Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]3[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=3)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[OH:56][C:57]1[CH:58]=[C:59]([CH:63]=[CH:64][C:65]=1[OH:66])C(O)=O>>[OH:56][C:57]1[CH:58]=[C:59]([CH:63]=[CH:64][C:65]=1[OH:66])[C:16]([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]1[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=1)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:17]
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(O)c(O)c1
Product: O=C(C[C@H](NC(=O)c1ccc(O)c(O)c1)C(=O)NCCc1ccc(O)c(O)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nγ-trityl-L-asparagyl]dopamine (1.3 g, 1.7 mmol, example 7, step A) as described for example 7 (step B) using 3,4-dihydroxybenzoic acid (402 mg, 2.6 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using a solvent gradient from 30% to 60% EtOAc/CH2Cl2 containing 1% AcOH. The title compound was obtained as white crystals (579 mg, 52%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]3[C:17](=[CH:18][C:19]([O:33][CH3:34])=[C:20]([O:31][CH3:32])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>C(O)C.O1CCOCC1>[ClH:35].[ClH:35].[CH3:32][O:31][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:33][CH3:34])[N:16]=[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[N:24]=[C:23]2[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc(N3CCCCC3)c2cc1OC
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc2nc(NC3CCNCC3)nc(N3CCCCC3)c2cc1OC

Procedure:
A solution of 4-(6,7-dimethoxy-4-piperidin-1-yl-quinazolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.90 g, 4.03 mmol) in ethanol (10 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 372.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21].Cl>C(Cl)Cl.CN(C)C=O>[CH2:20]([N:22]([CH2:23][CH3:24])[C:9]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=1)=[O:11])[CH3:21]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCNCC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 120 ml of methylene chloride was suspended 6.0 g of 4-(methoxycarbonyl)-benzoic acid, to which were added 3.5 ml of oxalyl chloride and 0.05 ml of N,N-dimethylformamide at 0-5° C. After a reaction at the same temperature as above for 3 hours, the mixture was stirred at ambient temperature for 24 hours. Then, a 90.7 g portion of the reaction mixture was taken out, and 6.9 ml of diethylamine was added thereto. The mixture was stirred at ambient temperature for 3 hours, and then poured into ice water. pH was adjusted to 1.0 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 5.89 g of methyl 4-[(diethylamino)carbonyl]-benzoate was obtained as a red oily product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.C(OCC)(=O)C>[Si:16]([O:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: OCc1csc2cncn12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1csc2cncn12
Temperature: 0 °C
Yield: 98.8 %

Procedure:
To an ice-cooled solution of 3.39 g of 3-hydroxymethylimidazo[5,1-b]thiazole in 22 ml of DMF were added 1.95 g of imidazole and 3.81 g of t-butyldimethylsilyl chloride. After the reaction mixture was reacted at room temperature for 6 hours, it was diluted with 150 ml of ethyl acetate, and washed three times with saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give 5.83 g of 3-(t-butyldi methylsilyloxy)methylimidazo[5,1-b]thiazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([C:17]1[C:18]([CH:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]3[N:32]([Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:33]=[CH:34][C:27]=23)[OH:25])=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:42])[N:7]([C:17]1[C:18]([C:24]([C:26]2[C:27]3[CH:34]=[CH:33][N:32]([Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])[C:28]=3[N:29]=[CH:30][CH:31]=2)=[O:25])=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(Cl)cnc2C(O)c2ccnc3c2ccn3[Si](C)(C)C(C)(C)C)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(Cl)cnc2C(=O)c2ccnc3c2ccn3[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
