Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([OH:41])=O)([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:45])[C:13]([O:43][CH3:44])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:87][S:88]([CH:91]6[CH2:93][CH2:92]6)(=[O:90])=[O:89])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:87][S:88]([CH:91]6[CH2:93][CH2:92]6)(=[O:90])=[O:89])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:45])[C:13]([O:43][CH3:44])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 17-[2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (58) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=736 (M+H)+. 1H NMR (CDCl3): 0.90-1.01 (m, 1H), 1.05-1.15 (m, 1H), 1.15-1.45 (m, 5H), 1.45 (d, J=6.9 Hz, 6H), 1.4-1.55 (m, 3H), 1.6-1.8 (m, 2H), 2.85-2.95 (m, 1H), 2.15-2.25 (m, 2H), 2.3-2.4 (m, 1H), 2.45-2.55 (m, 1H), 2.6-2.7 (m, 1H), 2.65 (s, 3H), 2.9-3 (m, 1H), 3-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.85 (d, J=10.8 Hz, 1H), 3.95 (s, 3H), 4.1 (dd, J=11.3 Hz, J=3.6 Hz, 1H), 4.6 (t, J=8.0 Hz, 1H), 5.0 (t, J=10.6 Hz, 1H), 5.5 (t, J=3.2 Hz, 1H), 5.60-5.70 (m, 1H), 6.75 (s, 1H), 7.02 (s, 1H), 7.2 (d, J=9.2 Hz, 1H), 7.5 (s, 1H), 7.9 (d, J=9.2 Hz, 1H), 11 (br s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28]C(=O)OC(C)(C)C)=[O:18])=[C:11]([F:36])[C:10]=1[O:37][C:38]1[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=1>ClCCl>[NH2:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[NH:20][C:19]([C:17]([NH:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([O:37][C:38]3[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=3)[C:11]=1[F:36])=[O:18])=[CH:27]2
Reactant: CC(C)(C)OC(=O)Nc1cccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cccc(N)c4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
Trifluoroacetic acid (0.028 mL, 0.369 mmol) was added to a solution of 1,1-dimethylethyl (2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-7-yl)carbamate (0.021 g, 0.037 mmol) in dichloromethane. The mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to give the title compound (0.009 g, 45%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.46 (s, 1H), 9.07 (s, 1H), 7.81 (s, 1H), 7.43-7.58 (m, 3H), 7.32-7.43 (m, 1H), 7.09-7.22 (m, 2H), 6.82-6.97 (m, 1H), 6.62-6.75 (m, 1H), 4.58 (s, 2H), 4.20 (br s, 2H). MS: m/z 469 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=2[O:14]1.C(O)(C(F)(F)F)=O>>[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH:18]3[C:5]4[NH:6][C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]=4[CH2:3][CH2:2][NH:1]3)=[CH:16][C:15]=2[O:14]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Yield: 62.7 %

Procedure:
This product was prepared using the same procedure as for intermediate 1 with tryptamine (20.0 g, 120 mmol), 3,4-methylenedioxybenzaldehyde (20.6 g, 1.1 equiv.) and TFA (18 mL, 2 equiv.) to give the title compound (22 g, 60%) as white crystals after recrystallization from ethanol.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:5][C:6](=[O:9])[O:7][CH3:8])[CH3:4].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>ClCCl>[N:22]([CH2:2][C@@H:3]([NH:5][C:6](=[O:9])[O:7][CH3:8])[CH3:4])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)N[C@@H](C)CO
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@@H](C)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate (S)-methyl 1-hydroxypropan-2-ylcarbamate (2.65 g, 20 mmol) and triethylamine (7.0 ml, 50 mmol) in anhydrous dichloromethane (100 mL) was added methanesulfonyl chloride (1.91 mL, 23.9 mmol). The mixture was stirred at rt for 3 h and was then extracted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide solution and brine, and was then dried over sodium sulfate, filtered and concentrated. The crude mesylate product was then dissolved in dry DMF (70 mL) and sodium azide (5.2 g, 80 mmol) was added. The mixture was heated with stirring at 80° C. for 2 h. The cooled reaction mixture was concentrated and the residue was partitioned between ethyl acetate and brine. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (8:1 hexane/ethyl acetate eluant) to afford (S)-methyl 1-azidopropan-2-ylcarbamate. MS m/z 159.1(M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH2:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=O)[CH2:6][CH2:5][NH:4][CH2:3]1.O.NN.[OH-].[Na+]>C(O)COCCO>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[CH2:9][CH2:8][CH:7]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[CH3:1]
Reactant: COc1ccc2nccc(C(=O)CC3CCNCC3C)c2c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc2nccc(CCC3CCNCC3C)c2c1

Procedure:
The operation is as in Example 14, but starting from 3.7 g of 2-(3-methyl-4-piperidyl)-1-(6-methoxy-4-quinolyl)-ethanone (trans isomer, racemic), prepared as indicated in Example 4, 3.7 g of 98% hydrazine hydrate and 3.7 g of sodium hydroxide in 37 ml of diethylene glycol. 1.7 g are obtained of 6-methoxy-4-[2-(3-methyl-4-piperidyl)-ethyl]-quinoline (trans isomer), the acid fumarate of which prepared by the action of fumaric acid in ethanol, melts at 224° C.
