Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:38])[C@H:22]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[NH:23]C(OC(C)(C)C)=O)[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21](=[O:38])[C@H:22]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[NH2:23])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
N-tert-Butoxycarbonyl-3-(3-pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (84) (2.08 g; 4.03 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 4 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.59 g) as an oil. ESMS: MH+ 416.2
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][C:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH2:13][C@@H:12]1[C:30](=[O:42])[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH3:41])=[CH:35][CH:34]=1)=O)C1C=CC=CC=1>CO.[C].[Pd]>[C:26]([O:25][C:23]([C:19]1[S:18][C:17]([N:14]2[CH2:15][CH2:16][NH:11][C@@H:12]([C:30](=[O:42])[NH:31][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][CH3:41])=[CH:37][CH:38]=3)[CH2:13]2)=[N:21][C:20]=1[CH3:22])=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCCc1ccc(CNC(=O)[C@H]2CN(c3nc(C)c(C(=O)OC(C)(C)C)s3)CCN2C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc(CNC(=O)[C@H]2CN(c3nc(C)c(C(=O)OC(C)(C)C)s3)CCN2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
A mixture of the compound (1.00 g) obtained in Step 5 and 7.5% palladium carbon (1.0 g) in methanol (15 ml) was stirred under a hydrogen atmosphere (5 atm) at room temperature for 4 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. 10% Palladium carbon (500 mg) and methanol (15 ml) were added again to the residue, and the mixture was stirred under a hydrogen atmosphere (5 atm) at room temperature for 6 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (3%-5% methanol/chloroform) to give the title compound (688 mg).
Reaction SMILES: [O-]CC.[Mg+2].[O-]CC.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:19][C:20]1[C:21]([Cl:31])=[C:22]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[C:23](Cl)=[O:24].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Br:19][C:20]1[C:21]([Cl:31])=[C:22]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[C:23]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])=[O:24]
Reactant: O=C(Cl)c1cc(F)c(F)c(Br)c1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
To the magnesium ethoxide (3.93 g) suspension was added a solution of diethyl malonate (4.65 g) in anhydrous toluene (30 ml) dropwise during 25 minutes at 20° to 25° C. The mixture was stirred at 50° to 60° C. for 3 hours, and then cooled in an acetone-dry ice bath. A solution of 3-bromo-2-chloro-4,5-difluorobenzoyl chloride (7.65 g) in anhydrous toluene (15 ml) was added dropwise to the resulting solution at -16° to 0° C. during 25 minutes. The mixture was stirred for 2.5 hours below 0° C., then further stirred at room temperature for 40 minutes, and then mixed with ice water (15 ml) containing concentrated sulfuric acid (1 ml). The resulting organic layer was collected and the water layer was extracted with toluene. The combined organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated to give the title compound (11.44 g) as pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][C:8]([Cl:13])([Cl:12])[C:9](Cl)=[O:10].C(N(CC)CC)C>C(Cl)Cl>[Cl:7][C:8]([Cl:13])([Cl:12])[C:9]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Cn1ccnc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ccnc1C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.3 %

Procedure:
To the solution of 1-methyl-1H-imidazole (2 g, 24.4 mmol) in 16 mL of DCM was added dropwise 4.4 g of trichloroacetyl chloride and the resulting mixture was stirred at 25° C. for 6 h. The mixture was cooled to 0° C. and 3.4 mL of triethylamine was added dropwise with stirring. The solvent was evaporated and the residue was purified by flash column chromatography (petroleum ether/DCM=4/1) to give 2,2,2-trichloro-1-(1-methyl-1H-imidazol-2-yl)ethanone (3.1 g, yield 56%). 1H NMR (300 MHz, CDCl3) δ 7.35 (s, 1H), 7.16 (s, 1H), 4.06 (s, 3H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3C4C(=CC=3S[C:5]=2[CH:4]=[CH:3][CH:2]=1)C=CC(=O)C=4.S1C(B(O)O)=CC2C=CC=CC1=2.I[C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34]>>[CH3:8][C:9]1[CH:5]=[CH:4][C:3]2[C:33](=[O:34])[C:32]3[C:31]([C:2]=2[CH:1]=1)=[CH:39][CH:38]=[CH:37][CH:36]=3
Reactant: O=C1C=CC2=Cc3sc4ccccc4c3C2=C1
Reactant: O=C(O)c1ccccc1I
Agent: OB(O)c1cc2ccccc2s1
Product: Cc1ccc2c(c1)-c1ccccc1C2=O