1.76 g (2.89 mmol) of (2-{[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-hydroxy-methyl}-5-chloro-pyridin-3-yl)-(4-methoxy-benzyl)-carbamic acid tert-butyl ester and 3.08 g (7.22 mmol) of Dess-Martin periodinane were dissolved in 10 mL of DCM and stirred at r.t. for 2 h. The reaction was worked up with aqueous sodium bicarbonate and sodium thiosulfate followed by purification on silica with 0-50% ethyl acetate in hexanes to afford 0.97 g of a mixture of the expected product and its desilylated analog as a yellow solid. LC-MSD, m/z for C32H39ClN4O4Si [M+H]+=607.2, 609.2;
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:17])[C@@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([OH:16])[CH2:6]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1>CS(C)=O>[CH3:3][N:4]([CH3:17])[C@@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([O:16][C:22]2[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=2)[CH2:6]1
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](O)C1
Reactant: Fc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc(Br)cc2)C1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A mixture of 8 ml of dimethylsulfoxide and 0.820 g of sodium hydride as a 50% oil dispersion was heated at 50° C. for 45 minutes and was then cooled to 20° C. 3 g of cis 7-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol were added thereto and the mixture stood at room temperature for 15 minutes after which 2 ml of p-bromo-fluorobenzene were added thereto. The mixture was heated at 90°±5° C. for one hour and was then cooled to 20° C. and extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness to obtain 6 g of cis N,N-dimethyl-5-[4-bromophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine in the form of a yellow oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[CH:24]=[O:25])[CH3:19].Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:24]=[O:25])[CH:26]=[CH:27][C:28]=1[O:29][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH3:19]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: CCOc1cc(C=O)ccc1Oc1ccccc1CC(=O)OC
Yield: 92 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.02 mmol) of 3-ethoxy-4-hydroxybenzaldehyde was alkylated with 1.52 g (6.62 mmol) of methyl 2-bromophenylacetate to afford 1.74 g (92%) of the title compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][C@@H:6]1[C@H:8](/[CH:9]=[CH:10]/[C:11](/[CH3:18])=[CH:12]/[C:13]([O:15]CC)=[O:14])[C@@:7]1([CH3:31])[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[CH:20]=1.Cl>C1COCC1.CO.C(OCC)(=O)C>[CH3:3][O:4][CH2:5][C@@H:6]1[C@H:8](/[CH:9]=[CH:10]/[C:11](/[CH3:18])=[CH:12]/[C:13]([OH:15])=[O:14])[C@@:7]1([CH3:31])[C:19]1[CH:20]=[C:21]([CH:28]([CH3:29])[CH3:30])[CH:22]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
Sodium hydroxide solution (1N, 1 mL) was added to a solution of Compound 24 (20 mg, 0.05 mmol) in 4 mL of THF/MeOH (1:1) at 50° C. After stirring at 50° C. for 16 h, the mixture was diluted with ethyl acetate (10 mL) and acidified with 1 mL of 1 HCl at 0° C. The organic layer was then washed with brine (1×5 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography using 30% EtOAc in hexane to give the title compound (17 mg, 91% yield) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-]>CO.O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15]
Reactant: O=[N+]([O-])c1c(Cl)cccc1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1c(Cl)cccc1Nc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of (3-chloro-2-nitrophenyl)phenylamine (0.0109 mol) in MeOH (150 mL) and water (50 mL) were added NH4Cl (3.51 g, 0.0656 mol) and iron powder (2.45 g, 0.0438 mol) and the reaction mixture was heated to reflux temperature for 3 h. After cooling to RT, the solid was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo affording 3-Chloro-N1-phenylbenzene-1,2-diamine as a light brown solid (2.61 g, quantitative). LCMS: RT 3.72 min [M+H]+ 219.0
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1B(O)O
