Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@:5]([CH3:38])([C:14](=[O:37])[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=2)=O)[CH2:4][O:3]1.Cl.[NH2:41]O.C(O)(C(F)(F)F)=O.C(Cl)Cl>N1C=CC=CC=1>[NH2:6][C@@:5]([C:14]1[O:37][N:41]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=2)[CH:15]=1)([CH3:38])[CH2:4][OH:3]
Reactant: NO
Reactant: CCCCCCCCOc1ccc(C(=O)CC(=O)[C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2cc([C@@](C)(N)CO)on2)cc1C(F)(F)F

Procedure:
The solution of (S)-tert-butyl 2,2,4-trimethyl-4-(3-(4-(octyloxy)-3-(trifluoromethyl)-phenyl)-3-oxo-propanoyl)oxazolidine-3-carboxylate (27 mg, 0.05 mmol, 1.0 equiv) and hydroxylamine hydrochloride (6.6 mg, 0.10 mmol, 2.0 equiv) in pyridine (0.5 mL) was stirred at 60° C. for 2 days. The reaction was condensed and the residue was treated with 20% TFA-DCM for 30 min. After removal of excess amount of TFA and DCM, the crude product was purified by prep. HPLC and afforded the title compound as mono-TFA salt (6.0 mg). MS (ESI, M+H+)=415.0; 1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 8.04 (d, 1H, J=9.6 Hz), 7.31 (d, 1H, J=9.6 Hz), 7.03 (s, 1H), 4.16 (t, 2H, J=6.0 Hz), 4.01, 3.83 (AB, 2H, J=12.0 Hz), 1.87-1.80 (m, 2H), 1.75 (s, 3H), 1.56-1.47 (m, 2H), 1.40-1.32 (m, 8H), 0.91 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]([NH:4][NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])(=[O:3])[CH3:2].[CH3:21][N:22]=[C:23]=[O:24]>C(Cl)(Cl)Cl>[C:1]([NH:4][N:5]([C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])[C:23](=[O:24])[NH:22][CH3:21])(=[O:3])[CH3:2]
Reactant: CN=C=O
Reactant: CC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Solvent: ClC(Cl)Cl
Product: CNC(=O)N(NC(C)=O)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Temperature: 40 °C

Procedure:
Trans-4-(2-acetylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, 330 dissolved in 4 ml of chloroform, 0.3 ml of methyl isocyanate was added to this, and the mixture was heated on a water bath at 40° C. for 130 minutes. The solvent was distilled off under a reduced pressure and the residue obtained was recrystallized from ethyl acetate-ethanol to give 350 mg of trans-4-(2-acetyl-1-methylcarbamoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol.monohydrate as white crystals, m.p. 225°-226° C. (decomposed).
Reaction SMILES: N1([C:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH:14]=O)[NH:11][C:12]=2[CH3:13])=[O:7])C=CN=C1.[NH2:17][CH2:18][C@@H:19]([OH:27])[CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH2:32]2.C(N(CC)CC)C>C1COCC1>[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])/[C:32]/2=[CH:14]\[C:10]1[NH:11][C:12]([CH3:13])=[C:8]([C:6]([NH:17][CH2:18][C@@H:19]([OH:27])[CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:7])[C:9]=1[CH3:16]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: NC[C@@H](O)CN1CCOCC1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NC[C@@H](O)CN1CCOCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 29.4 %

Procedure:
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (7.0 g, 32.3 mmol), (2R)-1-amino-3-morpholin-4-ylpropan-2-ol (15.5 g, 96.9 mmol), 5-chlorooxindole (5.48 g, 32.6 mmol), triethylamine (14 ml), and THF (88 ml) were mixed and heated to 60° C. A red solution formed. After stirring for 16 h at 60° C., the yellow slurry was cooled to room temperature and filtered. The cake was washed with 2×50 ml of THF and dried overnight at 50° C. under house vacuum. 5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2R)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (4.36 g) was obtained in 29% yield.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[C:24]([C:32]1[CH:58]=[CH:57][C:35]2[N:36]=[C:37]([C:39]3[C:40]([CH3:56])=[C:41]([C:45]([N:47]4[CH2:52][CH2:51][CH:50]([C:53]([OH:55])=O)[CH2:49][CH2:48]4)=[O:46])[NH:42][C:43]=3[CH3:44])[NH:38][C:34]=2[CH:33]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH3:59][N:60]([CH3:64])[CH2:61][CH2:62][NH2:63]>N1C=CC=CC=1>[CH3:59][N:60]([CH2:61][CH2:62][NH:63][C:53]([CH:50]1[CH2:51][CH2:52][N:47]([C:45]([C:41]2[NH:42][C:43]([CH3:44])=[C:39]([C:37]3[NH:38][C:34]4[CH:33]=[C:32]([C:24](=[O:31])[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:58]=[CH:57][C:35]=4[N:36]=3)[C:40]=2[CH3:56])=[O:46])[CH2:48][CH2:49]1)=[O:55])[CH3:64]
Reactant: Cc1[nH]c(C(=O)N2CCC(C(=O)O)CC2)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: Cc1[nH]c(C(=O)N2CCC(C(=O)NCCN(C)C)CC2)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 60 °C
Reaction time: 10 h
Yield: 54.3 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31 mg, 0.16 mmol) and 1-hydroxybenzotriazole monohydrate (25 mg, 0.16 mmol) were added to a pyridine (4 ml) solution of the ((4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrol-2-yl)-carbonyl)piperidine-4-carboxylic acid (70 mg, 0.15 mmol) obtained in Example 45. N,N-Dimethylethylenediamine (13 mg, 0.15 mmol) was added to the reaction mixture and heated. The reaction mixture was stirred at 60° C. (internal temperature) for 10 hours, and then allowed to cool to room temperature with stirring. The solvent was evaporated, and the residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2) to afford N-dimethylaminoethyl-1-((4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrol-2-yl)-carbonyl)piperidine-4-carboxamide (44 mg, 55%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][NH:12][CH3:13].[O:14]=[C:15]1[CH2:20][O:19][C:18]2[CH:21]=[C:22](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)[CH:23]=[N:24][C:17]=2[NH:16]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][N:12]([CH3:13])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[N:24][C:17]2[NH:16][C:15](=[O:14])[CH2:20][O:19][C:18]=2[CH:21]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Reactant: CNCc1oc2ccccc2c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1oc2ccccc2c1Cl)C(=O)/C=C/c1cnc2c(c1)OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
To a solution of (3-chlorobenzofuran-2-yl)-N-methylmethanamine (100 mg, 0.51 mmol) in DMF (5 mL) were added in sequential order (E)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (107 mg, 0.46 mmol), 1-hydroxybenzotriazole (71 mg, 0.51 mmol), diisopropylethylamine (243 uL, 1.39 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (102 mg, 0.51 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water was added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield title compound as a white solid (55 mg, 30%): 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.12-8.19 (m, 1H), 7.28-7.6 (m, 7H), 4.81-4.95 (rotamers, 2s, 2H), 4.714 (s, 2H); 3.21 (s, 3H); MS (ESI) m/e 398 (C20H16ClN3O4+H)+.
