Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:25]=[CH:24][C:18]([CH2:19][C:20]4([NH2:23])[CH2:22][CH2:21]4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45](=O)[O:46]C1C=CC([N+]([O-])=O)=CC=1)([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45]([NH:23][C:20]1([CH2:19][C:18]2[CH:24]=[CH:25][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:26])[F:27])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)[CH2:21][CH2:22]1)=[O:46])([CH3:30])[CH3:29]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: NC1(Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)CC1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC2(Cc3ccc(-c4ncn(-c5ccc(OC(F)(F)F)cc5)n4)cc3)CC2)c1

Procedure:
The title compound was prepared as described in Example 95 using 1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanamine (CB30) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as red oil (0.104 g, 37%).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[OH-].[Na+].C(O)(=O)C.O>C(O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:16][CH2:17][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20]3)[O:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CN1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NN=Cc1ccc(C2=NOC3(CCN(CC(=O)O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.12 g (0.315 mmol) of the ester from Example 5 were dissolved in 2 ml ethanol, and after addition of 0.4 ml 2 N aqueous sodium hydroxide solution the mixture was stirred overnight at room temperature. It was adjusted to pH 4 with diluted acetic acid. The solvent was removed from the clear solution under reduced pressure to leave a brown oil, which solidified by stirring with a mixture of ethanol and water. It was filtered, stirred in a small amount of hot ethanol, filtered again, and dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.O>CC(O)=O.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:12]=[CH:13][CH:14]=[C:15]([NH2:16])[CH:10]2[NH2:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cc(F)cc(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: NC1=CC=CN(c2cc(F)cc(F)c2)C1N
Temperature: 100 °C

Procedure:
To a solution of N-(3,5-difluorophenyl)-3-nitro-pyridin-2-amine (2.0 g, 7.96 mmol) in AcOH (24 mL) was added iron powder (1.33 g, 23.8 mmol) and the reaction mixture was heated to 100° C. for 1 h. The reaction mixture was cooled to rt and water (70 mL) was added. The organic layer was extracted with EtOAc (350 mL) and was basified by using satd. sodium bicarbonate solution (150 mL), dried over sodium sulfate and concentrated in vacuo to provide N1-(3,5-Difluorophenyl)-pyridine-2,3-diamine. The crude product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:55])[C:7]1[CH:15]=[C:14]([NH:16][C:17](=[O:54])[CH2:18][N:19]([CH2:45][CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:20](=[O:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:69]1[C:74](=[O:75])[CH2:73][CH2:72][C:70]1=[O:71])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:71]=[C:70]1[CH2:72][CH2:73][C:74](=[O:75])[N:69]1[O:11][C:10](=[O:12])[C:9]1[CH:8]=[C:7]([CH:15]=[C:14]([NH:16][C:17](=[O:54])[CH2:18][N:19]([CH2:45][CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:20](=[O:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH:13]=1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:55]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)Nc1cc(C(=O)O)cc(C(=O)OC(C)(C)C)c1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)Nc1cc(C(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
5-{2-[(2-tert-Butoxycarbonyl-ethyl)-(17-tert-butoxycarbonyl-heptadecanoyl)-amino]-acetylamino}-isophthalic acid mono-tert-butyl ester (214 mg) was dissolved in dry THF and TSTU (0.105 mg) and DIPEA (0.1 ml) was added. The mixture was stirred at room temperature under nitrogen. After 20 h the reaction mixture was concentrated. The residue was redissolved in EtOAc and filteret. The filtrate was extracted with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4) and concentrated to give 5-{2-[(2-tert-Butoxycarbonyl-ethyl)-(17-tert-butoxycarbonyl-heptadecanoyl)-amino]-acetylamino}-isophthalic acid 1-tert-butyl ester 3-(2,5-dioxo-pyrrolidin-1-yl) ester as a yellow sirup in 90% yield (218 mg).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:24]=[C:23]([C:25](=[O:27])[CH3:26])[C:22]([CH3:28])=[C:21]([CH2:29][O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[N:20]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1>C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:24]=[C:23]([C:25]([OH:27])([CH3:1])[CH3:26])[C:22]([CH3:28])=[C:21]([CH2:29][O:30][CH2:31][C:32]([F:33])([F:34])[F:35])[N:20]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)c(C)c(C(C)=O)n2)ccc1-n1cnc(C)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)c(C)c(C(C)(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (0.199 mL of 3M solution, 0.28 mmol) was added slowly to a solution of 1-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)ethanone (25 mg, 0.06 mmol) in THF (3 mL). The mixture was stirred at RT for 1 h. The mixture was quenched with saturated solution of ammonium chloride in water (1.5 mL) and diluted with brine (10 mL). The mixture was extracted with EtOAc (2×20 mL). The organic phase was dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to give title compound as a dry film, 13 mg (45%).
Reaction SMILES: OS(O)(=O)=O.C([NH:9][C:10]1[CH:18]=[C:17]([O:19][CH2:20][CH3:21])[C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:11]=1C(O)=O)(=O)C.[OH-].[NH4+]>O>[CH2:20]([O:19][C:17]1[CH:18]=[C:10]([CH:11]=[CH:15][C:16]=1[N+:22]([O-:24])=[O:23])[NH2:9])[CH3:21]
Reactant: CCOc1cc(NC(C)=O)c(C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc(N)ccc1[N+](=O)[O-]
Temperature: 111 °C
Yield: 71 %