Procedure:
Benzo[b]indeno[1,2-d]thiophen-9-one: from 2-benzo[b]thiopheneboronic acid and 2-iodobenzoic acid following method A.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].CI.[C:14](=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:14][NH:11][C:6]1[C:7]([NH2:10])=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A 1 L round bottom flask was charged with 4-nitrobenzene-1,2-diamine (40 g, 0.26 mol), methyl iodide (13 ml, 0.21 mol) and DMF (300 ml), followed by the addition of saturated sodium carbonate (60 ml) over 2-3 minutes under rapid stirring. After stirring overnight at room temperature the reaction mixture was filtered and then concentrated in vacuo to a dark red oil. The residue was purified by flash column chromatography (15 to 30% ethyl acetate/petrol) to afford the title compound (27 g, 61% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].C(O)(=O)C.[F:23][C:24]([F:29])([F:28])[CH2:25][CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O.[OH-].[Na+]>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH2:18][CH2:17][N:16]([CH2:26][CH2:25][C:24]([F:29])([F:28])[F:23])[CH2:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=CCC(F)(F)F
Reactant: COc1cc(C2=CCNCC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C2=CCN(CCC(F)(F)F)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6.6 g (24.38 mmol) of the hydrochloride prepared in step 16.1 in 110 mL of dichloromethane is cooled in an ice-water bath. 14 mL (243.8 mmol) of glacial acetic acid, 8.19 g (73.14 mmol) of 3,3,3-trifluoropropionaldehyde and 12.9 g (60.95 mmol) of sodium triacetoxyborohydride are successively added portionwise. The mixture is stirred at room temperature for 3 hours and then diluted with dichloromethane, water and aqueous 1N NaOH solution. The aqueous phase is extracted with dichloromethane and the organic phases are combined, dried over Na2SO4, filtered and concentrated under vacuum. 8.4 g of a yellow oil very predominantly containing the expected product are recovered, and are used as obtained in the following step. Quantitative crude yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11]>[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Zn]
Product: Clc1cc(Cl)c(Cl)nc1Cl

Procedure:
at 95.07 percent pentachloropyridine conversion with 98.13 percent of the pentachloropyridine added accounted for in the final products. Of the metallic zinc used in the reaction, 95.61 percent reacts with chloropyridines with 91.72 percent resulting in the formation of 2,3,5,6-tetrachloropyridine. Of the metallic zinc added, 100 percent oxidizes during the reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:28])C(=O)C1.C(Cl)Cl>C(Cl)(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][Br:28])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncc(Br)cn1
Temperature: 70 °C
Reaction time: 30 h
Yield: 25.5 %

Procedure:
To an ice-cold solution of 5-bromo-2-methylpyrimidine (3.5 g, 20.23 mmol) in CCl4 (20 mL) was added AIBN (0.14 g, 2.02 mmol) followed by portion wise addition of NBS (3.6 g, 20.23 mmol) and the mixture stirred at 70° C. for 30 h. After completion of reaction (by TLC), DCM (150 mL) was added and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 2% EtOAc:hexane to obtain the desired product (1.30 g, 25% yield). 1H NMR (CDCl3): δ 4.68 (s, 2H) and 9.03 (s, 2H).
Reaction SMILES: [CH:1]([N:14]1[C:18]([C:19]([O:21]C)=[O:20])=[CH:17][N:16]=[C:15]1[SH:23])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1CCCC1>[NH:16]1[CH2:15][CH2:19][CH2:18][CH2:17]1.[CH:1]([N:14]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=[C:15]1[SH:23])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cnc(S)n1C(c1ccccc1)c1ccccc1
Solvent: C1CCNC1
Product: O=C(O)c1cnc(S)n1C(c1ccccc1)c1ccccc1