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: Cc1ccccc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 105 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 210 mg, 68%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:1→3:1) to give the title compound as a pale-yellow oil (yield 210 mg, 68%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:15]=[CH:16][C:10]=2[C:9]=1[C:24](=[O:26])[NH2:25])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:15]=[CH:16][C:10]=2[C:9]=1[C:24]([NH2:25])=[O:26]
Reactant: CC(C)(C)OC(=O)Nc1sc2cc(-c3ccc(F)cc3)ccc2c1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(N)sc2cc(-c3ccc(F)cc3)ccc12
Yield: 54.8 %

Procedure:
A solution of 1h (20 mg, 0.051 mmol) in CH2Cl2 (5 mL) was mixed with trifluoroacetic acid (0.5 mL). The resultant solution was stirred at room temperature for 1 h, then mixed with saturated NaHCO3 solution (30 mL), and extracted with ethyl acetate (30 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 1:1) provided the title compound (8 mg, 55%) as a white solid: MS (ES) m/z 287 (M+H)+; 1H NMR (400 MHz, CD3OD) δ7.73 (s, 1H), 7.63-7.50 (m, 3H), 7.42 (m, 1H), 7.08 (m, 2H).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Product: COC(=O)c1ccc2occ(-c3cc(F)ccc3F)c2c1
Yield: 70 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and (2,5-difluorophenyl)boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 70%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[OH:34][CH2:35][CH2:36][NH:37][C:38](=[O:41])[CH2:39][CH3:40].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:33][C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([OH:9])[C:10]3[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=3)[CH:17]=2)[N:22]=[C:21]([O:34][CH2:35][CH2:36][NH:37][C:38](=[O:41])[CH2:39][CH3:40])[C:20]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCC(=O)NCCO
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(=O)NCCOc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1-c1ccccc1
Temperature: 25 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.202 mmol, Example 65), N-(2-hydroxylethyl)propionamide (34.2 μL, 0.303 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 32.3 mg, 0.808 mmol) were combined in a round bottom flask under an N2 atmosphere. The reaction solution was heated to reflux and refluxed overnight. The reaction solution was cooled to room temperature then transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/MeOH) then via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI): mass calcd. for C31H28Cl2N4O3, 574.2; m/z found, 575.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.14 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.78 (s, 1H), 7.68 (dd, J=8.8, 1.7 Hz, 1H), 7.47-7.41 (m, 2H), 7.41-7.37 (m, 1H), 7.38-7.34 (m, 4H), 7.34-7.30 (m, 2H), 6.32 (s, 1H), 4.52 (t, J=5.6 Hz, 2H), 3.53-3.44 (m, 5H), 2.11 (q, J=7.6 Hz, 2H), 1.04 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1>[O-2].[V].[Ni]>[CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: CC1(C)COC(=O)C1O
Agent: [Ni]
Agent: [V]
Agent: [O-2]
Product: CC1(C)COC(=O)C1=O

Procedure:
Nickel vanadate on ceramic is used as the catalyst in the reactor described in Example 1 and the temperature of the air bath is adjusted to 270° C. 100 l of air and 32 g of pantolactone are subsequently added hourly to the evaporator. 99.2% of the pantolactone are transformed and ketopantolactone is formed with a selectivity of 79.8%.
Reaction SMILES: [CH:1]1([CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]2)[CH2:3][CH2:2]1.N1C2C(=CC=CC=2)C=CC=1>CCCCCC.[Pd]>[CH:1]1([CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]2)[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(CCC#CCC2CC2)O1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CC1(C)OCC(CCC=CCC2CC2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(5-Cyclopropyl-pent-3-ynyl)-2,2-dimethyl-[1,3]dioxolane (1.92 mmol, 0.40 g) in hexane (5 mL) was added quinoline (0.192 mmol, 24.8 mg), followed by addition of 5% Pd on BaSO4 (0.384 mmol). Stirred at room temperature under H2 atmosphere for 4 hrs. TLC showed reaction completed. Filtered through celite and concentrated. Diluted with hexane, washed with NH4Cl, brine and dried over MgSO4. Silica gel chromatography (2˜7% EtOAc/Hexane) 4-(5-Cyclopropyl-pent-3-enyl)-2,2-dimethyl-[1,3]dioxolane as clear oil 1H NMR (400 MHz, CDCl3): δ 5.52–5.45 (m, 1H), 5.40–5.34 (m, 1H), 4.11–4.04 (m, 1H), 4.02 (dd, 1H, J1=8.0 Hz, J2=6.0 Hz), 3.51 (t, 1H, J=7.5 Hz), 2.17–2.04 (m, 2H), 1.97 (t, 2H, J=7.0 Hz), 1.74–1.66 (m, 1H), 1.58–1.49 (m, 1H), 1.41 (s, 3H), 1.35 (s, 3H), 0.73–0.68 (m, 1H), 0.43–0.39 (m, 2H), 0.08–0.04 (m, 2H).