Procedure:
To 600 ml of H2O was slowly added 400 ml conc. H2SO4. To the hot mixture was added 118.5 g 0.44 mol)) of 2-acetylamino-4-ethoxy-5-nitro-benzoic acid. The mixture was heated to 110-112° C. with stirring. Initially there was a vigorous gas evolution. After I hr., the mixture was poured unto ice. The mixture was made basic with conc. ammonium hydroxide (an exothermic reaction ensued). The mixture was allowed to cool to room temperature and the solid was collected by filtration. The solid was washed several time with 500 ml portions of water and then dried in vacuum and then extracted several times with warm ethyl acetate. The extracts were filtered and solvent was removed giving 57.8 g (71%) of the product.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[Cl:39][C:40]1[CH:48]=[C:47]([C:49]#[C:50][C:51]([O:54][CH3:55])([CH3:53])[CH3:52])[C:43]2[O:44][CH2:45][O:46][C:42]=2[C:41]=1[NH2:56]>CN(C=O)C>[Cl:39][C:40]1[CH:48]=[C:47]([C:49]#[C:50][C:51]([O:54][CH3:55])([CH3:53])[CH3:52])[C:43]2[O:44][CH2:45][O:46][C:42]=2[C:41]=1[NH:56][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COC(C)(C)C#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(Nc3c(Cl)cc(C#CC(C)(C)OC)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.12 ml) in tetrahydrofuran (1.0M, 1.12 mmol) was added to a solution 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (0.189 g) and 5-chloro-7-(3-methoxy-3-methylbut-1-yn-1-yl)-1,3-benzodioxol-4-amine (0.150 g) in DMF (6 ml) that had been cooled to −15° C. and the mixture was stirred for 3 hours then the reaction was allowed to warm to room temperature. The reaction mixture was quenched into water and saturated ammonium chloride solution was added. The resulting white precipitate was filtered under suction, washing with water, giving a pale tan paste. This was then extracted into dichloromethane, dried over magnesium sulfate and solvents evaporated under reduced pressure to give a tan foam. This was triturated with diethyl ether, giving a white solid. The resulting solid was then gathered by filtration and air-dried. There was thus the title compound (0.225 g) as an off-white solid; NMR Spectrum: (CDCl3) 1.55 (s, 6H), 2.11 (quin, 2H), 2.47 (s(broad), 4H), 2.56 (t, 2H), 3.43 (s, 3H), 3.72 (t, 4H), 4.00 (s, 3H), 4.26 (t, 2H), 6.07 (s, 2H), 6.83 (s, 1H), 7.05 (s, 1H), 7.08 (s, 1H), 7.30 (s, 1H), 8.62 (s, 1H); Mass Spectrum: M+H+ 569/571.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10]#[N:11])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][NH:12][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][NH2:11])=[CH:16][CH:17]=1
Reactant: COc1ccc(CCNC(C#N)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(CCNC(CN)c2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
The crude (4-methoxyphenyl)-[2-(4-methoxyphenyl)ethylamino]-acetonitrile obtained in the above procedure is dissolved in diethyl ether (20 mL) and this solution is slowly added to an ice-cold solution of lithium aluminum hydride (1.0M, 16 mL, 16 mmol) in diethyl ether. The cooling bath is removed and the solution is allowed to stir for 1 hour. The reaction solution is then re-cooled to 5° C. and water (4 mL) is added, followed by 3N NaOH (3 mL). The ether is then decanted from the resulting solid and the solid is again washed with diethyl ether (20 mL). The combined ether washings are dried (Na2SO4) and concentrated in vacuo to afford 2.5 g (quantitative yield) of the desired compound. MS (301) (MH+).
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([CH3:34])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:32]#[N:33])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31])[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:32]([C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[CH:16]=2)[C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:35])([CH3:34])[C:6]([OH:36])=[O:5])=[O:11])[N:13]=1)#[N:33]
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3c(F)cccc3F)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3c(F)cccc3F)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A mixture of 3-{[1-Cyano-7-(2,6-difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid tert-butyl ester (36 mg), TFA (1 mL) and DCM (2 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (21 mg). LC MS ESI+: 442 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]12[O:16][CH:15]1[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[OH-].C1COCC1>CCOCC>[CH2:1]([O:8][CH2:9][C:10]1([OH:16])[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(COCc3ccccc3)OC2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
An Et2O (25 ml) solution of tert-butyl 6-[(benzyloxy)methyl]-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (3.37 g) was added dropwise under ice-cooling to an suspension of LAH (520 mg) in Et2O (75 ml), and was stirred at room temperature for 1 hour, Under ice-cooling, a saturated ammonia aqueous solution (1 ml) was added. After dilution with THF, stirring was performed at room temperature for 2 hours. After drying over anhydrous magnesium sulfate, Celite filtering was performed. The residue obtained by concentration was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 4-[(benzyloxy)methyl]-4-hydroxypiperidine-1-carboxylate (2.59 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:13][CH2:14][NH2:15])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:21][O:20][C:18](=[O:19])[CH2:17][NH:15][CH2:14][CH2:13][NH:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11]
Reactant: COC(=O)CBr
Reactant: NCCNC(=O)c1nc(Cl)c(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CNCCNC(=O)c1nc(Cl)c(N)nc1N
Yield: 74.2 %

