Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=O)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.[C:34]([C@H:38]([O:42][CH:43]1[CH2:48][CH2:47][N:46]([C:49](=[O:53])[CH:50]([NH2:52])[CH3:51])[CH2:45][CH2:44]1)[C:39]([OH:41])=[O:40])([CH3:37])([CH3:36])[CH3:35].CN(C)CCCN=C=NCC>CN(C)C=O>[C:34]([C@H:38]([O:42][CH:43]1[CH2:48][CH2:47][N:46]([C:49](=[O:53])[CH:50]([NH:52][C:13]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[C:3]([NH2:2])=[N:4][CH:5]=[CH:6]3)=[O:15])[CH3:51])[CH2:45][CH2:44]1)[C:39]([OH:41])=[O:40])([CH3:36])([CH3:35])[CH3:37]
Reactant: Nc1nccc2cc(C(=O)O)ccc12
Reactant: CC(N)C(=O)N1CCC(O[C@H](C(=O)O)C(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccc2c(N)nccc2c1)C(=O)N1CCC(O[C@H](C(=O)O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.3 %

Procedure:
To a solution of 0.33 g (1-amino-6-isoquinolinyl)carboxylic acid hydrochloride in 20 mL of N,N-dimethylformamide were added 0.34 g hydroxybenztriazole, 0.504 mL N-methylmorpholine, 0.525 g tert-butyl (S)-[[1-(2-amino-1-oxopropyl)piperidin-4-yl]oxy]acetic acid hydrochloride and 0.425 g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. After stirring at room temperature for three days the mixture was concentrated. Dichloromethane and 1% aqueous sodium hydrogencarbonate were added to the residue and the organic layer was separated. The aqueous layer was washed four times with dichloromethane, the combined organic layers dried (sodium sulfate) and concentrated. The residue was purified by chromatography (silica gel, dichloromethane/methanol: 10/1 v/v followed by a purification using silica gel, ethyl acetate/methanol: 10/1 v/v) to give 0.619 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[N+:9]([C:4]1[CH:3]=[C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])[CH:7]=[CH:6][C:5]=1[OH:8])([O-:11])=[O:10]
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1O
Yield: 40.1 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 4-amino-2-nitrophenol (1.00 g, 6.49 mmole), DMF (30 ml), TEA (0.5 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.30 g, 7.78 mmole), 1.00 g (40.0% yield) of 2-nitro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol was obtained as a reddish solid.:
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[C:8]2[CH2:15]O.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.C(OCC)C>[Cl:19][CH2:15][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:11]=[N:10][CH:9]=1
Reactant: COc1ccc2cncc(CO)c2c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1ccc2cncc(CCl)c2c1

Procedure:
The hydrochloride of the compound obtained in Step B (1.09 g; 0.005 mol) is suspended in 50 ml of chloroform. Thionyl chloride (2.80 ml; 0.04 mol) is added and then the reaction mixture is heated at reflux for 24 hours with stirring. After evaporation under reduced pressure, the residue obtained is taken up in ethyl ether. The precipitate formed is suction-filtered off and recrystallised from acetonitrile to yield the title compound in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:19][NH3+:20].C(=O)(O)[O-].[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:17])=[C:13](/[CH:14]=[N:20]/[OH:19])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH3+]O
Reactant: O=Cc1cc(OCc2ccccc2)ccc1Br
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O/N=C/c1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A mixture of 5-(benzyloxy)-2-bromobenzaldehyde (29.5 g), hydroxyl ammonium chloride (7.75 g), sodium bicarbonate (9.36 g), water (30 mL), and ethanol (270 mL) was stirred overnight at room temperature. To the reaction mixture, water (150 mL) was added, and the mixture was concentrated into half the volume under reduced pressure. Then, the residue was subjected to extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was washed with hexane to obtain the title compound (27.2 g)
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:6]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1nc(-c2ccc(N)cc2)c[nH]1
Yield: 97.2 %