Procedure:
In a nitrogen atmosphere 3.2 g (0.01 mol) of 1-benzhydryl-2-mercapto-5-methoxycarbonyl-imidazole (Example 1a) and 60 cc of pyrrolidine were refluxed for 3 days. Excess pyrrolidine was then removed in vacuo and the 1-benzhydryl-2-mercapto-5-imidazole-carboxylic acid pyrrolidine obtained was recrystallized from methanol (m.p. 263° C.). The yield was 3.3 g (91% of the theory).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[C:6]([CH3:12])=[C:5]([N+:13]([O-])=O)[CH:4]=1)#[N:2].[H][H]>CO.[Pd]>[NH2:13][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[C:6]=1[CH3:12]
Reactant: Cc1c([N+](=O)[O-])cc(C#N)c2nc[nH]c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)cc(C#N)c2nc[nH]c12

Procedure:
A mixture of 7-cyano-4-methyl-5-nitrobenzimidazole (0.91 g, 4.5 mmol) and 10% palladium-on-carbon (100 mg) in methanol (200 mL) is treated with an atmosphere of hydrogen (1 atm, balloon) for 14 hours. The resulting mixture is filtered through Celite and rotary evaporated. The residue is purified by flash chromatography (silica gel, 95:5 ethyl acetate:methanol) to afford 5-amino-7-cyano-4-methylbenzimidazole.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([F:32])[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:26]1[CH:27]=[C:28]([C:7]2[C:8]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CON(C)C(=O)c1ccc2cccnc2c1OS(=O)(=O)C(F)(F)F
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: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CON(C)C(=O)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Temperature: 100 °C
Yield: 81.7 %

Procedure:
To a mixture of 7- {[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.15 g, 0.41 mmol) and (3,5-difluorophenyl)boronic acid (0.078 g, 0.49 mmol) in 1,4-dioxane (2 mL) was added 1 N solution of sodium carbonate in water (0.62 mL, 34 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.020 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and concentrated. The residue was purified on silica gel (eluting with 0-80% EtOAc in Hexane) to give the desired product (110 mg, 81.4%). LCMS calculated for C18H15F2N2O2(M+H)+: m/z=329.1; found: 329.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[I:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.Cl>C(C(C)=O)C(C)C>[I:9][C:10]1[CH:11]=[C:12]([S:16]([NH:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: O=S(=O)(Cl)c1cccc(I)c1
Reactant: Cc1cccnc1N
Agent: Cl
Solvent: CC(=O)CC(C)C
Product: Cc1cccnc1NS(=O)(=O)c1cccc(I)c1
Reaction time: 8 h