Reaction SMILES: [I-].[Na+].C[Si](Cl)(C)C.[NH2:8][C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=1.C(N(CC)CC)C.[Cl:22][C:23]1[N:28]=[C:27]([O:29][CH3:30])[N:26]2[N:31]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:33]=[C:25]2[CH:24]=1>C(#N)C.CS(C)=O>[CH3:14][N:11]1[CH:12]=[CH:13][C:9]([NH:8][S:34]([C:32]2[N:33]=[C:25]3[N:26]([C:27]([O:29][CH3:30])=[N:28][C:23]([Cl:22])=[CH:24]3)[N:31]=2)(=[O:35])=[O:36])=[N:10]1
Reactant: COc1nc(Cl)cc2nc(S(=O)(=O)Cl)nn12
Reactant: Cn1ccc(N)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1nc(Cl)cc2nc(S(=O)(=O)Nc3ccn(C)n3)nn12

Procedure:
Sodium iodide (3.6 g, 24 mmol) and trimethylsilyl chloride 92.6 g, 24 mmol) were added to a solution of 3-amino-1-methylpyrazole (2.3 g, 24 mmol) and triethylamine (2.5 g, 25 mmol) in 20 mL of acetonitrile at ambient temperature with stirring and under dry nitrogen. The mixture was allowed to react until the 3-amino-1-methylpyrazole was essentially all consumed as determined by gas-liquid chromatography. The solvent was then removed by evaporation under reduced pressure and the residue was taken up in diethyl ether. The resulting mixture was filtered to remove solids and the ether was removed by evaporation under reduced pressure. The residue was dissolved in 10 mL of acetonitrile and the resulting solution was combined with 7-chloro-5-methoxy-1,2,4-triazolo[1,5-c]-pyrimidine-2-sulfonyl chloride (2.0 g, 7.0 mmol) and to this was added with stirring at ambient temperature about 0.2 mL of dimethyl sulfoxide catalyst. The resulting mixture was allowed to react for 24 hours and was then concentrated under reduced pressure and the residue was diluted with first water and then methylene chloride. The organic layer was recovered, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure to obtain the title compound as a white solid, which, after drying, amounted to 2.4 g (98 percent of theory) and melted at 185°-187° C.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[CH:5]1([C:8]2[C:15]([CH:16]3[CH2:18][CH2:17]3)=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([OH:19])[C:9]=2[F:20])[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:5]1([C:8]2[C:15]([CH:16]3[CH2:18][CH2:17]3)=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([O:19][CH:2]([CH3:4])[CH3:3])[C:9]=2[F:20])[CH2:6][CH2:7]1
Reactant: O=Cc1cc(C2CC2)c(C2CC2)c(F)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C=O)cc(C2CC2)c(C2CC2)c1F
Reaction time: 2 h
Yield: 97.6 %

Procedure:
2-Iodopropane (862 mg) was added at room temperature to a mixture of 4,5-dicyclopropyl-3-fluoro-2-hydroxybenzaldehyde (744 mg), potassium carbonate (934 mg), and DMF (20 mL), and the mixture was stirred at 60 C for 2 hours in a nitrogen atmosphere. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (865 mg).
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[CH:11]=[C:10]([CH3:12])[CH:9]=[N:8]1.[Li]CCCC.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>[NH4+].[Cl-]>[CH3:6][N:7]1[C:11]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)=[C:10]([CH3:12])[CH:9]=[N:8]1
Reactant: Cc1cnn(C)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
At 0° C., to above THF solution of 1,4-dimethylpyrazole was added n-BuLi (2.5M in hexane, 58.5 mL, 146 mmole). The reaction solution was stirred for 2 hour at RT and then cooled to −78° C. [J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.2 g, 146 mmole). After 15 min at −78° C., the reaction was allowed to warm to 0° C. and stir for 3 h. The reaction was diluted with saturated NH4Cl solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford the title compound as a brown solid (21 g, 78%) which was used directly without further purification: LC-MS: 141 (M-C6H12)+, 223 (M+H)+. 1H NMR (CDCl3): δ 7.28 (s, 1H), 4.03 (s, 3H), 2.22 (s, 3H), and 1.32 (s, 12H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([N:15]([CH3:17])[CH3:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[I:19].[CH2:20](OCC)C>CN(C)C=O>[I-:19].[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([N+:15]([CH3:20])([CH3:17])[CH3:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: CCOCC
