Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.C(O)C.[C]=O.[C:15]([O:18][CH:19]([CH2:25][CH2:26][S:27][CH3:28])[C:20]([O:22][CH2:23]C)=O)(=[O:17])[CH3:16]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:15]([O:18][CH:19]([CH2:25][CH2:26][S:27][CH3:28])[C:20]([O:22][CH3:23])=[S:8])(=[O:17])[CH3:16]
Reactant: CSCC=COC(C)=O
Reactant: CCOC(=O)C(CCSC)OC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: C1CCOC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C
Yield: 10.8 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z: E ratio 43:57), and 2.5 mmoles ethanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. Ten mole percent, based on 1-acetoxy-3-methylthiopropene, of a catalyst comprising bis(triphenylphosphine)dichloropalladium, (φ3P )2PdCl2, was added. Toluene was included as an internal standard. Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, ethyl ester was produced in a yield of 10.5 percent, and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester, was produced in a yield of 10.8 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Note that each of the products is hydrolyzable to methionine hydroxy analog.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:13](Cl)=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[C:17]2[O:22][CH3:23])(=[O:10])=[O:9].C([O-])=O.[NH4+]>CC(O)=O.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[C:17]2[O:22][CH3:23])(=[O:9])=[O:10]
Reactant: COc1ccnc2c(NS(=O)(=O)c3ccccc3N)c(Cl)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccnc2c(NS(=O)(=O)c3ccccc3N)cccc12
Temperature: 70 °C
Yield: 32.2 %

Procedure:
10% Pd—C (97 mg) was added to a solution of 2-amino-N-(7-chloro-4-methoxy-quinolin-8-yl)-benzenesulfonamide 570 (470 mg, 1.8 mmol), ammonium formate (571 mg, 9.2 mmol) in 50% AcOH (10 ml) and the mixture was heated to 70° C. for 15 h. After cooling, the solvent was removed in vacuo. The residue was dissolved in EtOAc (100 ml) and the organic phase was washed with sat. NaHCO3 solution (50 ml), dried (MgSO4) concentrated in vacuo. The crude residue was purified by column chromatography DCM/MeOH (99:1) as the eluent to give the title compound (191 mg, 32%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[C:5]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[N:7]=[C:6]([C:14]([F:17])([F:15])[F:16])[C:5]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(N=[N+]=[N-])cc(C(F)(F)F)nc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(N)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 81.2 %

Procedure:
A mixture of 2.0 g (0.00611 mol) of product of Example 27, 100 mg of 10% Pd-C and 20 ml of ethanol was hydrogenated with 30 lbs. hydrogen pressure for three hours and filtered. The filtrate was concentrated. The residual oil (1.7 g) was triturated with petroleum ether and filtered to give 1.5 g (87%) of product as a white powder; mp 43°-45° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:1][C:2]2[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(OCC(F)(F)F)cc1O
Product: COC(=O)c1ccc(OCC(F)(F)F)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 82.6 %

Procedure:
Using a procedure similar to that of Example 26-B, methyl 2-hydroxy-4-(2,2,2-trifluoroethoxy)benzoate (2.0 g, 7.99 mmol) is alkylated with 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.61 g, 7.99 mmol) to afford methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2,2,2-trifluoroethoxy)benzoate (2.86 g).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[CH:19]([Cl:22])(Cl)Cl>>[CH2:15]([O:14][C:12]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:12](=[N:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[C:11]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:9][CH:10]=2)=[CH:18][CH:17]=1)=[O:13])[CH3:16]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(N=C(Nc2ccc(C(=O)OCC)cc2)c2ccc(Cl)cc2)cc1

