Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:16])(=[N:10][C:11](=O)[CH2:12][O:13][CH3:14])=[O:9])=[CH:4][CH:3]=1>O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH3:16])(=[N:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9])=[CH:6][CH:7]=1
Reactant: COCC(=O)N=S(C)(=O)c1ccc(N)cc1
Solvent: C1CCOC1
Product: COCCN=S(C)(=O)c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
493 mg (2.03 mmol) (RS)—S-(4-aminophenyl)-N-(2-methoxy-acetyl)-S-methylsulphoximide is dissolved in 67.8 ml tetrahydrofuran, cooled in the ice-bath and treated dropwise with 6.13 ml (6.13 mmol) borane tetrahydrofuran complex. The mixture is stirred for 90 minutes and quenched with one drop of methanol and one drop of water. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 383 mg (82%) of the desired product is obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:21](O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH3:44][O:45][C:46](=[O:51])[C:47]([NH2:50])([CH3:49])[CH3:48]>CN(C=O)C>[CH3:44][O:45][C:46](=[O:51])[C:47]([CH3:49])([NH:50][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH:10]=[CH:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:22])[CH3:48]
Reactant: O=C(O)c1ccc2ccccc2c1C=CCCc1ccccc1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C=CCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
At 0° C. to a solution of 165 mg of a mixture of the (E)- and (Z)-isomers of 1-(4-phenyl-but-1-enyl)-naphthalene-2-carboxylic acid in 2 ml abs. DMF under inert atmosphere 95 mg 1-hydroxybenzotriazole, 110 μl N,N′-diiospropylcarbodiimide and 98 μl N,N-diisopropylethylamine were added. After 15 min at 0° C. 86 mg amino-isobutyric acid methyl ester hydrochloride and 98 μl N,N-diisopropylethylamine were added and the reaction was stirred for 0.5 h at 0° C. and for 4 h at room temperature. Then, the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sat. sodium hydrogen carbonate solution and brine. The organic layer was dried over sodium sulphate, concentrated and purified by chromatography on silica (ethyl acetate/heptane) to yield 85 mg of a mixture of the (E)- and (Z)-isomers of 2-methyl-2-{[1-(4-phenyl-but-1-enyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C@@H:9]([CH3:12])[CH2:8][C@H:7]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].[C:21](Cl)(=[O:23])[CH3:22].O>N1C=CC=CC=1.ClCCl>[C:21]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[C@H:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:8][C@@H:9]1[CH3:12])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](Nc2ccccc2F)c2cccc(F)c2N1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1c2c(F)cccc2[C@H](Nc2ccccc2F)C[C@@H]1C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
[Step 2] 60 mg of cis-8-fluoro-4-[(2-fluorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 0.5 mL of pyridine and 2 mL of dichloromethane, and 16 mg of acetyl chloride was added to the solution under ice cooling. The resulting mixture was stirred for 2 hour under ice cooling. After completion of the reaction, water was added to the reaction liquid, the mixture was extracted with chloroform, and then the organic layer was washed with a saturated solution of sodium hydrogen carbonate and saturated brine. The washed organic layer was dehydrated over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (chloroform), and thus 48 mg (70%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](=[O:40])[N:15]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=1)C.Cl.O>CO.[OH-].[Na+]>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:27])([F:28])[F:26])[CH:19]=2)[C:14]([C:8]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][C:4]([OH:41])=[O:3])=[O:40])=[CH:35][CH:34]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CCOC(=O)CNc1ccc(Cl)cc1C(=O)N(CCc1cccc(OC(F)(F)F)c1)Cc1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)(F)F)c2)C(=O)c2cc(Cl)ccc2NCC(=O)O)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 33 mg of (2-{(4-tert-butyl-benzyl)-[2-(3-trifluoromethoxy-phenyl)-ethyl]-carbamoyl}-4-chloro-phenylamino)-acetic acid ethyl ester (0.06 mmol) in 0.5 ml methanol and 0.11 ml 1N aqueous NaOH was heated for 2 hours to 50° C. After cooling down to RT the mixture was neutralized with 0.11 ml 1N aqueous HCl, treated with a small amount of water, and extracted twice with ethylacetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 26 mg (79%) of the title compound as an off-white solid. MS (ISP) 563.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13]([N:16](C(C)C)[CH2:17]C)(C)C.CC(C)(C)C(Cl)=O.CNC>ClCCl>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:13])=[O:5]
Reactant: O=C(O)c1cc(I)cc(F)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