Reactant: CI
Solvent: CN(C)C=O
Product: C[N+](C)(C)C1CCN(c2ccc([N+](=O)[O-])cc2)C1
Product: [I-]
Temperature: 60 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of [1-(4-nitrophenyl)-pyrrolidin-3-yl] dimethylamine (470 mg, 2.0 mmole) in dimethylforamide (2 mL) was added methyl iodide (567 mg., 4.0 mmole). The reaction mixture was stirred at 60° C. for 18 hrs and cooled to room temperature. Diethyl ether was added and the resulting precipitate was filtered and washed with ether three times to give 1-(4-nitrophenyl)-N,N,N-trimethylpyrrolidin-3-aminium iodide (894 mg, 92% yield): 1HNMR (400 MHz, DMSO-d6)δ 2.50 (m, 2H), 3.15 (s, 9H), 3.43 (m, 1H), 3.71 (m, 2H), 3.87 (m, 1H), 4.37 (m, 1H), 6.74 (d, 2H, J=9 Hz), 8.12(d, 2H, J=9 Hz). This compound was hydrogenated at 60 psi in menthol in the presence of 10% Pd/C at room temperature for about 18 hrs. The reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was evaporated in vacuo to produce 1-(4-aminophenyl)-N,N,N-trimethylpyrrolidin-3-aminium iodide (505 mg, 95% yield): 1HNMR (400 MHz, DMSO-d6)δ 2.32 (m, 2H), 2.94 (m, 1H), 3.09 (s, 9H), 3.17 (m, 2H), 3.71 (m, 2H), 4.25 (m, 1H), 4.66 (bs, 2H), 6.52 (s, 4H): MS m/z=219. This is Compound 1 of Table 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][S:18][CH2:19][C@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.O.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:17][S:18][CH2:19][C@H:20]([NH:27][C:13](=[O:15])[C@@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CSC[C@H](N)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CSC[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-tert-butoxycarbonyl-D-valine (2.39 g, 11.0 mmols) and 10.0 mmols of the above-obtained (R)-α-methylthiomethylbenzylamine hydrochloride were dissolved in 60 ml of methylene chloride. Triethylamine (1.53 ml, 11.0 mmols), 2.11 g (11.0 mmols) of water-soluble carbodiimide hydrochloride and 1.49 g (11.0 mmols) of HOBt were added to the solution while being cooled to 0° C. The mixture was stirred for 1 hour while being cooled, and then overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, 100 ml of water were added to the residue, and the solution was extracted twice with 100 ml of ethyl acetate. The organic layer was washed twice with a 5% citric acid aqueous solution, with 50 ml of a saturated aqueous solution of sodium chloride, twice with a 5% sodium hydrogencarbonate aqueous solution and with 50 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain N-tert-butoxycarbonyl-D-valine (R)-α-methylthiomethylbenzylamide as a solid in a quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:22]=[N:23][N:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:25]=2[CH2:26][OH:27])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:34]([OH:36])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.N1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>C(#N)C.O.C(N(CC)CC)C>[OH:27][CH2:26][C:25]1[N:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:23]=[N:22][C:21]=1[C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]1[CH2:11][C@@H:10]([C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:36])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13]1)=[O:20]
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1CO)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (2.18 g), 5 morpholine (0.46 ml), 1H-benzotriazol-1-ol (330 mg) and triethylamine (1.5 ml) were dissolved in acetonitrile (20 ml), WSC.HCl (1.25 g) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (2.35 g).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28](O)=[O:29])=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:32]OC(=O)CN.C1C=C[C:41]2[N:46](O)N=[N:44][C:42]=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28](=[O:29])[NH:46][CH2:41][CH2:42][NH:44][CH3:32])=[CH:23][C:22]=3[F:31])[CH2:19][CH2:20]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)O)cc3F)CC2)CC1
Reactant: COC(=O)CN