Reaction SMILES: [CH2:1]([N:3]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:4]1[C:5]([CH3:26])=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)[CH:12]=1)[C:7]([OH:9])=O)[CH3:2].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.[NH2:66][CH2:67][C:68]1[C:69](=[O:77])[NH:70][C:71]([CH3:76])=[C:72]([F:75])[C:73]=1[CH3:74]>CN(C=O)C>[CH2:1]([N:3]([CH:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)[C:4]1[C:5]([CH3:26])=[C:6]([C:7]([NH:66][CH2:67][C:68]2[C:69](=[O:77])[NH:70][C:71]([CH3:76])=[C:72]([F:75])[C:73]=2[CH3:74])=[O:9])[CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:17][CH:18]=2)[CH:12]=1)[CH3:2]
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)O)c1C)C1CCOCC1
Reactant: Cc1[nH]c(=O)c(CN)c(C)c1F
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: CN(C)C=O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)c(F)c(C)[nH]c2=O)c1C)C1CCOCC1
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
A stirred solution of 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzoic acid (100 mg, 0.22 mmol) in anhydrous DMF (4.0 ml) at 0° C. under a balloon of nitrogen, was treated with HATU (99 mg, 0.26 mmol) and DIPEA (75 μl, 0.43 mmol) dropwise. The resulting solution was stirred for 10 minutes and then treated with 3-(aminomethyl)-5-fluoro-4,6-dimethyl-1,2-dihydropyridin-2-one (50%, 81 mg, 0.24 mmol). The resulting suspension was stirred at 0° C. for 30 minutes and then stirred at room temperature for 18 hours. The reaction mixture was partitioned between water (20 ml) and CH2Cl2 (15 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×15 ml). The combined organics were washed with a saturated solution of NaHCO3 (aq) (40 ml), water (2×25 ml), brine (20 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-6% MeOH/CH2Cl2) and then dissolved in a mixture of EtOAc (40 ml) and CH2Cl2 (10 ml), and washed with water (6×30 ml), brine (2×30 ml), dried (MgSO4), filtered and concentrated in-vacuo. The solid was thoroughly dried in-vacuo at 40° C. for 40 hours to give 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((5-fluoro-4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide (93 mg, 73%) as a powdery white solid. LC-MS 100%, 2.76 min (7 minute LC-MS method), m/z=591.2; 1H NMR (500 MHz, Chloroform-d) δ 11.79 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.4 Hz, 3H), 7.08 (t, J=6.0 Hz, 1H), 4.56 (d, J=6.0 Hz, 2H), 3.95 (d, J=11.2 Hz, 2H), 3.76-3.66 (m, 4H), 3.51 (s, 2H), 3.31 (td, J=11.3, 2.7 Hz, 2H), 3.10 (q, J=7.0 Hz, 2H), 3.00 (tt, J=9.6, 4.6 Hz, 1H), 2.45 (s, 4H), 2.43 (d, J=1.8 Hz, 3H), 2.34 (s, 3H), 2.13 (d, J=2.7 Hz, 3H), 1.74-1.62 (m, 4H), 0.89 (t, J=7.0 Hz, 3H). One proton assumed to be coincident with a solvent peak.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]2[O:31][C:32]([CH3:35])=[N:33][N:34]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]3[O:31][C:32]([CH3:35])=[N:33][N:34]=3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nnc(-c2ccc(Cl)nc2C)o1
Product: Cc1nnc(-c2ccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)nc2C)o1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 6-chloro-2-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine (101 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[N:14]=[C:13]([C:15]([NH2:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:20]([NH:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[N:14]=[C:13]([C:15]([NH2:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1ccc(Oc2cccc(C(N)=O)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cccc(Oc2ccc(CCNCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
