Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg+2].[Br-].[Br-].[N:4]1[N:12]2[C:7]([CH2:8][O:9][CH2:10][CH2:11]2)=[CH:6][C:5]=1[CH:13]=[O:14].[N+:15]([C:18]1[CH:36]=[CH:35][C:21]([CH2:22][O:23][C:24]([C:26]2[N:27]3[C@H:30]([S:31][CH:32]=2)[C@@H:29]([Br:33])[C:28]3=[O:34])=[O:25])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(#N)C.C1COCC1>[C:44]([O:14][CH:13]([C:5]1[CH:6]=[C:7]2[CH2:8][O:9][CH2:10][CH2:11][N:12]2[N:4]=1)[C:29]1([Br:33])[C:28](=[O:34])[N:27]2[C@@H:30]1[S:31][CH:32]=[C:26]2[C:24]([O:23][CH2:22][C:21]1[CH:35]=[CH:36][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=1)=[O:25])(=[O:46])[CH3:45]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=CS[C@@H]2[C@@H](Br)C(=O)N12
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc2n(n1)CCOC2
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC(c1cc2n(n1)CCOC2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Temperature: -20 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
To a solution of MgBr2 (0.94 g, 5.1 mmol) in acetonitrile (25 ml) under nitrogen was added 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carbaldehyde (0.26 g, 1.7 mmol) at room temperature with stirring. A solution of (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester (0.58 g, 1.5 mmol) in THF (25 ml) was then added, and the mixture was cooled to −20° C. Triethylamine (0.71 ml, 5.1 mmol) was introduced, and the mixture was stirred at −20° C. in the dark for 5 hr. It was then treated with acetic anhydride (0.6 ml, 6.0 mmol), and 4-N,N-dimethylaminopyridine (24 mg, 0.2 mmol), and kept at 0° C. for 18 hr. The mixture was concentrated and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 5% citric acid, saturated sodium bicarbonate solution, and brine, dried over anhydrous sodium sulfate, and evaporated. The crude material was chromatographed with silica gel (EtOAc—CH2Cl2/1:5) to give 0.77 g of a white foam; MS (ESI) m/z 578.9 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH:16]=[O:17])[CH:8]=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:18])[C:3]=1[CH3:19].C(=O)([O-])O.[Na+].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH:16]=[O:17])[CH:8]=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:18])[C:3]=1[CH3:19])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)c1cc(C=O)c2nc(C)c(C)c(O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCC(C)c1cc(C=O)c2nc(C)c(C)c(OC(C)=O)c2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 13 %

Procedure:
800 Milligrams of the resultant 4-benzyloxy-6-s-butyl-8-formyl-2,3-dimethylquinoline was dissolved in 2.5 ml of 20% sulfuric acid and stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was neutralized with an aqueous saturated sodium hydrogencarbonate solution to produce precipitates, which were washed with water and n-hexane and then dried under reduced pressure to obtain 490 mg of 4-hydroxy-6-s-butyl-8-formyl-2,3-dimethylquinoline. 440 Milligrams of 4-hydroxy-6-s-butyl-8-formyl-2,3-dimethylquinoline was suspended in a mixture of 3 ml of acetic anhydride and 0.5 ml of pyridine and the mixture was stirred at 120° C. for 1.5 hours. The reaction mixture was cooled to room temperature, neutralized with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The resultant organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (10:1) to obtain 220 mg of 4-acetoxy-6-s-butyl-8-formyl-2,3-dimethylquinoline (yield 13%). Its NMR spectral data are shown in the following Table 2.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@@H:15]2[CH2:16][CH2:17][C@@H:12]([CH2:13][C@H:14]2[OH:18])[N:11]1C(OC(C)(C)C)=O)=[O:9])#[N:2].[ClH:26]>O1CCOCC1>[ClH:26].[OH:18][C@@H:14]1[CH2:13][C@@H:12]2[CH2:17][CH2:16][C@H:15]1[C@@H:10]([C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[C:1]#[N:2])=[O:9])[NH:11]2
Reactant: CC(C)(C)OC(=O)N1[C@H]2CC[C@H]([C@H](O)C2)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: C1COCCO1
Product: N#C[C@@H]1CCCN1C(=O)[C@H]1N[C@H]2CC[C@@H]1[C@H](O)C2

Procedure:
To a solution of tert-butyl (1S,3S,4S,5R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-5-hydroxy-2-azabicyclo[2.2.2]octane-2-carboxylate obtained in Example 2-7 (2.0 g) in dioxane (10 mL), was added 4N HCl in dioxane (1.43 mL) at room temperature.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:32]2[CH:37]=[CH:36][C:35]([O:38]CC3C=CC=CC=3)=[CH:34][CH:33]=2)[C:16]2[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=2[CH2:18][NH:19][CH:20]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H].C(=O)([O-])O.[Na+]>>[CH:20]1([NH:19][CH2:18][C:17]2[CH:28]=[CH:29][CH:30]=[CH:31][C:16]=2[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:32]2[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(C(c3ccc(OCc4ccccc4)cc3)c3ccccc3CNC3CCCCCCC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(C(c2ccc(O)cc2)c2ccccc2CNC2CCCCCCC2)cc1
Reaction time: 2 h
Yield: 54.5 %

