Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].C1(C)C=CC=CC=1.[CH2:23]([NH:31][CH2:32][C@@H:33]([C@H:35]([C@@H:37]([C@@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[OH:36])[OH:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O>[CH2:23]([NH:31][CH2:32][C@@H:33]([C@H:35]([C@@H:37]([C@@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[OH:36])[OH:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[OH:3][C:2]([C@H:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: CCCCCCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Temperature: 78 °C

Procedure:
Racemic ibuprofen (80 g, 390 mmol), toluene (200 mL), and water (0.5 mL) were stirred at 40° C., and N-octyl-D-glucamine (53.8 g, 183 mmol, N-octyl-D-glucamine/(S)-ibuprofen molar ratio=0.938) was added to the solution. The resulting thick slurry was heated to 78° C., forming a clear solution, and the solution then cooled to 15° C. over 3-4 hours. The resulting precipitate was recovered by filtration, washed with toluene (100 mL), and dried to give (S)-ibuprofen N-octyl-D-glucamine salt (72.2 g, 145 mmol, 74.6% yield, MR=136°-137° C.). The toluene liquors were saved for racemization and recycle of the contained (R)-ibuprofen.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1ccnc(N)n1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1-c1ccnc(Nc2ccccc2)n1
Yield: 36.5 %

Procedure:
To a solution of 50 mg (0.2 mmol) of 4-(5-methyl-3-phenyl-isoxazole-4-yl)-pyrimidin-2-ylamine in 1 mL of toluene was added successively 63 μL (0.6 mmol) of bromobenzene, 10 mg of tris(dibenzylideneacetone) dipalladium, 10 mg of BINAP and 39 mg (0.4 mmol) of sodium tert-butoxide. The mixture was heated at reflux for 16 h, diluted with ethyl acetate, filtered, washed successively with saturated aqueous sodium bicarbonate and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography over silica gel eluted with ethyl acetate-hexanes 1:3, to afford 24 mg (36%) of the title compound as a yellow oil.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CO[C:11](=[O:29])[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=O)=[C:14]([C:21]2[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=2[CH3:26])[CH:13]=1.CN(C[N:34]1[C:38]2=[N:39][C:40]([N:43]3[CH2:48][CH2:47][CH:46]([N:49]([CH3:51])[CH3:50])[CH2:45][CH2:44]3)=[CH:41][CH:42]=[C:37]2[N:36]=[CH:35]1)C>>[CH3:50][N:49]([CH3:51])[CH:46]1[CH2:47][CH2:48][N:43]([C:40]2[N:39]=[C:38]3[NH:34][C:35]([C:11]([C:12]4[CH:20]=[CH:19][C:15]([C:16]#[N:18])=[C:14]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])[CH:13]=4)=[O:29])=[N:36][C:37]3=[CH:42][CH:41]=2)[CH2:44][CH2:45]1
Reactant: COC(=O)c1ccc(C(N)=O)c(-c2c(C)nn(C)c2C)c1
Reactant: CN(C)Cn1cnc2ccc(N3CCC(N(C)C)CC3)nc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: Cc1nn(C)c(C)c1-c1cc(C(=O)c2nc3ccc(N4CCC(N(C)C)CC4)nc3[nH]2)ccc1C#N

Procedure:
Following General procedure P (LDA metallation, ketone formation and in situ deprotection) using 3-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-terephthalamic acid methyl ester and [1-(3-dimethylaminomethyl-3H-imidazo[4,5-b]pyridin-5-yl)-piperidin-4-yl]-dimethyl-amine to give 4-[5-(4-dimethylamino-piperidin-1-yl)-3H-imidazo[4,5-b]pyridine-2-carbonyl]-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzonitrile. (84%). HRMS m/z 501.2721 (M+H)+.
Reaction SMILES: [Br-].[C:2]([C:6]1[C:19]2[NH2+:18][C:17]3[C:12](=[CH:13][C:14]([Br:20])=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[C:8](Br)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[Br-:20].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:8]2[CH:7]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:19]3[C:10]([CH:9]=2)=[S+:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)[CH:13]=2)[N:18]=3)[CH2:25][CH2:24]1
Reactant: CC(C)(C)c1cc(Br)cc2c1[NH2+]c1ccc(Br)cc1S2
Reactant: CN1CCNCC1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc3nc4c(C(C)(C)C)cc(N5CCN(C)CC5)cc4[s+]c3c2)CC1
Reaction time: 3 h