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CNCCNC(=O)c1cc(F)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-1 (32 mg, 0.073 mmol), amino-acetic acid methyl ester (0.11 mmol) and HOBT (15 mg, 0.11 mmol) were combined in DCM (1 mL) and stirred at room temperature for 10 minutes. EDC(19 mg, 0.1 mmol) was added and the mixture was stirred for 18 h. The solution was washed with 2 mL of aqueous NaHCO3, concentrated and taken up with 1 mL of DCM. 1 mL of TFA was added and the mixture was stirred at room temperature for 1 h. It was then concentrated under a stream of nitrogen and purified on preparative HPLC to give 31-1: LC-MS 496.5 (MH).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[I-].[Na+].[C:24](=O)([OH:26])[O-:25].[Na+].[CH3:29][C:30]([S:33]([CH2:36][CH2:37][CH2:38][CH2:39]Br)(=[O:35])=[O:34])([CH3:32])[CH3:31]>CN(C=O)C.CO>[CH:24]([OH:26])=[O:25].[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:39][CH2:38][CH2:37][CH2:36][S:33]([C:30]([CH3:29])([CH3:32])[CH3:31])(=[O:34])=[O:35])[CH2:20][CH2:21]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])O
Reactant: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Reactant: CC(C)(C)S(=O)(=O)CCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1cc(OC2CCN(CCCCS(=O)(=O)C(C)(C)C)CC2)c2ncccc2c1
Product: O=CO
Temperature: 150 °C
Yield: 49.8 %

Procedure:
A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (65 mg, 0.23 mmol), sodium iodide (47 mg, 0.3 mmol), sodium bicarbonate (190 mg, 2.2 mmol) and 4-bromobutyl 1,1-dimethylethyl sulfone (for example, as prepared for Intermediate 22) (94 mg) in DMF (2 ml) was heated in a Smith Creator™ microwave oven at 150° C. for 20 min. The reaction mixture was applied to an SCX-2 cartridge (10 g), preconditioned with methanol, and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were combined and concentrated in vacuo and the residue (100 mg) was purified by MDAP to give the title compound (58 mg, 46%): LCMS RT=2.65 min, ES+ve m/z 461 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:32][CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: NCc1cccnc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCc1cccnc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z=537.95 (M+H+); retention time=0.57 minutes.
Reaction SMILES: I[C:2]1[CH:21]=[N:20][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:34]=[C:33]([C:2]3[CH:21]=[N:20][C:5]4[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]5[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=5)[C:4]=4[CH:3]=3)[CH:32]=[CH:31][N:30]=2)[CH2:27][CH2:28]1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Reactant: FC(F)(F)c1ccc(CN2CCNc3ncc(I)cc32)o1
Product: CN1CCN(c2cc(-c3cnc4c(c3)N(Cc3ccc(C(F)(F)F)o3)CCN4)ccn2)CC1
Yield: 30 %

Procedure:
7-Iodo-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (60 mg) was reacted with 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a beige foam (30% yield). M.p. (foam), 1H-NMR (CDCl3, 400 MHz) δ 2.31-3.36 (m, 4H), 2.38-2.53 (m, 4H), 3.42-3.48 (m, 2H), 3.48-3.58 (m, 1H), 3.61-3.66 (m, 2H), 3.74-3.84 (m, 2H), 5.02 (bs, 1H), 6.31 (s, 1H), 6.74 (s, 1H), 6.93 (s, 1H), 7.41-7.50 (m, 3H), 7.73 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.[C:29](N1C=CN=C1)([N:31]1C=CN=C1)=O.CN>CCOC(C)=O.C1COCC1>[CH3:29][NH:31][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH:9]=[C:10]2[C:20]([CH:22]1[C:23]([CH3:28])([CH3:27])[C:24]1([CH3:25])[CH3:26])=[O:21])=[O:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2c(c1)c(C(=O)C1C(C)(C)C1(C)C)cn2CC1CCOCC1
Yield: 14 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and methylamine (2 M solution in THF, 0.2 mL, 0.4 mmol) in 4 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (14 mg, 0.035 mmol, 14% yield). 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.27 (s, 12H), 1.30-1.46 (m, 4H), 2.03-2.17 (m, 1H), 2.22 (s, 1H), 2.79 (d, J=4.7 Hz, 3H), 3.22 (dt, J=11.4, 3.1 Hz, 2H), 3.80-3.88 (m, 2H), 4.17 (d, J=7.5 Hz, 2H), 7.63-7.77 (m, 2H), 8.32-8.37 (m, 1H), 8.38 (s, 1H), 8.74 (d, J=1.4 Hz, 1H); MS (DCI/NH3) m/z 397 (M+H)+; Anal. Calculated for C24H32N2O2.0.3H2O: C, 71.72; H, 8.18; N, 6.97. Found: C, 71.96; H, 8.19; N, 6.69.