Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[C@@H:10]([C@@H:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16]/[CH:17]=C/C1C=CC=CC=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C[OH:36]>ClCCl>[CH2:1]([O:8][C:9](=[O:32])[C@@H:10]([C@@H:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16][CH2:17][OH:36])[CH2:11][CH:12]([CH3:13])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)[C@H](CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 32.12 g of (E)-benzyl-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerate in 300 ml of dichloromethane was cooled to −78° C. and ozone was then bubbled through the mixture for 2.5 hours. 35 ml of dimethyl sulfide was then addded to the mixture and stirring continued overnight at room temperature. The solvent was evaporated to give an orange oil. This was dissolved in 300 ml of methanol, cooled to 0° C. under nitrogen and then treated portionwise with 5.6 g of sodium borohydride. The mixture was then quenched with glacial acetic acid and evaporated. The residue was dissolved in ethyl acetate and washed sequentially with 2M aqueous hydrogen chloride, water, 5% aqueous sodium hydrogen carbonate and brine and then dried over anhydrous magnesium sulfate. Filtration and evaporation gave a residue which was purified by flash column chromatography on silica gel, using ethyl acetate/hexane (2:8 increasing to 4:6) for the elution, to give 15.3 g of benzyl-2(R)-[1(S)-(tert-butoxycarbonyl)-3-hydroxypropyl]-4-methylvalerate in the form of a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([C:19]([CH3:24])([CH3:23])[C:20](O)=[O:21])[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:34]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(O)CCC.[Cl-].[NH4+]>CN(C=O)C.O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:34])=[O:21])[CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C(=O)O)N1CCc2cc(OCc3ccc(F)cc3)ccc2C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCO
Product: CC(C)(C(N)=O)N1CCc2cc(OCc3ccc(F)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-[6-(4-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-2-methyl-propionic acid (175 mg, 0.490 mmol) and benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP, 382 mg, 0.735 mmol) and butanol (99.3 mg, 0.735 mmol) in N,N′-dimethylformamide (6 mL) was stirred at room temperature for 10 min. Ammonium chloride (52.4 mg, 0.979 mmol) was added and the mixture was stirred 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase is successively washed with sodium hydrogencarbonate 10% and MCI 0.1M. Drying and evaporation of the solvent left a solid which was recrystallised with ethyl acetate and ether (120 mg, 69%). MS: m/e=357.2-(M+H+).
Reaction SMILES: [Li].[F:2][C:3]([F:18])([F:17])[C:4]1[C:12]2[N:11]=[C:10]([CH2:13][C:14]([OH:16])=O)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.ClCCl>[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:14](=[O:16])[CH2:13][C:10]2[NH:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([C:3]([F:2])([F:18])[F:17])[C:12]=3[N:11]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(O)Cc1nc2c(C(F)(F)F)cccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1nc2c(C(F)(F)F)cccc2[nH]1)N[C@@H]1CCN(Cc2ccccc2)C1
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a solution of the lithium salt of [4-(trifluoromethyl)-1H-benzimidazol-2-yl]acetic acid (3.5 mmol; prepared according to WO 2005020899 A2) in DMF (18 mL) was added (3R)-1-benzylpyrrolidin-3-amine (740 mg, 4.20 mmol), HOBt (709 mg, 5.25 mmol), EDCI (1.00 g, 5.25 mmol) and diisopropylethylamine (3.05 mL, 17.5 mmol). The reaction mixture was stirred for 16 hours then was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford N-[(3R)-1-benzylpyrrolidin-3-yl]-2-[4-(trifluoromethyl)-1H-benzimidazol-2-yl]acetamide (866 mg, 62%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([Br:23])[CH:8]=[CH:9][C:10]=2[NH:12]S(C2C=CC(C)=CC=2)(=O)=O)[C:5]([NH:24]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][CH:3]=1>OS(O)(=O)=O>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([Br:23])[CH:8]=[CH:9][C:10]=2[NH2:12])[C:5]([NH2:24])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Br)c3c(NS(=O)(=O)c4ccc(C)cc4)ccc(Br)c23)cc1
Agent: O=S(=O)(O)O
Product: Nc1ccc(Br)c2c(N)ccc(Br)c12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
