Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([O:66][C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:75](=[O:86])[C@@H:76]([NH2:85])[CH2:77][CH:78]2[CH2:82][O:81][C:80]([CH3:84])([CH3:83])[O:79]2)[CH2:71][CH2:70]1)=[O:68])[CH3:65]>CN(C=O)C.C(OCC)(=O)C>[CH2:64]([O:66][C:67]([N:69]1[CH2:70][CH2:71][N:72]([C:75](=[O:86])[C@@H:76]([NH:85][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:30])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:28])[CH2:77][CH:78]2[CH2:82][O:81][C:80]([CH3:83])([CH3:84])[O:79]2)[CH2:73][CH2:74]1)=[O:68])[CH3:65]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CC2COC(C)(C)O2)CC1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC2COC(C)(C)O2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 120 mg 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 3 ml DMF were added 50 μl DIPEA, 111 mg HATU and 96 mg 4-[(S)-2-Amino-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-propionyl]-piperazine-1-carboxylic acid ethyl ester. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent deprotection reaction. Yield: 238 mg.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26]>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:25]#[C:26][C:2]2[N:6]3[CH:7]=[C:8]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]3=[N:4][CH:3]=2)[CH:28]=1
Reactant: C#Cc1cccnc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3c2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(C#Cc4cccnc4)n3c2)cc1

Procedure:
The title compound was prepared from 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18 step 6) (460 mg, 1 mmol) and commercially available 3-ethynylpyridine (105 mg, 1 mmol) according to general procedure II. Obtained as a white solid (330 mg, 75%). MS (ISP) 432.1 [(M+H)+]; mp 169-170° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[F:17][C:18]([F:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](O)=[O:20]>>[F:17][C:18]([F:28])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]([NH:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:20]
Reactant: O=C(O)C(F)(F)c1ccccc1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(Nn1nc(C(F)(F)F)c2ccccc2c1=O)C(F)(F)c1ccccc1

Procedure:
The product of Example 11B and 2,2-difluoro-2-phenylacetic acid were treated using a method similar to that described in Example 51 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 13.10 (s, 1H), 8.43-8.47 (m, 1H), 8.16 (td, J=7.6, 1.6 Hz, 1H), 8.03-8.12 (m, 2H), 7.74-7.78 (m, 2H), 7.54-7.66 (m, 3H); MS (ESI+) M/Z 384 (M+H)+.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@@H](COC)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:31]([C@@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1)#N>>[CH3:1][O:2][CH2:31][C@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1
Reactant: COC[C@@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: COC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 90 %

Procedure:
The title compound II-aj was prepared in 90% yield from 3,3:17,17-bis(ethylendioxy)-6β-methoxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 70/10/20). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.45 (m, 2H), 3.27 (s, 3H), 2.80-0.80 (m, 21H), 1.10 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [CH:1]1([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH:42]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)[C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=3)=[O:31])[CH:23]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CN(C=O)C.[Pd].[C]>[NH2:39][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:30](=[O:31])[N:29]([CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:9]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=3)=[O:10])[CH:23]=2)[CH:42]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]2)=[CH:38][CH:37]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)N(Cc1cccc(CN(C(=O)Nc2ccc([N+](=O)[O-])cc2)C2CCCCCC2)c1)C1CCCCCC1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(NC(=O)N(Cc2cccc(CN(C(=O)Nc3ccc(N)cc3)C3CCCCCC3)c2)C2CCCCCC2)cc1
Yield: 55 %

Procedure:
To a solution of 3 g 1,3-bis[[1-cycloheptyl-3-(p-nitrophenyl)ureido]methyl]benzene (compound of Example 28) in 50 ml N,N'-dimethylformamide, was added 300 ml of 10% Pd-carbon powder, and the mixture was subjected to catalytic hydrogenation. After a predetermined volume of hydrogen gas was absorbed, the catalyst was filtered off, the solvent was distilled off under reduced pressure from the filtrate, and the residue was purified by silica gel column chromatography, giving 1.5 g of 1,3-bis[[3-(p-aminophenyl)-1-cycloheptylureido]methyl]benzene as amorphous powder. This was treated with ethanolic hydrogen chloride, and the solid thus obtained was recrystallized from aqueous ethanol, affording 1.1 g of 1,3-bis[[1-cycloheptyl-3-(p-aminophenyl)ureido]-methyl]benzene dihydrochloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:53][C:54]1[CH:55]=[C:56]([CH2:60][C:61](O)=[O:62])[CH:57]=[CH:58][CH:59]=1>CN(C=O)C.CO.C(Cl)Cl>[CH3:53][C:54]1[CH:55]=[C:56]([CH2:60][C:61]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:18]5[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=5[O:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:62])[CH:57]=[CH:58][CH:59]=1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: Nc1ncnc2occ(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4coc5ncnc(N)c45)ccc32)c1
Temperature: 0 °C