2,3-Difluoro-5-iodo-benzoic acid (7.20 g, 25.35 mmol), di-iso-propylethylamine (4.5 ml, 25.83 mmol), trimethylacetyl chloride (3.2 ml, 25.98 mmol), and dichloromethane (100 ml) were combined and stirred at room temperature for 1 hour. Dimethylamine (2 M in tetrahydrofuran, 22.0 ml, 44.00 mmol) was added to the reaction, and the combined mixture was stirred for an addition 18 hours at room temperature. The mixture was concentrated in vacuo, and the crude product was purified by flash chromatography on silica gel (0 to 40% ethyl acetate in hexanes) to afford 7.17 g (91%) of 2,3-difluoro-5-iodo-N,N-dimethyl-benzamide. 1H-NMR (250 MHz, d6-DMSO) δ 8.02-7.90 (m, 1H), 7.60-7.54 (m, 1H), 2.99 (s, 3H), 2.84 (s, 3H); LCMS m/z 400.0 (M+H+); MS: m/z 312.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][CH:13]=O)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1.Cl.[N:16]1([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:29])=[CH:23][CH:22]=2)[CH:20]=[N:19][N:18]=[N:17]1.C([BH3-])#N.[Na+].CO>C(O)(=O)C>[CH3:1][C:2]1[C:3]([CH2:12][CH2:13][N:33]2[CH2:32][CH2:31][N:30]([C:28](=[O:29])[CH2:27][C:24]3[CH:23]=[CH:22][C:21]([N:16]4[CH:20]=[N:19][N:18]=[N:17]4)=[CH:26][CH:25]=3)[CH2:35][CH2:34]2)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: Cc1cc2c(cc1CC=O)COC2=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc2c(cc1CCN1CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC1)COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with (6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (100 mg, 0.53 mmol) was added 1-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazine hydrochloride (162 mg, 0.53 mmol), sodium cyanoborohydride (165 mg, 2.6 mmol), methanol (10 mL), and a drop of acetic acid. The mixture was allowed to stir at RT for 16 hours. LC showed formation of the desired product. The solvent was removed under reduced pressure. The residue was redissolved in DMSO-water, and purified by mass-directed HPLC. LC/MS: (1E, m/z) (M+1)+=447.3;
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:28]=[C:27]([O:29][CH2:30][O:31][CH3:32])[CH:26]=[CH:25][C:6]=1[C:7](=[O:24])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[C:12]([O:20][CH2:21][O:22][CH3:23])[CH:11]=1>[Pd]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:28]=[C:27]([O:29][CH2:30][O:31][CH3:32])[CH:26]=[CH:25][C:6]=1[C:7](=[O:24])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[C:12]([O:20][CH2:21][O:22][CH3:23])[CH:11]=1
Reactant: COCOc1ccc(C(=O)C=Cc2ccc(OCOC)c(OCOC)c2)c(OCOC)c1
Agent: [Pd]
Product: COCOc1ccc(C(=O)CCc2ccc(OCOC)c(OCOC)c2)c(OCOC)c1
Yield: 97.4 %

Procedure:
Catalytic reduction of 5.05 g of the 2',3,4,4'-tetrakis(methoxymethoxy)chalcone obtained as the intermediate in Specific Example 19 was carried out by using 1.76 g of 5% palladium/carbon according to customary procedures. After the reaction, the reaction liquid was filtered and the solvent was removed from the filtrate by distillation to obtain 4.94 g (yield=97.3%) of 1-[2,4-bis(methoxymethoxy)phenyl]-3-[3,4-bis(methoxymethoxy)phenyl] -1-propanone.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:14]([OH:16])=O)=[N:11][NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1([CH2:23][C:24]2[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:10]([C:14](=[O:16])[NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH2:23][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:25][C:26]=2[NH2:31])=[N:11][NH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)O
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(CN2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
A mixture of 4-tert-butoxycarbonylamino-1H-pyrazole-3-carboxylic acid (10.0 g, 44.1 mmol), 4-morpholin-4-ylmethyl-benzene-1,2-diamine (10.0 g, 48.5 mmol), EDC (10.14 g, 52.9 mmol) and HOBt (7.15 g, 52.9 mmol) in DMF (150 mL) was stirred at ambient temperature for 20 h and then the majority of the solvent removed in vacuo. The residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL), the layers separated and the organic portion washed with brine, dried over MgSO4 and reduced in vacuo to give [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-1H-pyrazol-4-yl]-carbamic acid tert-butyl ester (17.6 g, 96%) as a brown solid. LC/MS analysis indicates product contains 15% of the di-amide. This shows at approx. 5% level in 1H NMR. Di-amide is cleaved in subsequent step.