Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.O>CN(C)C=O>[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][N:33]([C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:2]=3[F:1])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Br)cc1F)N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
A solution of 2-fluoro-4-bromobenzoic acid (0.24 g) in dry dimethylformamide (10 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.17 g) and stirred for 30 minutes at ambient temperature under argon. A solution of 1-(4-pyridyl)piperazine (1.6 g) in dry dimethylformamide (3 ml) was added to the mixture and the mixture cooled to 50° C. The reaction was then allowed to warm to room temperature and stirred overnight. The solution was poured into water and then extracted into diethyl ether, washed with aqueous sodium hydrogen carbonate solution, water, brine. dried (Na2SO4) and evaporated to yield a colourless oil. This oil was then triturated with diethyl ether and recrystallised from ethyl acetate/isohexane to give 1-(4-pyridyl)-4-(2-fluoro-4-bromobenzoyl)piperazine (0.14 g) as a solid, m.p. 125-126° C.: microanalysis, found: C, 52.6; H, 4.1; N, 11.2%; C16H15BrFN3O requires: C, 52.8; H, 4.15; N, 11.5%; NMR: (CDCl3) 3.32(t,2H), 3.46(t,4H), 3.94(t,2H), 6.68(dd,2H), 7.29-7.43(m,3H), 8.33(d,2H); MS: m/z 364 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:2]=1.C(O)(=O)C.[CH3:16][C:17]([CH3:21])=[CH:18][CH:19]=[O:20]>C1COCC1>[CH3:16][C:17]([CH3:21])([N:10]1[CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[CH:9]1)[CH2:18][CH:19]=[O:20]
Reactant: CC(C)=CC=O
Reactant: c1cncc(-c2c[nH]cn2)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(CC=O)n1cnc(-c2cccnc2)c1

Procedure:
To a solution of 4-pyridin-3-yl-imidazole (1 g) in THF (34 mL) was added acetic acid (1.6 mL) and 3-methyl-2-butenal (3.3 mL) and the resulting solution was heated under gentle reflux for 24 hours. THF was then removed in vacuo and the residue was purified on a Flash 75 long column eluting with MeOH—CH2Cl2 to give the title compound as slightly yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:24]3[CH2:25][CH2:26][C:21]([F:20])([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:22][CH2:23]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: FC1(c2ccccc2)CCNCC1
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 67.5 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1.55 g, 6.18 mmol) obtained in Example 19, step 2 and 4-fluoro-4-phenylpiperidine hydrochloride (2.0 g, 9.27 mmol), the title compound (1.72 g, 68%) was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][C:3]=1[F:19].[CH3:20][S:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:29]=3)=[C:3]([F:19])[CH:4]=2)[N:9]=1
Reactant: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1Br
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3cc2F)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloro-6-fluoroquinazolin-4-yl)morpholine (0.15 g, 0.0004 mol—Preparation 2), 3-methylsulfonylphenylboronic acid (0.078 g, 0.00039 mol), sodium carbonate (0.114 g, 0.0011 mol), DMF (6 mL) and water (2 mL) were added. The reaction vessel was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.015 g, 0.000022 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 90° C. for 3 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under the reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in n-hexane) to yield the desired product (0.12 g, 66%). 1H NMR (300 MHz, CDCl3): δ 8.23 (d, J=1.8 Hz, 1H), 8.06-7.90 (m, 3H), 7.68 (t, J=7.8 Hz, 1H), 7.64 (d, J=11.1 Hz, 1H), 3.92 (s, 8H), 3.12 (s, 3H): LC-MS (ESI): Calculated mass: 421.0; Observed mass [M+H]+: 422.1 (RT=1.45 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][CH:7]=1.Cl[C:12]1[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=2)[N:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: OB(O)c1cncc(Br)c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cncc(Br)c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 5-bromopyridin-3-ylboronic acid (288.0 mg, 1.43 mmol) in dioxane (5 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 140.0 mg, 0.48 mmol), K3PO4 (302.0 mg, 1.43 mmol), Pd(PPh3)4 (27.6 mg, 0.02 mmol) and three drops water. The reaction mixture was stirred for 1 h at 90° C. with an inert atmosphere of nitrogen and then concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(5-bromopyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150.0 mg, 72%) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[OH:18])[C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: c1cc(C2CO2)ccn1
Reactant: Cc1cccc2c3c([nH]c12)CCN(C)C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2c3c(n(CC(O)c4ccncc4)c12)CCN(C)C3
Reaction time: 0.17 h

