Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1ccc(CCl)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 121.1 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (150 mg, 0.43 mmol) was dissolved in DMF (3 mL) and triethylamine (150 μL, 1.07 mmol, 2.5 eq.) added, followed by 1-chloromethyl-4-methoxybenzene (58 mg, 0.43 mmol). The reaction mixture was stirred for 12 hours at 80° C. and then the solvent was evaporated. The residue was purified by flash chromatography to give 244 mg of the title compound 20 as a yellow oil: 1H NMR (CDCl3): δ 8.15-8.10 (m, 1H), 8.07-8.01 (m, 1H), 7.85-7.80 (m, 1H), 7.67-7.62 (m, 1H), 7.23-7.15 (m, 2H), 6.87-6.82 (m, 2H), 3.91-3.76 (m, 4H), 3.42 (s, 2H), 2.93-2.88 (m, 2H), 2.03-1.87 (m, 5H), 1.52-1.43 (m, 2H), 1.01-0.94 (m, 2H), 0.81-0.73 (m, 2H). LC: 100%. MS (EI): m/z 469 (M+H+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Cl.C(O[CH:15](OCC)[CH2:16][CH:17](OCC)OCC)C>CCO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]=[CH:16][CH:15]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(CC(OCC)OCC)OCC
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: Brc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirring suspension of (4-bromophenyl)hydrazine hydrochloride (3.28 g, 14.7 mmol) in EtOH (25 mL) was added concentrated HCl (0.147 mL, 1.47 mmol) and 1,1,3,3-tetraethoxypropane (3.87 mL, 16.1 mmol). The reaction mixture was heated at reflux for 2 h then cooled to room temperature. The reaction mixture was poured onto water (150 mL) and hexanes (20 mL) and stirred for 1 h. A brown precipitate was collected by filtration and washed with water (2×10 mL) and hexanes (10 mL). The resultant solid was dried in air then washed with toluene (10 mL) to afford 2 g (61%) of 1-(4-bromophenyl)-1H-pyrazole INT-84 as a light brown powder. LCMS-ESI (m/z) calculated for C9H7BrN2: 223; found 223/225 [M+H]+, tR=2.14 min (Method 10).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:9])[CH3:8].[CH3:10][C:11]1[C:12]([CH:17]=O)=[N:13][CH:14]=[CH:15][CH:16]=1.[BH4-].[Na+]>CO>[CH3:10][C:11]1[C:12]([CH2:17][NH:9][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:8])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccnc1C=O
Reactant: CC(N)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccnc1CNC(C)c1ccccn1
Yield: 60 %

Procedure:
Using General Procedure B, reaction of 1-Pyridin-2-yl-ethylamine and 3-methylpyridine-2-carbaldehyde in MeOH with NaBH4 gave (3-Methyl-pyridin-2-ylmethyl)-(1-pyridin-2-ylethyl)-amine as a pale yellow oil (0.21 g, 60%).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17]>[OH-].[Na+].O>[CH3:19][O:18][C:16]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)NC(C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of d-valine, (5.0 g) in 1N sodium hydroxide (42.7 mL) was added sodium carbonate (4.53 g). The solution was cooled to 0° C. and methyl chloroformate (0.289 mL) was added dropwise over 2 h and reaction mixture was stirred for 2 h at 0° C. White reaction mixture was diluted with enough H2O to form a colorless solution and washed with ethyl ether (3×30 mL). Aqueous layer was acidified to pH=2 with concentrated HCl to give a white precipitate that collected by filtration, washed with H2O and dried under high vacuum to give 2-Methoxycarbonylamino-3-methyl-butyric acid as a crystalline white solid (4.668 g). LCMS-ESI−: calc'd for C7H13NO4: 176.2 (M+H+). Found: 175.9 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4].CCN(C(C)C)C(C)C.[CH2:38]([N:45]([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:46]([NH:48][C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=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(#N)C>[CH2:60]([N:45]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:46]([NH:48][C@H:49]([C:57](=[O:58])[NH:1][C@H:2]([C:3](=[O:4])[NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:13])[CH3:14])[CH:10]=[CH2:11])[CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:47])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: O=C(O)[C@H](Cc1ccccc1)NC(=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)N(Cc1ccccc1)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
