Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(C2C3C(=CC=C(NC(C4(NC=O)CCN(CC(=O)N5CCN(C6C=CC(C7N=CC=CN=7)=CC=6)CC5)C4)=O)C=3)NN=2)=CC=1.[F:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([NH:65][C:66]([C:68]4([NH:96]C=O)[CH2:72][CH2:71][N:70]([CH2:73][C:74]([N:76]5[CH2:81][CH2:80][N:79]([C:82]6[CH:87]=[CH:86][C:85]([C:88]7[N:93]=[CH:92][C:91]([CH3:94])=[CH:90][N:89]=7)=[CH:84][CH:83]=6)[CH2:78][CH:77]5[CH3:95])=[O:75])[CH2:69]4)=[O:67])[CH:63]=3)[NH:58][N:57]=2)=[CH:52][CH:51]=1>>[F:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([NH:65][C:66]([C:68]4([NH2:96])[CH2:72][CH2:71][N:70]([CH2:73][C:74]([N:76]5[CH2:81][CH2:80][N:79]([C:82]6[CH:87]=[CH:86][C:85]([C:88]7[N:89]=[CH:90][C:91]([CH3:94])=[CH:92][N:93]=7)=[CH:84][CH:83]=6)[CH2:78][CH:77]5[CH3:95])=[O:75])[CH2:69]4)=[O:67])[CH:63]=3)[NH:58][N:57]=2)=[CH:54][CH:55]=1
Reactant: Cc1cnc(-c2ccc(N3CCN(C(=O)CN4CCC(NC=O)(C(=O)Nc5ccc6[nH]nc(-c7ccc(F)cc7)c6c5)C4)C(C)C3)cc2)nc1
Agent: O=CNC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Product: Cc1cnc(-c2ccc(N3CCN(C(=O)CN4CCC(N)(C(=O)Nc5ccc6[nH]nc(-c7ccc(F)cc7)c6c5)C4)C(C)C3)cc2)nc1

Procedure:
Following essentially the same procedure as Example 361 except substituting compound 6P with an equivalent quantity of 8P, the title compound 11P was obtained as a mixture of 2 isomers. LCMS (MH 648) Retention time=2.90 minutes.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38](=[O:45])[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccc1
Yield: 88 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide hydrochloride and benzoyl chloride. Yield: 88% of theory, C34H32N6O4 (588.7); Rf value: 0.37 (silica gel; dichloromethane/ethanol=19:1); 1H-NMR spectrum (D6-DMSO): 2.61 (t,2H), 3.54 (s,3H), 3.76 (s,3H), 4.10 (t,2H), 4.61 (d,2H), 6.83 (d,2H), 7.05 to 7.55 (m,12H),8.03 (d,2H), 8.25 (dd,2H), 8.98 (s,1H), 10.48 (s,1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[N+:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][NH:1]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCN2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)NCC2
Temperature: 10 °C
Yield: 95 %

