Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:11].O>C(Cl)Cl>[Cl:11]/[C:3](/[CH3:5])=[CH:2]/[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)/C=C(\C)Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 7.7 %

Procedure:
In a reaction vessel flushed with argon gas was placed 437.4 grams (3.36 moles) of ethyl acetoacetate in 500 ml of methylene chloride. The stirred solution was cooled to 0° C. and 700 grams (3.36 moles) of phosphorous pentachloride was added in portions at a rate such that the reaction mixture temperature did not exceed 5°. Upon completion of addition, the reaction mixture was stirred at 0°-5° for 16 hours. Five-hundred ml of water was added dropwise, and the layers in the resultant two-phase system were separated. The water layer was made alkaline with solid sodium bicarbonate and extracted with several 100-ml portions of methylene chloride. The organic layer from the reaction mixture was washed with water until all the solid material in it dissolved. The washed organic layer and the methylene chloride washings of the water layer were combined and dried with sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual oil. The oil was first distilled under reduced pressure using a Vigreux column. Fractions boiling at 52°-65°/0.40-1.07×103Pa were combined and subjected to a second distillation under reduced pressure using a spinning band distilling system. Fractions boiling at 66°-70°/0.40-1.07×103Pa from the first distillation and fractions boiling at 66.5°-82°/1.20×103Pa from the second distillation were subjected to a third distillation under reduced pressure using a spinning band distilling system. The fraction, bp 46°/1.33×103Pa from the second distillation was combined with the fractions, bp 42°-45°/1.20×103Pa from the third distillation to give 38.4 grams of ethyl [E]-3-chloro-2-butenoate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[CH:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CC=O)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (3.6 mL, 0.0425 mol) was dissolved in DCM (87 mL) at −78° C. Dimethyl sulfoxide (6.58 mL, 0.0927 mol) was added and the solution was held at −78° C. for 10 min. To the resultant mixture was added a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (from Oakwood, 8.90 g, 0.0386 mol) in DCM (44 mL) over 15 min. The reaction was stirred at −78° C. for 1 h, then triethylamine (26.9 mL, 0.193 mol) was added. The mixture was warmed to RT over 30 minutes and then stirred at RT for another 30 min. The mixture was diluted with DCM, washed with water (2×), brine (1×), dried over sodium sulfate, and concentrated. The crude product (8.10 g, 91.8%) was used directly in next step without further purification. 1H NMR (400 MHz, CDCl3): δ 9.70 (1H, s), 3.48 (4H, m), 3.19 (2H, s), 2.47 (4H, m), 1.45 (9H, s) ppm.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([OH:25])[CH:18]=1.[CH2:26]([N:28]([CH2:32][CH3:33])[C:29](Cl)=[O:30])[CH3:27].C(N(CC)CC)C>CN(C=O)C.N1C=CC=CC=1>[CH2:26]([N:28]([CH2:32][CH3:33])[C:29](=[O:30])[O:25][C:19]1[CH:18]=[C:17]([CH2:16][NH:15]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([I:1])=[CH:11][CH:10]=3)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24])[CH3:27]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
To a solution of (4Z)-6-iodo-4-{[(3-hydroxy-4-methoxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (0.30 g, 0.67 mmol) in 3 mL of N,N′-dimethylformamide and 2 mL of pyridine is added diethylcarbamylchloride (0.10 mL, 0.80 mmol) and 0.21 mL (2.00 mmol) of triethylamine. The reaction mixture is stirred at 80° C. for 4 h and then at room temperature over weekend under N2. Mass spectroscopy suggested the completion of reaction. The reaction mixture is concentrated, and 2 mL of MeOH is added to break up the solid, followed by addition of excess amount of Et2O. The precipitate is filtered, washed successively with water, methanol, ether and hexane, and dried in oven (60° C.) overnight to afford 0.207 g (56.6% yield) of tan solid: mp 128-130° C.; MS (ESI) m/z 548.2 (M−H)−1
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Br:42][C:43]1[CH:44]=[C:45]([NH:50][CH3:51])[C:46]([NH2:49])=[CH:47][CH:48]=1>CN(C=O)C>[Br:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][C:6]([CH:4]2[CH2:3][C:2](=[O:1])[CH2:5]2)=[O:8])=[C:45]([NH:50][CH3:51])[CH:44]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: CNc1cc(Br)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(Br)ccc1NC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a stirred solution of 3-oxocyclobutanecarboxylic acid (1.1 g) in DMF (50 ml) were added HATU (5.7 g) and N,N-diisopropylethylamine (4.2 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 30 min. A solution of 4-bromo-N2-methylbenzene-1,2-diamine (2.0 g) in DMF (2 ml) was added, and the resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo, and the residue was diluted with DCM (200 ml) and washed with saturated NH4Cl (100 ml), saturated NaHCO3 (60 ml), water (100 ml) and brine (100 ml). The DCM layer was then dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.7 g) as an off-white solid.
Reaction SMILES: [CH2:1]([S:3]([CH2:5][CH2:6]Cl)=[O:4])[CH3:2].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+]>>[CH2:1]([S:3]([CH2:5][CH2:6][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4])[CH3:2]
Reactant: CCS(=O)CCCl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)CCN1CCCCC1
Yield: 59.5 %

