Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(SC)C=CC=CC=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:53]=[CH:54][C:55]=1[OH:56])[C:20]([NH:22][N:23]1[CH2:28][CH2:27][N:26]([S:29]([NH:32][C:33]([N:35]2[CH2:38][C@H:37]([NH:39]C(=O)OCC3C=CC=CC=3)[C:36]2=[O:50])=[O:34])(=[O:31])=[O:30])[C:25](=[O:51])[C:24]1=[O:52])=[O:21]>CCOCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:39][C@H:37]1[CH2:38][N:35]([C:33]([NH:32][S:29]([N:26]2[CH2:27][CH2:28][N:23]([NH:22][C:20](=[O:21])[C:19]3[CH:53]=[CH:54][C:55]([OH:56])=[C:17]([OH:16])[CH:18]=3)[C:24](=[O:52])[C:25]2=[O:51])(=[O:30])=[O:31])=[O:34])[C:36]1=[O:50]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3ccc(O)c(O)c3)C(=O)C2=O)C1=O)OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3ccc(O)c(O)c3)C(=O)C2=O)C1=O
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a mixture of 12 ml of trifluoroacetic acid and 3 ml of thioanisole was added 2.92 g (4.94 mmol) of (S)-[1-[[[[4-[(3,4-dihydroxybenzoyl)amino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester at 0° C. After stirring overnight at 10° C., 150 ml of ether was added and the resulting precipitate was filtered off, washed with ether and dried in vacuo. For further purification, the salt was triturated two times with dichloromethane; yield: 2.56 g; melting point 206°-210° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2].[CH:17]1(C2C=C3C=NNC3=CN=2)[CH2:19][CH2:18]1>>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[C:10]([CH:17]3[CH2:19][CH2:18]3)[CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2]
Reactant: c1n[nH]c2cnc(C3CC3)cc12
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Product: NC(=O)c1nn(CC(=O)O)c2cnc(C3CC3)cc12

Procedure:
was prepared by using the same procedure as described for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid and by starting from 5-cyclopropyl-1H-pyrazolo[3,4-c]pyridine (Scheme A26). MS (LC-MS): 261 [M+H]+, tR (HPLC conditions c): 1.84 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:13][CH:14]=[CH2:15])[CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:16]O>S(=O)(=O)(O)O.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:13][CH:14]=[CH2:15])[CH2:9][C:10]([O:12][CH3:16])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: C=CCC(CC(=O)O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C=CCC(CC(=O)OC)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 43.2 (2.4 g, 12 mmol) in MeOH (25 mL) was added five drops of sulfuric acid. The mixture was stirred overnight at reflux, cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated. The crude product was chromatographed on silica gel (0-25% EtOAc/hexane) to afford 43.3 (2.2 g, 84%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: COc1ccc(C#N)c(N)c1
Product: COc1ccc(C#N)c(NC(=O)NC(=O)c2ccccc2)c1

Procedure:
Prepared as in Example 53a from 2-amino-4-methoxybenzonitrile and benzoyl isocyanate as white solid (99 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 6.87 (dd, J=2.5 Hz, 2.4 Hz, 1H), 7.54 (t, J=8 Hz, 2H), 7.66 (t, J=1.2 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 8.03 (d, J=2.8 Hz, 2H), 11.35 (s, 1H), 11.52 (s, 1H). MS 295 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:34][C:35]([CH:37]1[CH2:39][CH2:38]1)=[NH:36]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]3[O:18][N:36]=[C:35]([CH:37]4[CH2:39][CH2:38]4)[N:34]=3)=[CH:14][N:13]=2)[CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N=C(NO)C1CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)O)cn2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(C4CC4)no3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 380 %

Procedure:
To a solution of 6-(1-tert-butoxycarbonylamino-cyclopropyl)-nicotinic acid (0.10 g, 0.10 mmol) in DMF (5 mL) was added CDI (0.16 g, 0.10 mmol). The mixture was stirred at room temperature for 3 h. N-hydroxy-cyclopropanecarboxamidine (0.28 g, 0.10 mmol) was then added and the reaction mixture heated at 100° C. for 24 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, satd aqueous NaHCO3, brine and dried with MgSO4. The mixture was filtered and concentrated to give {1-[5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (0.13 g, 0.38 mmol) as a yellow oil, m/z 343.7 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].[CH3:42][NH:43][CH3:44].O.CN(C)C=O>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([N:43]([CH3:44])[CH3:42])=[O:17])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CN(C)C(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1