15 g (0.024 mol) of 4,8-dibromo-1,5-ditoluene-p-sulfonamidonaphthalene (J. S. Whitehurst, J. Chem. Soc., 221-226 (1951)) are dissolved in 75 ml of concentrated H2SO4 and the solution is left to stand for 24 h, excluding light. The solution is then poured on to 450 g of ice, whereupon a violet solution forms from which the product precipitates as HSO4 salt after a few minutes. The precipitate is isolated by suction filtration and the filter cake is squeezed out to give a pale beige-violet crude product that is further processed immediately.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1.[CH3:33][CH:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>>[CH:34]([S:36]([N:29]1[CH2:28][CH2:27][CH:26]([C:19]2[CH:18]=[C:17]3[C:22]([CH2:23][CH:24]([CH3:25])[N:15]([C:13]4[CH:14]=[C:9]([N:6]5[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]5)[N:10]=[C:11]([NH2:32])[N:12]=4)[CH2:16]3)=[CH:21][CH:20]=2)[CH2:31][CH2:30]1)(=[O:38])=[O:37])([CH3:35])[CH3:33]
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Product: CC1Cc2ccc(C3CCN(S(=O)(=O)C(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 138 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine HCl salt and propane-2-sulfonyl chloride. LCMS (M+H)+: m/z=528.3.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[NH:23]1C2C(=CC=C(C(C3C=CC=CC=3OC)CC(NC)=O)C=2)C=[CH:24]1>>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([CH:5]([C:6]3[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=3)[CH2:4][C:3]([NH:23][CH3:24])=[O:2])[CH:21]=2)[CH:17]=[CH:18]1
Reactant: CNC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Reactant: COC(=O)CC(c1ccc(Cl)cc1)c1ccc2cc[nH]c2c1
Product: CNC(=O)CC(c1ccc(Cl)cc1)c1ccc2cc[nH]c2c1

Procedure:
3-(1H-Indol-6-yl)-3-(4-chloro-phenyl)-N-methyl-propionamide XLIV (370 mg, 97%) was prepared from 3-(1H-indol-6-yl)-3-(4-chloro-phenyl)-propionic acid methyl ester following the procedure for 3-(1H-indol-6-yl)-3-(2-methoxy-phenyl)-N-methyl-propionamide XXXVIII (see Example 9).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=O)[NH:17][CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:18][NH:17][CH2:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]1
Reactant: CNC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCCC1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a 0° C. solution of 4-(2-methylcarbamoyl-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (3.00 g, 11.1 mmol) in THF (100 mL) was added LiAlH4 pellets (1.69 g, 4.47 mmol). The mixture was stirred at 0° C. for 1 h, and then was heated at 70° C. for 4 h. The mixture was cooled to 0° C. and quenched sequentially (slowly) with water (1.7 mL), 10% NaOH (1.7 mL), and water (1.7 mL). The resulting slurry was filtered through diatomaceous earth and the filtrate was concentrated to yield 1.6 g (85%) of the product as a yellow oil. MS: mass calcd. for C10H22N2, 170.18; m/z found, 171.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C(Cl)Cl.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:12]1[N:17]=[C:16]([C:6]2[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: N#Cc1ccc(B(O)O)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccnc(Cl)n2)s1
Temperature: 140 °C

Procedure:
A solution of 0.22 g (1.4 mmol) of 5-cyanothiophen-2-ylboronic acid, 0.21 g (1.4 mmol) of 2,4-dichloropyrimidine and 49 mg (0.070 mmol) of bis(triphenylphosphine)palladium(II) chloride in 2 mL of a 2 M Na2CO3 aqueous solution and 5 mL of 1,4-dioxane was as heated in a microwave for 30 min at 140° C., then cooled to rt, diluted with CH2Cl2 and MeOH, and dried over MgSO4. The organic solvent was removed in vacuo, and the resulting solid was purified by flash chromatography eluting with a linear gradient of 50% EtOAc in hexane to neat EtOAc to deliver the title compound. MS (M+H)+ 222.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][NH2:12])[O:7][C:6]=2[C:13]=1[CH3:14].[N+:15]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[O:21][CH2:22][CH2:23][CH2:24]Br)([O-])=O.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C.CO.[Pd]>[NH2:15][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[O:21][CH2:22][CH2:23][CH2:24][NH:12][CH2:11][CH:8]1[O:7][C:6]2[C:13]([CH3:14])=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9]1
Reactant: Cc1c(O)ccc2c1OC(CN)CO2
Reactant: O=[N+]([O-])c1cccc(OCCCBr)c1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1c(O)ccc2c1OC(CNCCCOc1cccc(N)c1)CO2
Temperature: 80 °C
Yield: 25.8 %

Procedure:
2,3-Dihydro-7-hydroxy-8-methyl-1,4-benzodioxin-2-methanamine (0.70 g, 3.6 mmole), 3-(3-nitrophenoxy)propyl bromide (0.94 g, 3.6 mmole) and diisopropylethylamine (0.47 g, 3.6 mmole) were combined in 50 ml of DMF and heated at 80° C. for 24 hrs. under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue dissolved in chloroform and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel using first chloroform and then 2% methanol/chloroform as eluant. The product-containing fractions were combined and concentrated in vacuum to give a dark yellow oil. This was dissolved in methanol (100 ml) and 0.5 g of 10% palladium on carbon added, along with 5 ml of 4N isopropanolic HCl. The mixture was hydrogenated at 50 psi on a Parr apparatus overnight, filtered through celite, concentrated in vacuum. to an off-white solid and column chromatographed on silica gel with 5% methanol/chloroform (with 1 ml/liter aqueous ammonia added). The product-containing fractions were combined and evaporated in vacuum and recrystallized from isopropanol with addition of 4N HCl/IPA to give 0.32 g of title compound as a yellow solid, dihydrochloride, hydrate, isopropanol solvate, m.p. 156° C. (d).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:6][C:7]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:8][CH:9]=1.N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH:15]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:6][C:7]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:40](=[O:42])[CH3:41])=[N:8][CH:9]=1
Reactant: NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a methylene chloride solution (5.0 ml) of N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diamine dihydrochloride (47 mg, 0.084 mmol) were added pyridine (17 μl, 0.34 mmol) and acetic anhydride (9.5 μl, 0.10 mmol). The resulting mixture was stirred for 1 hour. The residue obtained by concentrating the reaction mixture was purified by silica gel chromatography (ethyl acetate:methanol=10:1) to give the title compound (35 mg, 79%). The compound was crystallized in ether to afford a white solid (27 mg).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([Cl:10])=[N:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[CH:19].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:10][C:5]1[CH:6]=[C:7]([C:2]([C:19]#[C:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[CH:3][N:4]=1)[CH:8]=[O:9]
Reactant: O=Cc1cc(Cl)ncc1Br
Reactant: C#Cc1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=Cc1cc(Cl)ncc1C#Cc1ccccc1Cl
Temperature: 50 °C
Yield: 88.5 %

Procedure:
A mixture of 5-bromo-2-chloroisonicotinaldehyde (1.0 g, 4.5 mmol), 1-chloro-2-ethynylbenzene (650 mg, 4.7 mmol), N,N-diisopropylethylamine (1.6 mL, 9.1 mmol), copper(I) iodide (43 mg, 0.23 mmol), and bis(triphenylphosphine)palladium(II) chloride (159 mg, 0.23 mmol) in 1,4-dioxane (21 mL) was heated at 50° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-30% ethyl acetate in heptane) to afford the title compound as an off-white solid (1.1 g, 88%). 1H NMR (400 MHz, CDCl3) δ 10.64 (s, 1H), 8.77 (s, 1H), 7.77 (s, 1H), 7.62 (dd, J=7.5, 1.7 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.38 (td, J=7.8, 1.8 Hz, 1H), 7.32 (td, J=7.5, 1.2 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:24])[C@H:5]([OH:23])[CH2:6][C@H:7]([NH2:22])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)C.[O:25]=[C:26]([CH2:30][CH3:31])[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Li+].[OH-]>CN(C=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:22][C:27](=[O:28])[C:26](=[O:25])[CH2:30][CH3:31])[CH2:6][C@@H:5]([OH:23])[C:4]([OH:3])=[O:24])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCC(=O)C(=O)O
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)C(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
(2R,4R)-4-Amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (50 mg, 144 μmol) was added to a solution of 2-oxo-butyric acid (1.2 eq., 165 μmol) and HATU (71.1 mg, 187 μmol) in DMF (250 μL), followed by the addition of DIPEA (75 μL, 431 μmol). The resulting mixture was stirred at room temperature for 1 hour. 10 M aqueous LiOH (115 μL, 1.2 mmol) was added and the mixture was stirred for an additional 1 hour. The mixture was washed with DCM (1 mL) and the aqueous layer was acidified with concentrated HCl (250 μL) and extracted with DCM (2×1 mL). The DCM extracts were combined and concentrated in vacuo, and the resulting crude liquid was purified by reverse phase preparative HPLC to yield the title compound (2.9 mg). MS m/z [M+H]+ calc'd for C21H22ClNO5, 404.12. found 404.2.