Procedure:
A solution of 2-methyl-4-(4-nitro-phenyl)-1H-imidazole (28 g) in methanol (210 ml) was hydrogenated in the presence of 10% palladium-on-charcoal (1.35 g) at atmospheric pressure and at room temperature. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the solution was evaporated to dryness to give 23.2 g of the title compound as a spongy solid. Using the above procedure, and starting from the appropriate nitrophenyl derivative, the following aminophenyl derivatives were also prepared:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[H-].[Na+].[N+:20]([C:23]1[CH:28]=[C:27]([S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=1Cl)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:28]=[C:27]([S:29]([C:32]([F:35])([F:33])[F:34])(=[O:30])=[O:31])[CH:26]=[CH:25][C:24]=1[O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: O=C(O)c1ccc(Oc2cccc(O)c2)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(Oc2cccc(Oc3ccc(S(=O)(=O)C(F)(F)F)cc3[N+](=O)[O-])c2)cc1

Procedure:
Using procedure as in example 10, a reaction of 4-(3-hydroxyphenoxy)benzoic acid (100 mg, 0.4334 mmol), NaH (38 mg, 2.2 equiv.) and 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (126 mg, 1 equiv.) afforded 4-[3-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-phenoxy]-benzoic acid. 1HNMR (360 MHz, DMSO-d6) δ 12.8 (br s, 1H, COOH), 8.75 (d, J=2.7 Hz, 1H), 8.30 (dd, J=2.7 & 9.0 Hz, 1H), 7.95 (m, 2H), 7.6 (m, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.17-7.21 (m, 2H), 7.12 (m, 3H). MS-EI m/z 483 [M+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>CCOCC>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution containing 2-bromo-6-methylpyridine (1.48 g, 8.63 mmol) in ether (15 mL) at −78° C. was treated with n-butyllithium (5.39 mL, 1.6 M in hexanes) dropwise, stirred at −78° C. for 1 hour, treated with tributyltin chloride (4.21 mL, 12.94 mmol), stirred at −78° C. for 4 hours, quenched with saturated ammonium chloride solution, and partitioned between ether and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on neutral alumina eluting with 10% ethyl acetate in dichloromethane to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.CN(C)C=O.[CH:33](N(CC)C(C)C)(C)[CH3:34].ICC>>[CH2:33]([N:24]1[CH2:25][CH2:26][CH:21]([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:27])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1)[CH3:34]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C3CCNCC3)ncc2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CCC(C(=O)Nc2cc3ccc(-c4cc(F)ccc4C)cc3cn2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 41.4 %

Procedure:
To a solution of N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)piperidine-4-carboxamide (110.6 mg, 0.1936 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) was added N,N-diisopropylethylamine (0.1 mL, 0.574 mmol) and iodoethane (19.0 uL, 0.238 mmol). The reaction was stirred at room temperature for 19 hours, and then N,N-diisopropylethylamine (0.1 mL) and iodoethane (30 uL, 0.375 mmol) were added. After an additional 4 hours, the mixture was evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 31.4 mg (41%) of 1-ethyl-N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)piperidine-4-carboxamide. LCMS (ESI): RT (Min)=4.370, M+H=392.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.19 (s, 1H), 8.53 (s, 1H), 8.06 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J=8.9 Hz, 2H), 3.53 (unresolved, 2H), 3.08 (unresolved, 2H), 2.83 (unresolved, 3H), 2.25 (s, 3H), 2.07 (unresolved, 2H), 1.90 (unresolved, 2H), 1.22 (unresolved, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[C:6]([C:15]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])[CH:5]=1)([O-])=O.[ClH:23].[CH3:24]O>[Zn]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[C:6]([C:15]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH3:24])=[O:21])=[O:16])[CH:5]=1.[ClH:23]
Reactant: O=C(O)CCNC(=O)c1cc([N+](=O)[O-])c2ccccc2c1O
Reactant: CO
Agent: Cl
Agent: [Zn]
Product: COC(=O)CCNC(=O)c1cc(N)c2ccccc2c1O
Reaction time: 0.5 h