Procedure:
A solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxylate (intermediate 4, 60 mg, 0.11 mmol) in acetonitrile (1.5 mL) is treated with dimethylamine (2.0 M in tetrahydrofuran, 270 μL, 0.53 mmol) and the mixture is stirred at room temperature for 30 min Water and N,N-dimethylformamide are added and the mixture is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield 28 mg, ESI mass spectrum [M+H]+=469; Retention time HPLC: 0.87 min (Z018_S04).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[NH2:11].C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][C:33]#[N:34])[CH:30]=2)O1.O>COCCOC.C(#N)C.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>[NH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][C:33]#[N:34])[CH:30]=3)[CH:3]=2)[NH:7][N:6]=1
Reactant: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
Reactant: Nc1n[nH]c2ccc(Br)cc12
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: CC#N
Solvent: COCCOC
Solvent: O
Product: N#CCCn1cc(-c2ccc3[nH]nc(N)c3c2)cn1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a microwave vial was added 5-bromo-1H-indazol-3-amine (0.14 g, 0.66 mmol), tetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066 mmol), and sodium carbonate (0.147 g, 1.39 mmol) followed by a solution of Example 267A (0.212 g, 0.858 mmol) in 1,2-dimethoxyethane (2.50 mL) and then water (1.25 mL). The mixture was heated in a CEM microwave at about 150° C. for about 20 minutes (275 psi maximum pressure, about 2 minutes ramp, 200 maximum watts) and then the mixture was concentrated under reduced pressure. Methanol (20 mL) was added and the resulting mixture was stirred for about 1 hour. The insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure onto silica gel and purified via silica gel chromatography eluting with a stepwise gradient of dichloromethane/methanol/ammonium hydroxide (990:9:1 to 985:13.5:1.5 to 980:18:2) to afford a solid. This solid was dissolved in a minimum amount of hot acetonitrile (˜2 mL), filtered to remove minor amount of insolubles, while washing with methanol (<0.5 mL), and left to sit at ambient temperature. The resulting solid that formed overnight was collected by filtration, while washing with additional acetonitrile, and dried in a vacuum oven at about 60° C. for about 2 hours to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.35 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.44 (dd, J=8.54, 1.26 Hz, 1H), 7.23 (d, J=8.62 Hz, 1H), 5.32 (s, 2H), 4.42 (t, J=6.36 Hz, 2H), 3.10 (t, J=6.43 Hz, 2H). MS (ESI+) m/z 253.2 (M+H)+.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[C:6]([O:10][C:11]([NH:13][CH2:14][C@@H:15]([C:40](OC)=[O:41])[N:16]([C:21]([C:23]1[C:24]([NH:33][CH2:34][C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)=[N:25][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:27][CH:28]=1)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(O)C.C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:29]([C:26]1[N:25]=[C:24]([NH:33][CH2:34][C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)[C:23]([C:21]([N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C@H:15]([CH2:40][OH:41])[CH2:14][NH:13][C:11](=[O:12])[O:10][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:22])=[CH:28][N:27]=1)([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N(CC(C)C)C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H](CO)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
Calcium chloride (420 mg) was suspended in ethanol (5 ml), and sodium borohydride (286 mg) was added at 0° C. The mixture was stirred at 0° C. for 15 min, and a solution of methyl 3-[(tert-butoxycarbonyl)amino]-N-({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)-N-(2-methylpropyl)-L-alaninate (105 mg) in THF (5 ml) was added dropwise. The mixture was stirred at room temperature for 1.5 hr, the reaction mixture was diluted with 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC, and fractions eluted with water-acetonitrile (9:1) to acetonitrile were collected. The mixture was basified (pH 10) with saturated aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (65 mg).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([F:23])[CH2:19][CH2:18]2)[C:14]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32]3)(=[O:30])=[O:29])=[CH:27][C:13]=2[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C>[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([F:23])[CH2:19][CH2:18]2)[C:14]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([C:36]([OH:1])=[O:37])=[CH:32]3)(=[O:30])=[O:29])=[CH:27][C:13]=2[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCC(F)CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCC(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxone® (0.36 g, 0.53 mmol) was added to a solution of 1-({2-tert-butyl-1-[(4fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-1H-pyrrole-3-carbaldehyde (0.23 g, 0.53 mmol) in DMF (15 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was recovered in DCM, washed with 10% HCl solution, brine and dried over anhydrous Na2SO4. The solvent was concentrated to provide the pure title compound as white solid. Yield: 0.26 g (99%). MS (ESI) (M+H)+=462.1.
Reaction SMILES: [NH2:1][C:2]1([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.[C:17](OC([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:9]([N:4]1[CH2:3][C:2]([NH:1][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1(N)CN(Cc2ccccc2)CC12CC2
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)CC12CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane (7.3 g) was dissolved in toluene (30 mL). t-Butyl dicarbonate (9.3 mL) and 1N aqueous sodium hydroxide (10 mL) were added to the solution, followed by stirring for 15 hours at room temperature and then for 4 hours at 50° C. After completion of reaction, the toluene layer was separated and washed with water, followed by drying with sodium sulfate. The desiccant was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel chromatography (hexane:ethyl acetate), to thereby yield the title product (8.745 g, yield: 82%). Notably, when optically active 7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane is treated in accordance with the above-described procedure, the corresponding optically active target product can be yielded without decreasing optical purity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([S:28]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)(=[O:30])=[O:29])=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)=[C:14]([O:38][CH3:39])[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:39][O:38][C:14]1[CH:13]=[C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:17]=[CH:16][C:15]=1[C:18]1[C:27]2[C:22](=[CH:23][C:24]([S:28]([NH:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:30])=[O:29])=[CH:25][CH:26]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccccc2C)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 150 °C
Yield: 32.4 %