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:34][CH2:33][C@:10]([O:35][CH3:36])([C@@H:11]4[O:17][C:16]=5[C:18]([O:23]CC3C=CC(OC)=CC=3)=[CH:19][CH:20]=6)[C@@H:9]([CH2:37][NH2:38])[CH2:8]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:46]1([CH3:56])[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:34][CH2:33][C@:10]([O:35][CH3:36])([C@@H:11]4[O:17][C:16]=5[C:18]([OH:23])=[CH:19][CH:20]=6)[C@@H:9]([CH2:37][NH:38][S:52]([C:49]3[CH:50]=[CH:51][C:46]([CH3:56])=[CH:47][CH:48]=3)(=[O:54])=[O:53])[CH2:8]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(COc2ccc3c4c2O[C@H]2[C@@]5(OC)CC[C@@]6(C[C@@H]5CN)[C@@H](C3)N(CC3CC3)CC[C@]426)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@]12CC[C@@]3(C[C@@H]1CNS(=O)(=O)c1ccc(C)cc1)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Compound 5 (31 mg, 0.06 mmol, 1 eq) in DCM (2 mL) at 0° C. was added triethylamine (86 μL, 6.0 mmol, 10 eq.) followed by p-toluenesulfonyl chloride (34.3 mg, 0.18 mmol, 3 eq.). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated and the crude material dissolved in DCM (2 mL), TFA (0.5 mL) was added and the mixture stirred at 0° C. for 1 h. The residue, after evaporating the solvent, was purified by flash chromatography (SiO2, 1-5% MeOH (with 7% ammonia)/DCM) to provide Compound 124 as the free base. The free base was dissolved in DCM (1 mL) and 1M HCl in Et2O (1 mL) was added and the mixture stirred at 0° C. for 1 h. The solvents were evaporated and the residue was triturated with Et2O to give Compound 124 HCl salt as a white solid
Reaction SMILES: Br.[NH:2]([C:4]1[NH:5][CH2:6][CH2:7][N:8]=1)[NH2:3].Br.[OH:10][C@H:11]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@:17]3([OH:35])[CH2:18][CH2:19][C@@H:20]2/[CH:21]=[C:22](\[CH3:25])/[CH:23]=O)[CH2:12]1>O.O1CCOCC1>[NH:8]1[CH2:7][CH2:6][N:5]=[C:4]1[NH:2]/[N:3]=[CH:23]/[C:22](/[CH3:25])=[CH:21]/[C@H:20]1[CH2:19][CH2:18][C@:17]2([OH:35])[C@H:16]3[C@H:29]([CH2:28][CH2:27][C@:26]12[CH3:34])[C@:30]1([CH3:33])[C@@H:13]([CH2:12][C@@H:11]([OH:10])[CH2:32][CH2:31]1)[CH2:14][CH2:15]3
Reactant: C/C(C=O)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NNC1=NCCN1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CC(/C=N/NC1=NCCN1)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 72 h

Procedure:
A solution of 0.55 g of 2-hydrazino-2-imidazoline hydrobromide in 10 ml of water and 30 ml of dioxane was made acid to pH 3 with 0.1N HBr. A solution of 1.00 g of (E)-3β,14β-dihydroxy-21-methyl-5β-pregn-20-ene-21-carboxaldehyde (Prepn, 1) in 10 ml of dioxane was added at room temperature. After 3 days, the solution was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 90/10/1 as the eluant: the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with ethyl acetate and ethanol to give 0.85 g of the title compound (I-ab) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:16])=[N:5][N:6]([CH3:15])[C:7]=1[S:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:2].[OH-].[Na+].CO.Cl>O1CCCC1>[CH:1]([C:3]1[C:4]([CH3:16])=[N:5][N:6]([CH3:15])[C:7]=1[S:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: CCOC(=O)CSc1c(C=O)c(C)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(C)c(SCC(=O)O)c1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A mixture of ethyl [(4-formyl-1,3-dimethyl-1H-pyrazol-5-yl)sulfanyl]acetate obtained in Reference Example 2 (2.12 g), 8 M sodium hydroxide solution (5 mL), methanol (50 mL), and tetrahydrofuran (50 mL) was stirred at room temperature for 2 h. 6 M Hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-diisopropyl ether to provide the title compound (1.09 g, 58%) as a solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:11]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:34]>O1CCCC1.C(OCC)(=O)C>[ClH:34].[ClH:34].[NH2:8][CH2:9][C:10]1[C:11]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:14]=2
Reactant: COC(=O)c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2nc(CC(C)C)c(CN)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of methyl 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-phenylquinoline-6-carboxylate (0.10 g, 0.22 mmol) in tetrahydrofuran (2 ml) was added 4N solution of hydrogen chloride in ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether-ethyl acetate to give the title compound (0.084 g, yield 90%) as colorless crystals.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.C(O)(C)C.C(=O)=O.[CH2:14]([O:21][C:22]([O:24][CH:25]1[CH2:34][CH2:33][C:32]2[N:31]=[CH:30][C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:28](O)[C:27]=2[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:21][C:22]([O:24][CH:25]1[CH2:34][CH2:33][C:32]2[N:31]=[CH:30][C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:28]([Cl:4])[C:27]=2[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cnc2c(c1O)CC(OC(=O)OCc1ccccc1)CC2
