Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH:8]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]4[N:25]([CH2:35][C:36]5[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=5)[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)[CH:20]=3)[CH:15]=2)[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C1COCC1.CO>O>[C:1]1([CH2:7][CH:8]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]4[N:25]([CH2:35][C:36]5[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:40][CH:41]=5)[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)[CH:20]=3)[CH:15]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 30 °C
Yield: 71.2 %

Procedure:
In a similar manner as described in step 2 of Example 6, the title compound was prepared from methyl 3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoate (0.200 g, 0.330 mmol), prepared in the previous step, and 1N NaOH (0.50 mL, 0.50 mmol) in 1.33:1.33:1 THF:MeOH:water (33 mL) with the exception that this reaction was not complete after 18 hours (overnight) at ambient temperature. The reaction was warmed to 30° C. for 1.5 hours, an additional portion of 1N NaOH (0.50 mL, 0.50 mmol) was added and the mixture maintained at 30° C. for an additional 1.5 hours. The isolated yellow amorphous solid was purified by reverse-phase (C18) HPLC using 20% water in acetonitrile with 0.1% formic acid as the eluent. Isolation of the product from the chromatography fractions gave 3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoic acid as a greenish amorphous solid (0.139 g, 71%), mp 153–155° C. Elemental Analysis for C37H28F3NO3.0.24 H2O.0.10 C6H14 Calc'd: C, 74.70; H, 4.98; N, 2.32. Found: C, 74.67; H, 5.23; N, 2.25.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][Si](C)(C)C)[CH:3]=1.[OH-].[K+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH2:9])[CH:3]=1
Reactant: C[Si](C)(C)C#Cc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
To a solution of 1-bromo-3trimethylsilylethynylbenzene (20.5 g, 81.0 mmol) in degassed methanol (500 ml) was added potassium hydroxide (31 mg, 0.55 mmol) in water (1 ml). The solution was stirred at room temperature until G.C. analysis indicated the reaction was complete (5.0 h). The reaction mixture was diluted with an equal volume of water, and extracted with n-pentane (5×500 ml). The combined organic layers were dried (MgSO4) and the solvent removed under reduced pressure to yield a yellow liquid. The liquid was distilled via bulb-to-bulb vacuum distillation to yield the product (1c) (13.0 g, 90%) as a clear liquid: bp 40° C.C/1 torr; 1H NMR (200 MHz, CDCl3) c3.35(s), 7.23(t), 7.40(m), 7.65(t).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CC[C@H](C(=O)N[C@H](C)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)N[C@H](C)c2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
Into a sealable tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-[(1R)-1-phenylethyl]-3-piperidinecarboxamide (188 mg, 0.41 mmol), EtOH (5 ml), Hunig's base (0.072 ml, 0.41 mmol), and hydrazine anhydrous (0.077 mL, 2.46 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (78 mg) as a light yellow solid. LC-MS (ES) m/z=471 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.06-1.21 (m, 4H), 1.38 (m, 3H), 1.71 (m, 4H), 2.25-2.41 (m, 1H), 2.92 (m, 1H), 4.84-5.01 (m, 1H), 5.38 (s, H), 6.09 (s, 2H), 6.59 (s, 1H), 7.12-7.40 (m, 6H), 7.53-7.62 (m, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 8.41 (d, J=8.1 Hz, 1H), 11.50 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:5]2[OH:26].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[OH:26][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[CH:3]=2)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]=1[C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(-c3cccnc3)ccc2C(C)(C)C1=O
Temperature: 150 °C
Yield: 40 %

Procedure:
A suspension of 1,1-dimethylethyl N-((6-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (284 mg, 669 μmol, see Example 39), pyridin-3-ylboronic acid (165 mg, 1339 μmol), and Na2CO3 (2.0M aqueous solution (669 μL, 1339 μmol)) in 1,4-dioxane (5 mL) was treated with Pd(PPh3)4 (77 mg, 67 μmol) in a microwave vial. The vessel was capped, degassed, backfilled with argon (2×), and heated at 150° C. in a microwave for 1200 sec. The reaction was diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 20-28-40% EtOAc/hexane) affording 113 mg of the title compound. MS m/e=423.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N+:3]([O-])=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:4]1[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]2=[C:2]([Cl:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2ccsc2c1Cl
Product: Clc1cc2ccsc2c(Cl)n1
Temperature: 115 °C
Reaction time: 7 h
Yield: 70 %