Procedure:
To a solution of 1-t-butyl-3,7-dibromophenothiazinium bromide (400 mg, 0.8 mmol) in chloroform (15 mL) kept under argon, 1-methylpiperazine (400 mg, 4.0 mmol) was added (30 min) with vigorous stirring. The mixture was stirred for 3 h and after that extracted once with aqueous HBr (10 mL, 1% v/v) and twice with water. The organic layer was dried (Na2SO4), concentrated and dried under vacuum. Compound was purified by flash chromatography (solvent system: dichloromethane-methanol).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]>ClCCl>[CH2:39]([Sn:34]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1)[CH2:40][CH2:41][CH3:42]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC[Mg]Br
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 33.8 %

Procedure:
To a solution of 4-Iodo-1-trityl-1H-imidazole (5.0 g, 11.6 mmol) in dichloromethane (100 ml) added Ethylmagnesium bromide (3M in diethyl ether) (4.6 ml, 13.9 mmol). Stirred the reaction under argon atmosphere at room temperature for 1 h. At this point added tributyltin chloride (4.1 ml, 13.9 mmol) to the reaction mixture and left the resulting mixture stirring at room temperature overnight. The reaction mixture was diluted with dichloromethane (100 ml), successively washed with saturated ammonium chloride (100 ml), water (100 ml) and brine (100 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo to yield the crude title compound (2.35 g) as a white waxy solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC(O)=O.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([Br:27])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCc2ccsc2CC1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2cc(Br)sc2CC1
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
The product of Example 1, step (d) (80 mg, 0.35 mmol) was dissolved in 2 mL of 1:1 CHCl3:HOAc and treated with NBS (62 mg, 0.35 mmol). After 15 minutes, the reaction was concentrated to dryness, dissolved in a minimal amount of EtOAc and filtered through a pad of silica gel. The filtrate was evaporated to give 105 mg of the sub-title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.C(N(CC)CC)C>C(O)C>[Br:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)=[N:3][CH:4]=1
Reactant: Cc1nc(Br)ncc1Br
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N2CC(O)C2)ncc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from example 135 step (i) (0.75 g), azetidin-3-ol hydrochloride (0.66 g) and triethylamine (0.9 ml) in ethanol (10 ml) was stirred at RT for 2 h. The solvent was removed under reduced pressure and the residue purified by chromatography on silica eluting with 60% diethylether/isohexane as eluant, yield 0.7 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(COc1cccc(Br)c1)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Into a 3-L three neck round-bottom flask, was placed a solution of 3-bromophenol (50.00 g, 289.0 mmol) in N,N-dimethylformamide (1 L). The system was purged with nitrogen and the solution was cooled to 0° C., then sodium hydride (60%, 12.8 g, 320 mmol) was added portion-wise. To the resulting mixture was added 2-bromo-1,1-diethoxyethane (53.1 mL, 345 mmol) drop-wise at 0° C. The resulting mixture was stirred overnight at 120° C., behind a blast shield (CAUTION: NaH and DMF can become a runaway reaction. All necessary safety precautions were performed). The mixture was cooled to room temperature, then diluted with ethyl acetate (3 L). The mixture was washed with brine (4×500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50-1/30) as the eluent to yield the title compound as a light yellow oil (78.9 g, 94%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:12]1[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][S:15][N:16]=1.O>O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:12]1[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][S:15][N:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-butoxyethanol (1.06 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@@H:7]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:21])[C@@H:7]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@H](Nc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCC[C@H](Nc1ccccc1N)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of (S)-2-(2-Nitro-phenylamino)-pentanoic acid tert-butyl ester (0.69 g, 2.4 mmol) in MeOH (10 mL) was added a slurry of Pd/C (0.2 g) in MeOH (10 mL). The reaction mixture was degassed using house vacuum. The flask was saturated with H2 and stirred under H2 balloon for 2 h. When the reaction was completed, the mixture was filtered through a pad of celite and the filtrate was concentrated to afford 0.61 g (97%) of the desired product. The resulting residue was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:4]=1.C([O-])(=O)C.[Na+].[I:29]Cl>C(O)(=O)C.O>[I:29][C:11]1[N:10]=[CH:9][N:8]2[C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:6][C:7]=12
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3cncc3n2)cc1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3cnc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.1 %