Procedure:
To a stirred dark greenish solution of 5-(2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (500 mg, 1.98 mmol) and HATU (829 mg, 2.18 mmol, 1.1 equiv) in 5 mL of DMF was added DIEA (381 uL, 2.18 mmol, 1.1 equiv). To this mixture was added (3-methylphenyl)acetic acid portionwise (298 mg total, 1.98 mmol, 1 equiv), about 100 mg at 30 min intervals. After a total of 2.5 hours, the mixture was poured into 50 mL of ice cold water to give a suspension, which was filtered. The cake was washed with water (2×10 mL) and dried under house vacuum for 18 h to afford crude product (1.0 g), which was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. First pass purification was done on an SF25-60 g silica gel cartridge using gradient elution of 1% A in DCM to 55% A in DCM (A was a mixture of 3200/800/80 DCM/MeOH/NH4OH). The desired product eluted impure from 24-30% A. The fractions were combined and concentrated in vacuo, and reabsorbed onto a dryload cartridge. Second pass purification was done on an SF25-80 g silica gel cartridge using gradient elution of 1% B to 100% B in EtOAc. (B was a 2.5% MeOH in EtOAc). The desired pure product fractions combined, and concentrated in vacuo. The residue was taken up in CHCl3 (1 mL) and MTBE (7 mL) to give a suspension, which was filtered. The cake was washed with MTBE (2×3 mL) and hexane (3×3 mL) and dried under vacuum at 65° C. to afford 5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[2,3-d]pyrimidin-4-amine (431 mg) as beige-colored solids. LC-MS (ES) m/z=385 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H), 3.22 (t, J=8.5 Hz, 2H), 3.84 (s, 2H), 4.22 (t, J=8.6 Hz, 2H), 7.04-7.15 (m, 3H), 7.19-7.26 (m, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.37 (s, 1H), 7.92 (s, 1H), 8.18 (d, J=8.3 Hz, 1H), 8.25 (s, 1H), NH2 protons not visible.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C@@H:8]1[CH2:21][C:22]([O:24][CH3:25])=[O:23].O.[ClH:39]>[OH-].[Na+].CO.C(OCC)C>[ClH:39].[ClH:39].[OH:3][CH:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C@@H:8]1[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COC(=O)C[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12

