Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([O:13][C@H:14]([C@@H:43]([NH:51][C:52](=[O:71])[C@@H:53]([N:58]1[CH2:62][CH2:61][N:60]([CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:59]1=[O:70])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:15][C@@H:16]([NH:30][C:31](=[O:42])[C@H:32]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:33][C:34]([O:36][CH3:37])=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:19]=1)=[O:12])[CH3:10])=O)(C)(C)C.Cl>ClCCl.O1CCOCC1>[NH2:8][C@@H:9]([CH3:10])[C:11]([O:13][C@H:14]([C@@H:43]([NH:51][C:52](=[O:71])[C@@H:53]([N:58]1[CH2:62][CH2:61][N:60]([CH2:63][C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:59]1=[O:70])[C:54]([CH3:55])([CH3:57])[CH3:56])[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:15][C@@H:16]([NH:30][C:31](=[O:42])[C@@H:32]([NH:33][C:34]([O:36][CH3:37])=[O:35])[C:38]([CH3:39])([CH3:40])[CH3:41])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][CH:23]=1)=[O:12]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)[C@H](C)NC(=O)OC(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)[C@H](C)N)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Example 193A (0.098 g, 0.037 mmol) in dichloromethane (1.0 mL) at room temperature was added a solution of HCl in dioxane (0.13 mL, 4 N), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated to give the title compound as the bis hydrochloride salt (0.089 g). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.88 (s, 9 H), 0.91 (s, 9 H), 1.57 (d, J=7.4 Hz, 1 H), 1.69-1.74 (m, 2 H), 2.27 (q, J=9.6 Hz, 1 H), 2.53-2.56 (m, 2 H), 2.72-2.85 (m, 3 H), 2.94 (q, J=8.8 Hz, 1 H), 3.17-3.24 (m, 1 H), 3.46 (s, 3 ), 3.87 (d, J=9.9 Hz, 1 H), 4.14 (s, 1 H), 4.19-4.37 (m, 4 H), 4.31 (s, 2 H), 4.60-4.70 (m, 1 H), 5.14 (t, J=7.4 Hz, 1 H), 6.66 (d, J=9.6 Hz, 1 H), 7.00-7.08 (m, 3 H), 7.08-7.16 (m, 2 H), 7.26-7.47 (m, 8 H), 7.90-7.99 (m, 6 H), 8.46-8.57 (m, 3 H), 8.67-8.68 (m, 1 H).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(Nc1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(Nc2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg) obtained in Step C of Example 12 in toluene (20 ml) were added 4-aminobenzenesulfonamide (212 mg), tris(dibenzylideneacetone)dipalladium (37.6 mg), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)(47.5 mg) and cesium carbonate (669 mg), and the mixture was heated overnight with reflux under nitrogen atmosphere. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed successively with hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a residue (105 mg) containing 4-((1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)benzenesulfonamide. To a solution of the obtained residue (102 mg) in acetonitrile (10 mL) were added sodium iodide (64.8 mg) and chloro(trimethyl)silane (0.219 mL), and the mixture was stirred at 60° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was washed successively with water and ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (68.1 mg).
Reaction SMILES: [CH2:1]([S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O)[C:2]#[CH:3].[ClH:12].O1CCOCC1>O1CCOCC1>[Cl:12][CH2:3][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:4][CH:1]=1
Reactant: C#CCS(=O)c1ccccc1
Reactant: Cl
Solvent: C1COCCO1
Product: ClCc1csc2ccccc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
In 50 mL of 1,4-dioxane, was dissolved 5.02 g (30.6 mmol) of the compound obtained in Example 12. The resulting solution was heated at 100° C. After 5 hours and 30 minutes, the solution was cooled to keep the internal temperature of the reaction system at 10° C. To the cooled solution, was subsequently added 8.42 mL (33.7 mmol) of a 4 M hydrogen chloride-dioxane solution. The obtained mixture was allowed to stand at room temperature. After 15 minutes, the reaction liquid was concentrated and dissolved in 50 mL of ethyl acetate. The resulting solution was washed with 40 mL of water. The organic layer was dried with magnesium sulfate. After concentrating, the concentrate was redissolved in 50 mL of ethyl acetate in order to remove the dioxane. The obtained solution was washed with 40 mL of water three times. The organic layer was dried over magnesium sulfate and vacuum concentrated to provide 5.18 g of 3-(chloromethyl)-benzo[b]thiophene. The yield was 93%.