Procedure:
An amount of 210 g of 4-nitro-2-(2-carboxyethylamino)carbonyl-1-naphthol was dissolved in 28 liters of methanol at 40° C. Into this solution was added 1,200 ml conc. hydrochloric acid, followed subsequently by portionwise addition of 430 g of zinc powder. After 30 minutes, zinc was removed and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in 25 liters of ethyl acetate, washed with water and then dried over magnesium sulfate, followed by evaporation of the solvent, to give crystals. The crystals were washed with acetonitrile to obtain substantially pure desired product as hydrochloride. Yield was 75%. The product was confirmed by NMR, Mass spectra.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[CH:16]=CC(C#C)=CN=1>>[C:11]([C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1)#[CH:16]
Reactant: COc1ccc(Br)cn1
Reactant: C#Cc1ccc(Cl)nc1
Product: C#Cc1ccc(OC)nc1

Procedure:
5-Ethynyl-2-methoxy pyridine was prepared from 5-bromo-2-methoxy-pyridine (Aldrich) in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:34])[C:13]2[CH:18]=[N:17][C:16](S(C)(=O)=O)=[N:15][C:14]=2[N:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH:24]=1)=[O:10])[CH3:7]>>[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:34])[C:13]2[CH:18]=[N:17][C:16]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][C:14]=2[N:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH:24]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: COCCN
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCOC)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1 Step F, the title compound was prepared from 2-methoxy-ethylamine and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 1, Step E, 10 mg, 0.022 mmol). 7 mg of 8-indan-5-yl-2-(2-methoxy-ethylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.25 (s, 1H), 8.47 (s, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.14 (d, J=7.8 Hz, 1H), 5.99 (br, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.45-3.35 (m, 2H), 3.29 (s, 3H), 3.00 (m, 4H), 2.18 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C(O[CH:15](OCC)[CH2:16][CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])C>C(O)(=O)C>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][CH2:17][CH2:16][CH:15]=[N:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH2:9])=[O:8])=[CH:10][CH:11]=1
Reactant: NNc1ccc(C(N)=O)cc1
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Solvent: CC(=O)O
Product: NC(=O)c1ccc(NN=CCCCN2C(=O)c3ccccc3C2=O)cc1
Yield: 91.5 %

Procedure:
A solution of 4-hydrazinobenzamide (0.26 g), in 25% aqueous acetic acid (20 ml) was added to 4-[1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl]-butanal diethyl acetal (0.5 g). The mixture was heated on a steam bath for 2 hours and then cooled. The mixture was decanted to leave an oil which was triturated with methanol (3 ml). The solid that resulted was washed with water (5 ml) and dried in vacuo at 50° C. to give the title compound (0.55 g) as a yellow crystalline solid m.p. 147°-152° C. (decomp).
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:14].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C=O)C>[Si:22]([O:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:14])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: Cc1cc(C#N)cc(C)c1OCC(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#N)cc(C)c1OCC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.9 %