Procedure:
A mixture of 7-chlorothieno[2,3-c]pyridine 6-oxide (2.58 g, 13.8 mmol) and POCl3 (20 mL) was stirred at 115° C. under N2 for 7 h. After that time, the excess POCl3 was removed in vacuo, and the residue was poured into ice/water (100 mL), basified by addition of 8 N NaOH followed by saturated NaHCO3, and extracted with DCM (3×50 mL). The combined extracts were washed with saturated NaHCO3 (50 mL), water (50 mL) and brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by ISCO chromatography (0 to 40% EtOAc:heptane) to afford 1.97 g (70%) of the title compound as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 7.82 (d, J=5.6 Hz, 1 H), 7.68 (s, 1 H), 7.37 (d, J=5.6 Hz, 1 H); MS (ESI): 203.94, 205.94 [M+H]+; HPLC tR=1.55 min (TOF: polar—3 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.[NH3:10].[O-2].[Mg+2]>O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:9])[CH:3]=1)[NH2:10]
Reactant: Fc1cc(F)cc(F)c1
Reactant: N
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: Nc1cc(F)cc(F)c1
Temperature: 225 °C
Reaction time: 6 h

Procedure:
A 600 ml Hastelloy pressure reactor (Parr Instrument Co., Moline, Ill.) equipped with the standard stirrer, thermowell, and valves was used. The reactor was charged with 0.833 moles of 1,3,5-trifluorobenzene (110 g), 4.6 moles of 29% ammonia in water (270 g), and 0.44 moles of magnesium oxide (17.8 g). The reactor was purged with argon, and heated to 225° C. until the maximum pressure (about 1400 psig) was reached. As the reaction proceeded, the pressure dropped at a rate of about 20 lbs./hour for about 6 hours. The reactor was then cooled and the contents allowed to settle. The oils were drained from the reactor bottom until salts/water are observed. The salts float on the oils and settle slowly in the aqueous ammonia. The aqueous salts were extracted 2 or 3 times with MTBE. The MTBE was combined with the oils and charged to a distillation column packed with stainless steel packing (ProPak). The salts were centrifuged, washed with water, and discarded. The product was isolated by distilling MTBE at atm. Pressure, then distilling DFA at 20 to 50 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12].Cl.CN(C)CCCN=C=NCC.N=C=N>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:14][CH2:13][CH2:11][OH:12])=[O:8])=[CH:9][CH:10]=1
Reactant: NCCO
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N=C=N
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NCCO)cc1
Reaction time: 1 h

Procedure:
A solution of 4-aminobenzoic acid (2.7 g, 20 mmol), ethanolamine (1.4 g, 23 mmol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (4.1 g, 21 mmol) in dimethylformamide (60 ml) was stirred overnight at room temperature. More carbodiimide (0.3 g, 2 mmol) was added and after stirring for one hour the reaction mixture was concentrated in vacuo onto silica gel (15 g). Purification by chromatography on silica gel (125 g) eluting with methanol:methylene chloride (3.97 to 1:19) and recrystallization from methanol:ethyl acetate gave, after drying under high vacuum, 4-amino-N-(2-hydroxyethyl)benzamide (1.65 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ: 3.26 (q, J=6 Hz, 2H, NCH2), 3.46 (q, J=6 Hz, 2H, OCH2), 4.68 (t, J=5.5, 1H, OH), 5.58 (br s, 2H, NH2), 6.51 (d, J= 8.5 Hz, 2H, Ar), 7.56 (d, J=8.5 Hz, 2H, Ar), 7.94 (br t, J=5.4 Hz, 1H, CONH). Mass spectrum (CI-CH4): 181 (M+1, 100%). Anal. Calculated for C9H12N2O2 : C, 59.99; H, 6.71; N, 15.55. Found: C, 60.05; H, 6.72; N, 15.55.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[CH:17]=1)[CH2:11]2
Reactant: COc1cccc(CN)c1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(CN2Cc3cccc(I)c3C2=O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 3-methoxy-benzylamine (0.052 mL, 0.4 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(3-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.031 g, 27%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.78 (s, 3H), 4.16 (s, 2H), 4.74 (s, 2H), 6.79 (m, 3H), 7.14-7.38 (m, 3H), 7.91 (d, 1H). GC-MS: m/z 379 (M)+.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21](O)=[O:22])=[CH:14]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[O:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][NH2:53]>CN(C)C=O.O>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([NH:53][O:52][CH:47]2[CH2:48][CH2:49][CH2:50][CH2:51][O:46]2)=[O:22])=[CH:14]3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cnc2ccc(NS(=O)(=O)c3ccccc3)cc2c1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1cnc2ccc(NS(=O)(=O)c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-[(Phenylsulfonyl)amino]quinoline-3-carboxylic acid (0.11 g, 0.335 mmol) was dissolved in N,N-dimethylformamide (2.5 mL) and triethylamine (0.14 mL, 1 mmol) was added. Tetramethylfluoroformamidinium hexafluorophosphate (0.106 g, 0.402 mmol) was added and the reaction mixture was allowed to stir at room temperature for 15 min. Then O-(tetrahydropyran-2-yl)hydroxylamine (0.0471 g, 0.402 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate three times. The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-10% MeOH in methylene chloride gradient with 0.1% formic acid) to afford the product (Int-13, 0.027 g, 18%). LC-MS: (AA) ES+ 428.
Reaction SMILES: C1(C(O)=O)[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]1.[CH3:12]O.S(=O)(=O)(O)O.CO.[C:21]([O:24][CH2:25]C)(=[O:23])[CH3:22]>>[CH:22]1([C:21]([O:24][CH3:25])=[O:23])[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:12])=[O:7])[CH2:2]1
Reactant: O=C(O)C1CCC(C(=O)O)C1
Reactant: CCOC(C)=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCC(C(=O)OC)C1
Temperature: 7 °C
Yield: 100 %