Dissolve 6-[4-(2-aminoethyl)phenoxy]pyridine-2-carboxamide (0.0452 g, 0.176 mmol) in methanol (2.9 mL). Add benzaldehyde (0.018 mL) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (0.0066 g, 0.176 mmol). Stir for additional 6.5 hours before filtering and concentrating. Purify by reverse phase chromatography, eluting with 0-99% 0.1% TFA/acetonitrile and 0.1% TFA/water to give the title compound (9.4 mg, 15.4%): MS ES− 347.9 (M+H)+, HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=7.6 min, 100% purity.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[CH2:19]([NH:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31](Br)[CH:30]=[C:29]2[O:34][CH2:35][O:36][C:28]=12)[CH2:20][CH2:21][CH2:22][CH3:23]>C(OCC)(=O)C>[CH2:19]([NH:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH:30]=[C:29]2[O:34][CH2:35][O:36][C:28]=12)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: c1c[nH]cn1
Reactant: CCCCCNC(=O)Cc1cc(Br)cc2c1OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCCNC(=O)Cc1cc(-c2ncc[nH]2)cc2c1OCO2
Temperature: 200 °C
Reaction time: 10 h
Yield: 45.6 %

Procedure:
Imidazole (1.11 g, 16.3 mmol), potassium carbonate (2.78 g, 20.1 mmol), cuprous chloride (0.31 g, 3.1 mmol), and N-methylpyrrolidone (25 ml) were added to N-pentyl-(5-bromo-2,3-methylenedioxyphenyl)acetamide (4.65 g, 14.8 mmol), and the mixture was stirred at 200° C. for 10 hours. The reaction mixture was cooled and added with ethyl acetate (30 ml) and the precipitates were removed by filtration. The ethyl acetate layer was successively washed with 10% aqueous ammonia and with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gell C-300: 100 g, eluent: methanol/chloroform=1/50-1/20) to give N-pentyl-(5-imidazolyl-2,3-methylenedioxyphenyl)acetamide (2.13 g) as an oil.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]([OH:11])[CH2:8][CH2:9][CH:10]=1)/[CH:2]=[CH:3]\[CH2:4][CH3:5].[C:12](OC)(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>>[C:14]([O:16][CH3:17])(=[O:15])[CH2:13][C:12]([O:11][C@@H:7]1[CH2:8][CH2:9][CH:10]=[C:6]1[CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH3:5])=[O:18]
Reactant: CC/C=C\CC1=CCCC1O
Reactant: COC(=O)CC(=O)OC
Product: CC/C=C\CC1=CCC[C@H]1OC(=O)CC(=O)OC
Reaction time: 1.33 h

Procedure:
A mixture of (Z)-2-(2-pentenyl)-2-cyclopenten-1-ol (17.8 g; 117 mmol), dimethyl malonate (17.8 g; 135 mmol), ground KHCO3 (0.58 g; 5.8 mmol) and Novozym 435® (immobilized Candida antarctica from Novo Nordisk; 1.80 g) was gently swirled in a 100 ml flask connected to a Büchi rotavapor at 40° C. and 10 hPa. After 80 min., the reaction mixture was filtered, washed (sat. aq. NaHCO3, sat. aq. NaCl), dried (Na2SO4) and concentrated (30.8 g). Bulb-to-bulb distillation afforded 15.5 g of volatiles (oven temp. 70° C./10-0.1 hPa) and ca. 11.14 g (95% pure, 36%, 97% ee) of the desired product which is isolated at an oven temperature of 80-130° C./0.06 hPa.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[CH2:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][CH2:19][CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(C(=O)CCC2CCCC2)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(CCCC2CCCC2)c[nH]1

Procedure:
Triethylsilane (4.28 mL, 26.86 mmol) was added to a stirring, room temperature solution of 74 (2.2816 g, 8.66 mmol) in trifluoroacetic acid (TFA) (20.6 mL, 0.42 M) under N2. When the reaction was judged complete by HPLC, the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by preparative reverse phase HPLC with the following conditions: 30:70 H2O:CH3CN; 20 mL/min.; λ=254 nm. 75 was obtained as a fluffy white solid. 1H (CDCl3, 400 MHz): δ 9.43 (1H, broad s), 6.77 (1H, s), 6.74 (1H, s), 4.32 (2H, q, J=7.1 Hz), 2.46 (2H, t, J=7.6 Hz),1.83-1.71 (3H, m), 1.64-1.46 (6H, m), 1.35 (3H, t, J=7.1 Hz), 1.36-1.31 (2H, m), 1.14-1.02 (2H, m) ppm. 13C (CDCl3, 100 MHz): δ 161.46, 126.62, 122.33, 120.74, 114.86, 60.10, 40.00, 35.82, 32.65, 30.14, 26.94, 25.13, 14.39 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.39; CH2 carbons: 60.10, 35.82, 32.65, 30.14, 26.94, 25.13; CH carbons: 120.74, 114.86, 40.00ppm. HPLC: 12.379min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](C(OC(C)(C)C)=O)[C:6]3[C:18](=[O:21])[CH2:19][CH2:20][C:5]=3[C:4]=2[C:3]=1[Cl:22].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:18](=[O:21])[CH2:19][CH2:20][C:5]=3[C:4]=2[C:3]=1[Cl:22]
Reactant: CC(C)(C)OC(=O)n1c2c(c3c(Cl)c(Cl)ccc31)CCC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCc2c1[nH]c1ccc(Cl)c(Cl)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a solution of tert-butyl 7,8-dichloro-3-oxo-2,3-dihydrocyclopenta[b]indole-4(1H)-carboxylate (intermediate 27c) (0.4 g, 1.1 mmol) in CH2Cl2 (10 mL), cooled to 0° C., TFA (1 mL) mL) was added. The reaction mixture was warmed to room temperature and stirred for 90 min., quenched with saturated NaHCO3 (pH-8) and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound. The crude material was purified by washing with 5% EtOAc-hexane (3×20 mL) to provide the title compound (250 mg, 89%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 12.16 (s, 1H), 7.48 (d, J=15.0 Hz, 1H), 7.42 (d, J=15.0 Hz, 1H), 3.19 (m, 2H), 2.92 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20](O)=[O:21])[CH2:15][CH2:14]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]1[NH:26][C:27](=[O:35])[C:28]2[CH2:34][O:33][CH2:32][CH2:31][C:29]=2[N:30]=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH:23][CH2:24][C:25]4[NH:26][C:27](=[O:35])[C:28]5[CH2:34][O:33][CH2:32][CH2:31][C:29]=5[N:30]=4)=[O:21])[CH2:17][CH2:18]3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1
Solvent: CC#N
Product: O=C(CN1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Yield: 15 %

Procedure:
The title compound (14.8 mg, 0.031 mmol) was prepared following the general procedure of Example 1 from {4-[5-(4-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-piperidin-1-yl}-acetic acid (90 mg, 0.206 mmol, 1 eq) and 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (41.1 mg, 0.227 mmol, 1.1 eq). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38 (br s, 1H) 8.23-8.26 (m, 1H) 8.05 (dd, J=8.84, 5.31 Hz, 2H) 7.43-7.47 (m, 2H) 4.34 (s, 2H) 4.20 (d, J=5.56 Hz, 2H) 4.04-4.11 (m, 1H) 3.80-3.83 (m, 2H) 3.17 (d, J=5.05 Hz, 2H) 3.03-3.11 (m, 1H) 3.01 (s, 2H) 2.93-2.99 (m, 2H) 2.27-2.33 (m, 2H) 2.05-2.10 (m, 2H) 1.85-2.01 (m, 2H). HR-MS (m/z, MH+): 469.2001, 470.2061. HPLC retention time: 2.66 min (Agilent column 3.0×100 mm 3 um C18 column; flow rate of 1.0 mL/min with gradient from 5% to 95% acetonitrile in 10 min, 0.1% FA).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:29][C:30]([N:38]1[N:42]=[N:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][N:50]([NH2:75])[CH2:51][C@H:52]([OH:74])[C@@H:53]([NH:61][C:62](=[O:73])[C@H:63]([C:69]([CH3:72])([CH3:71])[CH3:70])[NH:64][C:65]([O:67][CH3:68])=[O:66])[CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:45][CH:44]=2)=[N:39]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31]>CN(C=O)C>[CH3:31][C:30]([N:38]1[N:42]=[N:41][C:40]([C:43]2[CH:44]=[CH:45][C:46]([CH2:49][N:50]([NH:75][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:51][C@H:52]([OH:74])[C@@H:53]([NH:61][C:62](=[O:73])[C@H:63]([C:69]([CH3:71])([CH3:70])[CH3:72])[NH:64][C:65]([O:67][CH3:68])=[O:66])[CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[CH:47][CH:48]=2)=[N:39]1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH3:29]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C(C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Reaction time: 0.25 h