Procedure:
32.4 g 3-methyl-2-pyridinamine (32.4 g, 0.3 mol) was dissolved in isobutylmethylketone (200 ml) and 3-iodo-benzenesulfonyl chloride (30.2 g, 0.1 mol) was added with stirring. The solution was kept at 40° C. for 8 h and then added to dilute hydrochloric acid. The precipitate was filtered off and the organic phase was separated and evaporated. The residue was combined with the first solid material and recrystallized from ethanol. The crystals were dissolved in 1M sodium hydroxide (about 200? ml) and extracted with isobutylmethylketone (3×100 ml). The aqueous phase was partially evaporated to remove isobutylmethylketone residues. Ethanol (100? ml) was added and the solution acidified with acetic acid. The precipitate was filtered off, washed with water and dried. Yield 23 g, 61%.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:29]=[CH:28][C:9]2[S:10][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][NH:24][C:23]4=[O:27])[N:14]=3)=[CH:12][C:8]=2[CH:7]=1.C(N(CC)CC)C.O>ClCCl>[O:27]=[C:23]1[NH:24][CH2:25][CH2:26][N:22]1[CH2:21][CH2:20][NH:19][C:15]1[N:14]=[C:13]([C:11]2[S:10][C:9]3[CH:28]=[CH:29][C:6]([NH:5][C:1](=[O:3])[CH3:2])=[CH:7][C:8]=3[CH:12]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2sc(-c3ccnc(NCCN4CCNC4=O)n3)cc2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc2sc(-c3ccnc(NCCN4CCNC4=O)n3)cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Acetyl chloride (61 mg, 0.78 mmol) was added to a mixture of 1-(2-(4-(5-aminobenzo[b]-thiophen-2-yl)pyrimidin-2-ylamino)ethyl)imidazolidin-2-one (230 mg, 0.65 mmol) and triethylamine (131 mg, 1.30 mmol) in dichloromethane (10 mL) at 0° C. and stirred at rt for 6 h. Water (50 mL) was added and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and filtered. After removing the solvent in vacuo the product was purified by column chromatography eluting with methanol/dichloromethane (1:20) to give the title compound as a slightly yellow solid (39 mg, 15%). MS (M+H)+ 397.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@H:13]3[NH:17][CH2:16][Si:15]([CH3:19])([CH3:18])[CH2:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26]([N:17]1[C@H:13]([C:10]2[NH:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[N:9]=2)[CH2:14][Si:15]([CH3:19])([CH3:18])[CH2:16]1)=[O:27])[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[Si]1(C)CN[C@H](c2nc(-c3ccc(Br)cc3)c[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[Si](C)(C)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Yield: 66.1 %

Procedure:
A mixture of (R)-5-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine (350 mg, 0.92 mmol, Preparation 9), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (170 mg, 0.97 mmol), HATU (400 mg, 1.05 mmol), and DIPEA (700 mg, 5.4 mmol), in DCM (50 mL) was stirred at RT overnight. The reaction mixture was washed with water and brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (20% EtOAc in petroleum ether) to give the title intermediate (300 mg, 66% yield) as a straw yellow solid. (m/z): [M+H]+ calcd for C21H29BrN4O3Si, 493.12 found 493.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:31])[C:25]=1[C:26]1([OH:30])[CH2:29][O:28][CH2:27]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([F:31])[C:25]=2[C:26]2([OH:30])[CH2:29][O:28][CH2:27]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: OC1(c2c(F)cncc2Br)COC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cncc(F)c2C2(O)COC2)cc1Cl
Temperature: 100 °C
Yield: 6.1 %