Procedure:
A mixture of 13.7 g (59.4 mmol) of 3,5-diamino-6-chloro-N-(2-aminoethyl)pyrazine-2-carboxamide, 3.03 g (19.8 mmol) of methyl bromoacetate and 2.0 g (19.8 mmol) of triethylamine was stirred overnight in 250 ml of tetrahydrofuran at ambient temperature. The solvent was evaporated and the residue was chromatographed on silica gel (300 g) using 3.5:96.5 (v/v) methanol:methylene chloride as eluent. There was obtained 4.45 g (14.7 mmol, 74%) of N-[2-[[(3,5-diamino-6-chloropyrazinyl)carbonyl]amino]ethyl]glycine methyl ester as a white powder; mp 145°-146.5° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([O:18][CH3:19])[CH:11]=[CH:10]2.C1(P([N:34]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>CCCCCC.O1CCCC1.C1(C)C=CC=CC=1>[NH2:34][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([O:18][CH3:19])[CH:11]=[CH:10]2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2cc(Br)cc(C)c2n1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccc2cc(N)cc(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
n-butyllithium (13.75 cm3 of a 1.6M solution in n-hexane) was added dropwise to a stirred solution of 6-bromo-2-methoxy-8-methylquinoline (5.04 g) in tetrahydrofuran (THF) (50 cm3) at -70° under nitrogen. After 15 minutes the fine suspension was transferred via a cannula to a stirred solution of diphenylphosphorylazide (5.5 g) in THF (50 cm3) at -70° under nitrogen. The dark solution was stirred at -70° for 2 hours, warmed to -20° over 1 hour and then re-cooled to -70°. A solution of sodium bis(2-methoxyethoxy)aluminium hydride (23.5 cm3 of a 3.4M solution in toluene) was slowly added and the solution was warmed to room temperature over 1.5 hours. The mixture was cooled to 0°, ice (100 g) was cautiously added, the resulting suspension was filtered, and the solid was washed with ethyl acetate. The aqueous filtrate was further extracted with ethyl acetate (2×100 cm') and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]). Elution with toluene, followed by combination and evaporation of appropriate fractions, gave a solid which was recrystallised from hexane to afford 6-amino-2-methoxy-8-methylquinoline, m.p. 115°-117° (1.07 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21](Cl)=[N:20][CH:19]=[C:18]([C:23]2[N:24]=[C:25]([N:32]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH2:44][CH2:43][N:42]([CH:45]5[CH2:48][O:47][CH2:46]5)[CH2:41][CH2:40]4)=[C:35]([O:49][CH2:50][CH2:51][O:52][CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][O:54]4)[CH:34]=3)[C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[CH:28]=2)[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:66]B(O)O>C(=O)([O-])[O-].[Na+].[Na+].COCCOC.C(Cl)Cl.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:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:66])=[N:20][CH:19]=[C:18]([C:23]2[N:24]=[C:25]([N:32]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH2:44][CH2:43][N:42]([CH:45]5[CH2:48][O:47][CH2:46]5)[CH2:41][CH2:40]4)=[C:35]([O:49][CH2:50][CH2:51][O:52][CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][O:54]4)[CH:34]=3)[C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[CH:28]=2)[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CB(O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)c(OCCOC4CCCCO4)c3)n2)cnc1Cl
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: ClCCl
Solvent: O
Solvent: COCCOC
Product: Cc1ncc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)c(OCCOC4CCCCO4)c3)n2)nc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
A microwave vial was charged with tert-butyl tert-butoxycarbonyl(6-(8-((tert-butoxycarbonyl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)amino)imidazo[1,2-a]pyrazin-6-yl)-3-chloropyrazin-2-yl)carbamate XXXIV (258 mg, 0.28 mmol), methylboronic acid (503 mg, 8.4 mmol), Pd(PPh3)4 (32 mg, 0.03 mmol) in sodium carbonate (0.8 mL, 1M in H2O) and DME (2.5 mL). The mixture was heated at 150° C. for 20 min. The reaction was cooled to room temperature, diluted with DCM and H2O. The aqueous layer was separated and extracted with DCM. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography ISCO Rf (4 g column) eluting with a gradient of 100% DCM—100% 75/18/7 DCM/Et2O/MeOH to provide the desired compound tert-butyl tert-butoxycarbonyl(6-(8-((tert-butoxycarbonyl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)amino)imidazo[1,2-a]pyrazin-6-yl)-3-methylpyrazin-2-yl)carbamate XXXV.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[CH:13][C:8]=2[C:7](=[O:22])[N:6]([CH3:23])[C:5]2[CH:24]=[CH:25][CH:26]=[N:27][C:4]1=2)[CH3:2]>C(OCC)(=O)C.[Pt]=O>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[CH:13][C:8]=2[C:7](=[O:22])[N:6]([CH3:23])[C:5]2[CH:24]=[CH:25][CH:26]=[N:27][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncc(/C=C/c3ccncc3)cc2C(=O)N(C)c2cccnc21
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2cccnc21