Procedure:
5.96 g (50 mmol) of indoline were dissolved in 25 ml of concentrated sulfuric acid, and a mixture of 3.75 ml of concentrated nitric acid (61%) and 25 ml of concentrated sulfuric acid was added to the solution while ice-cooling so that the internal temperature was maintained at 10° C. or lower. The mixture was then stirred while ice-cooling for 2 hours. At the end of this time, a 75% w/v aqueous solution of sodium hydroxide was added to the reaction mixture while ice-cooling to neutralize the reaction mixture, while maintaining the internal temperature at 60° C. or lower. The mixture was then extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and, after filtration, the solvent was removed from the filtrate by distillation under reduced pressure to obtain 7.8 g (47.5 mmol) of the title compound as crystals, melting at 65°-68° C. (yield: 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:44])[CH2:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:44])[CH2:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)[CH3:22]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1
Product: C=CCCC(C)Nc1c(C)noc1-c1ccc(-c2ccc(C3(CC(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-pent-4-enyl)-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Br:11][C:12]1[C:13]([NH2:21])=[C:14]([NH2:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18].C>[OH-].[Na+]>[Br:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]2[C:13]=1[NH:21][C:2](=[O:4])[C:1](=[O:8])[NH:20]2
Reactant: Nc1cc(F)c(F)c(Br)c1N
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2cc(F)c(F)c(Br)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.70 g, 18.5 mmol) and 3-bromo-4,5-difluoro-1,2-diaminobenzene (410 mg, 1.85 mmol) was heated to reflux under N2 for 15 h. The reaction was allowed to cool to room temperature and the dark-brown solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 215 mg (42%). A portion of this solid (150 mg) was taken and dissolved in 20 mL 1N NaOH with heating. The solution was treated with activated charcoal and filtered through a pad of Celite. The resulting solution was carefully acidified with 1N HCl (pH=1). Pale yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 20 mL of H2O and dried under vacuum (0.1 torr, 78° C.) to yield 67.8 mg of powdery pale yellow crystals, mp 306°-310° C. (dec). 1H NMR (d6 -DMSO) δ7.09 (dd, 1H, J=7.5, H-8), 11.3 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/z 278 (M+2, 75), 276 (M+, 77), 250 (56), 248 (57), 141 (bp). EIHRMS calc. for C8H4BrF2N2O2 275.9346, found 275.9331.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:21]1[O:29][C@@H:22]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(OC(C)C)(=O)C.[OH-].[Na+]>O1CCCC1.CN1CCCN(C)C1=O>[OH:29][C@H:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(N)cc1
Reactant: c1ccc([C@@H]2CO2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Solvent: CN1CCCN(C)C1=O
Product: NCCc1ccc(NC[C@H](O)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a 1000 mL 3-neck flask was added 10 g (74 mmol) of 2-(4-aminophenyl)ethylamine and 15 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimdinone (DMPU). The reaction flask was fitted with an overhead stirrer, a 125 mL addition funnel and a thermometer. The reaction flask was purged with nitrogen and placed in a cold water bath. The addition funnel was charged with 83 mL (83 mmol) of 1.0 M sodium bis(trimethylsilyl)amide in tetrahydrofuran. The sodium bis(trimethylsilyl)amide solution was added dropwise over 30 min with vigorous stirring. The addition funnel was removed and replaced with a rubber septum. (R)-styrene oxide (8.4 mL, 74 mmol) was added dropwise by syringe over 10 minutes. The rate of addition was controlled to maintain a temperature below 35° C. After 1 h, the reaction was quenched by dropwise addition of 88 mL water. The reaction mixture was transferred to a separatory funnel, diluted with 56 mL isopropyl acetate and washed with 84 mL saturated aqueous sodium chloride. The organic layer was washed a second time with a mixture of 84 mL water and 84 mL saturated aqueous sodium chloride and finally with 84 mL saturated aqueous sodium chloride. The organic layer was concentrated under vacuum. The residue was twice reconcentrated from isopropanol (55 mL portions) and then redissolved in isopropanol (235 mL) and heated to 70° C. with stirring. Concentrated hydrochloric acid (13.2 mL, 160 mmol) was added over two minutes. The mixture was allowed to cool to room temperature and stirred for 14 h. The precipitated product was isolated by filtration and washed with isopropanol and isopropyl acetate. The product was dried under vacuum for 3 h and then dissolved in 56 mL water and transferred to a separatory funnel. Isopropyl acetate (56 mL) and 10 N aqueous sodium hydroxide (19 mL, 190 mmol) were added. The separatory funnel was shaken and the phases separated. The organic layer was dried over sodium sulfate and concentrated to afford the product 2 as an orange-brown oil (11 g, 44 mmol, 59%). m/z: [M+H+] calcd for C16H20N2O 257.2; found 257.2.
Reaction SMILES: Cl.Cl.CO[C:5]1[CH:10]=[C:9]([NH2:11])[C:8](C)=[CH:7][C:6]=1[NH2:13].N.N[C:16]1[C:17](C)=[C:18]([OH:23])[C:19](C)=[CH:20][CH:21]=1.OO>O>[CH:16]1[C:21](=[N:13][C:6]2[CH:5]=[CH:10][C:9]([NH2:11])=[CH:8][CH:7]=2)[CH:20]=[CH:19][C:18](=[O:23])[CH:17]=1
Reactant: Cc1ccc(N)c(C)c1O
Reactant: COc1cc(N)c(C)cc1N
Agent: Cl
Agent: N
Agent: OO
Solvent: O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Reaction time: 4 h
Yield: 78.2 %