Procedure:
N,N'-Bis(4-ethoxycarbonylphenyl)-4-chlorobenzamidine (12) was prepared from ethyl 4-[N-(4-chlorobenzoyl)] aminobenzoate, phosphorus pentachloride, and ethyl 4-aminobenzoate; white crystals: mp 171.0°-172.5° C. 1H-NMR (CDCl3) 8.0-6.9 (m, 13H), 4.2 (q, 4H, J=7 Hz), 1.5 (t, 6H, J=7 Hz); IR (CHCl3) 3420, 3330, 1705, 1590; MS (m/e) 450, 452 (M+), 286 (base).
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH:13]([CH3:16])[CH2:14][NH2:15])[CH:10]=[CH:9][C:8]=2[O:17][CH3:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](OC2C=CC=CC=2)=[N:27][C:28]#[N:29])=[CH:21][CH:20]=1>C(O)C>[C:28]([N:27]=[C:26]([O:25][C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1)[NH:15][CH2:14][CH:13]([C:11]1[CH:10]=[CH:9][C:8]([O:17][CH3:18])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:12]=1)[CH3:16])#[N:29]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(C(C)CN)nc1OC1CCCC1
Solvent: CCO
Product: COc1ccc(C(C)CNC(=NC#N)Oc2ccccc2)nc1OC1CCCC1
Yield: 61.7 %

Procedure:
A solution of (±)-6-(cyclopentyloxy)-5-methoxy-β-methyl-2-pyridineethanamine (0.037 mol) and diphenyl N-cyanocarbonimidate (0.037 mol) in ethanol (100 ml) was stirred for one day at RT. The precipitate was filtered off, washed with ethanol, DIPE, then dried, yielding 9 g (61.7%) of (±)-phenyl N′-cyano-N-[2-[6-(cyclopentyloxy)-5-methoxy-2-pyridinyl]propyl]carbamimidate(interm. 9). The filtrate was evaporated under reduced pressure. The residue was dissolved in CH2Cl2. The organic solution was washed three times with 2 N NaOH. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 4.1 g of intermediate (9). Total yield is 89%.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH:4]([C:6]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])O.C(O)(=O)C>[Pd].CO>[NH2:17][C:15]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([CH2:4][C:3]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:2]=2[F:1])[CH:16]=1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1C(O)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(N)cc1Cc1ccc(F)cc1F
Reaction time: 9 h
Yield: 69.3 %

Procedure:
A mixture of 2'-(2,4-difluoro-α-hydroxybenzyl)-4'-nitromethanesulfonanilide (5.3 g), 10% palladium on carbon (1 g) and acetic acid (6 ml) in methanol (60 ml) was shaken under hydrogen atmosphere for 9 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with a saturated solution of sodium bicarbonate, dried, and evaporated. The sirupy residue was recrystallized from ethanol to give crystals of 4'-amino-2'-(2,4-difluorobenzyl)methanesulfonanilide (3.2 g).
Reaction SMILES: [CH2:1]([S:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([S:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCS(=O)CCCCCCl
Reactant: C1CCNCC1
Product: CC(C)CCS(=O)CCCCCN1CCCCC1

Procedure:
Heat 5-chloropentyl isopentyl sulfoxide (760 mg, 3.38 mmoL) and piperidine (2 mL) at 125° C. for 1 hour. Partition between 5N sodium hydroxide and ethyl ether. Separate the organic phase and extract the aqueous phase with ethyl ether (2×25 mL). Combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo to yield 1.01 g yellow oil. Purify by silica gel chromatography (CHCl3 :MeOH:NH4OH/100:10:1) to yield 740 mg (80%) yellow oil which crystallizes. Purify further by silica gel chromatography (50% methanol/methylene chloride) to yield 79 mg of the title compound as a white solid; mp 44°-45° C.
Reaction SMILES: N[C:2]([C:21]([F:24])([F:23])[F:22])=[C:3]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].Cl.CC[O:28]CC>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH:3]([C:2](=[O:28])[C:21]([F:24])([F:23])[F:22])[C:4]([C:6]2[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=2)=[O:5])=[CH:15][CH:16]=1
Reactant: CCOCC
Reactant: CSc1ccc(C(=O)C(=C(N)C(F)(F)F)c2ccc(F)cc2)cc1
Agent: Cl
Product: CSc1ccc(C(=O)C(C(=O)C(F)(F)F)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 4.0 g of product of step 1, 40 mL of ether, and 40 mL of 6 N hydrochloric acid was stirred at room temperature for 4 days. The ether layer was dried over magnesium sulfate and concentrated in vacuo to give 4.0 g of crude 2-(4-fluorophenyl)-1-[4-(methylthio)phenyl]-4,4,4-trifluoro-1,3-butandione. A mixture of 0.22 g (0.59 mmol)of this product, 0.09 g of phenylhydrazine, and 10 mL of glacial acetic acid was heated at 80 ° C. for 18 hours and poured into water. The insoluble solid was purified by HPLC (10% ethyl acetate-hexane) to give 8 mg of 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-1-phenyl-5-(trifluoromethyl)pyrazole and 140 mg of 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-1-phenyl-3-(trifluoromethyl)pyrazole.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].N#N.N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C1COCC1.O>[C:15]([Si:12]([CH3:14])([CH3:13])[O:3][CH2:2][CH2:1][OH:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: OCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N#N
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCO
Temperature: 25 °C
Yield: 20 %