100 mg (0.256 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide and 0.052 ml of Hunig base in 2 ml of acetonitrile were treated at room temperature with 100 mg of N-(dibenzylcarbamoyl)-3-phenyl-L-alanine and 113 mg of BOP and subsequently stirred at room temperature for 12 hours. Thereafter, the reaction solution was poured onto 1N hydrochloric acid/ice, extracted with ethyl acetate, the extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel using a 10:1 mixture of methylene chloride and methanol as the eluting agent yielded 130 mg of 1,1-dibenzyl-3-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]urea in the form of an amorphous solid. MS: 761 (M+H)+.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:11][CH2:12][CH:13]([OH:15])[CH3:14].C(N(CC)CC)C>ClCCl>[OH:15][CH:13]([CH3:14])[CH2:12][NH:11][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)CNC(=O)c1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
289 g isonicotinoyl chloride hydrochloride was added to 128 g 1-amino-propan-2-ol and 549 mL triethylamine in 2 L dichlormethane at 0° C. The reaction was stirred for 30 min. at 0° C. and then the solvent was removed. The residue was suspended in ethyl acetate and the precipitate was filtered. The filtrate was recrystallized from ethyl acetate to give 154 g of the desired product. Rf: 0.4 (DCM/MeOH=20/1), (M+H)+: 181
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]([CH3:10])[CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:9][CH2:8][CH:7]([O:6][C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:10])(=[O:23])=[O:22]
Reactant: CC(CO)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)Oc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A solution of 51.5 g of 2-(p-chlorophenoxy)-1-propanol and 57.5 ml of triethylamine in 680 ml of dichloromethane is chilled to -10° C. To the solution is added dropwise with stirring 25.8 ml of methanesulfonyl chloride in 20 ml of dichloromethane. The mixture is stirred for 1 hour at -7° C. to -10° C. and washed with ice cold water, saturated NaCl, saturated NaHCO3 and dried (MgSO4). The solvent is removed under reduced pressure to give 73 g of product as an oil.
Reaction SMILES: I[C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].CN([CH:26]=[O:27])C.CCCCCC>COC1CCCC1.C([Li])CCC>[CH3:11][C:10]1[CH:9]=[C:8]([CH3:12])[C:7]2[N:6]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=2[C:2]=1[CH:26]=[O:27]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(C)cc(C)c32)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: COC1CCCC1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(C)c32)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-iodo-5,7-dimethyl-1-tosyl-1H-indole (950 mg, 2.1 mmol) and DMF (0.33 mL, 4.2 mmol) in cyclopentyl methyl ether (22 mL), n-butyllithium in hexane (2.2 M, 1.3 mL, 2.8 mmol) was added at −78° C. After stirring for 1 h, additional n-butyllithium in hexane (2.2 M, 0.19 mL, 0.42 mmol) was added. After stirring for 15 min, the reaction was quenched with MeOH (2 mL) and 1M aq. NaHSO4 (4.5 mL), and diluted with EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave a residue that was purified by FCC [(10% DCM/heptane)/(20% EtOAc/DCM)=100/0 to 50/50] to give the title compound. MS (ESI+) m/z 328.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:33]=[CH2:34])=[C:4]([CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11]>C1C=CC=CC=1.C(O)C.[Rh](Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:33]([C:3]1[C:2]([CH3:1])=[C:10]2[C:6]([C:7](=[O:11])[O:8][CH2:9]2)=[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:4]=1[CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH3:34]