Procedure:
0.2 mole (4.5 g) 2-methoxy-5-methyl paraphenylenediamine dihydrochloride is dissolved in 200 cc water and the pH thereof is adjusted to 8 by the addition thereto of ammonia. This solution is immediately added to 0.02 mole (2.74 g) 3-amino-2,6-dimethyl phenol, previously dissolved in 200 cc water. To the resulting mixture there are added 60 cc ammonia 22° Be and 260 cc hydrogen peroxide to make 20 volumes. The mixture is allowed to stand at room temperature for four hours. On filtering the reaction mixture on a suction filter, then are obtained 3.1 g of said indoaniline in crystalline form, which after recrystallization from a mixture of pyridine and water, exhibits a melting point of 145°.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][Cl:23].C(=O)([O-])O.[Na+]>CO>[ClH:23].[ClH:18].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][S:15][C:13]1[NH:14][C:10]2[CH:9]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=[CH:16][C:11]=2[N:12]=1
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN(C)CCSc1nc2ccc(Cc3ccccc3)cc2[nH]1
Yield: 84.8 %

Procedure:
According to the method described in Example 2 g (25 mmoles) of 5-benzyl-benzimidazoline-2-thione, 4.32 g (30 mmoles) of 2-(dimethylamino)-ethylchloride hydrochloride and 2.55 g of sodium hydrogencarbonate are refluxed in methanol. The salt is filtered off, the filtrate is concentrated and treated with aqueous sodium hydroxide solution and dichloromethane. The organic phase is separated, concentrated and the salt is precipitated by adding hydrochloric ether. 8.15 g (84.8%) of 2-(2-dimethylaminoethylthio)-5-benzyl-benzimidazole dihydrochloride are obtained, which melts at 204° C. after recrystallization from isopropanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH:35]=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:35][C:34]2[CH:37]=[CH:38][C:39]([F:40])=[C:32]([Cl:31])[CH:33]=2)[CH3:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CNC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Product: CN(Cc1ccc(F)c(Cl)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1

Procedure:
As described for Example 75d, 2-[4-(1-benzyl-4-methylamino-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile was converted, using 3-chloro-4-fluorobenzaldehyde instead of 3,4-dichlorobenzaldehyde, to the title compound. MS m/e=546.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([O:23][P:24]([CH:28]([NH:33]C(OCC1C=CC=CC=1)=O)[CH2:29][CH2:30][CH2:31][CH3:32])([O:26][CH3:27])=[O:25])[C:11]([N:13]1[CH2:22][CH2:21][CH2:20][C@H:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12])=[O:4].N1CCC[C@H]1C(OCC)=O>CO.[OH-].[OH-].[Pd+2]>[F:44][C:2]([F:1])([F:45])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([O:23][P:24]([CH:28]([NH2:33])[CH2:29][CH2:30][CH2:31][CH3:32])([O:26][CH3:27])=[O:25])[C:11]([N:13]1[CH2:22][CH2:21][CH2:20][C@H:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12])=[O:4]
Reactant: CCCCC(NC(=O)OCc1ccccc1)P(=O)(OC)O[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)N1CCC[C@H]1C(=O)OCC
Agent: [Pd+2]
Agent: CCOC(=O)[C@@H]1CCCN1
Agent: [OH-]
Solvent: CO
Product: CCCCC(N)P(=O)(OC)O[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)N1CCC[C@H]1C(=O)OCC
Reaction time: 3 h