Procedure:
Heat 2-chloroethyl ethyl sulfoxide (1.0 g, 7.1 mmol) and piperidine (2 mL, 20 mmol) at 60° C. for 2 hours. Treat with 5N sodium hydroxide, extract with ethyl acetate (3×50 mL) and dry (MgSO4). Concentrate in vacuo to yield 800 mg orange oil. Purify by silica gel chromatography (50% ethyl acetate/methanol) to yield 560 mg (42%) of the title compound as a yellow oil. 438E-25 MDL 101135
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O1CCC[CH2:20]1.C([Li])CCC.COS(OC)(=O)=O>C([Li])CCC.O>[CH3:20][C:16]1[S:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: C1CCOC1
Reactant: CSc1ccc(-c2ccc(-c3cccs3)s2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CSc1ccc(-c2ccc(-c3ccc(C)s3)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.82 gram (0.003 mole) of 5-(4-methylthiophenyl)[2,2'-bithienyl] in 100 ml of freshly distilled tetrahydrofuran was cooled to 0° C. and 1.4 ml of n-butyllithium (2.6M in hexanes) was added dropwise via syringe during a ten minute period. Upon completion of addition the reaction mixture stirred at 0° C. for 30 minutes, then at ambient temperature for three hours. The reaction mixture was recooled to 0° C. and an additional five drops of n-butyllithium was added. The reaction mixture stirred at 0° C. for one hour then 0.32 ml (0.0034 mole) of dimethylsulfate was added. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was taken up in 70 ml of water and the organic layer was separated. The aqueous layer was washed with three 25 ml portions of chloroform. The organic layers were combined and washed, first with water, then with an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 0.78 gram of 5'-methyl-5-(4-methylthiophenyl)[2,2'-bithienyl]; m.p. 145°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][CH2:24][OH:25])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.C(Cl)Cl>[Pd].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]\[CH2:23][CH2:24][OH:25])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:27][CH:28]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCCO)cc2c1O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(/C=C\CCO)cc2c1O
Reaction time: 3 h
Yield: 55.2 %

Procedure:
A solution of the title compound of Example 94 (0.393 g), pyridine (3 mL), and Pd/C (10%, 80.0 mg) in 3:1 CH2Cl2 :MeOH is maintained under an atmosphere of H2 (balloon) for 3 hrs. More Pd/C (10%, 40 mg) is added and the reaction mixture is placed under the Parr hydrogenator at 25 psi H2 for an additional 3 hrs. The reaction mixture is filtered over celite. The filtrate is condensed and then placed under high vac to remove residual pyridine. The crude product is recrystallized with EtOAc/hexanes to afford 0.218g of the desired product as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([CH:17]=3)[NH2:16])=[CH:10][N:4]2[N:3]=1.C(#N)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:19])([F:20])[F:21])=[C:15]([NH:16][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[CH:17]=3)[N:8]=2)[N:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Yield: 93.4 %

Procedure:
A 40 mL vial is charged with 5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)aniline (0.531 g, 1.7 mmol), acetonitrile (14 mL), and pyridine (0.275 mL). The stirred mixture is added trimethylacetyl chloride (0.419 mL, 3.4 mmol) and heated for 20 min at 80° C. The reaction is concentrated, taken into EtOAc (25 mL), washed once with HCl (15 mL, 1M) then NaOH (15 mL, 1M). Organic is dried, concentrated and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (630 mg, 93% yield). LCMS (m/z)=397.4, 399.3 [M+H]+, tR=2.87 min. (compound same as Example 126)
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=1)(=O)=O.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH:7]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=1)=[CH2:6]
Reactant: CS(=O)(=O)OCCc1ccc(C#N)c(F)c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: C=Cc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(4-cyano-3-fluorophenyl)ethyl methanesulfonate (35.0 g, 144 mmol) and triethylamine (50 mL) in DCM (200 mL) was added DBU (50 mL) dropwise to at 0° C. After stirring at room temperature overnight, the solution was diluted with DCM, washed with 1 N HCl and brine, and dried over anhydrous sodium sulphate and concentrated. The residue was purified by column chromatography to give 4-ethenyl-2-fluorobenzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.53˜7.57 (m, 1H), 7.20˜7.26 (m, 2H), 6.64˜6.71 (m, 1H), 5.48˜5.90 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:31])[CH2:9][CH2:10][CH:11]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:13]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:12]2=[O:30])=[CH:4][CH:3]=1.[Br:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][O:29][C:26]2[CH:25]=[CH:24][C:23]([N:13]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[CH:11]([CH2:10][CH2:9][CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[OH:31])[C:12]3=[O:30])=[CH:28][CH:27]=2)=[CH:36][CH:35]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(OCc3ccc(CBr)cc3)cc2)cc1