Procedure:
To a stirred solution of ethylene glycol (2.44 mL; 6.0 eq.) in dry THF (35 mL), under inert atmosphere (N2), were added imidazole (497 mg; 1.0 eq.) and a solution of tert-butyldimethylsilyl chloride (1.10 g; 1.0 eq.) in dry THF (35 mL). The reaction mixture was stirred at rt over the weekend. Water was added and THF was removed under vacuum. The residual aq. layer was extracted with EA (3×) and the combined org. layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The title compound was obtained, after purification by CC (Hept/EA 100:0 to 60:40), as a colorless liquid (258 mg; 20% yield).
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:35][CH2:34]3)=C(C(OC)=O)N=1)CC2)=O.C(C1SC(N2CCC3C(=C(C(=O)/N=C4/SC5C=CC=CC=5N/4COCC[Si](C)(C)C)C=CC=3)C2)=NC=1C(OC)=O)=[O:54].C1C=CC(N2CCNCC2)=CC=1.N1(C2C=C(O)C=CC=2)CCNCC1>>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[C:43]([OH:54])[CH:42]=[CH:41][CH:40]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CN1CCN(c2ccccc2)CC1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1C=O
Agent: Oc1cccc(N2CCNCC2)c1
Agent: c1ccc(N2CCNCC2)cc1
Product: CN1CCN(c2cccc(O)c2)CC1