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(c1Cl)CC(OC(=O)OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (1.82 g) is added to 100 mL of DMF dropwise under stirring and cooling (isopropanol-dry ice) maintaining the temperature below -20°. Stirring is continued for 30 minutes at the same temperature. To the mixture, 2.66 g of ethyl 6-benzyloxycarbonyloxy-4-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate is added in one portion, and stirring is continued for 2 hours at -30° to -20°, then at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is taken up in CH2Cl2, washed with saturated NaHCO3, dried (MgSO4) and evaporated to leave an oil which is purified by flash chromatography on a silica gel column obtaining ethyl 6-benzyloxycarbonyloxy-4-chloro-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Product: OCCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 61.3 %

Procedure:
Following general procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.208 g, 0.78 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.118 g, 0.86 mmol) to afford the title compound (0.175 g, 61%) as a white solid. MW=365.86. 1H NMR (DMSO-d6, 500 MHz) δ 8.78 (s, 1H), 8.28-8.22 (m, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.53-7.49 (m, 2H), 7.22 (d, J=8.5 Hz, 2H), 4.62 (t, J=5.0 Hz, 1H), 3.65-3.59 (m, 2H), 2.29-2.84 (m, 4H), 2.72 (t, J=7.5 Hz, 2H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 366 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH:10]([CH3:23])[C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][C:57]1[CH:58]=[C:59]([C:64]2[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[C:66]([F:72])[CH:65]=2)[CH:60]=[CH:61][C:62]=1[NH2:63]>CN(C=O)C.O>[C:19]([O:18][C:16]([NH:15][C@H:11]([C:12]1[NH:63][C:62]2[CH:61]=[CH:60][C:59]([C:64]3[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[C:66]([F:72])[CH:65]=3)=[CH:58][C:57]=2[N:56]=1)[C@@H:10]([CH3:23])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(-c3ccc(C#N)c(F)c3)ccc2[nH]1
Temperature: 0 °C

Procedure:
To a solution of (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3-methyl-4-oxobutanoic acid (Preparation 66, 713 mg, 2.11 mmol) in DMF (15 mL) was added NMM (267 mg, 2.64 mmol) and the mixture was cooled to 0° C. HATU (871 mg, 2.29 mmol) was added and the reaction stirred warming to room temperature for 2 hours. 3′,4′-diamino-3-fluoro-[1,1′-biphenyl]-4-carbonitrile (Preparation 81, 400 mg, 1.76 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 20-40% EtOAc in heptanes. The residue was dissolved in AcOH (10 mL) and heated to 40° C. for 2 days. The reaction was cooled and concentrated in vacuo, azeotroping with DCM to afford a foam. The residue was purified using silica gel column chromatography eluting with DCM:EtOAc 94:6 to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH:38]1[CH2:41][CH:40]([NH:42]C(=O)OC(C)(C)C)[CH2:39]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CC(O)C>[NH2:42][CH:40]1[CH2:41][N:38]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:20][CH:19]=3)=[O:16])=[CH:4][N:3]=2)[CH2:39]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncc(F)c2)C1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
2-Chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Stage 236.1, 70 mg, 0.160 mmol) and DIPEA (0.070 mL, 0.4 mmol) were added to a vial with iPrOH (1 mL). tert-Butyl azetidin-3-ylcarbamate (70.2 mg, 0.4 mmol) was added. The mixture was stirred at 110° C. for 5 h. tert-Butyl azetidin-3-ylcarbamate (35 mg) was added and the RM was stirred for further 5 h at 110° C. The RM was treated with citric acid 10% (10 mL) and extracted with EtOAc. The combined extracts were washed with an aq. sat. solution of NaHCO3 (10 mL) and with brine (2×10 mL), dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to afford the crude product that was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 9:1). The resulting intermediate (33 mg, 0.054 mmol) was dissolved in DCM (1 mL). TFA (0.167 mL, 2.170 mmol) was added and the RM was stirred for 2 h at RT. The RM was treated sat. aq. Na2CO3 (20 mL) and extracted with DCM. The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a crude product that was purified by preparative HPLC. Fractions containing product were combined and treated with 100 mg Na2CO3 and the MeCN was removed. The aq. residue was extracted with DCM (3×10 mL) and the combined extracts were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to afford the title product as a white foam. HPLC (Condition 10) tR=5.77 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=448.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.36 (dd, J=8.60, 5.47 Hz, 2H) 3.56-3.68 (m, 1H) 3.84 (t, J=7.82 Hz, 2H) 7.35 (d, J=8.99 Hz, 2H) 7.85 (m, J=9.40 Hz, 3H) 8.06 (d, J=2.35 Hz, 1H) 8.53 (s, 1H) 8.62 (d, J=2.74 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 10.20 (s, 1H).