Reaction SMILES: [OH-].[K+].C([O:9][CH2:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]3[C:25]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[CH3:32])=[N:24][C:23]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])=[N:22][C:21]=3[N:40]=2)[CH:14]=[CH:13][C:12]=1[O:41][CH3:42])(=O)C(C)(C)C>CO>[CH3:39][C@H:34]1[CH2:35][O:36][CH2:37][CH2:38][N:33]1[C:23]1[N:24]=[C:25]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[CH3:32])[C:20]2[CH:19]=[CH:18][C:17]([C:15]3[CH:14]=[CH:13][C:12]([O:41][CH3:42])=[C:11]([CH2:10][OH:9])[CH:16]=3)=[N:40][C:21]=2[N:22]=1
Reactant: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1COC(=O)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1CO
Reaction time: 2 h

Procedure:
Potassium hydroxide solution (9.96 mL, 133.20 mmol) was added over 30 minutes to a solution of 5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxybenzyl pivalate prepared by the alternate method (25.16 g, 0.30 mmol) in methanol (244 mL) at 50° C. under an atmosphere of nitrogen. After 120 minutes at 50° C., HPLC analysis showed complete disappearance of the starting material. Seed crystals of the desired compound were then added (122 mg, 257 μmol) and the reaction was maintained at 50° C. for 2 hours to establish crystallisation of the desired product. Water, (244 mL) is then added over 15 minutes maintaining a reaction temperature of 50° C. The reaction mixture is then cooled to 20° C. and the resulting yellow solid isolated by filtration. The yellow solid was washed with water (3×97 mL) and dried initially in air and then in vacuo at 45° C. to give (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (6) as a yellow solid (19.33 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([O:32][CH2:31][C@H:29]2[CH2:28][C@@H:27]([C:8]3[N:4]4[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]4=[C:10]([C:11]4[CH:20]=[C:19]5[C:14]([CH:15]=[CH:16][C:17]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)=[N:18]5)=[CH:13][CH:12]=4)[N:9]=3)[CH2:30]2)=[O:41])=[CH:43][CH:44]=1)([O-:35])=[O:34]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn32)C1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of {3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol (46.52 g, 105.5 mmol) and 4-nitrobenzoyl chloride (23.55 g, 126.9 mmol) in methylene chloride (260 mL) was added N,N-diisopropylethyl amine (55.17 mL, 316.7 mmol). The mixture was stirred at rt for 15 h. Yellow precipitates were collected by filtration, washed with ethyl acetate, and dried to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 2.70-2.78 (m, 4H), 2.96-3.02 (m, 1H), 3.81-3.86 (m, 1H), 4.41 (d, J=4.8 Hz, 2H), 7.37 (d, J=5.2 Hz, 1H), 7.44-7.48 (m, 1H), 7.51-7.55 (m, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.88-7.96 (m, 5H), 8.16-8.19 (m, 214), 8.26-8.29 (m, 2H), 8.33 (d, J=8.8 Hz, 1H), 8.54 (s, 1H); MS (ES+): m/z 590 [MH+]; HPLC: tR=4.37 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:26])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH:15]([C:16](O)=[O:17])[C:5]2=1.[C:27](N1C=CN=C1)([N:29]1C=CN=[CH:30]1)=O.CNC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:26])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH:15]([C:16]([N:29]([CH3:30])[CH3:27])=[O:17])[C:5]2=1
Reactant: Cn1c2c(c3cc(F)ccc31)C(C(=O)O)CN(Cc1ccccc1)C2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CN(Cc2ccccc2)C(=O)c2c1c1cc(F)ccc1n2C

Procedure:
A solution of 4 g (11 mmol) of (±)-6-fluoro-9-methyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylic acid and 2.2 g (30 mmol) of 1,1'-carbonyldiimidazole in 200 ml of tetrahydrofuran is heated at 40° C. for 2 h. The reaction mixture is cooled and a large excess of liquefied dimethylamine is added and the mixture is allowed to stir for a few hours.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:24]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([O:22][CH3:21])[N:24]=[C:25]([NH:31][C:32](=[O:33])[NH:18][S:17]([C:9]2[CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:20])=[O:19])[N:26]=1
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)cc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)NC(C)C)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
2.6 g (8.6 mmol) of methyl 4-isopropylcarbamoyl-2-sulfamoylbenzoate and 2.8 g (10.3 mmol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate were initially charged in 50 ml of acetonitrile. At room temperature, 2.9 g (19 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added dropwise, and the mixture was stirred at this temperature for 3 h. The mixture was poured into ice-water and the pH was adjusted to 1 using 2N hydrochloric acid. The precipitated solid was filtered off with suction and washed with water. After drying, 3.9 g (94% of theory) of methyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyl]-4-isopropylcarbamoylbenzoate of m.p. 149-151° C. (decomp.) were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12](OC)(=[O:14])C>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8](=[NH:9])[O:14][CH3:12])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(C)=O
Solvent: CO
Product: COC(=N)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Part A: 4-Nitrobenzonitrile (5.4 g, 36.5 mmol) was dissolved in 200 mL of anhydrous methyl acetate and 20 mL of MeOH. The whole mixture was cooled to 0° C. and bubbled with dry HCL gas for 1 hour. The resulting mixture was placed at 5° C. for 12 hours, the solvent was removed to obtain 5.8 g of methyl 4-nitrobenzimidate as its HCl salt.