Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([C@@:16]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=2)([NH:24][C:25](=[O:37])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C@:16]([C:11]2[CH:10]=[C:9]([CH:14]=[C:13]([F:15])[CH:12]=2)[O:8][CH2:7][C:6]([OH:45])=[O:5])([NH:24][C:25](=[O:37])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:34])([F:35])[F:36])[CH:27]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)COc1cc(F)cc([C@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2ccc(Cl)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1cc(F)cc([C@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.8 %

Procedure:
To a solution of (S)-tert-butyl-2-(3-(1-(5-chloropyridin-2-yl)-1-(4-fluoro-3-(trifluoromethyl)benzamido)-2-phenylethyl)-5-fluorophenoxy)acetate (27 mg, 0.04 mmol) in CH2Cl2 (1 mL) was added TFA (95 mg, 0.836 mmol). The mixture was stirred at room temperature for 2 h, and the solvent was removed to give (S)-2-(3-(1-(5-chloropyridin-2-yl)-1-(4-fluoro-3-(trifluoromethyl)benzamido)-2-phenylethyl)-5-fluorophenoxy)acetic acid as an white foam (25 mg, 100% yield). LCMS: RT=4.08 min [M+H] 591.46 (LCMS Method 1); 1H NMR (400 MHz, CDCl3) δ 3.69 (d, J=12.74 Hz, 1 H), 4.40 (d, J=13.18 Hz, 1 H), 6.53 (d, J=7.47 Hz, 3 H), 6.76 (d, J=9.23 Hz, 1 H), 6.91 (s, 1 H), 7.05 (t, J=7.47 Hz, 2 H), 7.15 (t, J=7.47 Hz, 7.25 −7.34 (m, 2 H), 7.78 (dd, J=8.57, 2.42 Hz, 1 H), 7.86 (ddd, J=8.68, 2.31, 2.20 Hz, 1 H), 7.91-7.98 (m, 1 H), 8.36 (d, J=2.20 Hz, 1 H), 9.30 (s, 1 H).
Reaction SMILES: O[NH:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[OH:12].CN(C)C=O.S(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3]([OH:13])=[N:2][O:12][C:5]=2[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NO)c1ccc(CO)cc1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Oc1noc2cc(CCl)ccc12
Reaction time: 2 h

Procedure:
In 50 mL of methylene chloride was suspended 10.0 g of N,2-dihydroxy-4-(hydroxymethyl)benzamide. To this, 0.21 mL of N,N-dimethylformamide was added. This was cooled and 8.36 mL of thionyl chloride was added dropwise under ice-cooling. After 2 hours of stirring under heating reflux, 13 mL of solvent was distilled off under atmospheric pressure. To the reaction mixture was added 13 mL of methylene chloride, 4.64 mL of pyridine was added dropwise at 20-30° C., and the results were stirred for 1 hour at the same temperature. After adding 20 mL of water and 50 mL of acetone, 50 mL of solvent was distilled off under atmospheric pressure, solids were filtered, and 6.45 g of 6-(chloromethyl)-1,2-benzisoxazol-3-ol in the form of a pale yellowish-white solid was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([S:14][CH2:15][C:16]#[N:17])[N:3]=1.[CH2:18]([NH2:28])[C:19]1[CH:27]=[CH:26][C:25]2[O:24][CH2:23][O:22][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:24]1[C:25]2[CH:26]=[CH:27][C:19]([CH2:18][NH:28][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:5]=[C:4]([S:14][CH2:15][C:16]#[N:17])[N:3]=3)=[CH:20][C:21]=2[O:22][CH2:23]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: N#CCSc1nc(Cl)cc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CCSc1nc(NCc2ccc3c(c2)OCO3)cc(-c2ccccc2)n1
Yield: 57.4 %

Procedure:
A stirred suspension of 19.5 g (0.075 mole) of (4-chloro-6-phenyl-2-pyrimidinylthio)acetonitrile, 11.3 g (0.074 mole) of piperonylamine and 7.95 g (0.075 mole) of sodium carbonate was heated under reflux in 250 ml of ethanol for six hours. The mixture was filtered and the filtrate was cooled in ice. The precipitate was collected and recrystallized from ethanol to give 16 g of product, mp. 140°-142°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>CS(C)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[CH:4][CH:5]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Reactant: C1CSCCN1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CN2CCSCC2)cc1