Procedure:
A microwave vial charged with 2-methylphenylboronic acid (0.022 g, 0.158 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1′1′-biphenyl (4.33 mg, 10.54 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (7.99 mg, 10.54 μmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From Example 160; 45 mg, 0.105 mmol), potassium phosphate (90 mg, 0.422 mmol), 1 mL dioxane and 0.25 mL water was heated to 150° C. in the microwave for 30 minutes. LC/MS showed mostly product, so the aqueous layer was removed. The reaction mixture was acidified with 4N HCl in dioxane then was concentrated. The crude product was purified by reverse phase column chromatography [PREP LC/MS-2 System Column: XBridge 19×100 mm 12230326114 03 Mobile phase: 0.1% NH4OH in water/acetonitrile Flow rate: 40 ml/min Inj: 2200 uL. Gradient: 10 min 10-40%_LV_NH3] yielding 1-(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.017 g, 0.034 mmol, 32.6% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.36 (s, 3H) 3.68 (s, 3H) 6.95 (br. s., 1H) 7.08 (d, J=7.27 Hz, 1H) 7.14 (s, 1H) 7.27 (br. s., 1H) 7.29-7.44 (m, 5H) 7.78 (d, J=8.82 Hz, 1H) 7.97 (d, J=8.71 Hz, 1H) 8.08 (d, J=5.96 Hz, 1H) 8.18 (br. s., 1H) 8.52 (br. s., 1H) 8.62 (br. s., 1H) 8.68 (d, J=5.56 Hz, 1H); (M+H)+=483.0.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][NH:12][CH3:13].C(=O)([O-])[O-]>CC#N>[CH3:11][N:12]([CH2:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:13]
Reactant: N#Cc1ncccc1CBr
Reactant: CNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CN(C)Cc1cccnc1C#N
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 111.9 %

Procedure:
A solution of 3-bromomethylpyridine-2-carbonitrile (591 mg, 3.0 mmol) in MeCN (10 mL) was treated with dimethylamine (7.9-M in water, 1.9 mL, 15 mmol) and heated at 50° C. for 4 h. The solution was treated with MP-carbonate (2.0 g, 6.0 mmol), stirred for 30 min, filtered through Celite and the residue was washed with EtOAc. The filtrate was concentrated in vacuo, and the crude product was purified by chromatography [SiO2; MeOH:EtOAc:isohexane (0:4:1-1:9:0)] to give the title compound (541 mg, 96%) as an orange oil; NMR δH (400 MHz, CDCl3) 2.31 (6H, s), 3.67 (2H, s), 7.50 (1H, dd, J 8.0, 4.5 Hz), 7.94 (1H, dd, J 8.0, 1.5 Hz) and 8.61 (1H, dd, J 4.5, 1.5 Hz); M/Z 162 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:12][C:3]=1[C:4]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=O)=[O:5].S(Cl)([Cl:31])=O>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:12][C:3]=1[C:4]([O:6][C@@H:7]([CH3:11])[C:8]([Cl:31])=[O:10])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: C[C@H](OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl)C(=O)O
Product: C[C@H](OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl)C(=O)Cl