Reaction SMILES: B(F)(F)F.CSC.[C:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:37][C:38]#[N:39])[C:27]=3[C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([O:35]C)[CH:29]=3)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH3:9]>ClCCl>[C:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:37][C:38]#[N:39])[C:27]=3[C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([OH:35])[CH:29]=3)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: COc1cc(C)cc(-c2c(-c3ccc(-c4cccc(C(C)=O)c4)nc3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)c1cccc(-c2ccc(-c3cnn(CC#N)c3-c3cc(C)cc(O)c3)cn2)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (50.7 mg, 0.12 mmol) prepared in Example 71 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (35 mg, 71%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([C@H:22]4[CH2:33][CH2:32][C:24]5([NH:28][C:27](=O)[N:26](C)[C:25]5=[O:31])[CH2:23]4)=[CH:18][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>O1CCOCC1>[NH2:28][C:24]1([C:25]([NH:26][CH3:27])=[O:31])[CH2:32][CH2:33][C@H:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[N:12]=[C:11]([C:8]4[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=4)[O:15][N:14]=3)=[CH:17][CH:18]=2)[CH2:23]1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc([C@H]4CCC5(C4)NC(=O)N(C)C5=O)cc3)no2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)C1(N)CC[C@H](c2ccc(-c3noc(-c4ccc(CC(C)C)cc4)n3)cc2)C1
Yield: 35 %

Procedure:
(7S)-7-(4-(5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (0.052 g, 0.117 mmol) was taken up in dioxane (1.0 ml). To this was added sodium hydroxide (1.0 ml, 2.000 mmol) as 2M solution. The resulting suspension was heated to 120° C. for about 70 hours, during which more sodium hydroxide solution was added to push the hydrolysis to completion. Heating was stopped and the reaction mixture was concentrated in vacuo. The resulting material was brought up in 1-2 mL DMSO and filtered. The filtrate was purified on a Prep HPLC system using 30-100% acetonitrile in 50 mM NH4OAc buffer at 21 mL/min to yield (3S)-1-amino-3-(4-(5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-N-methylcyclopentanecarboxamide (0.017 g, 0.041 mmol) as off-white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)=[O:6])=[N+]=[N-].CO.[ClH:20]>[H][H].[Pd]>[ClH:20].[NH2:1][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(C(=O)CN=[N+]=[N-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ccc(C(=O)CN)cc1
Reaction time: 1 h

Procedure:
To a solution of 2-azido-4′-ethoxycarbonylactophenone (1.44 g), methanol (41.3 ml) and conc. hydrochloric acid (1.38 ml) was added 10% palladium-activated carbon (73 mg), and stirred for 3 hours in hydrogen atmosphere at 2.8 atm. After 1 hour, the reaction mixture was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in diisopropyl ether, and collected by filtration to give 2-amino-4′-ethoxycarbonylacetophenone hydrochloride (1.40 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:36][CH2:37][O:38][CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:36][CH2:37][O:38][CH3:39])[CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COCCBr
Reactant: CCCCc1nc(C)n(-c2cccc(O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cccc(OCCOC)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[4-butyl-1-(3-hydroxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.69 g) and 1-bromo-2-methoxyethane (0.43 mL) in N,N-dimethylformamide (7 mL) was added cesium carbonate (0.99 g), and the mixture was stirred at 70° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.69 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH3:23][Sn](C)(C)C>CN(C)C=O.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>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH3:23])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2nc(-c3ccccc3)sc2c1O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (301 mg, 0.80 mmol), tetramethyltin (442 μL, 3.18 mmol) and bis(triphenylphosphine)palladium(II) dichloride (56 mg, 0.08 mmol) in dimethylformamide (5 mL) was stirred at 130° C. for 30 min before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (218 mg): 1H NMR (CDCl3, 200 MHz): δ=11.39 (s, 1H), 8.09 (m, 2H), 7.50 (m, 3H), 4.57 (q, J=7.0 Hz, 2H), 2.96 (s, 3H), 1.52 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([N:11]1[CH2:19][C@@H:18]([OH:20])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(#N)C.[CH3:24][N:25]=[C:26]=[O:27]>C(N(CC)CC)C>[C:1]([N:11]1[CH2:19][C@@H:18]([O:20][C:26]([NH:25][CH3:24])=[O:27])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CN=C=O
