Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])(=[O:12])=[O:11])[CH3:2].[N:27]1([CH2:36][C:37](O)=[O:38])[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])(=[O:12])=[O:11])[C:37](=[O:38])[CH2:36][N:27]1[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-])C(=O)Cn1cc(C)c(=O)[nH]c1=O
Yield: 95.1 %

Procedure:
The title compound (2.69 g, 95%) was synthesized by the reaction of N-[2-(2-Nitro-4-trifluoromethyl-benzenesulfonylamino)-ethyl]-glycine ethyl ester (2.00 g, 5 mmol) and (thymin-1-yl)-acetic acid (0.92 g, 5 mmol) as per the procedure of example 46. 1H-NMR (500 MHz; DMSO-d6) δ 11.31 (s, 0.55H), 11.28 (s, 0.45H), 8.57 (s, 0.55H), 8.54 (s, 0.45H), 8.50 (t, 0.55H), 8.38 (t, 0.45H), 8.29˜8.18 (m, 2H), 7.31 (s, 0.55H), 7.22 (s, 0.45H), 4.64 (s, 1.1H), 4.46 (s, 0.9H), 4.21 (s, 0.9H), 4.16 (q. 0.9H), 4.07 (q. 1.1H), 3.95 (s, 1.1H), 3.49 (t, 1.1H), 3.37 (q, 1.1H), 3.25 (t, 0.9H), 3.09 (t, 0.9H), 1.75 (s, 3H), 1.23 (t, 1.35H), 1.18 (t, 1.65H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:11][C:12]([CH3:16])([CH2:13][OH:14])[CH2:15][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: CC(C)(CO)CBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CO)COc1ccccc1C=O