Reactant: C=Cc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: Cl[Rh](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCO
Product: CCc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2

Procedure:
A solution of methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoate (17.7 g) and tris(triphenylphosphine) rhodium chloride (1.2 g) in benzene (180 ml) and ethanol (180 ml) was hydrogenated for 11 hours. The solvents were removed under vacuum and the residue was crystallized from ethyl acetate/tert butyl methyl ether to afford methyl (E) 6-(1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate, mp 101.3°-102.8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH2:16][N:17]1C(=O)C3C(=CC=CC=3)C1=O)[C:7]([CH3:28])=[C:6]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.NN.[ClH:37]>CO.[Cl-].[Na+].O>[Cl-:37].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH2:16][NH3+:17])[C:7]([CH3:28])=[C:6]2[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc2c(=O)n(CCCN3C(=O)c4ccccc4C3=O)c(C)c(-c3ccccc3)c2c1
Reactant: Cl
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(=O)n(CCC[NH3+])c(C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[3-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)propyl]-1H-isoindole-1,3(2H)-dione (0.46 g) was dissolved in 20 mL methanol, and hydrazine (0.100 mL) was added. The reaction was stirred overnight at room temp, then diluted with brine and extracted with EtOAc (3×). The combined organic solutions were dried (Na2SO4) and concentrated. Flash chromatography (5% MeOH in CH2Cl2) gave a solid, which was treated with excess HCl and recrystallized from isopropanol/diethyl ether to give the titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]([C:13]3[CH:25]=[CH:24][C:23]4[C:22]5[C:17](=[CH:18][C:19](I)=[CH:20][CH:21]=5)[C:16]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:15]=4[CH:14]=3)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.O.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>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]([C:13]3[CH:25]=[CH:24][C:23]4[C:22]5[C:17](=[CH:18][C:19]([C:18]6[C:17]7[C:16]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:15]8[C:23](=[CH:24][CH:25]=[CH:13][CH:14]=8)[C:22]=7[CH:21]=[CH:20][CH:19]=6)=[CH:20][CH:21]=5)[C:16]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:15]=4[CH:14]=3)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(I)ccc2-c2ccc(-c3ccccc3-c3ccncc3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCC1(CCCCCCCC)c2cc(-c3ccccc3-c3ccncc3)ccc2-c2ccc(-c3cccc4c3C(CCCCCC)(CCCCCC)c3ccccc3-4)cc21
Temperature: 110 °C
Reaction time: 48 h

Procedure:
To a solution of 400 mg (0.60 mmol) of 2-(6-p-pyridyl-phenyl)-7-iodo-9,9-dioctylfluorene, 362 mg (0.60 mmol) of 2-(4,4,5,5 tetramethyl-1,3,2-dioxaborolane)-9,9-dihexylfluorene in 10 mL of toluene was added: 4 mg (0.004 mmol) Pd(PPh3)4 and 2.5 ml of an 20% (3.1 mmol) Et4NOH solution in water. This two-phase reaction mixture was stirred for 48 h at 110° C. after which it was extracted using dichloromethane/water. The organic layer was dried on MgSO4 and the solvents were removed under reduced pressure. The crude product was purified using flash chromatography. Yield 450 mg (86%). 1H NMR (400 MHz, CDCl3): δ=8.74 (d, 3J=4.9 Hz, 1H; CH—N), 8.13 (d, 3J=4.6 Hz, 2H; CH—C—C(CH)—N), 7.84-7.77 (mp, 6H, ArH), 7.74 (d, 3J=6.0 Hz, 2H, CH—CH—CH—N), 7.69-7.63 (mp, 6H; ArH), 7.39-7.30 (mp, 3H; ArH), 7.27-7.24 (mp, 1H (obscured by CDCl3 peak; ArH), 2.11-2.02 (mp, 8H, C—CH2), 1.18-1.09 (mp, 32H, CH2), 0.81-0.74 (mp, 20H, CH2—CH3). 