Procedure:
To a stirred solution of 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (1.05 g, 3.17 mmol) in acetic acid (4 mL) was added at room temperature sodium acetate (0.29 g, 3.58 mmol) and drop wise a solution of iodine monochloride (0.53 g, 3.58 mmol) in acetic acid (4 mL). The reaction mixture was stirred at room temperature for 19 h, diluted slowly with water (100 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 8-iodo-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (1.45 g, 100%) as an orange solid. MS (EI) 457.0 [(M)+]; mp 141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20](C)[CH:19]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.OO.[CH3:34][NH:35][CH:36]=[O:37]>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[CH3:34][NH:35][C:36]([C:20]1[CH:19]=[C:18]([CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)[CH:23]=[CH:22][N:21]=1)=[O:37]
Reactant: Cc1cc(Cc2nnc(Nc3ccc(Cl)cc3)c3ccccc23)ccn1
Reactant: CNC=O
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CNC(=O)c1cc(Cc2nnc(Nc3ccc(Cl)cc3)c3ccccc23)ccn1
Temperature: 70 °C
Reaction time: 5 h
Yield: 17 %

Procedure:
To a 3-necked flask charged with 1-(4-chloroanilino) 4-[(2-methyl-4-pyridyl)methyl] phthalazine (for preparation see Novartis patent WO98/35958, 11.02.98) (0.828 g, 2.39 mmol) in anhydrous N-methylformamide (4.8 mL) was added concentrated sulfuric acid)0.12 mL. 2.39 mmol) and iron (II) sulfate heptahydrate (0.33 g, 1.19 mmol). Hydrogen peroxide (0.256 mL, 8.35 mmol; 30 wt. % solution in water) was added dropwise to keep the internal temperature below 80° C. The resultant wine color reaction was then stirred at 70° C. for 5 h. The reaction mixture was cooled to RT and quenched with 10% aqueous sodium hydroxide (10 mL) followed by 10% aqueous ammonia (˜100 mL). The resultant brown precipitate was filtered through a pad of celite, and the filtrate was extracted with 10% methanol-dichloromethane (3×100 mL). The combined organic phases were washed with water (2×50 mL) and brine (1×50 mL), dried over MgSO4, filtered, and evaporated in vacuo. The crude oil was purified by flash column chromatography (10% acetone-dichloromethane followed by 1:4:20 v/v methanol-acetone-dichloromethane). Recrystallization from methanol afforded 0.165 g (0.404 mmol, 17% yield) of the title compound as a yellow solid. 1H-NMR (DMSO-d6) 9.28 (s, 1H), 8.70 (d, J=4.9, 1H), 8.58 (d, J=7.4, 1H), 8.49 (d, J=5.4, 1H), 8.12 (d, J=8.4, 1H), 7.89 to 7.99 (m, 5H), 7.51 (dd, J=5.1, 1.7, 1H), 7.38 (dd, J=7.1, 1.9, 2H), 4.67 (s, 2H), 2.75 (d, J=4.9, 3H); MS ES 404 (M+H)+, calc. 403; TLC (1:4:15 v/v methanol-acetone-dichloromethane) Rf=0.74.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-]>>[OH:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[NH:6][C:4](=[O:5])[CH2:3][CH2:2]2
Reactant: O=C(CCCl)Nc1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cc(O)ccc2N1
Temperature: 180 °C
Yield: 80.4 %