Procedure:
Two grams of 2-[bis(4-benzyloxyphenyl)methyl]-N-(cyclooctyl)benzylamine obtained by Example 82 was dissolved in 120 ml of a mixture of ice-cooled hydrogen bromideacetic acid solution. The solution was stirred for 2 hours, and the mixture was added to a mixture of ice and a saturated aqueous sodium hydrogencarbonate, stirred and then neutralized with sodium hydrogencarbonate. Thereafter, it was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to recrystallization to afford 0.76 g of the desired compound (Compound 85).
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7](O)(=[O:9])[CH3:8].C(OC(=O)C)(=O)C>C(OCC)(=O)C>[C:7]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:9])[CH3:8]
Reactant: CC(N)C(=O)O
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)C(=O)O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
134 g (1.50 mol) of DL-alanine are introduced into acetic acid and treated dropwise with 230 g (2.25 mol) of acetic anhydride. The mixture is additionally stirred at 100° C. for 2 h to complete the reaction and the solvent is then stripped off in vacuo. The solid obtained is suspended in ethyl acetate and filtered off with suction. For purification, the solid is washed several times with diethyl ether.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](N)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 1 g portion of Boc-(D)-Arg(Tos)-Gly-OBn (1.74 mmol) was dissolved in 10 mL of CH2Cl2, cooled to 0° C. and treated with 10 mL of TFA. The solution was stirred at 0° C. for 3 h. Solvent and excess TFA were evaporated thoroughly to give the title compound as an oil which was used directly in Example 10.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[CH3:19])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:19][C@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C[C@H]1CCCN1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CCCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 165.5 %

Procedure:
To a chilled solution of Intermediate (viii), 4-((S)-2-methyl-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester, (2.43 g, 9.05 mmol) in 1,4-dioxane (9 mL) at 0° C. was added 4N HCl in dioxane (6 mL) and allowed to stir for 20 h at ambient temperature. The reaction mixture was concentrated to afford an oil which was dried under high vacuum to afford 2.52 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:13][O:12]1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CCO>[OH:12][CH:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])[CH2:13][N:24]1[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@H:23]1[CH2:27][OH:28]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: Cc1c(C2CO2)cccc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)cccc1[N+](=O)[O-]

Procedure:
2-(2-Methyl-3-nitrophenyl)oxirane (1.47 g, 8.20 mmol) was dissolved in EtOH (10 mL) then added (S)-4N—BOC-2-hydroxymethyl-piperazine (3.19 g, 14.77 mmol) and microwaved at 140° C. for 1 hr. Solvent was evaporated and the residue was purified by chromatography through a 120 g ISCO Redi-Sep column eluting with 0-20% ethyl acetate:hexane to yield the title compound: LC-MS (IE, m/z): 396 [M+1];
Reaction SMILES: C([O:5][C:6](=[O:39])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[N:19](COCC[Si](C)(C)C)[CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.CCO>C(Cl)Cl>[C:23]([C:21]1[N:22]=[C:18]([C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([OH:39])=[O:5])=[CH:10][C:11]=2[C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)=[O:17])[NH:19][CH:20]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C=CC(=O)O)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of 3-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-acrylic acid tert-butyl ester (30 mg, 0.055 mmol)(as prepared in the previous step) in 1.0 mL of DCM was added 0.30 mL of TFA, 0.026 mL of EtOH and stirred at RT for 2 h. The mixture was concentrated and the residue triturated with MeOH to give 19 mg (95%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 14.39 (br s, 1H), 9.83 (s, 1H), 8.38 (d, J=2.5 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.65 (dd, J=8.5, 1.9 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.56 (d, J=16.0 Hz, 1H), 6.53 (d, J=16.0 Hz, 1H), 5.83 (m, 1H), 2.31-2.14 (m, 4H), 1.81-1.65 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H18N4O3, 363.1 (M+H). found 363.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>ClCCl.C(N(CC)CC)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1)N1CCNCC1
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a stirred solution of piperazine (10.8 g) in dry dichloromethane (160 ml) and triethylamine (20 ml) at 0° C. was added slowly a solution of 4-bromobenzenesulphonyl chloride (16 g) in dichloromethane (80 ml) and stirred for 24 hours. The reaction was then quenched by removal of the dichloromethane solvent by evaporation, taken up in water and extracted with ethyl acetate. The organic extracts were washed with aqueous sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and then evaporated to give a white crystalline solid which was recrystallised from ethyl acetate/isohexane to afford 1-(4-bromophenylsulphonyl)piperazine (14.1 g) as a solid, m.p. 102-104° C.; microanalysis found: C, 39.5; H, 4.4; N, 9.1%: C10H13BrN2O2S requires: C, 39.4; H, 4.3; N, 9.2%; NMR (CDCl3): 1.52(s,1H), 2.97(dt,8H), 7.61(d,2H), 7.69(d,2H): MS m/z 305 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:5]([F:23])=[CH:4][N:3]=1.[CH2:24]1[CH2:34][O:33][C:32]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=2[O:25]1>>[CH2:21]([O:20][C:18]([C:15]([CH3:17])([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[C:5]([F:23])=[CH:4][N:3]=[C:2]([NH:29][C:28]3[CH:30]=[CH:31][C:32]4[O:33][CH2:34][CH2:24][O:25][C:26]=4[CH:27]=3)[N:7]=2)=[CH:10][CH:11]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C(C)(C)c1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Product: CCOC(=O)C(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to produce N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.31 (s, 1H), 8.97 (s, 1H), 8.03 (d, 1H, J=3.5 Hz), 7.70 (d, 2H, J=8.8 Hz), 7.29 (d, 1H, J=2.3 Hz), 7.23 (d, 2H, J=8.8 Hz), 6.98 (dd, 1H, J=2.1 and 8.8 Hz), 6.66 (d, 1H, J=8.2 Hz), 4.19–4.15 (m, 4H), 4.07 (qt, 2H, J=7.0 Hz), 1.48 (s, 6H), 1.10 (t, 3H, J=7.0 Hz). LCMS: ret. time: 24.51 min.; purity: 100%; MS (m/e): 453 (MH+).
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:18])[N:15]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[C:7]([N:6]1[C:2]([C:36]2[CH:35]=[CH:34][C:33]([N:30]3[CH2:29][CH2:28][O:27][CH2:32][CH2:31]3)=[CH:38][CH:37]=2)=[C:3]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:18])[N:15]=2)[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(N2CCOCC2)cc1