Procedure:
A solution of 20 g of salicylaldehyde, 30 g of 3-bromo-2,2-dimethylpropanol and 22 g of potassium carbonate in DMF was refluxed for 24 hours. After evaporation, the residue was dissolved in ethyl acetate and the solution was washed with water. The organic phase was dried over magnesium sulfate and evaporated. The residue was purified by chromatography (silica; dichloromethane).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:31]=[CH:30][C:13]2[S:14][CH:15]=[C:16]([CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[O:28][CH3:29])[C:12]=2[CH:11]=1.CN1CCOCC1.O>ClCCl>[C:1]([NH:9][C:10]1[CH:31]=[CH:30][C:13]2[S:14][CH:15]=[C:16]([CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[O:28][CH3:29])[C:12]=2[CH:11]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(Cc2csc3ccc(N)cc23)c(OC)c1
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2scc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Hexanoyl chloride (0.024 g.) was added to a stirred solution of methyl 4-(5-aminobenzo[b]thien-3-ylmethyl)-3-methoxybenzoate (H) (0.06 g.), and N-methylmorpholine (0.1 ml.) in dichloromethane (3 ml.). The mixture was stirred for 1 hour and then poured into water (20 ml.). The aqueous mixture was extracted with dichloromethane (2×20 ml.). The combined extracts were dried (MgSO4), and evaporated. The mixture was recrystallized from a mixture of ethyl acetate and hexane to give the title compound (0.05 g., 75%) as a colorless solid; NMR (250 MHz, DMSO-d6): 0.87(t,3H, CH2CH3), 1.28(m,4H, CH2.CH2.CH3), 1.59 (quintet,2H, CH2CH2CON), 2.29(t,2H, CH2CON), 3.84(s, 3H, OCH3), 3.91(s,3H, OCH3), 4.11(s,2H, CH2 --Ar), 7.14 (d,1H), 7.34(s,1H), 7.49(m,3H), 7.86(d,1H), 8.11(d, 1H), 9.95(s,1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1NCCC(C)C)=[O:5])[CH3:2].CS(NC1C=CC2NC(CC(O)=O)=NS(=O)(=O)C=2C=1)(=O)=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of cis-2-(3-methylbutylamino)-cyclopentanecarboxylic acid ethyl ester (53.5 mg, 0.237 mmol) in N,N-dimethylformamide (3.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 157.4 mg, 0.472 mmol) and a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.47 mL, 0.47 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with dichloromethane and the precipitated N,N′-dicyclohexylurea byproduct was removed by filtration. The filtrate was concentrated and dried in vacuo to afford the crude product, cis-2-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methylbutyl)amino]-cyclopentanecarboxylic acid ethyl ester, which was used in the next step without further purification. LC-MS (ESI) calcd for C23H34N4O7S2 542.19, found 543.2 [M+H+].
Reaction SMILES: CCC1NC(=O)C(NC(C2N=CC=CC=2O)=O)C(C)OC(=O)C(C2C=CC=CC=2)NC(=O)C2N(CCC(C2)=O)C(=O)C(CC2C=CC=CC=2)N(C)C(=O)C2N(CCC2)C1=O.[CH3:61][CH:62]1[CH:93]([CH:94]([CH3:96])[CH3:95])[O:92][C:90](=[O:91])[C:89]2[N:85]([CH2:86][CH2:87][CH:88]=2)[C:83](=[O:84])[C:80]2=[CH:81][O:82][C:78](=[N:79]2)[CH2:77][C:75](=[O:76])[CH2:74][CH:73]([OH:97])[CH:72]=[C:71]([CH3:98])[CH:70]=[CH:69][CH2:68][NH:67][C:65](=[O:66])[CH:64]=[CH:63]1>C(Cl)Cl>[CH3:61][C@H:62]1[C@@H:93]([CH:94]([CH3:95])[CH3:96])[O:92][C:90](=[O:91])[C:89]2[N:85]([CH2:86][CH2:87][CH:88]=2)[C:83](=[O:84])[C:80]2=[CH:81][O:82][C:78](=[N:79]2)[CH2:77][C:75](=[O:76])[CH2:74][C@H:73]([OH:97])[CH:72]=[C:71]([CH3:98])[CH:70]=[CH:69][CH2:68][NH:67][C:65](=[O:66])[CH:64]=[CH:63]1
Reactant: CC1=CC(O)CC(=O)Cc2nc(co2)C(=O)N2CCC=C2C(=O)OC(C(C)C)C(C)C=CC(=O)NCC=C1
Agent: CC1=C/C(O)CC(=O)Cc2nc(co2)C(=O)N2CCC=C2C(=O)OC(C(C)C)C(C)/C=C\C(=O)NC/C=C\1
Agent: CC1=C\[C@@H](O)CC(=O)Cc2nc(co2)C(=O)N2CCC=C2C(=O)O[C@H](C(C)C)[C@H](C)/C=C/C(=O)NC\C=C\1
Agent: CCC1NC(=O)C(NC(=O)c2ncccc2O)C(C)OC(=O)C(c2ccccc2)NC(=O)C2CC(=O)CCN2C(=O)C(Cc2ccccc2)N(C)C(=O)C2CCCN2C1=O
Solvent: ClCCl
Product: CC1=C[C@@H](O)CC(=O)Cc2nc(co2)C(=O)N2CCC=C2C(=O)O[C@H](C(C)C)[C@H](C)C=CC(=O)NCC=C1
Reaction time: 8 h

