Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1.N1CCCC1>CO>[C:18]([N:15]1[CH2:16][CH2:17][C:12]2([CH2:9][C:8](=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:13][CH2:14]1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(=O)c1ccccc1O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21

Procedure:
The synthesis of compound 19A-19D is outlined in Scheme 19. The 2′-hydroxyacetophenone 1.1a was condensed with benzyl 4-oxopiperidine-1-carboxylate (19.1) in refluxing methanol in the presence of pyrrolidine to provide N-Cbz-spiro[2H-1-benzopyran-2,4′-piperidine]-4(3H)-one (19.2). Conversion of the ketone 19.2 to the enol triflate derivative 19.3 was achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating reagent. Conversion of the enol triflate 19.3 to the corresponding boron derivative 19.4 was achieved using 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 1.14 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, abbreviated as [Pd(dppf)Cl2.CH2Cl2]. Suzuki type coupling of the boronate derivative 19.4 with tert-butyl 4-bromophenylcarbamate 19.5 in ethylene glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium(0), lithium chloride, and an aqueous solution of sodium carbonate afforded the tert-butyloxycarbonyl (Boc) protected aniline derivative 19.6. Acidic hydrolysis of 19.6 provided the aniline derivative 19.7 which reacted with acyl chlorides 19.8a, 19.8b, isopropylsulfonyl chloride (6.5b) or ethyl isocyanate (19.11) to give the corresponding amide derivatives 19.9, sulfonamide derivative 19.10 or urea derivative 19.12, respectively. The derivatives 19.9, 19.10 and 19.12 were converted to compounds 19A-19D by treatment with iodotrimethylsilane.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)=[CH:8][CH:7]=1.[N:18]1([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[S:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([N:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]4[N:13]=[C:14]([NH2:17])[S:15][CH:16]=4)=[CH:8][CH:7]=3)[CH2:22][CH2:23]2)=[N:25]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: Nc1nc(-c2ccc(CCCCCl)cc2)cs1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: Nc1nc(-c2ccc(CCCCN3CCN(c4nsc5ccccc45)CC3)cc2)cs1

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.22 g (3.52 mmol) (4-(4-(4-chlorobutyl)phenyl)-2-aminothiazole, 0.90 g (3.52 mmol) 3-piperazinyl-benzisothiazole, 1.84 ml (10.57 mmol) diisopropylethylamine, 0.75 g (7.04 mmol) sodium carbonate, 2 mg sodium iodide, and 35 ml methylisobutylketone. The reaction mixture was refluxed 6 days, cooled, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent, and the product fractions dissolved in methylene chloride/methanol and precipitated by addition of methylene chloride saturated with HCl. The precipitate was filtered and dried to give a solid, 242 mg (13%), m.p. 258-261° C. NMR (DMSO-d6): 1.6-1.8 (m, 4H), 2.7 (t, 2H), 3.2-3.6 (m, 8H), 4.1 (m, 2H), 7.20 (s, 1H), 7.3-8.2 (m, 8H).
Reaction SMILES: [CH2:1]([O:6][C:7](=[O:31])[C:8]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:12][N:11]=[C:10]([NH2:30])[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:1]([O:6][C:7](=[O:31])[C:8]1[C:13]([S:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:12][N:11]=[C:10]([NH:30][S:40]([C:34]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=2[Cl:32])(=[O:42])=[O:41])[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOC(=O)c1cc(N)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 29327.1 %