Procedure:
A 5-L, 3-neck, round bottom flask was equipped with a mechanical stirrer, a J-KEM temperature controller, and a reflux condenser. The flask was charged with cyclopentane-1,3-dicarboxylic acid (357 g, 2.262 mol) and methanol (1.75 L). The solution was cooled to 7° C. using an ice/water bath. Concentrated sulfuric acid (70 mL) was added dropwise over 30 min resulting in an exotherm up to 12° C. The reaction mixture was heated to reflux and stirred for 16 h when TLC analysis (10% methanol/ethyl acetate) indicated that the reaction was complete. The reaction mixture was concentrated, redissolved in methyl tert-butyl ether, and washed with saturated aqueous sodium bicarbonate (2×150 mL) and brine (2×150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting clear oil was dissolved in hexane (2 L) and treated with a 2 N aqueous sodium hydroxide solution (950 mL) until the pH˜10. The layers were separated and the aqueous layer was extracted with hexane (4×1 L). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to provide 360 g (100%) of dimethyl cyclopentane-1,3-dicarboxylate as a clear oil. 1H NMR (500 Hz, CDCl3) δ ppm 3.67 (s, 6H), 2.75-2.83 (m, 2H), 2.20-2.26 (m, 1H), 2.05-2.12 (m, 1H), 1.90-2.0 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11])(=[O:23])[CH2:21][CH3:22]
Reactant: O=C(O)C1Cc2ccccc2N1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1c2ccccc2CC1C(=O)O
Reaction time: 0.25 h

Procedure:
To a solution of indoline-2-carboxilic acid (8.16 g, 50 mmol) and triethyl amine (10 mL, 71.74 mmol) in anhydrous CH2Cl2 (60 mL) containing catalytic amount of DMAP was added dropwise a solution of propionyl chloride (5.55 g, 60 mmol) in CH2Cl2 (20 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min and then at room temperature for 2.5 hours. The reaction mixture was washed successively with 5% aqueous KHSO4 solution (2×20 mL), brine (25 mL), dried over Na2SO4, and evaporated under reduced pressure to dryness. The residue was crystallized from methanol to yield 1-propionyl-2,3-dihydro-1H-indole-2-carboxylic acid as a white solid, 9.19 g (83%): mp 173-175° C.; 1H NMR (DMSO-d6) δ1.05 (3H, t, J=7.6 Hz, Me), 2.51 (2H, d, J=7.6 Hz, CH2), 3.17 (1H, d, J=16.0 Hz, CH), 3.57 (1H, dd, J=11.0 Hz, J=16.0 Hz, N—CH), 5.15 (1H, d, J=16.0 Hz, CH), 6.98-7.01 (1H, m, ArH), 7.15-7.23 (2H, m, 2×ArH), 8.07-8.09 (1H, m, ArH), 13.26 (1H, brs, exchangeable, OH). Anal. Calcd. for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.73; H, 6.07; N, 6.34.
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Na+:14].[Na+].[Na+].Cl[Pd:18]Cl>O>[Pd:18].[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Na+:14].[Na+:14].[Na+:14]
Reactant: Cl[Pd]Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: O
Product: [Pd]
Reaction time: 10 h