Procedure:
To a solution of 2,6-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 5.00 mmol) in DMF (10 mL) was added sodium hydride (600 mg, 15 mmol) under nitrogen atmosphere at 0° C. and stirred for 10 min. 4-(Oxiran-2-yl)pyridine (1.08 g, 8.92 mmol) was added dropwise under nitrogen atmosphere. The reaction mixture was stirred at RT for 12 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was poured in ice-cold water and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was crystallized with diethyl ether to yield 2-(2,6-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.58 (d, 2H), 7.23 (m, 3H), 7.0 (t, 1H), 6.9 (d, 1H), 4.81 (t, 1H), 4.3-4.4 (m, 2H), 3.5 (dd, 2H), 3.0 (m, 1H), 2.8 (m, 1H), 2.75 (s, 3H), 2.7 (m, 1H), 2.6 (m, 1H), 2.43 (s, 3H). Separation by chiral HPLC provides enantiomers 82a and 82b.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C:9]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].Cl.N1CCCCC1.C(C1C=C2C(CCCC2=[O:43])=CC=1)(C)(C)C.C=O>C(O)C.Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12]([CH2:11][CH2:10][CH:9]([CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:8]2=[O:43])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)CCC2
Reactant: CC(C)(C)c1ccc2c(c1)C=C(CN1CCCCC1)CC2
Agent: C=O
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1ccc2c(c1)C(=O)C(CN1CCCCC1)CC2
Yield: 43 %

Procedure:
This Example illustrates the preparation of 6-tert-butyl-3-piperidinomethyl-1,2-dihydronaphthalene (Compound number 4 of Table I). Piperidine hydrochloride (8.9 g, 0.073 mol), 7-tert-butyl-1,2,3,4-tetrahydronaphthalen-1-one (7.0 g, 0.035 mol) and paraformaldehyde (2.2 g, 0.073 mol) were refluxed together in ethanol (150 ml) along with concentrated hydrochloric acid (1 ml) as a catalyst for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water then extracted with diethyl ether. The resulting aqueous solution was neutralized with sodium bicarbonate and extracted with diethyl ether (2×200 ml); the ethereal extracts were dried over magnesium sulphate and concentrated under reduced pressure to give 7-tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (4.5 g, 43% yield) as a buff coloured solid melting at 62°-3°. The 7-tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (4.5 g, 0.015 mol) was dissolved in methanol (100 ml) and sodium borohydride (0.6 g, 0.016 mol) was added portionwise over 30 minutes at room temperature. It was stirred for 3 hours at room temperature then the methanol was evaporated under reduced pressure and the residue treated with water (100 ml) and extracted with ether (2×100 ml) which was washed with brine, dried over magnesium sulphate and evaporated under reduced pressure to give a viscous oil (4.0 g) which crystallised on standing. Separation by column chromatography on silica gel (Merck 60) using a gradient elution of petrol 60°-80° to ethyl acetate gave the alcohol as two isomers:
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.CSC.[N:11]1([CH:16]([C:18]([C:20]([CH3:30])([CH3:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=O)[CH3:17])[CH:15]=[N:14][CH:13]=[N:12]1.C[O-].[Na+]>C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:20]([C:18]2([CH:16]([N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH3:17])[CH2:7][O:6]2)([CH3:29])[CH3:30])=[CH:23][CH:24]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(C(=O)C(C)(C)Cc1ccc(Cl)cc1)n1cncn1
Agent: C[O-]
Agent: [Na+]
Solvent: CSC
Solvent: CC#N
Product: CC(n1cncn1)C1(C(C)(C)Cc2ccc(Cl)cc2)CO1
Reaction time: 20 h
Yield: 98.1 %