Procedure:
A simplified modification of the procedure of Sharma, et el. is suitable for use in the invention. In this procedure, 500 g STAFAC® is placed in an Erlenmeyer flask with 3.75 L methylene chloride. The mixture is stirred overnight with a mechanical stirrer. The STAFAC® is filtered, and rinsed with a Buchner funnel under vacuum, giving a cloudy yellow solution. A second filtration is performed through a glass-frit (medium) filter, giving a clear yellow solution. This solution is concentrated in vacuo to give a crude mixture of VM and VS. 10 g of this yellow/brown solid is purified with a medium pressure liquid chromatography (MPLC) column using gradients of 0.5, 1, 1.5, 3, 4, 6 and 8% methyl alcohol in methylene chloride. The fractions are separated by thin layer chromatography, and the fraction containing VM is concentrated with rotary evaporation. The VM1 is then recrystallized using ethyl acetate. 1.105 g of virginiamycin M1 is obtained.
Reaction SMILES: I[C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.C(C1C(C2C=C(N)C=CC=2)=C2C=CC=CN2N=1)(C)C>>[CH:11]([C:3]1[C:2]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)([CH3:13])[CH3:12]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)c1nn2ccccc2c1I
Agent: CC(C)c1nn2ccccc2c1-c1cccc(N)c1
Product: CC(C)c1nn2ccccc2c1-c1cnn(C)c1

Procedure:
2-Isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine was prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and 1-Methylpyrazole-4-boronic acid pinacol ester following the method used in Step 3 of the synthesis of 3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine (Example 59) (138 mg, 13%). 1H-NMR (250 MHz, DMSO-d6) δ 8.59 (d, J=6.8 Hz, 1H), 7.93 (s, 1H), 7.64 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 6.80 (t, J=6.8 Hz, 1H), 3.91 (s, 3H), 3.29 (sept, J=7.0 Hz, 1H), 1.29 (d, J=6.8 Hz, 6H); LC/MS 241.1 m/z (M+H+). Compound 1112.
Reaction SMILES: [C:1]([C:3]1[N:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1)#[N:2].C(N(CC)CC)C.[SH2:17]>C(O)C>[CH3:9][N:4]1[C:5]([CH3:8])=[CH:6][CH:7]=[C:3]1[C:1](=[S:17])[NH2:2]
Reactant: Cc1ccc(C#N)n1C
Reactant: S
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(N)=S)n1C

Procedure:
5 g of 2-cyano-1,5-dimethylpyrrol are dissolved in 40 ml of ethanol and treated with 10 ml of triethylamine. 50 ml of an ethanolic H2S solution (3.8 g/100 ml) are added and the mixture is heated for ca. 15 hours in an autoclave at 70°. The reaction mixture is cooled and the solvent is evaporated off to obtain ca. a quarter of its volume. 1,5-dimethylpyrrol-2-carbothioamide crystallizes upon cooling at 0° in the form of a light yellow precipitate.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[CH3:9].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:16][CH:13]1[CH2:14][CH2:15][CH:10]([CH2:8][CH3:9])[CH2:11][CH2:12]1)[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CCC1CCC(O)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1CCC(OC(=O)OC(C)Cl)CC1
Reaction time: 20 h