Procedure:
1 drop of 5N aqueous sodium hydroxide solution and then, portionwise, 0.17 g of sodium borohydride were added, with stirring, to a solution, maintained at a temperature in the region of 20 ° C., of 0.84 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate in 12 cm3 of methanol. The mixture was stirred for 3 hours at a temperature in the region of 20° C. After adding 10 cm3 of water, the methanol was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was extracted with 2 times 20 cm3 of dichloromethane and then the combined extracts were washed with 2 times 30 cm3 of water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. An oil was obtained, which oil was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 2.5 cm; silica volume 150 cm3), elution was carried out with a dichloromethane/methanol (99/1 by volume) mixture. Fractions 56 to 115 were combined and then concentrated as above. An oil was obtained, the hydrochloride of which was prepared in the following way: the oil was dissolved in 20 cm3 of diethyl ether and then poured onto 2 cm3 of a 1 N solution of hydrochloric acid in ether. The precipitate formed was filtered off and dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 40° C. 0.3 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate dihydrochloride was obtained in the form of a white solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1.[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].[NH4+].[Cl-]>O1CCCC1>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([CH:28]([OH:29])[CH2:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[O:19])=[CH:30][CH:31]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
4.0 ml of LDA 1M in THF (4.0 mmol) are added under nitrogen to a solution of p-methoxyacetophenone (500 mg, 3.3 mmol) in THF (tetrahydrofuran) (15 ml) at −78° C. The mixture is stirred for 1 h before 5 ml of a THF solution of p-tert-butylbenzaldehyde (594 mg, 3.7 mmol) are added. The reaction is allowed to reach −40° C. over the course of 1 h. A cold aqueous solution of NH4Cl 1N is subsequently added to the reaction mixture. The resultant mixture is partitioned between water (30 ml) and dichloromethane (30 ml). The resultant aqueous phase is subsequently extracted with dichloromethane (2×30 ml). The combined organic phases are dried over MgSO4. Removal of the solvent gives 3-(4-tert-butylphenyl)-3-hydroxy-1-(4-methoxyphenyl)propan-1-one.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[C:19](O)=[O:20].C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:19](=[O:20])[C:18]([CH3:17])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: CC(C)(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 2-methyl-2-phenylpropanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.49-7.38 (m, 4H), 7.31 (ddd, J=7.3, 14.4, 22.5, 5H), 7.08 (d, J=7.3, 1H), 4.46-4.35 (m, 1H), 3.58 (d, J=13.2, 1H), 3.43 (d, J=13.2, 1H), 2.84 (d, J=6.7, 1H), 2.36 (d, J=4.8, 3H), 2.31 (d, J=9.6, 1H), 2.21-2.13 (m, 1H), 2.04 (td, J=5.9, 11.7, 1H), 1.70 (dd, J=6.7, 12.3, 1H), 1.67 (s, 6H), 1.53-1.41 (m, 1H), 1.38-1.26 (m, 1H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][CH2:7][CH:8]([OH:19])[CH2:9][NH:10][C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])([O-:3])=[O:2].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>[OH:19][CH:8]([CH2:7][O:6][C:5]1[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:9][N:10]([C@@H:11]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:25](=[O:26])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](NCC(O)COc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(CC(O)COc1ccccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
The product from Example 1B (31.3 g, 100 mmol) in THF (300 mL) and 10% Na2CO3 (250 mL) at 0° C. was treated dropwise with benzyl chloroformate (18.0 g, 105 mmol), stirred vigorously for 30 minutes, and extracted with diethyl ether. The organic layer was washed with brine, dried (MgSO4), and concentrated to provide the title compound.
Reaction SMILES: O[CH:2]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[CH:16]=1)[CH2:3][N:4]([CH2:12][CH2:13][OH:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[CH3:24][C:17]1[CH:16]=[C:15]([CH:2]2[O:14][CH2:13][CH2:12][N:4]([C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])[CH2:3]2)[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: Cc1cc(C(O)CN(CCO)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-hydroxy-2-(3-methyl-4-nitrophenyl)ethyl(2-hydroxyethyl)carbamate (6.55 g) and triethylamine (3.22 ml) in THF (50 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (1.65 ml). The reaction mixture was then stirred at room temperature for 30 min to afford a yellow suspension. TLC analysis showed a small amount of starting material remaining and so further aliquots of triethylamine (0.5 ml) and methanesulfonyl chloride (0.2 ml) were added. The reaction mixture was stirred at room temperature for a further 20 min and was then filtered to remove triethylamine hydrochloride, washing the filter with THF (20 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (17.0 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 30 min and then poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford tert-butyl (RS)-2-(3-methyl-4-nitrophenyl)morpholine-4-carboxylate (2.21 g, 36%) as a yellow oil. MS (ISP): 223.1 ([M+H—O5H8O2]+).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:19](=[O:21])[NH2:20])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:19]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[OH:8])[C:13]([O:15][CH3:16])=[O:14])(=[O:21])[NH2:20]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(C(N)=O)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(O)c(C(N)=O)c1
Yield: 96.4 %