Procedure:
A solution of 9.8 g (0.77 mole) of dimethyl sulphate and 5.3 g (0.085 mole) of dimethyl sulphide in 50 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 13 g (0.044 mole) of 4-chlorophenyl-tert.butyl 1-(1,2,4-triazol-1-yl)-ethyl ketone in 20 ml of acetonitrile is then added dropwise at room temperature. At the same temperature, 4.8 g (0.088 mole) of sodium methylate are introduced and the mixture is subsequently stirred for 20 hours and then concentrated in vacuo. The residue is stirred overnight with a mixture of 35 ml of ethyl acetate and 25 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 13.2 g (98.2% of theory) of 2-(4-chlorophenyl-tert.-butyl)-2-[1-(1,2,4-triazol-1-yl)-ethyl]oxirane of refractive index nD20 1.5431 are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([CH3:22])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[CH2:15]([C:11]1[C:12]([OH:14])=[N:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[CH2:31][Cl:30])=[CH:3][CH:4]=2)=[N:9][C:10]=1[CH3:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(NC(=O)CCl)cn2)nc(O)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 54 (0.050 g, 0.17 mmol) in THF (3 mL), was added triethylamine (0.025 g, 0.25 mmol) and chloroacetylchloride (0.029 g, 0.25 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: C[C:2]1[N:3]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11]CC1C=CC=CC=1)[CH:7]=[C:6]([CH3:19])[N:5]=2>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:19][C:6]1[N:5]=[C:4]2[N:3]([C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])[CH:2]=[N:10][C:9]2=[C:8]([NH2:11])[CH:7]=1
Reactant: Cc1cc(C)c(-n2c(C)nc3c(NCc4ccccc4)cc(C)nc32)c(C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(C)c(-n2cnc3c(N)cc(C)nc32)c(C)c1
Reaction time: 20 h

Procedure:
Add palladium hydroxide (0,05 g) to a solution of [2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]benzylamine (0.15 g, 0.42 mmol) in acetic acid (10 mL). Hydrogenate the mixture at a pressure of 50 psi for 20 hr. Filter the reaction mixture through celite, evaporate to dryness under reduced pressure, dilute with EtOAc and successively wash with aq NaHCO3 and aq NaCl. Dry the organic layer over Na2SO4, filter, and concentrate. Purify by flash column chromatography (3% MeOH in CH2Cl2) to obtain the title compound as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].[F:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][NH:27][S:28]([C:31]2[C:32](Br)=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>ClCCl.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>[F:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][NH:27][S:28]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[C:3](=[O:20])[CH2:4]4)[CH:36]=2)(=[O:29])=[O:30])=[CH:24][CH:23]=1
Reactant: O=S(=O)(NCc1ccc(F)cc1)c1cccnc1Br
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C(=O)Cc2cc(-c3cncc(S(=O)(=O)NCc4ccc(F)cc4)c3)ccc21
Temperature: 100 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 3a (124 mg, 0.45 mmol) was added bromo-pyridine-3-sulfonic acid 4-fluoro-benzylamide (140 mg, 0.41 mmol), tripotassium phosphate (260 mg, 1.25 mmol) and DMF (2.5 mL). The reaction mixture was degassed and placed under an argon atmosphere, at which time tetrakis(triphenylphosphine)palladium(0), (23 mg, 0.02 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 60 minutes. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (heptane-ethyl acetate, 20 to 100%) to furnish 5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridine-3-sulfonic acid 4-fluoro-benzylamide; HRMS: (ESI) m/z 412.1136 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (s, 3H), 3.65 (s, 2H), 4.12 (s, 2H), 7.03 (t, J=8.8 Hz, 2H), 7.14 (d, J=8.1 Hz, 1H), 7.25 (dd, J=8.6, 5.6 Hz, 2H), 7.65 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 8.20 (t, J=2.3 Hz, 1H), 8.44 (t, J=6.3 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 9.04 (d, J=2.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][N:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC>O1CCCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[C:2]([B:16]([OH:21])[OH:17])=[C:3]2[CH2:15][CH2:14][CH2:13][N:4]2[N:5]=1
Reactant: Brc1c(-c2ccccn2)nn2c1CCC2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 54.8 %

