Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[N:7]=1)=[O:5]
Reactant: Nc1ccc(-n2ccncc2=O)cc1F
Reactant: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Product: O=C(Nc1ccc(-n2ccncc2=O)cc1F)c1nc(CNC(=O)c2ccc(Cl)s2)no1

Procedure:
In analogy to example 1E 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5carboxylic acid ethyl ester (example 1D) was reacted with 1-(4-amino-3-fluoro-phenyl)-pyrazine-2-one (CAS 863015-77-4) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid [2-fluoro-4-(2-oxo-2H-pyrazine-1-yl)-phenyl]-amide. Yellow solid. MS 475.0 ([M+H]−)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1c[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1ccc2c(c1CN1CCNCC1)O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.106 g, 0.210 mmol) in methylene chloride (4 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (4 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate (4 mL), and the precipitated solid was collected by filtration. The resulting solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-ethoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0653 g, 77%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][CH2:34][NH2:35])[CH3:27]>C(N(CC)CC)C>[CH2:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][CH2:34][NH:35][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:27]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CCN1CCC[C@H]1CCN
Solvent: CCN(CC)CC
Product: CCN1CCC[C@H]1CCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 140 °C
Yield: 16.5 %

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.1 g), 2-((S)-1-ethylpyrrolidin-2-yl)ethylamine (Intermediate 136, 0.5 g) and triethylamine (0.5 mL) was stirred and heated in a sealed tube at 140° C. overnight. After cooling, the mixture was concentrated under vacuum and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (10%). The product was repurified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethylamino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.022 g) as a white solid.
Reaction SMILES: C(OC([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:30])[C@@H:23]4[C@H:27]([OH:29])[CH3:28])[C:20]=3[C:31]([O:33]CC=C)=[O:32])[S:16][CH:17]=2)[CH2:9][C@@H:8]1[CH2:37][OH:38])=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>ClCCl>[OH:29][C@@H:27]([C@H:23]1[C:22](=[O:30])[N:21]2[C@@H:24]1[C@@H:25]([CH3:26])[C:19]([S:18][C:15]1[S:16][CH:17]=[C:13]([C:10]3[CH2:9][C@H:8]([CH2:37][OH:38])[NH:7][CH2:12][CH:11]=3)[N:14]=1)=[C:20]2[C:31]([OH:33])=[O:32])[CH3:28]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@@H](CO)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(Sc3nc(C4=CCN[C@@H](CO)C4)cs3)[C@H](C)[C@H]12
Temperature: 0 °C
Yield: 58.3 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-({4-[(2R)-1-[(allyloxy)carbonyl]-2-(hydroxymethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (110 mg, 0.20 mmol) in dichloromethane (15 ml) were added acetic acid (28 μl) and tributyltin hydride (0.54 ml, 2.6 mmol) and then was added at room temperature bis(triphenylphosphine)palladium chloride(II) (14 mg, 0.020 mmol). Ten minutes later the reaction mixture was poured into a mixture of ice (10 g) and phosphate buffer (pH7.0, 10 ml). After separation of the mixture with a separating funnel, the organic layer was extracted twice with water and the aqueous layer was washed twice with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with 1–3% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-({4-[(2R)-2-(hydroxymethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (51 mg, yield 54%) as a white amorphous.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:19][CH3:20])=[C:6]([C:11]2[S:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][CH:12]=2)[CH:7]=[C:8]([CH3:10])[CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5]([O:19][CH3:20])=[C:6]([C:11]2[S:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][CH:12]=2)[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: COc1c(-c2ccc(C(=O)O)s2)cc(C)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(N)cc(C)cc1-c1ccc(C(=O)O)s1
Yield: 98.7 %