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)O[C@H]1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 86 %

Procedure:
To a stirred solution of 5.4 g. (0.019 mole) of N-carbobenzyloxy-cis-4-hydroxy-L-proline, methyl ester, in 120 ml. of acetonitrile is added 5.4 ml. of triethylamine, followed by 5.4 ml. of methyl isocyanate. After keeping overnight at room temperature and refluxing for two hours, the reaction mixture is worked up as in Example 1c to give 5.6 g (86%) of a pale yellow viscous oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=O.OC(C(F)(F)F)=O.[NH2:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40].C[O-].[Na+]>CCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:6][C:5]=1[C:3]([NH:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40])=[O:2]
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1nc(-c2ccccc2)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(-c2ccccc2)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 74.1 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-1-phenyl-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.13 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (125 mg, 0.54 mmol) and NaOMe (58 mg, 1.08 mmol) in EtOH (2 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water (30 mL) and EtOAc (30 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 44 mg of the title compound as a yellow solid. MS: (+) m/z 457.26 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH:2]([CH3:4])[CH3:3].[CH3:18][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:18])=[O:10])=[CH:7][C:6]=1[C:14]([F:15])([F:16])[F:17])[CH:2]([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(CC(C)C)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To 4-isobutyl-3-(trifluoromethyl)benzoic acid (Preparation 23A, 0.55 g, 2.234 mmol) in dichloromethane (5 mL) and methanol (2.00 mL) was added trimethylsilyldiazomethane (1.452 mL, 2.90 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Excess trimethylsilyldiazomethane was quenched by the slow addition of acetic acid (˜0.5 ml) at room temperature. The reaction mixture was concentrated and partitioned between ethyl acetate (20 mL) and sat. aq. sodium bicarbonate (10 mL). The ether layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated. The resulting dark oil was subjected to silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield an oil. The oil was azeotroped with THF (2×5 mL) and dried under high vacuum to yield methyl 4-isobutyl-3-(trifluoromethyl)benzoate (0.52 g, 1.998 mmol, 89% yield) as a clear liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7](Cl)[C:6]=2[C:13]#[N:14].[NH3:15]>CO>[NH2:15][C:7]1[C:6]([C:13]#[N:14])=[C:5]2[C:10]([CH:11]=[C:2]([Cl:1])[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: N
Reactant: N#Cc1c(Cl)ccc2cc(Cl)cnc12
Solvent: CO
Product: N#Cc1c(N)ccc2cc(Cl)cnc12
Yield: 53 %

Procedure:
110 g of 3,7-dichloro-8-cyanoquinoline, 500 ml of methanol and 500 ml of liquid ammonia were heated at 150° C. for 10 hours in an autoclave. The pressure was let down, after which the discharged mixture was filtered under suction, and the solid was recrystallized from methylglycol, in the presence of active charcoal. 54 g of 7-amino-3-chloro-8-cyanoquinoline of melting point 246° C. were obtained. Yield: 53% of theory.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([O-])=[O:37])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:45]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:45][C:36](=[O:37])[CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C:25]1[C:24]([C:39]([F:40])([F:41])[F:42])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)=[CH:15][CH:16]=2)[N:26]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I27) (0.246 g, 0.416 mmol) was dissolved in dry THF (10 mL) and dry DMF (2 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.067 g, 0.50 mmol) and EDCI (0.096 g, 0.50 mmol) and N,N-diisopropylethylamine (0.290 mL, 1.66 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (0.160 g, 1.66 mmol) was added in one portion, and the reaction was stirred at room temperature for 45 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (70 mL) and sat. aq. NaHCO3 (70 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL), the combined organic layers were washed with water (70 mL), brine (70 mL), dried (MgSO4), filtered and concentrated in vacuo to give an off-white solid. The crude product was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-10% methanol in EtOAc) to give the title compound (I28) (0.186 g, 77% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.17 (s, 1H), 8.67 (s, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.44 (br s, 1H), 7.28-7.11 (m, 6H), 6.93 (br s, 1H), 4.02-3.89 (m, 2H), 3.50 (s, 2H), 3.15-3.07 (m, 2H), 3.06-2.98 (m, 2H), 2.89-2.67 (m, 2H), 2.61-2.51 (m, 1H), 1.88 (d, J=11.1 Hz, 1H), 1.74-1.55 (m, 2H), 1.50-1.35 (m, 10H). LCMS Method C: it 6.57 min; m/z 584.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34]O)[CH2:30][CH2:29]3)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1>>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][O:14][C:13]([C:7]4[CH:8]=[N:9][C:10]5[C:5]([CH:6]=4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)=[O:15])[CH2:30][CH2:29]3)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: COc1ccc2ncc(C(=O)O)cc2c1
Reactant: OC[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)cc2c1

Procedure:
The title compound is prepared as an off-white semisolid (24 mg, 26% yield) following Scheme 2 and in analogy to Example 28 using 6-methoxy-quinoline-3-carboxylic acid (40 mg, 0.19 mmol, 1.0 eq) and {trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-methanol (55 mg, 0.19 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4]([NH:10][NH2:11])[N:3]=1.[CH:12]1([CH2:17][C@H:18]([CH2:22][N:23]([CH:32]=[O:33])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19](O)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH:12]1([CH2:17][C@@H:18]([C:19]([NH:11][NH:10][C:4]2[C:5]([F:9])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=2)=[O:20])[CH2:22][N:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[O:33])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: NNc1nc(Cl)nc(Cl)c1F
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(Cl)c1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
2,4-Dichloro-5-fluoro-6-hydrazinopyrimidine (358 mg 1.817 mmol), (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (746 mg, 1.508 mmol), and HOAt (247 mg, 1.817 mmol) were dissolved in 15 mL of DMF. NMM (0.798 mL, 7.27 mmol) was added, followed by EDC (348 mg, 1.817 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide {(2R)-2-(cyclopentylmethyl)-3-[2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl}[(phenylmethyl)oxy]formamide (442 mg, 50%). LCMS: (M+H)+: 483.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:34]([NH:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[O:16])[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1)(=[O:36])[CH3:35]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCCC3)CC2)c1

Procedure:
Example 75 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.44 (s, 1H), 7.40–7.37 (m, 2H), 7.32–7.25 (m, 4H), 6.96 (d, 1H, J=7.2 Hz), 6.81 (br s, 1H), 3.30 (dd, 2H, J=5.6, 11.6 Hz), 2.94 (d, 2H, J=12.4 Hz), 2.49 (m, 1H), 2.34 (t, 4H, J=6.4 Hz), 2.20 (s, 3H), 1.99–1.81 (m, 6H), 1.72–1.55 (m, 10H); ESMS m/e: 496.2 (M+H)+.