Procedure:
A solution of 1-chloroethyl chloroformate (5.46 g) in dry dichloromethane (20 ml) was added dropwise, under nitrogen at 0°, to a stirred solution of 4-ethylcyclohexanol (5 g) in dry dichloromethane (20 ml) in presence of 3A molecular sieves. A solution of pyridine (3 g) in dry dichloromethane (20 ml) was added dropwise to the reaction mixture during 20 min at 0° the mixture was then warmed to 20°, stirred for 20 hours, washed with brine (2×50 ml) and dried. The solvent was removed under vacuum and the residue was distilled to give the title compound as a colourless oil (7.9 g; b.p. 130°/5.2 mbar; t.l.c. cyclohexane/ethyl acetate 9/1 Rf=0.88; IR (CDCl3), Vmax (cm-1): 1757 (C=O); 1H-NMR (300 MHz, CDCl3): 6.43 (q), 6.42 (q), 4.93 (bs), 4.59 (tt), 2.14-2.01 (bs), 2.00-1.88 (bs), 1.88-1.78 (m), 1.83 (d), 1.82 (d), 1.60-1.50 (m), 1.50-1.32 (m), 1.30-1.15 (m), 1.28-1.18 (m) 1.05-0.95 (m), 0.95-0.85 (m).
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]1([C:18]([F:21])([F:20])[F:19])[C:15]2[C:10](=[C:11]([CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:17].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.CCCCCC>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][C:7]([OH:17])=[C:6]2[C:18]([F:19])([F:20])[F:21]
Reactant: Cc1cccc2c1CCC(=O)C2(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cccc2c(C(F)(F)F)c(O)ccc12
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Thionyl chloride (0.33 mL, 4.52 mmol) was added dropwise at about 5° C. to a stirred solution of 3,4-dihydro-1-hydroxy-5-methyl-1-(trifluoromethyl)-2(1H)-naphthalenone (1.04 g, 4.26 mmol) and 4-(dimethylamino)pyridine (3.5 mg) in pyridine (0.73 mL) under dry nitrogen. The reaction mixture was stirred and allowed to warm slowly to 25° C. (about 45 min). The reaction was judged to be complete by tlc using silica gel thin layer plates and 20% (v/v) ethyl acetate in hexane as the mobile phase. The reaction mixture was poured onto ice and extracted with diethyl ether. The ether extract was washed with water and a saturated solution of NaHCO3 in water, dried (MgSO4) and concentrated under reduced pressure to give the title compound (961 mg, 100% yield). A small sample, purified by sublimation (30°-34° C., 0.05 mm), had mp 83°-84° C.; nmr (CDCl3) δ 2.65 (s, 3H), 7.1 (d, J=9 Hz, 1H), 7.25 (m, 1H), 7.35 (q, J=8 Hz, 1H), 7.85 (m, 1H), 8.05 (d, J=9 Hz, 1H); uvλmax (MeOH) 335 nm (ε2,770), 322 (2,420), 293 (4,050), 281 (4,680), 222 (46,400); Anal Calcd for C12H9F3O: C, 63.72% H, 4.01%; Found: C, 63.47% H, 3.96%.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[C:10]1[CH:15]=[C:14]([NH:16][CH2:17][CH3:18])[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=1.O>C1COCC1>[CH2:17]([NH:16][C:14]1[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=[C:10]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=1)[CH3:18]
Reactant: [O-]c1ccccc1
Reactant: CCNc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]

Procedure:
A solution of sodium phenoxide (prepared from phenol and NaH) (6 mmol) in THF (3 mL) was added to a solution of the product from Step 1 (600 mg, 3.0 mmol) in THF (2 mL) and the resulting solution was heated to reflux overnight. The solution was cooled, poured into H2O and extracted with EtOAc. The organic layers were washed with H2O and brine, dried, filtered and concentrated to give a residue which was purified by column chromatography (5-80% EtOAc in hex) to give the title compound which was used directly in the next step. MS (ES+) m/e 260. [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=2)[CH2:4][CH:3]1C(OCC)=O.[OH-].[Na+]>Cl>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCOc1ccc(N2CCC(=O)C(C(=O)OCC)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCOc1ccc(N2CCC(=O)CC2)cc1
Yield: 84.2 %

Procedure:
A solution of Ethyl 4-oxo-1-(4-n-hexyloxyphenyl)piperidine-3-carboxylate (1.437 g) in 20% hydrochloric acid (7.2 ml) was refluxed for 2 hours, cooled, basified with 60% aqueous sodium hydroxide, and extracted with ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure to give 1-(4-n-Hexyloxyphenyl)-4-piperidone (0.959 g).
Reaction SMILES: [NH2:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C(O[C:24](SC(OCC)=S)=[S:25])C.[K]>N1C=CC=CC=1.C(OCC)(=O)C>[S:25]=[C:24]1[NH:1][C:2]2[C:19](=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)[O:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Reactant: CCOC(=S)SC(=S)OCC
Agent: [K]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc3[nH]c(=S)oc3cc2CC1
Temperature: 70 °C
Yield: 69.4 %