Procedure:
4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) was dissolved in DMSO (1 mL) and stirred for 1 h with thiomorpholine. The reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiomorpholinomethyl)benzamide. MS (Q1) 424.0 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(Cl)cc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 54.9 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0291 g, 0.0630 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0530 mL, 0.378 mmol) and 2,4-dichlorobenzenesulfonyl chloride (0.0436 g, 0.189 mmol) to obtain 4-(2,4-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0232 g. yield 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]=[O:15])[CH:9]=2)=[C:4]([CH3:16])[CH:3]=1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O1CCCC1>>[CH:17]1([CH:14]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:16])[O:12][C:11]=2[CH3:13])[OH:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(F)ccc1-c1cc(C=O)c(C)o1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1cc(C(O)C2CCCCC2)c(C)o1
Yield: 72 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-(4-fluoro-2-methylphenyl)-2-methyl-3-furaldehyde (2.6 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (18 mL) to give the title compound (2.6 g, 72%) as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[Na+].O.Cl.[CH3:10][CH:11]([CH3:15])[C:12]([NH2:14])=[NH:13]>C(OCC)C>[CH3:5][O:4][C:2]([NH:14][C:12](=[NH:13])[CH:11]([CH3:15])[CH3:10])=[O:3]
Reactant: CC(C)C(=N)N
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COC(=O)NC(=N)C(C)C
Yield: 86 %

Procedure:
165 parts of methyl chloroformate and 141.8 parts of sodium hydroxide in 590 parts of water are added via two inlets to 221 parts of 2-methylpropionamidine hydrochloride in 1,000 parts of diethyl ether, at from 25° to 30° C., in the course of 40 minutes, while stirring. The mixture is stirred at room temperature for one hour, and the organic phase is separated off. The aqueous phase is extracted again with 200 parts of diethyl ether, and the solvent is removed from the combined organic extracts to give 223 parts (86% of theory) of N-methoxycarbonyl-2-methylpropionamidine of melting point 127°-130° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44](=[O:46])[CH3:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([N:38]5[CH2:39][CH2:40][N:41]([C:44](=[O:46])[CH3:45])[CH2:42][CH2:43]5)=[CH:36][CH:37]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 116 °C
Reaction time: 48 h
Yield: 26 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (340 mg, 0.78 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (204 mg, 0.93 mmol) and trimethylsilyl chloride (TMSCl) (0.200 mL, 1.58 mmol) in n-butyl alcohol (8 mL) was heated at 116° C. overnight. More 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (204 mg, 0.93 mmol) was added. The mixture was then stirred at 116° C. for another 48 h. It was then purified by HPLC to give 1-(4-(4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone as a solid (126 mg).
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>>[F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:21][S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccc(OCC(F)F)nc1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)F)nc1
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (1.24 g, colorless oil) from 1-(6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone (1.0 g, 4.97 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[F:13][C:14]([F:41])([F:40])[C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:39]=[CH:38][C:23]([O:24][CH:25]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH:19]=1.Cl.[NH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:40][C:14]([F:13])([F:41])[C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:39]=[CH:38][C:23]([O:24][CH:25]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])=[O:35])=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH:19]=1
Reactant: COC(=O)CCN
Reactant: CCCC(Oc1ccc(-n2cnc(C(F)(F)F)c2)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(Oc1ccc(-n2cnc(C(F)(F)F)c2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) was added to a room temperature solution of (+/−)-4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzoic acid (80 mg, 0.20 mmol), methyl 3-aminopropanoate hydrochloride (28 mg, 0.20 mmol), 1-hydroxy-7-azabenzotriazole (30 mg, 0.22 mmol), and triethylamine (31 μL, 0.22 mmol) in dichloromethane (2 mL). The solution was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (20 mL) and washed with water, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give (+/−)-methyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzamido)propanoate (89 mg, 90%). 1H NMR (400 MHz, CDCl3, δ): 7.74-7.70 (m, 2H), 7.69-7.66 (s, 1H), 7.44-7.41 (m, 1H), 7.40-7.36 (m, 2H), 7.18-7.13 (m, 2H), 6.91-6.86 (m, 2H), 6.83-6.75 (m, 1H), 5.16-5.12 (m, 1H), 3.72-3.66 (m, 5H), 2.66-2.60 (m, 2H), 2.06-1.93 (m, 1H), 1.86-1.74 (m, 1H), 1.55-1.35 (m, 2H), 0.99-0.91 (m, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][CH:6]=1.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][CH:6]=1)([CH3:20])[CH3:19]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: N#Cc1cnccc1NCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCNc1ccncc1C#N)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 4-(2-hydroxy-ethylamino)-nicotinonitrile (500 mg, 3.07 mmol) and imidazole (250 mg, 3.68 mmol) in DMF (15 mL) was added triisopropylsilyl chloride (0.723 mL, 3.37 mmol). The reaction mixture stirred at room temperature for 2 hours. The mixture was then partitioned between ethyl acetate and water, the organic layer isolated and washed with brine, dried (Na2SO4), filtered and concentrated. The resultant residue was purified by flash chromatography (Si-PPC, pentane:ether, gradient 50:50 to 30:70) to provide the title compound as a white solid (753 mg, 77%). LCMS (method B): RT=2.92 min, M+H+=320.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:37]([NH:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C=Nc1ccccc1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(Nc1ccccc1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 67 %