Procedure:
5.7 g (14 mmol) of (S)-2-[2-chloro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)benzoyloxy]-propionic acid from example 3.2 were dissolved in 50 ml of thionyl chloride, and the reaction mixture was heated under reflux for 3.5 hours. The solution was allowed to cool and concentrated, which gave 5.9 g of (S)-2-[2-chloro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)-benzoyloxy]propionyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH2:19][CH2:20][O:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)[N:13]=2)=[CH:8][C:7]=1[Cl:34].Cl[Si](C)(C)C.[I-].[Na+]>C(Cl)Cl>[Cl:34][C:7]1[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH2:19][CH2:20][O:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)[N:13]=2)[CH:10]=[CH:11][C:6]=1[C:5]1[NH:4][CH2:3][CH2:2][N:1]=1
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(C(=O)NCCN)c(Cl)c4)ccc3=O)ccnc2c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(OCCn3nc(-c4ccc(C5=NCCN5)c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A suspension of N-(2-aminoethyl)-2-chloro-4-(1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzamide (50 mg, 101 μmol), chlorotrimethylsilane (39 μl, 304 μmol), sodium iodide (46 mg, 304 μmol), and TEA (42 μL, 304 μmol) in DCM (2 mL) was stirred for 3 hours at 40° C. in an appropriately sealed vial. The reaction was then partitioned between DCM (5 mL) and 1 M NaOH (2 mL). The organic layer was then separated and dried over MgSO4, concentrated onto dry silica (2 g) then purified on silica (4 g) by washing with 5% MeOH, then eluting product with 4->10% NH3 in MeOH (2M)/DCM. The product was isolated as a white solid. (ESI pos. ion) m/z: 476 (MH+); calc'd for C25H22ClN5O3: 475. 1H NMR (400 MHz, DMSO-d6) □ ppm 3.65 (s, 4 H) 3.87 (s, 3 H) 4.69 (dd, J=7.34, 3.42 Hz, 4 H) 6.95 (d, J=5.28 Hz, 1 H) 7.03 (dd, J=9.10, 2.45 Hz, 1 H) 7.12 (d, J=9.78 Hz, 1 H) 7.28 (d, J=2.35 Hz, 1 H) 7.67 (d, J=8.22 Hz, 1 H) 7.83-7.92 (m, 2 H) 7.97 (d, J=1.56 Hz, 1 H) 8.13 (d, J=9.78 Hz, 1H) 8.62 (d, J=5.28 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([CH2:11][O:12]CC2C=CC=CC=2)[CH2:9][CH2:8][CH2:7][N:6]1[CH3:10])=[O:4]>[OH-].[OH-].[Pd+2].C(O)(=O)C>[CH3:1][O:2][C:3]([C@:5]1([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][N:6]1[CH3:10])=[O:4]
Reactant: COC(=O)[C@]1(COCc2ccccc2)CCCN1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)[C@]1(CO)CCCN1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 99.7 %

Procedure:
A suspension of Intermediate 85d (2.59 g, 9.84 mmol), palladium hydroxide on charcoal (10%, 250 mg) and glacial acetic acid (1 mL) in IMS (20 mL) under an atmosphere of hydrogen (1 atm) was stirred at RT for 5 d. The mixture was filtered and concentrated in vacuo to give the title compound as a clear oil (1.70 g, 99%), as a mixture of methyl and ethyl esters. Data for major product, methyl ester: 1H NMR (400 MHz, CDCl3): 1.75-1.95 (2H, m), 2.01-2.18 (2H, m), 2.36 (3H, s), 2.86-2.99 (2H, m), 3.65 (3H, s), 4.19 (2H, m), 4.91 (1H, br s).
Reaction SMILES: [O:1]=[C:2]([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5].[CH:9]#[N:10].[NH4+]>>[C:9]([C:2]([OH:1])([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5])#[N:10]
Reactant: C#N
Reactant: O=C(O)CC(=O)CCl
Agent: [NH4+]
Product: N#CC(O)(CCl)CC(=O)O

Procedure:
In an alternate procedure, the 3-oxo-4-chlorobutyric acid from 11 is reacted at 12 directly with HCN in the absence of ammonium or metal cations to produce 3-cyano-3-hydroxy-4-chlorobutyric acid for feed to hydrolysis step 15.
Reaction SMILES: CCOCC.Cl[C:7]1[N:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1.CCN(CC)CC>CC(O)(C)C.ClCCCl.[Cl-].[Cl-].[Zn+2]>[Cl:13][C:11]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=[C:7]([NH:18][C:19]2[CH:24]=[N:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:12]=1
Reactant: COc1ccc(N)cn1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Reaction time: 0.17 h

Procedure:
A 1.0 M solution of ZnCl2 in Et2O (5.07 mL, 5.07 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.00 g, 4.61 mmol) in t-BuOH (25 mL) and DCE (25 mL). The mixture was stirred for 10 minutes and then diluted with t-BuOH (25 mL) and DCE (25 mL) before 5-amino-2-methoxypyridine (629 mg, 5.07 mmol) and Et3N (1.93 mL, 13.8 mmol) were added. The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The resultant residue was suspended in water (250 mL) and sonicated for 10 minutes before the solid was isolated by vacuum filtration. The filter cake was washed with water and air dried and then dissolved in DCM and adsorbed onto silica gel. Purification by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) gave the title compound A68 as a white solid (944 mg, 67%). LCMS-A: rt 6.62 min; m/z 305 [M+H]+.