 240 g silica gel cartridge with 40 to 100% EtOAc in hexane, then 0 to 50% MeOH in EtOAc to yield 6-(1H-imidazol-1-yl)pyrimidin-4-amine (1.43 g, 40%). LCMS: RT=0.39 min, MH+=162.1.
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:10])=O)C.C(Cl)(Cl)[Cl:33].CO>Cl.C(O)(=O)C>[ClH:33].[NH2:7][C@@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])=[O:10]
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
A solution of the phenylmethyl ester product from part (a) (13.65 g., 32 mmole) in 1.5N hydrogen chloride gas in acetic acid solution (90 ml.) is stirred for 90 minutes at room temperature, and then the solvent is evaporated in vacuo. The residue is triturated in ether and the resulting white precipitate is collected to give 11.45 g. of crude product as a powdery white solid; m.p. 169°-175°. TLC (silica gel; chloroform:methanol:acetic acid, 6:1:1) Rf =0.52. One recrystallization from acetonitrile gives an analytical sample of 3-[[(S)-2-amino-1-oxo-3-phenylpropyl]amino]propanoic acid, phenylmethyl ester, hydrochloride as white needles; m.p. 170.5°-175°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH2:42]([N:46]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:47][CH2:48][NH2:49])[CH2:43][CH2:44][CH3:45]>C(Cl)(Cl)Cl.O>[CH2:42]([N:46]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:47][CH2:48][NH:49][C:34]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[O:40])[CH2:43][CH2:44][CH3:45]
Reactant: CCCCN(CCN)CCCC
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCN(CCCC)CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (151 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-dibutyl-1,2-ethanediamine (88 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (110 mg, yield 65%).