Procedure:
To the solution of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (409 mg, 1.55 mmol), 3-(3-Bromo-5-fluoro-pyridin-4-yl)-oxetan-3-ol (350 mg, 1.41 mmol) and PdCl2(dppf).CH2Cl2 adduct (115 mg, 0.141 mmol) in DMF (7 mL) was added a solution of Na2CO3 (2M in water, 1.76 ml, 3.53 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and saturated NH4Cl solution. After extraction with DCM and separation, the combined extracts were concentrated and purified by ISCO 12 g (0-40%, v/v, EtOAc/Heptane) to give 2-Chloro-4-[5-fluoro-4-(3-hydroxy-oxetan-3-yl)-pyridin-3-yl]-benzonitrile (26 mg, 6%) as colorless solid; ESI-MS m/z: 305 [M++1]+, Retention time 1.27 min; 1H-NMR (CDCl3, 400 MHz) δ 4.42 (d, J=8.4 Hz, 2H), 4.66 (d, J=8.4 Hz, 2H), 7.57 (d, J=6.8 Hz, 1H), 7.76 (s, 1H), 7.80 (d, J=6.8 Hz, 1H), 8.41 (s, 1H), 8.59 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[NH:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15]1.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:14]2[CH2:18][CH2:17][C@@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:15]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cc1ccc2c(Cl)nc(Cl)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
2,4-Dichloro-7-methylquinazoline (2.0 g, 9.4 mmol) was suspended in 40 mL of dichloromethane under an N2 atmosphere and cooled to 0° C. (R)-tert-Butyl pyrrolidin-3-ylcarbamate (1.75 g, 9.4 mmol) was dissolved in a solution of 10 mL of dichloromethane and Et3N (2.62 mL, 18.8 mmol) and added dropwise to the above reaction mixture. The reaction was warmed to RT and stirred for 16 hours. The reaction was quenched with water, extracted with DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography using 0%-10% EtOAc in DCM gave (R)-tert-butyl 1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (2.82 g, 83% yield). LC/MS: m/z 363.1 (M+H)+ at 3.26 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=3)[S:10][C:3]=12.[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:29].C(=O)([O-])[O-].[K+].[K+].CO.C(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[O:29][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=3)[S:10][C:3]=12
Reactant: CCCn1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CO
Product: CCCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 195 °C
Yield: 85.5 %

Procedure:
To a solution of 131 (3.37 g, 12.13 mmol) in Ph2O (40 ml) was added 2-fluoro-4-nitrophenol (3.81 g, 24.26 mmol) and potassium carbonate (6.70 g, 48.52 mmol). The reaction mixture was heated to 195° C. for 20 hrs then cooled to room temperature. The residue was purified by column chromatography, eluents EtOAc/Hex (9/1 to 5/5), then MeOH/DCM (98/2), to afford title compound 132 (4.13 g, 85% yield) as a yellow solid. MS (m/z): 399.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](N)=[CH:4][C:5](OC)=[O:6].[CH3:12][NH:13][NH2:14].Cl>O>[CH3:12][N:13]1[C:3]([C:2]([F:11])([F:10])[F:1])=[CH:4][C:5]([OH:6])=[N:14]1
Reactant: COC(=O)C=C(N)C(F)(F)F
Reactant: CNN
Agent: Cl
Solvent: O
Product: Cn1nc(O)cc1C(F)(F)F
Temperature: 50 °C
Yield: 76 %

Procedure:
A mixture of 33.82 g (0.20 mole) of methyl 4,4,4-trifluoro-3-amino-2-butenoate and 10.1 g (0.22 mole) of methylhydrazine was heated at 50° C. for 22.25 hr. The mixture was then cooled, and 15 ml. of water and about 12 ml. of conc. hydrochloric acid were added to bring the pH of the mixture to 6.5-7.0. The precipitated product was filtered off and dried to obtain 25.26 g (76% yield) of the product m.p. 130.5°-131° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:30])[N:14]([CH3:29])[N:15]=[C:16]([CH3:28])[C:17]=1S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[OH-:31].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:30])[N:14]([CH3:29])[N:15]=[C:16]([CH3:28])[C:17]=1[OH:31])[CH3:2]
Reactant: [OH-]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(C)nn(C)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 25 °C
Yield: 35.8 %

Procedure:
To a 10 ml volume two-necked flask with Dean-Start, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-(4-methylphenylsulfonyl)-2,3-dihydro-3-pyridazinone ((2-36)-(1)-39) (699 mg), toluene (2.45 ml), tetrabutylammonium bromide (27 mg), and 48 w/w % of aqueous sodium hydroxide solution (550 mg) were added. Water was removed by azeotropic distillation under reflux for 33 hours. After the mixture was cooled to room temperature, water was added, and the organic layer was removed. To the aqueous layer, 20 w/w % of sulfuric acid was added to adjust pH to 4, and extracted with toluene 2 times. The organic layers were combined, and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate=5:1) to give 169 mg of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).