Procedure:
To a solution of 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.90 g, 13.2 mmol) in anhydrous DMF (20 mL) was added imidazole (2.7 g, 40 mmol) and tert-butyldimethylsilylchloride (2.19 g, 14.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 d. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude compound was purified by column chromatography to give 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (2.24 g, 54%). N-Butyl lithium (6.2 mL, 6.6 mmol, 1.6 M solution in hexanes) was added to a solution of 2,4-dimethoxy-6-N-dimethylbenzamide (0.9 g, 4.3 mmol) in anhydrous THF (10 mL) drop-wise at −10° C. over a period of 10 min under nitrogen. The stirring was continued at 0° C. for 1 h. The reaction mixture was cooled to −50° C. A solution of 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (1.58 g, 4.73 mmol) in anhydrous THF (5 mL) was quickly added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The stirring was continued at room temperature for 1 h. An aqueous ammonium chloride solution (10 mL) was added followed by ethyl acetate (100 mL). The organic layer was separated, washed with water (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 0-5% methanol in CH2Cl2 as eluent) to give 3-{4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylphenyl}-6,8-dimethoxy-2H-isoquinolin-1-one (0.82 g, 37%), as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (78.0 g, 394 mmol, Ark Pharm) in anhydrous DMF (272 mL) was added drop-wise over about 60 min to a stirred suspension of NaH (12.8 g, 532 mmol) in anhydrous DMF (543 mL) at about 0-5° C. The brown reaction solution was stirred for about 30 min at about 0-5° C. then a solution of p-toluenesulfonyl chloride (94.0 g, 492 mmol) in anhydrous DMF (272 mL) was added drop-wise over about 60 min at about 0-5° C. The reaction mixture was stirred at about 0-5° C. for about 1 h then allowed to warm to ambient temperature and stirred for about 18 h at ambient temperature. The reaction mixture was poured slowly into ice water (6 L), followed by the addition of aqueous 2.5 N NaOH (50.0 mL, 125 mmol). The precipitate was collected by filtration and stirred with cold water (3×200 mL). The solid was collected by filtration and dried in air over about 3 days and finally dried to constant weight in a vacuum oven at about 55° C. to yield 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (134.6 g, 97%) as a pale beige solid: LC/MS (Table 2, Method d) Rt=1.58 min; MS m/z: 352/354 (M+H)+.
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][C@H:15]1[C:24]([OH:26])=[O:25])=[O:13])(=O)C1C=CC=CC=1.[OH-].[NH4+]>O>[SH:9][CH2:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][C@H:15]1[C:24]([OH:26])=[O:25])=[O:13]
Reactant: O=C(SCCC(=O)N1c2ccccc2CC[C@H]1C(=O)O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H]1CCc2ccccc2N1C(=O)CCS
Reaction time: 3 h

Procedure:
(S)(-)-(3-Benzoylthio-1-oxopropyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid (3 g), concentrated ammonium hydroxide (18 ml), and water (36 ml) were combined and stirred at 40°-45° under nitrogen for three hours. After this time, another portion of concentrated ammonium hydroxide (6 ml) was added and the solution was heated at 40°-45° for an additional three hours under nitrogen. The reaction mixture was then diluted with water (100 ml) and extracted well with ethyl acetate. The aqueous phase was then cooled in an ice bath and the pH adjusted to 2 with concentrated hydrochloric acid. The product was extracted with ether. The extract was dried over sodium sulfate and concentrated under reduced pressure to yield (S)(-)-1,2,3,4-tetrahydro-1-(3-mercapto-1-oxopropyl)-2-quinolinecarboxylic acid; yield 1.6 g, m.p. 130°-132°, [α]D20 -302.3° (c 1, methanol).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:46])[CH2:10][CH2:9][CH2:8][N:7]([C:11](=[O:45])[C@@H:12]([NH:14][C:15](=[O:44])[C@@H:16]([NH:20][C:21](=[O:43])[C:22]([CH3:42])([CH3:41])/[CH:23]=[CH:24]/[C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[CH:30][C:31]([C@H:35]([O:37]C(=O)C)[CH3:36])=[N:32]3)=[CH:27][CH:26]=2)[CH:17]([CH3:19])[CH3:18])[CH3:13])[NH:6]1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[OH:37][C@@H:35]([C:31]1[CH:30]=[CH:29][C:28]2[C:33](=[CH:34][C:25](/[CH:24]=[CH:23]/[C:22]([CH3:42])([CH3:41])[C:21]([NH:20][C@@H:16]([CH:17]([CH3:19])[CH3:18])[C:15]([NH:14][C@@H:12]([CH3:13])[C:11]([N:7]3[CH2:8][CH2:9][CH2:10][C:5]([CH3:46])([C:3]([OH:4])=[O:2])[NH:6]3)=[O:45])=[O:44])=[O:43])=[CH:26][CH:27]=2)[N:32]=1)[CH3:36]
Reactant: COC(=O)C1(C)CCCN(C(=O)[C@H](C)NC(=O)[C@@H](NC(=O)C(C)(C)/C=C/c2ccc3ccc([C@@H](C)OC(C)=O)nc3c2)C(C)C)N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)O)nc2c1)C(=O)N[C@@H](C)C(=O)N1CCCC(C)(C(=O)O)N1
Temperature: 0 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
To a solution of 1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoylamino}-3-methyl-butyrylamino)-propionyl]-3-methyl-hexahydro-pyridazine-3-carboxylic acid methyl ester (790 mg, 1.24 mmol) in tetrahydrofuran/water (60 mL, 5:1) at 0° C. was added lithium hydroxide monohydrate (380 mg, 9.04 mmol). After stirring at 0° C. for 5 h, the reaction was quenched with hydrochloric acid (1 M, 12 mL). The volatiles were removed in vacuo and residual acetic acid and methanol were azeotroped off with toluene (3×). The residue was partitioned between ethyl acetate and water. After separation of the layers, the aqueous phase was extracted with ethyl acetate (4×) and dichloromethane (5×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound (668 mg, 93%) as a pale yellow solid and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 582 [M+H], Tr=1.54 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:24]3[CH2:27][C@H:26]([CH2:28]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:40][NH:41][CH3:42].C1COCC1>CO>[CH3:40][N:41]([CH2:28][C@@H:26]1[CH2:27][C@H:24]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:25]1)[CH3:42]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)C2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C[C@H]1C[C@@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Temperature: 60 °C