Procedure:
A solution of the 2-amino-5-[4-(piperidine-1-sulfonyl) -phenylsulfanyl]-isonicotinic acid pentyl ester (500 mg, 1.1 μmol), 2,4-dichlorobenzenesulfonylchloride (327 mg, 1.33 mmol) and 4-dimethylaminopyridine (134 mg, 1.1 mmol) in pyridine (10 ml) was stirred at 40° C. overnight. The pyridine was removed under reduced pressure and the residue purified by flash column chromatography using ethyl acetate 1/2 hexane as eluent to afford 2-(2,4-dichloro-benzenesulfonylamino)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinic acid pentyl ester as a yellow foam (217 mg, 29%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][C@:20]2([CH3:27])[C:24]([OH:26])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(ON)(C)(C)C>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[C:24](=[O:26])[C@:20]3([CH3:27])[C@H:19]2[CH2:23][CH2:22][CH2:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(C(=O)O)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)ON
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@]12CCC[C@H]1N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2=O

Procedure:
According to the procedure of Example 53, Step 5, using (1S,2R)-2-({[4-(benzyloxy)phenyl]sulfonyl}amino)-1-methylcyclopentanecarboxylic acid (677 mg, 1.74 mmol), BOP (424 mg, 2.09 mmol), O-tert-butylhydroxylamine (480 mg, 3.82 mmol), and triethylamine (1.2 mL), (1S,5R)-6-{[4-(benzyloxy)phenyl]sulfonyl}-1-methyl -6-azabicyclo[3.2.0]heptan-7-one was obtained (480 mg, 1.29 mmol, 74%) as a colorless solid after purification via column chromatography on silica gel, eluting with 25% ethyl acetate/hexanes. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.19-1.28 (m, 1H) 1.30-1.41 (m, 4H) 1.47-1.58 (m, 2H) 1.75 (dt, J=12.69, 6.41 Hz, 1H) 2.02-2.11 (m, 1H) 2.21 (dd, J=14.15, 5.31 Hz, 1H) 4.10 (d, J=4.04 Hz, 1H) 5.11-5.16 (m, 2H) 7.04-7.10 (m, 2H) 7.35-7.44 (m, 5H) 7.92-7.97 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10]CC=C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]1(OC2C=CC=CC=2)[CH:19]=CC=C[CH:15]=1>>[CH2:19]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[OH:10])[CH:14]=[CH2:15]
Reactant: C=CCOc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Product: C=CCc1cc([N+](=O)[O-])ccc1O
Temperature: 250 °C

Procedure:
A mixture of allyl 4-nitrophenyl ether (78 g) and diphenyl ether (150 ml) was heated at 250° C. for 30 minutes. The reaction mixture was cooled to ambient temperature, and partitioned between diethyl ether and 2M aqueous sodium hydroxide solution. The aqueous layer was separated and acidified to pH3 with concentrated hydrochloric acid. The aqueous mixture was extracted with ethyl acetate the ethyl acetate extract dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (Merck 7736) using a gradient of 0% to 20% methanol in dichloromethane as eluent to give 2-allyl-4-nitrophenol (21.4 g); microanalysis, found: C, 60.6; H, 5.1; N, 7.9%; C9H9 NO3 requires: C, 60.3; H, 5.06; N, NMR): 3.36(2H,d), 5.1(2H,m), 5.98(1H,m), 6.97(1H,d), 8.0(2H,m); m/z 197 (M+NH4).
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([CH3:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C(O)C>[F:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([CH3:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:27][CH:24]1[CH2:26][CH2:25]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(C)c(F)c(F)c(F)c1F
Temperature: 5 °C
Reaction time: 2.5 h
Yield: 97.3 %

Procedure:
To a solution of 9.0 g (27.0 mmol) of ethyl 2-(2,3,4,5-tetrafluoro-6-methylbenzoyl)-3-ethoxyacrylate in 30 ml of absolute ethanol at 5° C. was added 1.68 g (29.4 mmol) of cyclopropylamine. The mixture was stirred at 5° C. for 1.5 hours and at room temperature for 2.5 hours. The solution was concentrated to an oil which was triturated with hexane to give a tan solid. The crude product was recrystallized from hexane to give 9.07 g of the title compound, mp 72°-74° C.
Reaction SMILES: [Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[C:13]([O:16][C@@H:17]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[C@@H:25]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[S:24][CH:18]1[O:19][Si](C)(C)C)(=[O:15])[CH3:14].C(C1C=CC(CC2C=CC=CC=2C[Si](O[Si](CC2C=CC=CC=2CC2C=CC(CC)=CC=2)(C)C)(C)C)=CC=1)C>C(Cl)Cl>[C:13]([O:16][C@@H:17]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[C@@H:25]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[S:24][CH:18]1[OH:19])(=[O:15])[CH3:14]
Reactant: CC(=O)OC[C@H]1SC(O[Si](C)(C)C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCc1ccc(Cc2ccccc2C[Si](C)(C)O[Si](C)(C)Cc2ccccc2Cc2ccc(CC)cc2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 54 %