Procedure:
5-(3-Nitro-2-methoxy-5-methyl-phenyl)thiophene-2-carboxylic acid 24b (0.29 g, 1 mmol) was dissolved in 30 mL of ethyl acetate followed by addition of 0.06 g of palladium on carbon and ammonium formate (0.25 g, 4 mmol). Upon completion of the addition, the reaction mixture was heated to reflux for 45 minutes. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered to remove palladium on carbon. The filtrate was concentrated under reduced pressure and dried to obtain the title compound 5-(3-amino-2-methoxy-5-methyl-phenyl)-thiophene-2-carboxylic acid 24c (0.26 g, yield 99%) as a green solid.
Reaction SMILES: [CH:1]12[CH2:24][CH2:23][CH:4]([C:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]4=[CH:9][CH:8]=3)=[CH:6]1)[CH2:3][NH:2]2.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:2]1[CH2:3][CH:4]2[CH2:23][CH2:24][CH:1]1[CH:6]=[C:5]2[C:7]1[N:12]=[C:11]2[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:19])([CH3:20])[CH3:18])[C:10]2=[CH:9][CH:8]=1)(=[O:36])[CH3:35]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4)nc21
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC2CCC1C=C2c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(2-Azabicyclo[2.2.2]oct-5-en-5-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2-5, 25 mg, 0.08 mmol, 1.0 equiv) was added to anhydrous DCM (0.80 mL). To this solution was added DIPEA (40 μL, 0.23 mmol, 3.0 equiv) and acetyl chloride (11 μL, 0.15 mmol, 2.0 equiv) and the resulting mixture was allowed to stir at room temperature for 10 min. Following this duration, LCMS showed consumption of starting material. Saturated NaHCO3 (3 mL) and ethyl acetate (3 mL) were then added and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3×3 mL) and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a yellow oil. Purification by reverse-phase HPLC (10-100% CH3CN:0.1% TFA in H2O) afforded 3-1 as a white solid. MS m/z (M+H): calculated=369.2285; observed=369.2284.
Reaction SMILES: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1.[CH3:39][Si:40]([CH3:76])([CH3:75])[CH2:41][CH2:42][O:43][CH2:44][N:45]([CH2:67][O:68][CH2:69][CH2:70][Si:71]([CH3:74])([CH3:73])[CH3:72])[C:46]1[N:51]2[N:52]=[CH:53][CH:54]=[C:50]2[N:49]=[C:48]([CH:55]2[CH2:60][CH2:59][CH2:58][C:57](=[CH:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:56]2)[CH:47]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(=CC(OCC)=O)CC2)C=1>>[CH3:74][Si:71]([CH3:72])([CH3:73])[CH2:70][CH2:69][O:68][CH2:67][N:45]([CH2:44][O:43][CH2:42][CH2:41][Si:40]([CH3:76])([CH3:75])[CH3:39])[C:46]1[N:51]2[N:52]=[CH:53][CH:54]=[C:50]2[N:49]=[C:48]([CH:55]2[CH2:60][CH2:59][CH2:58][CH:57]([CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:56]2)[CH:47]=1
Reactant: CCOC(=O)C=C1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)C1
Agent: CCOC(=O)C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Product: CCOC(=O)CC1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)C1