Procedure:
Compound 87A was prepared in a similar manner to the synthesis of compound 62A by substituting compound 45C and phenylpiperazine with paraformahyde and 3-(piperazin-1-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.07 (s, 1H), 6.94-6.98 (m, 1H), 6.36 (d, J=8.13, 2.4 Hz, 2H), 8.28-8.29 (m, 1H), 6.18-6.21 (m, 1H), 3.04-3.07 (m, 4H), 2.41-2.43 (m, 4H), 2.21 (s, 3H). ESI (+)/MS: 193 (M+H)+.
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[C:14]2[O:13][C:12]([C:15](OCC)=[O:16])=[CH:11][C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:3]>C(O)C.O1CCCC1>[N+:2]([C:5]1[C:14]2[O:13][C:12]([C:15]([NH2:1])=[O:16])=[CH:11][C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CCOC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Reactant: N
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
Gas ammonia was bubbled for 30 minutes in a solution of ethyl 8-nitro-4-oxo-4H-benzopyran-2-carboxylate (2.109 g, 8.02 mmol) in anhydrous ethanol (50 ml) and anhydrous tetrahydrofuran (50 ml). After that the mixture was evaporated to dryness and the resulting solid residue was suspended in concentrated hydrochloric acid (20 ml) stirring at room temperature for 4 h. Then the mixture was diluted with water, the solid was recovered by filtration, washed repeatedly with water and dried under vacuum on phosphorous pentoxyde, to obtain 1.515 g of the title product (81% yield).
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][CH2:13][CH2:14]O)[C:8]([CH3:11])=[CH:9][N:10]=1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][CH2:13][CH2:14][Br:25])[C:8]([CH3:11])=[CH:9][N:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cnc(NCC(F)(F)c2ccccc2)c(=O)n1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cnc(NCC(F)(F)c2ccccc2)c(=O)n1CCCBr
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a magnetically stirred solution of 3-(2,2-difluoro-2-phenylethylamino)-1-(3-hydroxypropyl)-6-methylpyrazinone (2-12) (0.267 g, 0.82 mmol) and carbon tetrabromide (0.328 g, 0.99 mmol) in dichloromethane (10 mL), was added triphenylphosphine (0.26 g, 0.99 mmol) portionwise with ice-bath cooling. After the addition was complete, the mixture was stirred for an additional 2 hours. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate/n-hexane (2:1 to 1:1 gradient) as eluent to afford the title compound (0.309 g, 96.9%) as a yellow solid. Rf 0.45 ((EtOAc/hexane 1/1); 1H-NMR (CDCl3): δ 2.20 (d, J=1.2 Hz, 3H), 2.19-2.26 (m, 2H), 3.44 (t, J=6.4 Hz, 2H), 4.01-4.10 (m, 4H 6.12 (t, J=6.4 Hz, 1H), 6.62(d, J=1.2 Hz, 1H), 7.37-7.41 (m, 3H), 7.50-7.53 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:11]=[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][N:5]2[N:4]=1>[Pd].C(O)C>[F:12][C:2]([F:1])([F:13])[C:3]1[N:11]=[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[N:4]=1
Reactant: FC(F)(F)c1nc2cnccn2n1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1nc2n(n1)CCNC2

Procedure:
2-(Trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrazine (340 mg, 1.81 mmol, from Step C) was hydrogenated under atmospheric hydrogen with 10% palladium on carbon (60 mg) as a catalyst in ethanol (10 mL) at ambient temperature for 18 h. Filtration through Celite followed by concentration gave a dark colored oil. Flash chromatography (eluted with 100% ethyl acetate followed by 10% methanol/dichloromethane) gave the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reaction time: 24 h
Yield: 52.7 %

Procedure:
To a suspension of 100 g of 2-methyl-3-nitrobenzoic acid, methyl ester and 100 g of N-bromosuccinimide in 1000 ml carbon tetrachloride was added 3 g of benzoyl peroxide and the mixture was stirred at reflux temperature for about 24 hours. Additional benzoyl peroxide was then added and refluxing was resumed for another 24 hours. The reaction mixture was cooled, filtered, and the filtrate concentrated in vacuo to afford an oil which crystallized upon cooling. This crude product was dissolved in diethyl ether and the organic layer was washed with saturated aqueous sodium sulfite (one 500-ml portion), water (two 500-ml portions), 2.5% aqueous sodium hydroxide solution (one 500-ml portion), water and brine. Drying and evaporation of the organic layer in vacuo gave a yellow oil which crystallized on standing. Recrystallization from 350 ml n-butyl chloride/cyclohexane (2:1) gave 74 g of 2-(bromomethyl)-3-nitrobenzoic acid, methyl ester, m.p. 67°-70°.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:14]=[C:13](O)[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=1)[CH3:3].C(Cl)(Cl)[Cl:19]>P(Cl)(Cl)(Cl)=O>[Cl:19][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[N:14]=1
Reactant: ClC(Cl)Cl
Reactant: COc1ccc2c(O)nc(CN(C)C)nc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(CN(C)C)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-[(dimethylamino)methyl]-7-(methyloxy)quinazolin-4-ol (6.6 g, 28.0 mmol) in a mixture of chloroform (15.0 mL) and phosphorous oxychloride (15.0 mL) was heated to reflux for 90 minutes. After cooling it to room temperature the reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate (100 mL) and ethyl acetate (400 mL) and the mixture was stirred for 30 minutes. The organic layer was separated and washed with saturated sodium bicarbonate (2×100 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography using 15% methanol containing 0.5% triethylamine in ethyl acetate provided 1-[4-chloro-7-(methyloxy)quinazolin-2-yl]-N,N-dimethylmethanamine (7.0 g, quantitative). MS (EI) for C12H14ClN3O: 252 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])[S:9][C:5]=2[CH:4]=1)#[N:2].[N:18]([Sn](CCCC)(CCCC)CCCC)=[N+:19]=[N-:20]>O1CCCC1>[CH2:14]([NH:13][C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([C:1]3[N:18]=[N:19][NH:20][N:2]=3)[CH:17]=[CH:16][C:6]=2[N:7]=1)=[O:12])[CH3:15]
Reactant: CCNC(=O)Nc1nc2ccc(C#N)cc2s1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2ccc(-c3nn[nH]n3)cc2s1
Reaction time: 0.5 h