Procedure:
Place tetrahydrofuran (60.0 mL) in a 100 mL round-bottom flask equipped with a temperature probe, a magnetic stirrer, and a septum and put under a nitrogen atmosphere. Add 3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Preparation 3, Part D; 3.00 g, 11.4 mmol) and triisopropyl borate (6.80 mL, 29.5 mmol). Cool the mixture to −78° C. using a dry ice/acetone bath. Add 1.41M n-butyllithium in hexanes (19.3 mL, 27.3 mmol) dropwise via a syringe pump over 10 min keeping the temperature below −40° C. Remove the dry ice/acetone bath and allow the reaction mixture to warm to room temperature. Add saturated aqueous ammonium chloride (20 mL) and extract with chloroform (2×150 mL). Combine the organic layers, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to afford an oil. Purify by normal phase flash chromatography (120 g Biotage KP-Sil 40L: ethyl acetate for 25 min, 0-10% methanol in ethyl acetate in ramp over 15 min, then 10% methanol in ethyl acetate) to obtain 1.43 g (55%) of the title product. MS (ES) m/z=230 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 65 h

Procedure:
To 4-hydroxy-3-nitrobenzoic acid (10 g) were added pyridine (12 ml) and acetic anhydride (55 ml), and the mixture was stirred at room temperature for 65 hours. The reaction solution was concentrated under reduced pressure, and thereto was added a 5% aqueous sodium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (11.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20](OCC)(OCC)(OCC)[CH3:21]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:20]([CH3:21])=[N:13][N:12]=[C:7]1[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1cc(-c2ccccc2)c2cc(Br)ccc2n1
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3)c3cc(Br)ccc3n12

Procedure:
In the manner given in Example 2, 6-bromo-4-phenyl-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 7-bromo-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:37]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[O:40][CH2:39][CH:38]1[CH2:47][NH2:48]>CN(C=O)C>[O:37]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[O:40][CH2:39][CH:38]1[CH2:47][NH:48][CH2:13][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)OCC(CNCCCCc1c[nH]c3ccccc13)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
3-Indolebutyric acid (1.2 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (2.3 ml, 14.4 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2methanamine hydrochloride (1.2 g, 6.0 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.2 g (57%) of the desired product, (2,3-dihydro-benzo [1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-butanamide, as an oil.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:26]2[O:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][N:38](C)[C:39](=O)OC(C)(C)C)=[CH:33][CH:32]=3)=[N:28][N:27]=2)=[N:11][C:12]([N:15]2[CH2:20][C@H:19]3[C@H:17]([CH:18]3[C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH2:16]2)=[CH:13][N:14]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:20][C@H:19]3[C@H:17]([CH:18]3[C:21]([N:22]([CH3:23])[CH3:24])=[O:25])[CH2:16]2)=[N:11][C:10]=1[C:26]1[O:30][C:29]([C:31]2[CH:32]=[CH:33][C:34]([CH2:37][NH:38][CH3:39])=[CH:35][CH:36]=2)=[N:28][N:27]=1
Reactant: CN(C)C(=O)C1[C@H]2CN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccc(CN(C)C(=O)OC(C)(C)C)cc5)o4)n3)C[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2nnc(-c3nc(N4C[C@@H]5C(C(=O)N(C)C)[C@@H]5C4)cnc3N)o2)cc1

Procedure:
A solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-[(1R,5S)-6-(dimethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (75 mg, 0.1 mmol) in 0.8 mL of 50% TFA-DCM mixture was stirred under an atmosphere of nitrogen at room temperature for 1 h. The solvents were evaporated and the crude material was purified via reverse phase HPLC using 10 to 99% methanol in water (TFA modifier) to obtain (1R,5S)-3-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-3-azabicyclo[3.1.0]hexane-6-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 8.16 (d, J=8.2 Hz, 2H), 7.91 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 6.76 (s, 2H), 4.26 (t, J=5.7 Hz, 2H), 3.86 (d, J=10.2 Hz, 2H), 3.49-3.46 (m, 2H), 3.10 (s, 3H), 2.84 (s, 3H), 2.63 (t, J=5.2 Hz, 3H), 2.09 (s, 2H), 1.90 (t, J=3.1 Hz, 1H). LC/MS m/z 435.2 [M+H]+.