Procedure:
A mixture of 3-chloro-N-(4-hydroxyphenyl)propanamide (122 g, 0.61 mol) and AlCl3 (327 g, 2.45 mol) were slowly heated with vigorous stirring at 180° C. (a thick melt formed) and after 5 hours the liquid was poured over ice. The solids were collected by filtration, washed with water, and recrystallized from MeOH to afford 6-hydroxy-3,4-dihydro-2(1 H)-quinolinone (80 g, 40% yield). 1H NMR (400 MHz, DMSO) δ, 2.32-2.36 (m, 2 H), 2.74 (t, 2 H, J=7.2 Hz), 6.50 (m, 1 H), 6.54 (d, 1 H, J=2.8 Hz), 662(d, 1 H, J=8.4 Hz), 9.00 (br, 1 H), 9.78 (br, 1 H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[N:54]([C:57]1[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=1[C:59]#[N:60])=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:55]([NH:54][C:57]2[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=2[C:59]#[N:60])=[O:56])[CH2:48]1
Reactant: N#Cc1ccccc1N=C=O
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1NC(=O)N1CC[C@@H](CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 77 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 2-isocyanatobenzonitrile as the starting materials in 77% yield. LCMS for C31H29ClN9O2 (M+H)+: m/z=594.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]([CH3:15])=[CH2:14].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:13]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])([CH3:15])=[CH2:14]
Reactant: C=C(C)Br
Reactant: N#Cc1cccc(B(O)O)c1
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: O
Solvent: COCCOC
Product: C=C(C)c1cccc(C#N)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-cyanophenylboronic acid (10.0 g, 68.05 mmol) dissolved in DME (340 mL) is added 2-bromopropene (6.86 g, 56.7 mmol), and sodium carbonate (62.3 mL of a 2 M solution in water, 124.7 mmol). The reaction mixture is degassed for 20 min with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (2.54 g, 2.2 mmol) is added, the reaction mixture degassed for 10 min, and heated at reflux overnight. The reaction mixture is cooled to room temperature and then partitioned between hexanes and water. The aqueous layer is extracted with hexanes (3×75 mL). The combined organic layers are washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (9:1 hexanes/ethyl acetate) provides the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.96 (m, 1H), 7.85 (d, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.56 (m, 1H) 5.58 (s, 1H), 5.23 (m, 1H), 2.13 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH3:21])=O)(C)(C)C.[ClH:22]>CO>[ClH:22].[CH3:21][CH:9]1[NH:8][CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[N:16]=[C:10]12
Reactant: CC1c2nc(C(F)(F)F)nn2CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC1NCCn2nc(C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-N-(tert-butoxycarbonyl)-8-methyl-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (2.40 g, 7.83 mmol) in 40 mL of methanol was added 50 mL of methanol saturated with hydrogen chloride. The reaction was stirred at ambient temperature for 1 h. Concentration in vacuo gave the title compound as an off-white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.[CH2:22]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:32])=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCOc1ccc(C(=O)NC2CCC(OC(C)=O)CC2c2ccc(OC)c(OC)c2)cc1

Procedure:
790 mg of (±)-acetic acid (1RS,3RS,4RS)-4-amino-3-3,4-dimethoxyphenyl)cyclohexyl ester (compound B1), 620 mg of 4-butoxybenzoic acid, 614 mg of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride and 2 mg of 4-dimethylaminopyridine are stirred in 7 ml of dichloromethane for 18 h. 5 ml of water are added, the phases are separated and once the organic layer is extracted with 3 ml of dichloromethane. Then the organic layer is washed with 2.5 ml of saturated aqueous potassium bicarbonate solution and the aqueous solution is once extracted with 5 ml of dichloromethane. The combined organic layers are dried over magnesium sulfate, then the solvent is removed to give 1172 mg of the title compound as a colorless foam.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:31])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:29])=[N:27][O:28][C:24]=3[CH:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:29][C:26]1[C:25]2[C:20]([O:19][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:31])[NH2:5])=[CH:18][CH:17]=3)=[CH:21][C:22]([CH3:30])=[CH:23][C:24]=2[O:28][N:27]=1
Reactant: Cc1cc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cc2)c2c(C)noc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c2c(C)noc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-dimethylethyl[(1R)-2-({4-[(3,6-dimethyl-1,2-benzisoxazol-4-yl)oxy]phenyl}amino)-1-methyl-2-oxoethyl]carbamate) (Intermediate 22, 74 mg) was dissolved in 3.0 ml of dichloromethane. TFA (1.5 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. After removal of the volatiles, the residue was purified with a SCX cartridge and eluted with DCM/MeOH/NH3 (2.0 M solution in MeOH). The evaporation of the volatiles, afforded 54 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]=[CH2:29])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[CH2:30]([Zn]CC)C.CCCCCC.ICI.[Cl-].[NH4+]>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]2[CH2:30][CH2:29]2)[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CC[Zn]CC
Reactant: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: ClCCl
Solvent: CCCCCC
Product: CCC(OC1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
To a solution of 9-chloro-1-(2-chloro-4-methoxyphenyl)-6-[1-(ethenyloxy)propyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (170 mg, 0.39 mmol) in dichloromethane (4.0 mL) was added a solution of diethyl zinc in hexane (1.0 M, 2.0 mL, 2.0 mmol) and diiodomethane (0.31 mL, 3.84 mmol) at 0° C. After stirring at 0° C. for 1.5 hr, aqueous ammonium chloride was added to the reaction mixture at 0° C. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (87.7 mg, 0.196 mmol, 50%) as a pale yellow solid.