Procedure:
Ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([OH:22])[CH2:15]2.O>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:9](=[O:10])([O:22][C@@H:16]1[CH:17]2[CH2:20][CH2:21][N:14]([CH2:19][CH2:18]2)[CH2:15]1)[O:11][CH2:12][CH3:13]
Reactant: CCOC(=O)Cl
Reactant: O[C@H]1CN2CCC1CC2
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)O[C@H]1CN2CCC1CC2
Temperature: 20 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
In 100 ml of chloroform and in the presence of 16 g of triethylamine and 0.1 g of 4-dimethylaminopyridine, 12.8 g of ethyl chloroformate was added to 10.0 g of (R)-quinuclidin-3-ol at 10° C. This was heated to 20° C., stirred for 2 hours and mixed with 50 ml of water, the thus obtained organic layer was washed with 50 ml of water, and then the organic layer was concentrated under a reduced pressure and dried in vacuo to obtain 15.49 g of a oily substance. By purifying this oily substance by a silica gel column chromatography, 7.24 g of ethyl (R)-quinuclidin-3-yl carbonate was obtained (1H-NMR (DMSO-d6, tetramethylsilane internal standard): δ 1.21 (3H, t, J=7.2 Hz), 1.26-1.37 (1H, m), 1.42-1.53 (1H, m), 1.55-1.70 (2H, m), 1.91-1.98 (1H, m), 2.48-2.76 (5H, m), 3.06-3.17 (1H, m), 4.11 (2H, q, J=7.2 Hz), 4.56-4.64 (1H, m), mass spectrum: m/z=200 [M+H]+ (FAB)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([NH:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(N)cccc2Cl)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
4-(2-Amino-6-chloro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (163 mg, 0.53 mmol) in CH2Cl2 was treated with 62 □L (0.80 mmol, 1.5 eq) of methanesulfonyl chloride and 148 □L (1.06 mmol, 2 eq) of triethylamine and the reaction mixture stirred at 25° C. for 1 h. EtOAc (40 mL) and sat. NaHCO3 (20 mL) were added. The organic layer was separated and washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, and concentrated. Column chromatography (silica, 0-5% acetone/CH2Cl2) provided 145 mg (70%) of 4-(2-chloro-6-methanesulfonylamino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. TLC (silica, 5% acetone/CH2Cl2): Rf=0.35. MS (electrospray): exact mass calculated for C16H24ClN3O4S, 389.12; m/z found, 388.1 (negative). 1H NMR (400 MHz, CDCl3): 7.41 (dd, J=8.2, 1.6 Hz, 1H), 7.11 (t, J=8.2 Hz, 1H), 6.99 (dd, J=8.2, 1.6 Hz, 1H), 4.25-3.91 (m, 2H), 3.66-3.52 (m, 2H), 3.01 (s, 3H), 3.01-2.84 (m, 2H), 2.70-2.56 (m, 2H), 2.55-2.43 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11](N)=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[CH:39]=[CH:38][N:37]([CH3:40])[N:36]=2)[C:30]([NH2:33])=[CH:31][CH:32]=1>C(Cl)Cl.CCO>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:10]1[N:34]([C:35]2[CH:39]=[CH:38][N:37]([CH3:40])[N:36]=2)[C:29]2[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:33]=1)[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: Cn1ccc(Nc2cc(F)ccc2N)n1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccn(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a suspension of (S)-Boc-alaninamide (614 mg, 3.27 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (621 mg, 3.27 mmol) in one portion under a nitrogen atmosphere. The resulting mixture stirred at RT for 1 h. The volatiles were removed in vacuo and to the resulting residue was added 4-fluoro-N2-(1-methyl-1H-pyrazol-3-yl)-benzene-1,2-diamine (350 mg, 1.70 mmol) in absolute EtOH (5 mL) and the mixture stirred at 80° C. for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and an aqueous solution of NaHCO3. The organic fraction was dried, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in DCM) to afford the title compound as a purple oil (187 mg, 31%). LCMS (Method B): RT 3.18 min [M+H]+ 360.05
Reaction SMILES: C(OC(N1CCC2N(C)C3C(C(F)(F)F)=CC(NC4C=CC=CN=4)=CC=3C2C1)=O)(C)(C)C.C(OC([N:40]1[CH2:56][CH2:55][C@@H:43]2[N:44]([CH3:54])[C:45]3[C:46]([C:52]#[N:53])=[CH:47][C:48](Br)=[CH:49][C:50]=3[C@@H:42]2[CH2:41]1)=O)(C)(C)C.[NH2:57][C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1.CC([O-])(C)C.[Na+]>>[CH3:54][N:44]1[C:45]2[C:50](=[CH:49][C:48]([NH:57][C:58]3[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=3)=[CH:47][C:46]=2[C:52]#[N:53])[C@@H:42]2[CH2:41][NH:40][CH2:56][CH2:55][C@H:43]12
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: Nc1cccnc1
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3ccccn3)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Agent: [Na+]
Product: CN1c2c(C#N)cc(Nc3cccnc3)cc2[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method for (5-Methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method A) as an oil (40 mg, 26%) from (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 196 mg, 0.5 mmol), 3-amino-pyridine (141 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 306 (base, M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Si:30]([O:47][C@@H:48]([CH3:52])[C:49](O)=[O:50])([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:30]([O:47][C@@H:48]([CH3:52])[C:49]([N:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[S:12][C@@:11]1([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:50])([C:43]([CH3:45])([CH3:46])[CH3:44])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1N=C(c2cccc(F)c2)S[C@@]1(CCCNC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.1 %

Procedure:
To a solution of tert-butyl 3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (0.54 g, 1.30 mmol) and (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid (0.64 g, 1.95 mmol) in DMF (10 mL) was added PyBOP (1.01 g, 1.95 mmol) followed by DIEA (0.34 g, 2.60 mmol). After stirring at room temperature for 14 hours, the reaction mixture was partitioned between 10% Na2CO3 (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (40 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (1:9 to 1:4 ethyl acetate/hexanes) to provide the less polar diastereomer product (180 mg, 19%) as a yellow syrup.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].N1C2C(=CC=CC=2)C(CC[CH2:18][C:19]([N:21](CC(N)=O)[CH2:22][CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=O)=C1.O>O1CCCC1>[CH2:19]([NH:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[CH3:18]
Reactant: NC(=O)CN(CCc1c[nH]c2ccccc12)C(=O)CCCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCNCCc1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 185.2 %