Procedure:
TMSOTf was added at 0° C. to a mixture of 2,3,4,6-tetra-O-acetyl-1-O-trimethylsilyl-5-thio-D-glucopyranose (5), 2-(4-ethylbenzyl)phenyltrimethylsilyl ether, MS4A and CH2Cl2. Instead of a product of interest (10), this reaction provided 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (7) as a by-product in a yield of 54%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[O:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=O>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:2][CH2:1][O:3][C:4]([C:6]1[N:7]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:23])[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
4-Benzyloxy-1H-indole-2-carboxylic acid ethyl ester (50 g, 169.3 mmol) is dissolved in 500 ml of ethyl acetate and DMAP (141 mg, 3.4 mmol) is added. Then the mixture is cooled to 0° C. and BOC2O (36.9 g, 169.3 mmol), dissolved in 20 ml of ethyl acetate, is added dropwise. After completion of addition the reaction mixture is allowed to stir over night at room temperature. The mixture is washed with 1M tartaric acid and brine. The organic layers are dried over sodium sulfate and evaporated
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl.CN(C=O)C.[H-].[Na+]>C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[CH:9]=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reaction time: 4 h
Yield: 139 %

Procedure:
To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (6.2 g, 0.031 mol) and [β-(trimethylsilyl)ethoxy]methyl chloride (6.7 mL, 0.038 mol) in DMF (62 mL, 0.80 mol) was added sodium hydride (1.5 g, 0.038 mol) at 0° C., and the resulting solution turned opaque. The mixture was stirred for additional 4 h, then diluted with methyl tert-butyl ether (MTBE). The organic layer was separated and washed with water (×2) and brine aqueous solution successively. The organic phase was dried and concentrated in vacuo to give 14.1 g of a product as a pale orange oil. The oil was purified by column chromatography eluting with 5-20% ethyl acetate/hexanes to give the purified product as a colorless oil (9.66 g, 94% yield).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][OH:19])[C:12]=2[Cl:20])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[C:1]([NH:4][CH2:5][C:6]1[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][O:19][S:29]([CH3:28])(=[O:31])=[O:30])[C:12]=2[Cl:20])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cccn1-c1ccc(Cl)c(CO)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cccn1-c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a mixture of 2-acetamidomethyl-1-(2,4-dichloro-3-hydroxymethylphenyl)pyrrole (51 mg) and triethylamine (19.8 mg) in dichloromethane (2 ml) was added methanesulfonyl chloride (20.5 mg) under nitrogen atmosphere in ice-methanol bath, and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water, saturated sodium bicarbonate solution and brine, dried over magensium sulfate and evaporated in vacuo to give 2-acetamidomethyl-1-[2,4-dichloro-3-(methanesulfonyloxymethyl)-phenyl]pyrrole (64 mg) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:31])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:32][C:33]1[CH:34]=[C:35]([OH:41])[CH:36]=[CH:37][C:38]=1[C:39]#[N:40].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[O:31])[CH:8]=[CH:7][C:3]=1[C:4]([O:41][C:35]1[CH:36]=[CH:37][C:38]([C:39]#[N:40])=[C:33]([Cl:32])[CH:34]=1)=[O:5]
Reactant: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)Cl)c(Cl)c3)cc2)cc1
Reactant: N#Cc1ccc(O)cc1Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)Oc4ccc(C#N)c(Cl)c4)c(Cl)c3)cc2)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 2-chloro-4-{[p-(p-hexylphenyl)benzoyl]oxy}benzoyl chloride obtained was dissolved in 125 ml of benzene and then added dropwise to a solution of 4.0 g of 3-chloro-4-cyanophenol in 100 ml of pyridine. The mixture was stirred at a bath temperature of 65° C. overnight, then poured into ice-cold, dilute hydrochloric acid and extracted with diethyl ether. The extract was washed several times with 3N hydrochloric acid, then washed neutral with water, dried and evaporated. The crude 4'-hexyl-4-biphenylcarboxylic acid 3-chloro-4-[(3-chloro-4-cyanophenoxy)carbonyl]phenyl