Procedure:
1,1-Dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (3.6 mmol) and potassium [(ethyloxy)carbonothioyl]sulfide (3.96 mmol) were suspended in pyridine (6 ml) and the reaction mixture was heated at 70° C. for 3 h. The solvent was removed under reduced pressure providing a crude product that after dissolution in ethyl acetate, washing with water and evaporation of the organic phase under reduced pressure gave the title compound as a yellow solid (2.5 mmol, 69% yield).
Reaction SMILES: ClC1C=CC([C@H]2CC[C@H](C3C=CC(Cl)=C([N+]([O-])=O)C=3)N2C2C=CC(NC(C)(C)C)=C(F)C=2)=CC=1[N+]([O-])=O.[CH3:38][O:39][C:40](=[O:104])[NH:41][C@@H:42]([CH:101]([CH3:103])[CH3:102])[C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56]([C@H:59]3[CH2:63][CH2:62][C@H:61]([C:64]4[CH:65]=[CH:66][C:67]5[N:71]=[C:70]([C@@H:72]6[CH2:76][CH2:75][CH2:74][N:73]6[C:77](=[O:87])[C@@H:78]([NH:82][C:83]([O:85][CH3:86])=[O:84])[CH:79]([CH3:81])[CH3:80])[NH:69][C:68]=5[CH:88]=4)[N:60]3[C:89]3[CH:94]=[CH:93][C:92]([NH:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[C:91]([F:100])[CH:90]=3)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44].[C:105](OC(=O)C)(=[O:107])[CH3:106].N1C=CC=CC=1>>[CH3:38][O:39][C:40](=[O:104])[NH:41][C@@H:42]([CH:101]([CH3:103])[CH3:102])[C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56]([C@H:59]3[CH2:63][CH2:62][C@H:61]([C:64]4[CH:65]=[CH:66][C:67]5[N:71]=[C:70]([C@@H:72]6[CH2:76][CH2:75][CH2:74][N:73]6[C:77](=[O:87])[C@@H:78]([NH:82][C:83]([O:85][CH3:86])=[O:84])[CH:79]([CH3:81])[CH3:80])[NH:69][C:68]=5[CH:88]=4)[N:60]3[C:89]3[CH:94]=[CH:93][C:92]([N:95]([C:105](=[O:107])[CH3:106])[C:96]([CH3:97])([CH3:99])[CH3:98])=[C:91]([F:100])[CH:90]=3)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc([C@H]3CC[C@H](c4ccc5nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c5c4)N3c3ccc(NC(C)(C)C)c(F)c3)cc2[nH]1)C(C)C
Agent: CC(C)(C)Nc1ccc(N2[C@@H](c3ccc(Cl)c([N+](=O)[O-])c3)CC[C@@H]2c2ccc(Cl)c([N+](=O)[O-])c2)cc1F
Solvent: c1ccncc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc([C@H]3CC[C@H](c4ccc5nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c5c4)N3c3ccc(N(C(C)=O)C(C)(C)C)c(F)c3)cc2[nH]1)C(C)C