Procedure:
3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-azetidin-2-one was reacted with 1,4-bisbromomethylbenzene and potassium carbonate analogously to Example IV, giving a colorless solid (25) of molecular weight 604.52 (C33H31BrFNO4); MS (ESI): 605.2 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]=[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)[NH:10]1>ClCCl>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:10][C:9](=[S:8])[O:13][N:12]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2noc(=S)[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2noc(=S)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
At 0° C., 0.8 ml of TFA was added to a solution of 119 mg (0.40 mmol) of tert-butyl [4-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]carbamate in 4 ml of dichlormethane, and the mixture was stirred at RT for 40 min. Subsequently, the reaction mixture was concentrated under reduced pressure. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the residue. After phase separation, the aqueous phase was extracted with ethyl acetate. The aqueous phase was concentrated and the crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 30 mg (38% of theory)
Reaction SMILES: O.[CH2:2]([Cl:5])[CH:3]=[CH2:4].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:2]([Cl:5])[CH:3]=[CH2:4].[NH+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccncc1
Solvent: O
Solvent: C=CCCl
Product: c1cc[nH+]cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
of water are placed in the reactor. 229.58; (3 mol) of allyl chloride are added and the mixture is heated to 50° C. 237.0g (3 mol) of pyridine are then added dropwise over a period of one hour with vigorous stirring. Following a further eight hours at 50° C. the reaction mixture is subjected to steam distillation at 500 mbar/80° C. During the steam distillation the pH is kept at 5 by means of dilute NaOH. Distillation is continued until the content of pyridine in the bottoms is less than 0.1%. The yield is 90%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][CH:21]([N:24]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25]2)[CH2:20][CH2:19]1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([Cl:47])[C:33]=1[OH:48]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH:18]2[CH2:23][CH2:22][CH:21]([N:24]4[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25]4)[CH2:20][CH2:19]2)=[CH:3][C:2]([C:36]2[CH:37]=[C:32]([Cl:31])[C:33]([OH:48])=[C:34]([Cl:47])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: COC1CCN(C2CCC(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: COC1CCN(C2CCC(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)CC2)C1
Yield: 63.8 %

Procedure:
Following general procedure D, (6-bromo-4-(4-(3-methoxypyrrolidin-1-yl)cyclohexylamino)quinolin-3-yl)(cyclopropyl)methanone (60 mg, 0.13 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (55 mg, 0.19 mmol) to afford the desired product (46 mg, 64%) as a brown solid: 1H NMR 1H NMR (500 MHz, MeOD+TFA-d) δ 9.42 (s, 1H), 8.46 (s, 1H), 8.31-8.23 (m, 1H), 8.04-7.97 (m, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 4.99 (br s, 1H), 4.23-4.14 (m, 1H), 3.82-3.61 (m, 2H), 3.43-3.30 (m, 6H), 3.27-3.19 (m, 1H), 2.93-2.82 (m, 1H), 2.60-2.03 (m, 7H), 2.02-1.61 (m, 3H), 1.37-1.18 (m, 4H).; ESI MS m/z 554 [C30H33Cl2N3O3+H]+; HPLC>99.0% (AUC), tR=10.97 min.
Reaction SMILES: FC1C=CC=C(F)C=1C[NH2:5].C(N(CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[F:39][C:40]1[CH:69]=[C:68](OC)[CH:67]=[C:66]([F:72])[C:41]=1[CH2:42][N:43]1[C:48]2[N:49]=[CH:50][CH:51]=[CH:52][C:47]=2[S:46](=[O:54])(=[O:53])[N:45]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])C=2)[C:44]1=[O:65]>CN(C=O)C>[F:39][C:40]1[CH:69]=[CH:68][CH:67]=[C:66]([F:72])[C:41]=1[CH2:42][N:43]1[C:48]2[N:49]=[CH:50][CH:51]=[CH:52][C:47]=2[S:46](=[O:53])(=[O:54])[N:45]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[N:5]=2)[C:44]1=[O:65]
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Reactant: NCc1c(F)cccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)N(Cc3c(F)cccc3F)c3ncccc3S2(=O)=O)nc1OC