Procedure:
The title compound was prepared from 5,11-Dihydro-11-ethyl-5-methyl-8-[trans-2-(4-pyridyl)ethen-1-yl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.38 g, 1.0 mmol) by catalytic hydrogenation over platinum oxide in ethyl acetate at 150 p.s.i. and 60° C. Recrystallization from ethyl acetate/hexanes afforded 0.18 g of the product as off-white crystals, m.p. 109°-110° C.
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CN[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[N:57]=[CH:56][CH:55]=[N:54]1)=[O:45].ClC1C(C(F)(F)F)=CC=CN=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44]([C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[N:57]=[CH:56][CH:55]=[N:54]2)=[O:45])[C@@H:37]1[CH2:36][NH:35][C:27]1[C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=[CH:25][N:26]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: FC(F)(F)c1cccnc1Cl
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncccc2C(F)(F)F)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-3-(trifluoromethyl)pyridine. ESI-MS (m/z): 459 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH2:10][C:11]1([OH:18])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:8][C:9](=[O:19])[CH2:10][C:11]1([OH:18])[CH2:16][CH2:15][CH:14]([NH:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC(O)(CC(=O)OCc2ccccc2)CC1
Product: O=C(CC1(O)CCC(NCc2ccccc2)CC1)OCc1ccccc1

Procedure:
Prepared from (1-Hydroxy-4-oxo-cyclohexyl)-acetic acid benzyl ester and benzylamine following the procedure described in Step 2 of Example 43. The crude product was purified by flash chromatography on silica gel (0-10% CH3OH:CH2Cl2). ESI-MS m/z 354 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24](O)=[O:25])[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[C:29]([O:33][C:34]([NH:36][CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:35])[NH:36][CH:37]1[CH2:41][CH2:40][N:39]([C:24](=[O:25])[CH2:23][N:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][C:12]3[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=4)[S:10][CH:11]=3)[CH2:18][CH2:19]2)[CH2:38]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)CN2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Cl)cc4)n3)CC2)C1

Procedure:
In analogy to example 22.3, (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid (example 22.2) was coupled with 3-(tert-butyloxycarbonylamino)pyrrolidine, using general method C, to give {1-[2-(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester. Off-white solid. MS 591.3 ([M+H]+)