13C{1H} NMR (500 MHz, CDCl3): δ=157.1 (CN), 151.8, 151.4, 151.0 (C—C—CH2), 149.8 (CH—N), 142.2, 140.8, 140.6, 140.42; 140.39, 140.3, 139.9, 139.3, 138.1 (ArC), 136.8 (CH—CH—CH—N), 127.5, 127.3, 126.9, 126.8, 126.1, 126.0, 122.1, 122.0, 121.44, 121.38, 120.4, 120.0, 119.8, 119.7 (CH), 55.3, 55.1 (C—CH2), 40.4 (C—CH2), 31.7, 31.5, 30.0, 29.7, 29.18, 29.16 (CH2), 23.8, 23.7 (C—CH2—CH2), 22.6, 22.5 (CH3—CH2), 14.03, 13.99 (CH3). Exact Mass (IE): 875.6367 [M]+(calcd 875.6369) fractions m/z: 762.3 (m; [M-(C8H17)]+, 650.4 (m; [M-(C8H17)2]+. C65H81N: calcd. C, 89.09; H, 9.32; N, 1.60. found: C, 88.60; H, 9.25; N, 1.52.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][O:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2ccoc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ccoc12
Temperature: 25 °C
Yield: 78 %

Procedure:
Furo[3,2-d]pyrimidin-4(3H)-one (Intermediate 83) (1.49 g) and phosphorus oxychloride (15 mL) were heated to 120° C. for 45 minutes, cooled to ambient temperature, and evaporated under high vacuum. The residue was added to 50% saturated sodium carbonate (100 mL) and extracted into DCM (3×100 mL). The combined organics were dried and the solvent removed to afford the title compound as an orange solid (1.32 g, 78%);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH3:2].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)CCc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCc1cc(C(=O)CCC(=O)O)ccc1OC
Yield: 77.6 %

Procedure:
Starting with a mixture of 3.12 g (15.0 mmol) of 2-methoxybenzenepropanoic acid ethyl ester, 1.53 g (15.3 mmol) of succinic anhydride, 4.46 (33.5 mmol) of aluminum chloride and 20 mL of methylene chloride, the title compound (3.59 g, 77.7%) was obtained as a white solid, mp 128°-129° C. (recrystallized from ethanol), using the procedure of example 139.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[C:5]1=[O:24].CSC(SC)=C1C(=O)C(CCCC)(CCCC)C2C(=CC=CC=2)C1=O.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([I:59])=[CH:55][C:54]=1[S:60]([NH2:63])(=[O:62])=[O:61]>>[CH2:15]([C:12]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[C:5]([OH:24])=[C:4]([C:3]2[NH:52][C:53]3[CH:58]=[CH:57][C:56]([I:59])=[CH:55][C:54]=3[S:60](=[O:62])(=[O:61])[N:63]=2)[C:13]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2cc(F)ccc21
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Agent: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 5D, substituting the compound of Example 18G for the compound of Example 5C, and substituting the compound of Example 20A for the compound of 2D. 1H NMR (300 MHz, CDCl3): δ 0.56 (m, 2 H) 0.77 (m, 6 H) 0.90 (m, 2 H) 1.18 (m, 4 H) 1.90 (m, 2 H) 2.30 (m, 2H) 7.08 (dd, J=8.46, 4.41 Hz, 2 H) 7.43 (m, 2 H) 7.93 (m, 2 H) 8.28 (d, J=1.84 Hz, 1 H) 16.58 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH3:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:39][C:40]([OH:42])=O)[CH:25]=[CH:26][C:27]=1[N:28](C1C=CC=CC=1C)[C:29]([NH2:31])=[O:30]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:40](=[O:42])[CH2:39][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:29]([NH:31][C:4]2[CH:3]=[CH:13][CH:12]=[CH:11][C:5]=2[CH3:6])=[O:30])=[C:22]([O:21][CH3:20])[CH:23]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCNCCOc1ccc(C(=O)OCC)cc1OC
Reactant: COc1cc(CC(=O)O)ccc1N(C(N)=O)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 8 h
Yield: 180.7 %

Procedure:
To a stirred solution of ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (290 mg, 1.08 mmol) and pentafluorophenyl ester of 3-methoxy-4-[N-(2-methylphenyl)ureido]phenylacetic acid (502 mg, 1.05 mmol) in DMF (7 mL) was added Et3 N (250 μl, 1.79 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by column chromatography on silica-gel with CHCl3-MeOH (40:1, v/v) as an eluent to give 550 mg (93%) ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate as an amorphous solid. 1H-NMR (CDCl3) δ 1.11–1.18 (m, 3 H), 1.37–1.41 (m, 3 H), 2.30 (s, 3 H), 3.47–3.53 (m, 2 H), 3.61–3.75 (m, 7 H), 3.84 (s, 3 H), 4.03–4.27 (m, 2 H), 4.33–4.39 (m, 2 H), 6.34–8.07 (series of m, total 12 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.[F:19][C:20]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:21]=1[CH2:22]Br>O1CCCC1>[CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[C@@H:7]([CH2:22][C:21]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:20]=2[F:19])[N:8]=1