Procedure:
Starting from 4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-N-tert-butyl-2-fluoroaniline, the initial product of the sequence outlined above was methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(tert-butylamino)-3-fluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (ACD Name v12). The N-acetyl group was added by reaction with acetic anhydride/pyridine to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73-0.90 (m, 12 H), 1.13 (d, J=5.20 Hz, 9 H), 1.37-1.44 (m, 4 H), 1.62-1.72 (m, 2 H), 1.92-2.02 (m, 9 H), 2.10-2.26 (m, 5 H), 2.51-2.58 (m, 2 H), 3.52 (s, 6 H), 3.73-3.85 (m, 4 H), 3.98-4.12 (m, 2 H), 5.09-5.17 (m, 2 H), 5.36-5.48 (m, 3 H), 6.08-6.18 (m, 3 H), 6.74-6.87 (m, 1 H), 7.08 (dd, J=13.72, 8.29 Hz, 3 H), 7.20 (s, 1 H), 7.24-7.31 (m, 4 H), 7.40 (d, J=8.24 Hz, 1 H), 7.48 (d, J=8.13 Hz, 1 H), 12.01 (s, 1 H), 12.17 (s, 1 H); MS (ESI+) m/z 964 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]2[C:23]3[CH:22]=[N:21][CH:20]=[N:19][C:18]=3[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)=[CH:10][N:9]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[C:23]4[CH:22]=[N:21][CH:20]=[N:19][C:18]=4[NH:17][CH:16]=3)=[CH:10][N:9]=2)=[CH:37][CH:38]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(N(Cc3ccc(Cl)cc3)C(=O)OC(C)(C)C)nc2)c2cncnc21
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncncc34)cn2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(4-Chloro-benzyl)-5-[hydroxy-(7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-pyridin-2-yl-carbamic acid tert-butyl ester (43, 0.1 g, 0.16 mmol) was dissolved in 5 mL of acetonitrile and triethylsilane (0.25 mL, 1.6 mmol) was added followed by trifluoroacetic acid (0.12 mL, 1.6 mmol). The reaction was stirred overnight at 80° C., then cooled and concentrated under vacuum. Ethyl acetate was added and the mixture was washed with 1 M potassium carbonate and brine. The organic portion was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 0-20% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound, which was further washed with a mixture of ethyl acetate in hexane (P-0001, 0.025 g, 44%). MS (ESI) [M+H+]+=349.9.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]2[CH:38]=[N:39][C:40]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:42]=2)=[CH:29][CH:28]=1.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37]3[CH:38]=[N:39][C:40]([CH2:43][N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[CH:41][CH:42]=3)=[CH:29][CH:28]=2)=[O:6])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:22])([CH3:21])[CH3:23]
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(-c3ccc(CN4CCOCC4)nc3)c3ccccc23)cc1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26 mmol), duisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])([O-:4])=[O:3].C(=O)(O)[O-].[Na+].[N+](C1C=C(C=CC=1)CN)([O-])=O.[CH2:29]([O:31][C:32](=[O:46])[CH:33]([C:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:34][C:35](=O)[CH3:36])[CH3:30].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:29]([O:31][C:32]([C:33]1[CH:34]=[C:35]([CH3:36])[N:9]([CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:38]=1[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:46])[CH3:30]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(Cc2cccc([N+](=O)[O-])c2)c1-c1ccccc1

Procedure:
m-Nitrobenzylamine hydrochloride (3 g) was suspended in an aqueous solution of saturated sodium bicarbonate (30 mL), and extracted with chloroform. The organic layer was dried over MGSO4, the solids saturated and solvents removed under vacuum to yield the free base. The m-nitrobenzylamine (5 mmol, 0.8 g) prepared above, 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid were combined in ethanol, then heated under reflux. The resulting residue was purified over silica gel to yield the named product, 1H-NMR (CDCl3, ppm): 1.10 t (3H), 3.16 s (3H), 4.08 q (2H), 5.04 s (2H), 6.55 s (1H), 7.07-7.53 bm (7H), 7.72 bs (1H), 8.04 bd (1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O:36][CH2:37][CH:38]1[O:40][CH2:39]1)(=O)C(C)=C.[OH-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[OH:36][CH2:37][CH:38]([OH:40])[CH2:39][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccc(O)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccc(OCC(O)CO)cc3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
In a reaction vessel equipped with a stirrer, a thermometer, a condenser, and a dropping funnel, 11.75 g of 4-hydroxy-4′-(di-p-tolylamino)stilbene, 4.35 g of glycidyl methacrylate, and 8 ml of toluene are contained, and the mixture is heated to 90° C. Further, 0.16 g of triethylamine is added thereto, and the mixture is agitated for 8 hours at 95° C. Next, 16 ml of toluene and 20 ml of a 10% aqueous solution of sodium hydroxide are added thereto, and the mixture is further agitated for 8 hours at 95° C.