Procedure:
About 30 mg N-(6-cyano-1,3-benzothiazol-2-yl)-N′-ethylurea was charged into about 5 mL dry tetrahydrofuran. Added about 2 g of azidotributylstannane then refluxed for about 48–72 hours. The solvent was removed under reduced pressure then the crude oil was taken up in dichloromethane. About 0.5 mL of dilute aqueous hydrochloric acid was added and a white precipitate formed. This was allowed to sit for about 30 minutes then the precipitate was collected by filtration, washed with warm THF then dried under vacuum. 1H NMR 1.10 (t, 3H), 3.2 (m, 2H), 6.76 (br s, 1H), 7.78 (d, 1H), 8.0 (d, 1H), 8.58 (s, 1H), 10.91 (s, 1H); LC/MS 1.37 min, 290 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[F:22][C:23]1([F:33])[O:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([NH2:32])[C:25]=2[O:24]1>>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:32][C:31]4[C:25]5[O:24][C:23]([F:33])([F:22])[O:27][C:26]=5[CH:28]=[CH:29][CH:30]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1cccc2c1OC(F)(F)O2
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cccc4c3OC(F)(F)O4)ncc21

Procedure:
The title compound was synthesized from 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one and 2,2-difluorobenzo[d][1,3]dioxol-4-amine using the procedure described in the general Buchwald Reaction Scheme. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.84 (m, 9H) 3.97 (t, J=14.40 Hz, 2H) 4.50-4.70 (m, 1H) 7.14 (d, J=2.27 Hz, 1H) 7.31 (dd, J=7.45, 2.15 Hz, 1H) 8.21 (s, 1H) 9.39 (s, 1H). [M+H] calculated for C20H19F4N5O3, 454. found 454.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.Cl.Cl.[CH3:46][O:47][C:48](=[O:57])[C@H:49]([CH2:51][C:52]1[N:56]=[CH:55][NH:54][CH:53]=1)[NH2:50].CN1CCOCC1>C(#N)C.C(Cl)(Cl)Cl.CN(C)C=O.C(N(CC)CC)C>[CH3:46][O:47][C:48](=[O:57])[C@H:49]([CH2:51][C:52]1[N:56]=[CH:55][NH:54][CH:53]=1)[NH:50][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(O)C(CCCCc1ccccc1)Cc1cccc2ccccc12
Agent: Cl
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CCCCc1ccccc1)Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 63.4 %

Procedure:
To a solution of 3.32 g of 2-(1-naphthylmethyl)-6-phenylhexanoic acid in 50 ml of dry acetonitrile were added 2.70 g of N,N'-disuccinimidylcarbonate and 2.0 ml of triethylamine with stirring at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was added dropwise to a mixture of 2.42 g of L-histidine methyl ester dihydrochloride, 6 ml of N-methylmorpholine, 120 ml of dry N,N-dimethylformamide and 300 ml of dry chloroform, and the resulting mixture was stirred for 24 hours at 50° C. The reaction mixture was concentrated under reduced pressure and a 5% aqueous sodium bicarbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=30/1 by volume) to obtain 3.06 g of N-[2-(1-naphthylmethyl)-6-phenylhexanoyl]-L-histidine methyl ester as a white powder.