ester obtained was chromatographed on silica gel with toluene/dichloromethane (1:1). The fractions (8.2 g) which were practically pure according to thin-layer chromatography were recrystallized once from ethyl acetate and once from ethyl acetate and a small amount of hexane; m.p. (C-N) 95° C., cl.p. (N-I) 235° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2C=C[CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1CN(C(OC(C)(C)C)=O)C1>>[NH:48]1[CH2:43][CH:44]([NH:49][C:26](=[O:28])[C:25]2[CH:29]=[C:30]([O:31][CH3:32])[C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[CH:23][C:24]=2[F:33])[CH2:47]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CC(C)(C)OC(=O)N1CC(N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid as described in the general procedure for amide bond synthesis using HATU and 3-amino-N—Boc-azetidine. The Boc group was then removed by treatment with 1:1 trifluoroacetic acid and dichloromethane for 1 hour. At this time the solvent was removed and NaHCO3 (sat.) and EtOAc were added to the residue. The layers were separated, the organic layer was then dried over MgSO4, filtered, the solvent was removed and the final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.79 (m, 6 H) 1.93 (br. s., 2 H) 3.52-3.66 (m, 4 H) 3.94 (s, 3 H) 4.05 (t, J=14.02 Hz, 2 H) 4.56-4.84 (m, 2 H) 7.45-7.58 (m, 2 H) 7.98 (s, 1 H) 8.26 (s, 1 H) 8.28 (d, J=8.34 Hz, 1 H) 8.75 (d, J=7.07 Hz, 1 H). [M+H] calculated for C24H29F2N7O3, 502; found 502.
Reaction SMILES: Br[CH:2]1[C:8](=[O:9])[CH:7](Br)[C:6]2([CH3:12])[O:11][C:3]1([CH3:13])[CH:4]=[CH:5]2.[Cl-].[NH4+]>[Zn].[Cu]>[CH3:12][C:6]12[O:11][C:3]([CH3:13])([CH:4]=[CH:5]1)[CH2:2][C:8](=[O:9])[CH2:7]2
Reactant: CC12C=CC(C)(O1)C(Br)C(=O)C2Br
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Product: CC12C=CC(C)(CC(=O)C1)O2
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a stirred slurry of 2,4-dibromo-1,5-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one (18.0 g) in a saturated methanolic solution of ammonium chloride (514 ml) was added portionwise zinc/copper couple (51 g) over 30 minutes at 23° C. The suspension was stirred for an additional 2 hours and filtered. The filtrate was diluted with a saturated Na2H2 -ethylenediaminetetraacetic acid solution (400 ml). Extraction with methylene chloride (5×100 ml) and drying (MgSO4) produced, upon evaporative removal of solvent, the desired ketone (9.0 g). Bulb-to-bulb distillation <80° C. and 0.5 mm afforded the desired product (7.3 g) as colorless crystals, m.p. 62°-63° C.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[OH-].[Na+].Br[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:19][C:20]([C:22]2[CH:23]=[CH:24][C:25](=[O:29])[N:26]([CH3:28])[CH:27]=2)=[O:21])=[CH:14][CH:13]=1.[CH3:37][S:38]([O-:40])=[O:39].[Na+]>[Cu]I.CS(C)=O>[CH3:28][N:26]1[CH:27]=[C:22]([C:20](=[O:21])[CH2:19][C@H:18]([C:15]2[CH:14]=[CH:13][C:12]([S:38]([CH3:37])(=[O:40])=[O:39])=[CH:17][CH:16]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH:23]=[CH:24][C:25]1=[O:29]
Reactant: CS(=O)[O-]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
L-proline (44.9 mg, 390 μmol) was combined with dimethyl sulfoxide (5 mL), then sodium hydroxide (15.6 mg, 390 μmol) was added and the reaction stirred at room temperature for 30 min. Then (R)-5-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-1-methylpyridin-2(1H)-one (example 223, step 3; 200 mg, 487 μmol), sodium methanesulfinate (410 mg, 3.9 mmol) and copper(I) iodide (74.3 mg, 390 μmol) were added. The reaction mixture was heated at 120° C. for 21 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. Chromatography (SiO2; gradient ethyl acetate/heptane 1:1 to ethyl acetate) afforded the title compound (176 mg, 88%). White foam, MS (ESI+): m/z=: 410.2 [M+H]+.
Reaction SMILES: C[C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([F:21])[C:14]=1[Cl:22])(C([O-])=O)[C:3]([O:5][C:6](C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[CH2:2][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([F:21])[C:14]=1[Cl:22]
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)[O-])c1ccc(C#N)c(F)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc(C#N)c(F)c1Cl
Reaction time: 20 h