Reactant: COC1=N[C@@H](C(C)C)C(OC)=NC1
Reactant: Fc1cc(F)c(CBr)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](Cc2cc(F)c(F)cc2F)C(OC)=N[C@H]1C(C)C
Reaction time: 0.33 h

Procedure:
To a solution of 3.42 g (18.5 mmol) of commercially available (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 100 mL of tetrahydrofuran at −70° C. was added 12 mL (19 mmol) of a 1.6M solution of butyllithium in hexanes. After stirring at this temperature for 20 min, 5 g (22.3 mmol) of 2,4,5-trifluorobenzyl bromide in 20 mL of tetrahydrofuran was added and stirring was continued for 3 h before warming the reaction to ambient temperature. The reaction was quenched with water, concentrated in vacuo, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried, and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-5% ethyl acetate in hexanes) afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:12].[CH3:13]O.S(Cl)(Cl)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:4][C:3]=1[F:12]
Reactant: O=C(O)Cc1ccc(Br)c(F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Br)c(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
To a solution of 2-(4-bromo-3-fluorophenyl)acetic acid (500 mg, 2.146 mmol) in MeOH (10 mL, 247 mmol) was added sulfurous dichloride (0.232 mL, 3.22 mmol). The resulting mixture was stirred at 60° C. After 3 h, LCMS analysis showed the starting material had disappeared and the solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield a yellow oil of methyl 2-(4-bromo-3-fluorophenyl)acetate (500 mg, 1.774 mmol, 83.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.53 (t, J=8.0 Hz, 1H), 7.15 (dd, J=9.8, 1.7 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 3.75-3.61 (m, 5H); ES-LCMS m/z 248.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[C:7]([CH:12]3[CH2:14][CH2:13]3)[NH:8]2)=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[N:18][N:19]([CH2:21][CH3:22])[CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[C:7]([CH:12]3[CH2:14][CH2:13]3)[N:8]2[C:16]2[CH:17]=[N:18][N:19]([CH2:21][CH3:22])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: Fc1c(Cl)ccc2cc(C3CC3)[nH]c12
Reactant: CCn1cc(Br)cn1
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Temperature: 140 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of compound 3 (4.3 g, 20.5 mmol) in toluene (50 mL) were added 4-bromo-1-ethyl-1H-pyrazole 4 (4.0 g, 22.8 mmol), potassium phosphate (11.0 g, 51.2 mmol), N,N′-dimethylethylenediamine (722 mg, 8.2 mmol) and Cu(I)I (390 mg, 2.0 mmol) at RT under inert atmosphere. The reaction solution was purged with argon for 15 min and then sealed the tube. The reaction mixture was heated to 140° C. and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was cooed to RT, diluted with EtOAc (50 mL) and filtered. The filtrate was washed with water (40 mL), brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 9% EtOAc/Hexanes) to afford compound 5 (3.9 g, 63%) as a pale brown solid. 1H NMR (400 MHz, CDCl3): δ 7.64 (s, 1H), 7.60 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.01 (dd, J=8.4, 6.4 Hz, 1H), 6.12 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.69-1.62 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 0.92-0.87 (m, 2H), 0.76-0.72 (m, 2H); LC-MS (ESI): 98.6%; m/z 304.3 (M+H+); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 4.23 min; 5 mM NH4OAc: ACN; 0.8 mL/min).