Procedure:
A mixture of cis-toluene-4-sulfonic acid 3-[8-amino-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethyl ester (30.0 mg, 0.0555 mmol), 2 M of dimethylamine in MeOH (2 mL) and THF (5 mL, 0.06 mol) was heated to 60° C. overnight in a sealed tube. The material was concentrated in vacuo, redissolved in minimal MeOH/DCM, and loaded onto a prep TLC plate, eluting with 6% (7N NH3 in MeOH)/DCM. The band containing the pure product was collected, and the product was filtered off using 1:1 MeOH/DCM. The filtrate was concentrated in vacuo, and hexanes was added. The mixture was sonicated until a white precipitate crashed out. The solid was filtered off, washing several times with hexanes, to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ=2.23 (s, 6H), 2.26-2.33 (m, 2H), 2.42 (d, J=6.3 Hz, 2H), 2.57-2.70 (m, 3H), 3.60-3.71 (m, 1H), 5.03 (s, 2H), 7.03-7.17 (m, 7H), 7.34-7.41 (m, 2H), 7.61-7.65 (m, 2H). MS (ES+): m/z 414.19 (100) [MH+]. HPLC: tR=1.98 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:35])([CH3:34])[C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:22][C:21]=3[O:36][CH2:37][CH3:38])=[N:9]2)=[CH:4][CH:3]=1.[C:39](Cl)([Cl:41])=[O:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:39]([Cl:41])=[O:40])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([C:27](=[O:28])[N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])([CH3:35])[CH3:34])=[CH:22][C:21]=3[O:36][CH2:37][CH3:38])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C(=O)N(CC)CC)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Product: CCOc1cc(C(C)(C)C(=O)N(CC)CC)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Yield: 55.9 %

Procedure:
2-{4-[4,5-Bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-phenyl}-N,N-diethyl-isobutyramide (90 mg, 0.163 mmol) was reacted with phosgene (101 uL, 0.196 mmol, 20% solution in toluene) using the procedure as described in example 12 to give cis-4,5-bis-(4-chloro-phenyl)-2-[4-(1-diethylcarbamoyl-1-methyl-ethyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (56 mg, 56% yield) as white solids.