Procedure:
Lithium aluminum hydride in tetrahydrofuran (1M, 30 mL) was added dropwise to a stirring solution of N-[2-(1H-indol-3-yl)ethylacetyltryptamineacetamide (2.02 g) in tetrahydrofuran (10 mL) at 0° C. The solution was then heated at reflux overnight. The solution was cooled to 0° C. and water was very carefully added dropwise. The white solid was filtered and rinsed with ether/methanol (9:1, 2×25 mL). The solvent was removed from the filtrate, giving N-ethyl-2-(1H-indol-3-yl)ethanamine as a viscous pale yellow oil (1.75 g, 93%).
Reaction SMILES: CC1(C)C(=O)N([C@@H](CC2CC2)[C:9]([NH:11][C@H:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])C(=O)N1CC1C=CC(NC(NC2C=CC=CC=2C)=O)=C(OC)C=1.[F:44][C:45]([F:86])([F:85])[C:46]1([C:81]([F:84])([F:83])[F:82])[C:50](=[O:51])[N:49]([C@@H:52]([CH2:56][CH:57]([CH3:59])[CH3:58])C(O)=O)[C:48](=[O:60])[N:47]1[CH2:61][C:62]1[CH:67]=[CH:66][C:65]([NH:68][C:69]([NH:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=2[CH3:78])=[O:70])=[C:64]([O:79][CH3:80])[CH:63]=1>>[F:44][C:45]([F:85])([F:86])[C:46]1([C:81]([F:83])([F:82])[F:84])[C:50](=[O:51])[N:49]([C@@H:52]([CH2:56][CH:57]([CH3:59])[CH3:58])[C:9]([NH:11][C@H:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:48](=[O:60])[N:47]1[CH2:61][C:62]1[CH:67]=[CH:66][C:65]([NH:68][C:69]([NH:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=2[CH3:78])=[O:70])=[C:64]([O:79][CH3:80])[CH:63]=1
Reactant: COc1cc(CN2C(=O)N([C@@H](CC(C)C)C(=O)O)C(=O)C2(C(F)(F)F)C(F)(F)F)ccc1NC(=O)Nc1ccccc1C
Reactant: COc1cc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CC(=O)O)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C
Product: COc1cc(CN2C(=O)N([C@@H](CC(C)C)C(=O)N[C@H](C)CC(=O)O)C(=O)C2(C(F)(F)F)C(F)(F)F)ccc1NC(=O)Nc1ccccc1C

Procedure:
The title compound was prepared as described in Examples 1f and 1g from 500 mg (0.809 mmol) of (S)-2-(4,4-bis(trifluoromethyl)-3-(4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetic acid of the formula
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:17]=2[CH3:33])[OH:15])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.C([Sn]([C:47]#[N:48])(CCCC)CCCC)CCC>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CN1C(=O)CCC1>[F:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([CH:14]([OH:15])[C:4]3[CH:3]=[C:2]([CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[CH:5]=3)[C:47]#[N:48])=[C:17]([CH3:33])[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:19]2)=[CH:24][CH:23]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1C(O)c1cc(Cl)cc(N2CCOCC2)c1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1C(O)c1cc(C#N)cc(N2CCOCC2)c1

Procedure:
A solution of (3-chloro-5-morpholinophenyl)(7-fluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-yl)methanol (0.050 g, 0.108 mmol), tributyltin cyanide (0.034 g, 0.108 mmol), XPhos precatalyst (CAS 1028206-56-5; 0.014 g, 0.022 mmol), and NMP (1.0 mL) was heated in a microwave at 150° C. for 2 h. Upon completion, the reaction mixture was partitioned between EtOAc and water, and the organic phase was dried over magnesium sulfate and concd. This afforded a crude material that was purified by column chromatography (silica; 0-100% EtOAc in hexanes) to yield 3-((7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)(hydroxy)methyl)-5-morpholinobenzonitrile as an amorphous beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, d), 8.31 (1H, m), 8.01 (1H, d, J=1.8 Hz), 7.83 (1H, d, J=7.8 Hz), 7.72 (1H, d), 7.51 (1H, m), 7.41 (1H, m), 7.33 (1H, s), 7.24 (1H, s), 6.85 (1H, s), 6.75 (1H, d, J=4.3 Hz), 6.59 (1H, d), 3.71 (4H, t, J=4.8 Hz), 3.14 (4H, q, J=4.4 Hz), 2.46 (3H, s). Mass Spectrum (ESI) m/e=455.0 (M+1).