Procedure:
With the exclusion of air, 261 mg (1.38 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 496 mg (2.58 mmol) of EDC and 232 mg (1.72 mmol) of HOBT are dissolved in 7.5 ml of DMF. After 15 min, 0.72 ml (5.17 mmol) of TEA and 585 mg (0.86 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane hydrochloride (Example 25h) in 3.5 ml of DMF are added. After 20 hours, the mixture is worked up as described under Example 25i. Precipitation with DIPE from a concentrated solution in methylene chloride yields the title compound: HPLC20-100 : tRet =17.5; FAB MS (M+H)+ =814.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[N+:4]([O-:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.O>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([CH2:10][CH2:9][NH:8][C:6]2[CH:5]=[N+:4]([O-:17])[CH:3]=[C:2]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[N:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [O-][n+]1cc(Cl)nc(NCCc2ccccc2)c1
Reactant: OB(O)c1ccncc1
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: CCO
Solvent: O
Product: [O-][n+]1cc(NCCc2ccccc2)nc(-c2ccncc2)c1

Procedure:
A mixture containing 0.250 g (1.0 mmol) of 6-chloro-N-(2-phenylethyl)pyrazin-2-amine 4-oxide, 0.296 g (2.40 mmol) of 4-pyridine boronic acid, 0.60 mL (1.2 mmol) of a 2M solution of sodium carbonate in water and 0.116 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0) in 5 mL of a mixture of ethanol/water in the proportions 5/1 was stirred under reflux for 16 h. Cooled water was added and the mixture extracted with dichloromethane, dried over sodium sulfate and evaporated to dryness. The residue obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/diethylamine in the proportions 98/2/0.2 to give after trituration with diethyl ether 0.058 g (20%) of pure product as a yellow solid.
Reaction SMILES: C([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:20]2[NH:29][C:23]3=[N:24][CH:25]=[C:26]([F:28])[CH:27]=[C:22]3[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1)(C)(C)C.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH:15]1([CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]#[N:5])=[CH:8][CH:9]=2)[C:20]2[NH:29][C:23]3=[N:24][CH:25]=[C:26]([F:28])[CH:27]=[C:22]3[CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)NC(=O)c1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a stirred solution of N-tert-butyl-4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-benzamide (250 mg, 0.61 mmol) in chloroform (6 mL) at room temperature was added phosphorus oxychloride (0.32 mL, 3.15 mmol). The mixture was heated at 80° C. and stirred for 3 h. The resulting mixture was concentrated in vacuo and the residue was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-benzonitrile (120 mg, 58.8%) as a white solid: LC/MS m/e calcd for C21H20FN3 [M+H]+ 334.41, observed 334.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (s, 1H), 7.63-7.70 (m, 3H), 7.53 (d, J=8.3 Hz, 2H), 6.39 (s, 1H), 4.28 (t, J=7.8 Hz, 1H), 2.23-2.31 (m, 1H), 2.03-2.13 (m, 1H), 1.61-1.87 (m, 5H), 1.51 (dd, J=7.3, 4.0 Hz, 2H), 1.17-1.35 (m, 2H).