Procedure:
To a solution of t-butyl methyl(2-chloro-4-cyano-3-fluorophenyl)malonate (4.8 g, 15 mmol) in DCM (50 mL) was added TFA (50 mL) at room temperature and the mixture was aged for 20 hours. LC-MS and TLC (20% ethyl acetate/hexanes) indicated lack of starting malonate diester, but still some mono-acid/mono-ester intermediate. The volatiles were removed in vacuo and the residue was taken up in methanol and heated to reflux for 1 hour. The volatiles were again removed in vacuo and the residue was purified on a CombiFlash Rf (40 gm, 10-40% ethyl acetate/hexanes) to give several main fractions of clean title product by NMR. 1H-NMR (500 MHz, CDCl3) δ ppm 3.734 (s, 3H), 3.860 (s, 2H), 7.234 (d, J=8.0 Hz, 1H), 7.512 (dd, J=6.1 and 8.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=2)[CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[NH:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[CH2:19][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39]([NH:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])=[CH:30][CH:29]=1)[CH:9]1[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1
Reactant: O=C=NCc1ccccc1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 26.8 %

Procedure:
To a cold (0° C.) solution of (4-aminomethyl-benzyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.130 g, 0.33 mmol) in CH2Cl2 (3.5 mL) was added benzyl isocyanate (45 μL, 0.36 mmol) and the resultant solution was stirred for 100 minutes. The cooling bath was removed and the mixture was concentrated under reduced pressure. Purification of the crude material by column chromatography on silica gel (25:1:1 CH2Cl2—CH3OH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2—CH3OH—NH4OH) provided the free base of the title compound (0.047 g, 28%) as a white solid.
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:34]C2CCCCO2)[C:26]([CH3:33])([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.O1CCCC1>[Cl:1][C@@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([OH:34])[C:26]([CH3:33])([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)=CCC(C)(C)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)=CCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1O
Yield: 51.4 %

Procedure:
1.04 g of (5Z,13E)-(8R,9R,11R,12R,15R)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,16,19-trimethyl-5,13,18-prostatrienoic acid was stirred under argon at room temperature for 19 hours with 21 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture was then evaporated under vacuum and the residue purified by column chromatography on silica gel with hexane/0-100% ethyl acetate as the eluent, thus obtaining 380 mg of the title compound.