Procedure:
Hydrogenolysis is effected by dissolving 1.2 gm (4.2 mmol) of methyl 4-benzyloxy-3-carbamoylbenzoate in 60 mL of methanol (warmed to effect solution), adding 1 gm of 10% Pd/C (50% water) catalyst, and stirring under 48 psi of hydrogen overnight at room temperature. The reaction mixture is filtered, and the catalyst is repeatedly washed with 10% MeOH/DCM. The combined filtrates are evaporated to dryness to give 0.79 gm (4.05 mmol, 96% yield) of methyl 3-carbamoyl-4-hydroxybenzoate.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(OC1C=CC(C(O)=O)=CC=1)CCCCCCCCCCCCCCCCC>>[CH2:1]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
This compound was prepared by hydrolysis of methyl 4-docosyloxybenzoate in a manner analogous to that described above for 4-octadecyloxybenzoic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[CH2:15][CH:14]([CH3:19])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)CC(=O)O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Yield: 66.7 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 3-methylbutanoic acid (isovaleric acid) (222 mg, 2.17 mmol) and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) was processed as described in Example 56, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide (182 mg, 67% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (s, 1H), 9.46 (s, 1H), 8.34 (d, 1H), 7.56 (s, 1H), 2.20 (d, 2H), 2.11-2.05 (m, 1H), 0.96 (d, 6H); LCMS (APCI+) m/z 314, 316 (M+H)+, Retention time=3.02 minutes (Method 2).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@H:16]1[C@@H:25]([C:26]([OH:28])=[O:27])[C:24]2[C:19](=[CH:20][C:21]([O:31][CH3:32])=[C:22]([O:29][CH3:30])[CH:23]=2)[C:18](=[O:33])[N:17]1[CH3:34])=[O:8].[C:35](=O)(O)[O-].[Na+]>CO>[CH3:5][O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@H:16]1[C@H:25]([C:26]([O:28][CH3:35])=[O:27])[C:24]2[C:19](=[CH:20][C:21]([O:31][CH3:32])=[C:22]([O:29][CH3:30])[CH:23]=2)[C:18](=[O:33])[N:17]1[CH3:34])=[O:8]
Reactant: COC(=O)Nc1ccccc1[C@H]1[C@@H](C(=O)O)c2cc(OC)c(OC)cc2C(=O)N1C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Nc1ccccc1[C@H]1[C@H](C(=O)OC)c2cc(OC)c(OC)cc2C(=O)N1C
Temperature: 0 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Thionyl chloride (10 mL) was added slowly to a suspension of cis 10 (0.75 g, 1.8 mmol) and trans 10 (1.35 g, 3.3 mmol) in methanol (100 mL) at 0° C. The resulting mixture was stirred for 6 h at 0° C. After completion of the reaction (TLC), the reaction mixture was poured slowly into a mixture of ice (200 g) and a saturated solution of sodium bicarbonate (100 mL). The resulting mixture was extracted with chloroform (3×150 mL), and the combined extracts were dried with sodium sulfate, filtered though a thin pad of silica gel, and evaporated to dryness to obtain 11 as amorphous glassy solid (2.1 g, 96%). IR (film) 1733, 1637 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.67 (s, 1 H), 7.52 (d, J=7.7 Hz, 1 H), 7.25 (t, J=7.0 Hz, 1 H), 7.03 (t, J=7.5 Hz, 1 H), 6.83 (d, J=7.8 Hz, 1 H), 6.73 (s, 1 H), 6.54 (s, 1 H), 5.45 (s, 1 H), 3.95 (s, 3 H), 3.89 (s, 1 H), 3.82 (s, 3 H), 3.72 (s, 3 H), 3.63 (s, 1 H), 3.03 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 172.06, 164.17, 155.49, 152.15, 149.18, 134.39, 132.53, 129.10, 126.67, 126.53, 125.93, 125.14, 121.60, 111.86, 110.17, 59.32, 56.29, 56.20, 53.27, 53.06, 48.66, 34.57; ESIMS m/z (rel intensity) 429 (MH+, 100), 451 (56); ESIHRMS m/z MH+ calcd. for C22H24N2O7, 429,1662; found, 429.1665.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([N+:19]([O-])=O)=[CH:14][C:5]=1[C:6]([O:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]>C(O)C.[Fe]>[NH2:19][C:15]1[C:16]([F:18])=[CH:17][C:4]([Cl:3])=[C:5]([CH:14]=1)[C:6]([O:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(OC1CCCC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(C(=O)OC2CCCC2)c(Cl)cc1F
Temperature: 75 °C
Reaction time: 2 h

Procedure:
71 g of iron powder are placed in 190 ml of ethanol, 50 ml of water and 5 ml of 32% hydrochloric acid while stirring and the whole is heated to 75° C. (internal temperature). A warm solution of 100 g of cyclopentyl 2-chloro-4-fluoro-5-nitrobenzoate in 50 ml of ethanol is added dropwise to this mixture. The reaction mixture is stirred at 70°-75° C. (internal temperature) for a further 2 hours, cooled, after cooling suction filtered over Celite and the residue on the suction filter is rinsed with 500 ml of water followed by 200 ml of ethyl acetate. The filtrate is brought to a PH value of 8 with saturated potassium bicarbonate solution and the resulting brown precipitate is filtered off over Celite. The filtrate is extracted twice with 400 ml of ethyl acetate each time. the combined organic phases are washed twice with 200 ml of saturated sodium chloride solution each time, dried over anhydrous magnesium sulphate and concentrated. Then, the residue is purified by chromatography on a silica gel column using ethyl acetate/n-hexane (1:4) as the eluent and crystallized from diisopropyl ether/n-hexane. In this manner there is obtained cyclopentyl 5-amino-2-chloro-4-fluorobenzoate, m.p. 61°-62° C.