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[C:13]([C:15]2[N:16]=[C:17]([N:24]([C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:43][CH2:42][N:41]([CH:44]5[CH2:47][O:46][CH2:45]5)[CH2:40][CH2:39]4)=[CH:34][CH:33]=3)C(=O)OC(C)(C)C)[C:18]3[N:19]([CH:21]=[CH:22][N:23]=3)[CH:20]=2)[CH:12]=[N:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[N:16]=[C:17]([NH:24][C:32]3[CH:33]=[CH:34][C:35]([N:38]4[CH2:43][CH2:42][N:41]([CH:44]5[CH2:47][O:46][CH2:45]5)[CH2:40][CH2:39]4)=[CH:36][CH:37]=3)[C:18]3[N:19]([CH:21]=[CH:22][N:23]=3)[CH:20]=2)[CH:12]=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)cc3)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cncc(-c2cn3ccnc3c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)n2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate XVI (200 mg, 0.269 mmol) in DCM (2 ml) was added TFA (0.5 ml, 6.578 mmol). The reaction was stirred at rt for 16 h, saturated sodium bicarbonate was added, extracted with EtOAC and purified on silica gel, eluted with 5% MeOH/EtOAc, 20% MeOH/EtOAc. The desired fractions were combined and concentrated to provide the title compound 2. LCMS-ESI+ (m/z): [M+H]+: 444.2. 1H NMR (300 MHz d6-DMSO) δ: 9.5 (s, 1H), 8.588 (s, 1H), 8.47 (s, 1H), 8.12 (d, 1H), 7.95-7.92 (d, 2H), 7.88 (s, 1H), 7.62 (s, 1H), 6.99-6.96 (d, 2H), 6.46 (s, 2H), 4.57-4.53 (m, 2H), 4.48-4.44 (m, 2H), 3.43 (m, 1H), 3.15-3.12 (m, 4H), 2.41-2.38 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[C:8]([F:20])[CH:7]=2)[CH2:2]1.[C:21]1([C:27]2[O:31][C:30]([C:32](OCC)=[O:33])=[N:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:20][C:8]1[CH:7]=[C:6]([O:5][CH:3]2[CH2:4][N:1]([C:32]([C:30]3[O:31][C:27]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:28][N:29]=3)=[O:33])[CH2:2]2)[CH:19]=[CH:18][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Reactant: CN1CCN(Cc2ccc(OC3CNC3)cc2F)CC1
Product: CN1CCN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)cc2F)CC1
Yield: 41.2 %

Procedure:
Using a similar protocol as described in Example 10 employing 29D (0.10 g, 0.36 mmol) and ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.10 g, 0.46 mmol) as starting materials afforded 67 mg (41%) of 29 as a foam. 1H NMR (500 MHz, DMSO-d6): δ 2.10 (s, 3H), 2.12-2.50 (bm, 8H), 3.43 (s, 2H), 4.05-4.16 (m, 1H), 4.50-4.70 (m, 2H), 5.03-5.23 (m, 2H), 6.68-6.84 (m, 2H), 7.25-7.37 (m, 1H), 7.57-7.75 (m, 3H), 8.00-8.13 (m, 2H), MS (APCI+) m/z 452 [M+H]+, LC purity: 97%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[C:15]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:17])[CH3:16].CN1CCOCC1>CC(N(C)C)=O.CN(C)C=O>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:27](=[O:28])[C@H:19]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:18][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 22.4 %

Procedure:
0.38 g of L-phenylalanine methyl ester hydrochloride (1.8 mmol), 0.37 g of N-acetyl-L-phenylalanine (1.7 mmol) and 1.6 ml of N-methylmorpholine (14.6 mmol) are dissolved in 30 ml of dimethylacetamide and cooled to 0° C. 1.2 ml of OPA, prepared as described in EP 0 527 442, example 1 (50% in dimethylformamide, molar amount not possible because the composition is not known) are then added. The mixture is stirred at 0° C. for another 1 h and at room temperature for 12 h. The solution is concentrated by evaporation and extracted with ethyl acetate and 1N HCl solution, sat. NaHCO3, sat. NaCl and dist. water. The organic phase is dried over magnesium sulfate, filtered off and concentrated by evaporation. 0.14 g of the white N-acetyl-L-phenylalaninyl-L-phenylalanine methyl ester is obtained (22%).