Procedure:
Using 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide and (4-morpholinophenyl)boronic acid and by reaction and purification in the same manner as in the method described in Example 43, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][C:12]=2[CH3:26])[CH:5]=[CH:6][N:7]=1.[C:33](O)(=[O:37])[C:34]#[C:35][CH3:36]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][N:28]3[C:33](=[O:37])[C:34]#[C:35][CH3:36])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][C:12]=2[CH3:26])[CH:5]=[CH:6][N:7]=1
Reactant: Cc1cc(C(=O)Nc2ccccn2)ccc1-c1nc([C@@H]2CCCCN2)n2ccnc(N)c12
Reactant: CC#CC(=O)O
Product: CC#CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2C)c2c(N)nccn12
Yield: 59.1 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from 4-(8-amino-3-((S)-piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-3-methyl-N-(pyridin-2-yl)benzamide (intermediate 43) and 2-butynoic acid, to afford the title compound (13.7 mg, 59.1%). Data: UPLC(C) Rt: 2.28 min; m/z 494.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3cccnc32)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(CCCn2c(=O)ccc3cccnc32)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.5 %

Procedure:
To a solution of 0.53 g of 1-tert-butyl 4-ethyl 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate in 6 mL of chloroform, 25 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the resultant residue and the mixture was neutralized, and chloroform was then added thereto. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.47 g of ethyl 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-4-carboxylate as a colorless oily substance.
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:23].[Cl:24][C:25]1[CH:30]=[C:29](OC)[CH:28]=[CH:27][C:26]=1[OH:33]>>[C:7]1([CH2:8][O:33][C:26]2[CH:27]=[CH:28][C:29]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:30][C:25]=2[Cl:24])[CH:6]=[CH:5][C:4]([CH2:9][O:23][C:13]2[CH:14]=[CH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:12]=2[Cl:11])=[CH:3][CH:2]=1
Reactant: COc1ccc(O)c(Cl)c1
Reactant: Cc1ccc(C)c(Br)c1Br
Reactant: CCOC(=O)c1ccc(O)c(Cl)c1
Product: CCOC(=O)c1ccc(OCc2ccc(COc3ccc(C(=O)OCC)cc3Cl)cc2)c(Cl)c1