Procedure:
The ethyl ester product from part (e) (1.75 g., 2.63 mmole) is dissolved in methanol (75 ml.) at room temperature under argon. The solution is hydrogenated with 20% palladium hydroxide on carbon catalyst (300 mg.) at room temperature and atmospheric pressure for 3 hours. The reaction is filtered through Celite to remove the catalyst, and the volatiles are evaporated to give 1.7 g. of 1-(S)-6-[(Trifluoroacetyl)amino]-2-[[[(1-amino)pentyl]methoxyphosphinyl]oxy]-1-oxohexyl]-L-proline, ethyl ester.
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH2:26][CH2:27][CH2:28]CCCC(F)(F)C(F)(F)F)[C:23]([OH:25])=[O:24])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:71])([C:67]([F:70])([F:69])[F:68])[CH2:49]CCCC(CCCCCCC=C)C(OCC)=O>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH2:26][CH2:27][CH2:28][CH2:49][C:48]([F:71])([F:47])[C:67]([F:70])([F:69])[F:68])[C:23]([OH:25])=[O:24])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate prepared in Example 5, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+]>>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:30](=[NH:31])[C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)[CH:16]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)c1ccc(OC)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)c(NC(=N)c2ccc(F)cc2)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Anhydrous p-toluene sulfonic acid (41.99 g, 220.76 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38 mmol) obtained in step 1 of Preparation Example 1 and 4-fluorobenzonitrile (20.00 g, 165.57 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO3 thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent—MeOH:CDCl3=5:95, Merck, Silicagel 60) to obtain the title compound (22.67 g, 75.06 mmol) in a yield of 68%.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]3[C:10]4[C:14](=[CH:15][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)[NH:13][C:12]3=[O:16])[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 8.7 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (30 mg, 0.15 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (40 mg) to give 5.9 mg (8.5%) of the title compound as a yellow-orange solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[C:10]=2[CH:11]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[Li+].C[Si]([N-:46][Si](C)(C)C)(C)C.Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[NH2:46][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1cccc2cnc(Cl)cc12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc2cnc(N)cc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A 20 mL microwave vial was charged with methyl 3-chloroisoquinoline-5-carboxylate (0.36 g, 1.63 mmol), [1,1′-biphenyl]-2-yldicyclohexylphosphine (57 mg, 0.163 mmol), LHMDS (1.96 mL, 1.96 mmol) and Pd2(dba)3 (75 mg, 0.082 mmol) and then with 8 mL of THF. Reaction mixture was capped and stirred at 65° C. overnight. Then 2M HCl (4.08 mL, 8.17 mmol) was added and stirred at rt for 20 min. The reaction mixture was filtered and added with sat NaHCO3. Extracted with EtOAc. Combined organic layer was dried, filtered, concentrated in vacuo. Purified by silica gel chromatography (0-50% EtOAc in hexane) yielded 58% Methyl 3-aminoisoquinoline-5-carboxylate (26-2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5](O)[C:6]([OH:8])=[O:7].C(N(S(F)(F)[F:20])CC)C.[F:23][C:24]1[CH:25]=[C:26]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH:27]([OH:32])[C:28]([O:30][CH3:31])=[O:29].[OH-].[Li+]>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH:27]([OH:32])[C:28]([O:30][CH3:31])=[O:29].[F:1][C:2]1[CH:3]=[C:4]([CH:5]([F:20])[C:6]([OH:8])=[O:7])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: CCN(CC)S(F)(F)F
Agent: COC(=O)C(O)c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)C(F)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 3,5-difluoromandelate was prepared following General Procedure G below and using commerically available 3,5-difluoromandelic acid. The resultant α-hydroxy methyl ester was fluorinated according to the general procedure described in W. J. Middleton, et al., Org. Synth. CoL Vol. VI, 835. Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq) in CH2Cl2 was cooled to 0° C. and treated with methyl 3,5-difluoromandelate (1.0 eq) as a solution in CH2Cl2. After 10 min. the cooling bath was removed and the reaction was stirred at ambient temperature for 30 min. The reaction was monitored by tlc (Rf=0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers separated. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo, The product was purified by LC2000 chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 eq.). No starting material remained by tlc after 2 h. The dioxane was removed via rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude solid was recrystallized from ethyl acetate/hexanes affording 3,5-difluorophenyl-α-fluoroacetic acid as a white solid having a melting point of 90-110° C.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:17][C:16]([Br:27])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>>[Br:27][C:16]1[CH:17]=[C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=1
Reactant: O=C(NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1
Yield: 84.2 %

Procedure:
Following the procedure in Example 7, Step D, 1-benzoyl-3-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (1150 mg, 2.58 mmol) and 3M sodium hydroxide (1.7 mL, 5.1 mmol) provided 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (743 mg, 84.3% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH2:23][CH2:24][CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:17]3)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClCCl.Cl>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH2:23][CH2:24][CH2:25][NH:26][CH3:27])=[CH:17]3)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)c2ccc3[nH]c(CCCN(C)C(=O)OC(C)(C)C)cc3c2)cc1OC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CNCCCc1cc2cc(C(=O)Nc3ccc(OC)c(OC)c3)ccc2[nH]1
Reaction time: 2.5 h

Procedure:
A 250 round bottom flask was charged with tert-butyl 3-(5-(3,4-dimethoxyphenylcarbamoyl)-1H-indol-2-yl)propyl(methyl)carbamate (2.75 g, 5.88 mmol), dichloromethane (32 mL), and 1M hydrochloric acid in diethyl ether (32 mL) and the resulting mixture stirred for 2.5 h. The resulting mixture was then concentrated in vacuo, the residue triturated with diethyl ether, and placed under high vacuum to yield 2-(3-methylamino-propyl)-1H-indole-5-carboxylic acid (3,4-dimethoxy-phenyl)-amide. MS (ES+) 368 (M+1); HPLC: Kromasil C18 column (50×2 mm; 3.5μ), gradient 10-90% (MeCN+0.16% TFA) in (water+0.2% TFA) over 4 min, tR=2.72 min.