Procedure:
Sodium citrate (8.07 g) was dissolved in 807 ml of water, to which was added 56 ml of 6.7×1031 3 M PdCl2. This mixture was further diluted with 403 ml of water. The mixture was heated to boiling for 10 hours to form a Pd-sodium citrate colloid solution. To this was added 2 g fluorinated carbon (fluorine content 28%, median particle size less than one micrometer, surface area 130 m2 /g) together with 100 ml methanol. The solution was evaporated and the solid was reduced in hydrogen for 14 hours at 300° C. The resultant catalyst contained approximately 0.7% Pd. The catalyst was a partially wettable, black, slightly sticky powder.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.C1C=CC=CC=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]1[C:33](=[O:34])[NH:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(C(CO)CO)N(C(=O)Nc1ccccc1)CC2
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 0.01 mole (2.7 g) of 1-[bis-(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in 30 ml of absolute benzene 0.01 mole (0.3 g) of phenyl isocyanate is added, and the mixture is refluxed for 30 to 60 minutes. The reaction mixture is allowed to cool to room temperature, the precipitated crystals are filtered off, washed with ether and crystallized. The aimed compound is obtained with a melting point of 191° to 192° C. (ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:34][CH2:35][C:36](Br)=[O:37].C(=O)([O-])O.[Na+]>ClCCl.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:36](=[O:37])[CH2:35][Br:34])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CBr)c3ccccc32)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a solution of (3aR*,10aS*)-9-[4-(benzyloxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (610 mg, 1.4 mmol) in dichloromethane (7 mL) was added bromoacetyl bromide (0.15 mL, 1.7 mmol) dropwise and the mixture was stirred at room temperature for 15 minutes. This reaction mixture was diluted with water (5 mL) with vigorous stirring and neutralized with sodium hydrogen carbonate. The aqueous layer was separated and the organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from chloroform-ethyl acetate to provide 519 mg (yield 66%) of the title compound. m.p. 222°-223° C. (decomp.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23](Cl)=[O:24])[CH3:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:23](=[O:24])[CH:22]([CH2:20][CH3:21])[CH2:26][CH2:27][CH2:28][CH3:29])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: CCCCC(CC)C(=O)Cl
Product: CCCCC(CC)C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-ethylhexanoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-ethylhexanamide as a tan powder, m.p. 163.0-164.0° C. 1H NMR (300 MHz, DMSO-d6) δ8.19 (s, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.79 (m, 1H), 7.61 (dd, J=8.1, 1.2 Hz 1H), 7.44 (dt, J=7.5, 1.2 Hz, 1H), 7.26 (dt, J=7.5, 1.2 Hz, 1H), 6.63 (s, 2H), 4.61 (t, J=6.9 Hz, 2H), 3.12-3.05 (m, 2H), 1.94-1.82 (m, 3H), 1.49-1.03 (m, 10H), 0.76 (t, J=7.2 Hz, 3H), 0.67 (t, J=7.2 Hz, 3H), MS (EI) m/e 381.2533 (381.2529 calcd for C22H31N5O).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH2:21])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.[Li+].[OH-]>N1C=CC=CC=1.C1COCC1>[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH:21][C:8](=[O:9])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
Picolinoyl chloride hydrochloride (501 mg, 2.82 mmol) was added to a solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (324 mg, 1.41 mmol, Example 1, Step H) in pyridine (5 mL). The reaction was stirred at room temperature for 10 minutes, and the pyridine was removed in vacuo. The residue obtained was dissolved in THF (5 mL), treated with 2N LiOH (3 mL), and stirred for 20 minutes. THF was then removed in vacuo, and water (20 mL) was added. The solid formed was collected by filtration and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide (389 mg, 82% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.17 (br s, 1H), 10.39 (s, 1H), 8.76 (d, 1H), 8.40 (d, 1H), 8.17-8.15 (m, 1H), 8.09 (dt, 1H), 7.87 (d, 1H), 7.71-7.68 (m, 1H).