Procedure:
The title compound (57 mg, 0.12 mmol) was prepared in two steps from (IntC3) (165 mg, 0.5 mmol), 2,6-difluorobenzylamine (70 uL, 0.6 mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by 1,1′-carbonyldiimidazole (305 mg, 1.88 mmol), triethylamine (0.13 mL, 0.93 mmol) in DMF (1.5 mL) using the methods of (95).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:13][CH:12]([CH2:14][OH:15])[CH:11]1[CH2:16]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(Cl)Cl>[C:1]([O:9][CH:10]1[CH2:13][CH:12]([CH2:14][OH:15])[C:11]1=[CH2:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC1CC(CO)C1CBr)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1C(CO)CC1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
1-Benzoyloxy-2-bromomethyl-3-hydroxymethylcyclobutane (2.5 g, 8.36 mmol) from Step F and tetra-n-butylammonium fluoride ((8.1 g, 25 mmol) were combined in 200 mL of freshly distilled THF and the reaction mixture was stirred at ambient temperature, under a nitrogen atmosphere, overnight. The volume of the reaction mixture was then reduced to 25 mL and this was dissolved in 250 mL of methylene chloride. The methylene chloride solution was washed with 150 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (4.9 g) was dissolved in ~5 mL of methylene chloride and purified on a 2.5×35 cm silica gel column eluted @ 5 psi with a step-wise (4×200 mL steps) of methanol in methylene chloride from 0% to 3% methanol to give 1.54 g (85% yield) of the title compound as a syrup; 1H NMR (CDCl3) δ 2.38 (m, 2H), 3.22 (m, 1H), 3.69-3.85 (m, 2H), 5.13 (t, 1H), 5.32 (t, 1H), 5.79 (M, 1H), 7.45 (m, 2H), 7.58 (m, 1H), 8.08 (m, 2H); MS DCI-NH3M/Z: 219 (M+H)+, 236 (M+NH4)+.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:5]1.[I-].[K+].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([N:30]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:7]=[C:8]2[C:9]1=[O:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)nn1CCBr
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2cc(-c3ccc(F)cc3)nn2CCN1Cc1ccccc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
To a solution of Intermediate 1C (80 g, 234 mmol) and potassium iodide (78 g, 469 mmol) in acetonitrile (800 mL) was added benzyl amine (28.2 mL, 258 mmol) and the reaction mixture was stirred at 90° C. for 12 h. Acetonitrile was removed under reduced pressure, crude was diluted with water and the aqueous layer was extracted with DCM (3×500 mL). The combined organic layer washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (120 g REDISEP® column, eluting with 1-2% methanol in chloroform). Collected fractions were concentrated together to afford Intermediate 1D (35 g, 46%). MS(ES): m/z=322 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 7.71-7.83 (m, 2H), 7.29-7.42 (m, 5H), 7.14 (s, 1H), 7.06-7.12 (m, 2H), 4.78 (s, 2H), 4.32-4.40 (m, 2H), 3.63-3.75 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2].[CH3:16][C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:22]3[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@@H:17]3[CH3:16])[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 125 °C
Yield: 60.1 %

Procedure:
To a solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (0.75 g, 3.3 mmol) in NMP (10 mL) was added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (1.0 g, 5.0 mmol). The mixture was heated to 125° C. for 60 hours. After cooling, the mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give (S)-tert-butyl 4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.775 g, 60%). 1H NMR (CDCl3, 400 MHz) δ 8.60-8.59 (d, 1H), 6.07-5.89 (m, 1H), 4.73-4.60 (m, 1H), 4.30-3.80 (m, 3H), 3.60-3.35 (m, 1H), 3.22 (m, 1H), 3.02 (br, 1H), 2.78 (m, 1H), 2.35-1.60 (m, 5H), 1.49 (s, 9H), 1.32-1.20 (m, 6H). MS (APCI+) [M+H] +391. The resulting mixture of diastereomers was purified by chiral separation by HPLC (Chiralcel ODH column, 250×20 mm, 15 mL/min, Hexane/EtOH 50:50). The first peak (RT=3.864 min) gave (S)-tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.281 g, 36%) and the second peak (RT=5.064 min) gave (S)-tert-butyl 4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.389 g, 50%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH2:11])[CH2:2]1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:41]([C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[N:32]([CH2:31][C:28]2[CH:27]=[CH:26][C:25]([C:20]4[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:30][CH:29]=2)[C:33]([CH3:45])=[C:34]3[CH3:44])=[O:42])[CH2:2]1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NC1COc2ccccc2C1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC3COc4ccccc4C3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using chroman-3-amine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.