Procedure:
Follow the procedure of Example 6 except add 6 g of dibromo p-xylene and substitute 10.0 g of 2-chloro-4 ethoxycarbonyl phenol for 2-chloro-4-methoxyphenol to obtain 6.8 g of 1,1'-[1,4-phenylene bis(methyleneoxy)]-bis-[2-chloro-4-ethoxycarbonylbenzene].
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]1([C@H:14]([CH3:17])[CH2:15][NH2:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)(=O)C>[C:8]1([C@H:14]([CH3:17])[CH2:15][NH:16][C:1](/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5])=[O:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C[C@H](CN)c1ccccc1
Solvent: CC(=O)O
Product: C[C@H](CNC(=O)/C=C/C(=O)O)c1ccccc1
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of maleic anhydride (765 mg, 7.8 mmol) in acetic acid (20 mL) at rt was added (S)-2-phenylpropylamine. The mixture was stirred overnight then was partially concentrated. Water (50 mL) was added causing precipitation of the product acid. The white solid was collected by suction filtration, washed with water, and dried to provide 1.44 g (79%) of the pure acid. 1H NMR (400 MHz, CDCl3): 7.38-7.32 (m, 2H), 7.29-7.24 (m, 1H), 7.24-7.20 (m, 2H), 6.68 (br m, 1H), 6.29 (d J=12.7, 1H), 6.18 (d, J=12.7, 1H), 3.78-3.69 (m, 1H), 3.47-3.38 (m, 1H), 3.11-3.00 (m, 1H), 1.33 (d, J=7.0, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[CH:14][CH:15]=1>ClCCl.O>[Br:1][C:19]1[S:18][C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)=[N:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1cccc(Nc2nccs2)c1
Solvent: ClCCl
Solvent: O
Product: Clc1cccc(Nc2ncc(Br)s2)c1
Temperature: 25 °C
Reaction time: 0.16 h
Yield: 20.5 %

Procedure:
N-Bromosuccinimide (7.60 g, 42.7 mmol) was added to a solution of 26B (10 g, 47.5 mmol) in dichloromethane (150 mL), and the mixture was stirred at room temperature for 0.16 h. The reaction mixture was diluted with dichloromethane and water, separated organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 15% ethyl acetate in hexane to afford the title compound (2.54 g, 18%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 7.87 (t, J=2.0 Hz, 1H), 7.41-7.26 (m, 3H), 7.01 (dt, J1=7.3 Hz, J2=1.8 Hz, 1H). ESI-MS m/z: 291 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([O:36]C)=[O:35])=[O:31])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.[OH-].[Na+].Cl>CO>[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)CNC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-methyl 2-(3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanamido)acetate 2,2,2-trifluoroacetate (18 mg, 0.034 mmol) in MeOH (0.5 mL) was added 5M sodium hydroxide (0.048 mL, 0.241 mmol). The reaction was stirred at room temperature overnight. The mixture was added 1M HCl (2 mL) and purified by HPLC to give the title compound. LCMS m/z=395.2 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:24][C:25]([OH:27])=[O:26])=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:7](CC(O)=O)=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[H-].[CH3:29][O:30]CCO[Al+]OCCOC.[Na+].[H-].C1(C)C=CC=CC=1>O1CCCC1>[CH:10]([C:8]1[C:7]([CH2:29][OH:30])=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:5]([CH2:24][C:25]([OH:27])=[O:26])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1)([CH3:11])[CH3:12]
Reactant: COCCO[Al+]OCCOC
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(-c2ccc(F)cc2)c1CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C(C)C)c(CC(=O)O)c(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of the intermediate obtained in Step C (37.3 g, 100 mmol) in anhydrous tetrahydrofuran (350 mL) stirred under argon at 0° C. was added a solution of 3.4M of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (Red-Al) (105 mL, 204 mmol, 65 wt % in toluene) via syringe over 20 min. The reaction mixture was allowed to stir at room temperature for 24 hr, then cooled again to 0° C. and carefully quenched by the dropwise addition of water. The solution was decanted from the solid which forms and the solvent removed in vacuo. The residue was purified by flash chromatography (500 g silica) via step gradient. Elution with 5% diethyl ether/hexane affords 9.8 g (26.3 mmol, 28%) of recovered starting material and elution with 40% diethyl ether (Et2O)/hexane affords the desired product as a white solid (26.8 g, 77.8 mmol, 78%). mp 124-126° C. Rf=0.2 (10% ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3): δ 7.35 (s, 1H), 7.27 (m, 2H), 7.08 (m, 2H), 4.44 (d, J=5.5 Hz, 2H), 3.43 (m, 4H), 2.92 (sept, J=6.6 Hz, 1H), 1.59 (s, 1H), 1.28 (m, 12H). FAB-MS: calculated for (C21H25FO3) 344, found 345 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Cl)c(C(=O)O)cc1Cl
Agent: O=S(=O)(O)O
Product: Cc1c(Cl)cc(C(=O)O)c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
41 g of 2,5-dichloro-4-methylbenzoic acid are added in portions to a mixture of 100 ml of concentrated H2SO4 and 20 ml of 68% strength HNO3. The mixture is kept at 50° for 3 hours and then poured onto 600 g of ice. The solid which has precipitated is isolated, dried and stirred with a little toluene. Melting point: 210°-18°, yield: 43.8 g.