Procedure:
The compound (0.15 g) obtained in Example 1 and phenyl isocyanate (0.074 ml) were reacted and treated in the same maimer as in the method described in Example 6 to obtain the title compound as colorless oil (0.12 g, 67%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[N:4]=1.[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:23][N:24]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:22])([F:1])[F:21])=[N:4]2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CNCCc1ccccc1
Product: CN(CCc1ccccc1)C(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid and N-methylphenethylamine using a similar procedure to that described for Example 2.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1([CH3:23])[O:22][CH2:21][CH2:20][NH:19][CH2:18]1>CC(O)C>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][O:22][C:17]([CH3:23])([CH3:16])[CH2:18]2)[C:11]=1[CH3:12]
Reactant: CC1(C)CNCCO1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: CC(C)O
Product: Cc1c(N2CCOC(C)(C)C2)nc2cc(F)cc(F)c2c1Cl
Temperature: 120 °C

Procedure:
2,4-dichloro-5,7-difluoro-3-methylquinoline (1.0 g, 4.03 mmol) and 2,2-dimethylmorpholine (0.46 mL, 4.03 mmol) were slurried in 2-propanol (10 mL) and heated in a microwave reactor at 120° C. for 5 h. The reaction was then concentrated to dryness and purified by column chromatography (hexanes:EtOAc, 1:0 to 1:1) to give 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2,2-dimethylmorpholine. 1H NMR (400 MHz, chloroform-d) δ ppm 7.31 (1H, ddd, J=9.7, 2.7, 1.5 Hz), 6.89 (1H, ddd, J=12.3, 8.9, 2.5 Hz), 3.93-3.98 (2H, m), 3.23-3.28 (2H, m), 3.10 (2H, s), 2.47 (3H, s), 1.37 (6H, s). Mass Spectrum (ESI) m/e=327.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([C@@H:10]1[CH2:13][CH2:12][N:11]1C(OC(C)(C)C)=O)=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([C@@H:10]1[CH2:13][CH2:12][NH:11]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)Nc1cnccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cnccn1)[C@@H]1CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (S)-tert-butyl 2-(pyrazin-2-ylcarbamoyl)azetidine-1-carboxylate (1.05 g, 3.77 mmol) in CH2Cl2 (40 mL) was added TFA (1.453 mL, 18.86 mmol). The reaction mixture was stirred at RT overnight and concentrated. The residue was used for the next step without purification. LC/MS [M+H]+: 179; Ret time (Method F): 0.29 min.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][C:23]=3[F:31])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:32][O:33][CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:29])[NH:36][CH2:35][CH2:34][O:33][CH3:32])=[CH:24][C:23]=3[F:31])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: COCCN
Reactant: Cc1c(Oc2ccc(C(=O)O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNC(=O)c1ccc(Oc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2C)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[6-(4-Carboxy-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (150 mg, 0.346 mmol), 2-Methoxy-ethylamine (31 mg, 0.41 mmol), HATU (157 mg, 0.42 mmol) and triethyl amine (70 mg, 0.7 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The mixture was purified through HPLC to provide Compound C122 (115 mg, 68%) as a solid. 1H NMR (MeOH-d4, 400 MHz) δ 1.22 (d, J=6.82 Hz, 6H), 1.71-1.74 (m, 2H), 1.97-2.00 (m, 2H), 2.16 (s, 3H), 3.34 (s, 3H), 3.35-3.39 (m, 2H), 3.53 (s, 4H), 3.71-3.74 (m, 2H), 4.81-4.84 (m, 1H), 5.33-5.36 (m, 1H), 7.30 (t, J=8.1 Hz, 1H), 7.66-7.69 (m, 2H), 8.09 (s, 1H). Exact mass calculated for C24H31FN4O6490.2, found 491.4 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH:16]1([CH2:19][NH2:20])[CH2:18][CH2:17]1>C(O)C>[CH:16]1([CH2:19][NH:20][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:18][CH2:17]1
Reactant: COC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CC1
Solvent: CCO
Product: COC(=O)Nc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
Following general procedure 2B: To methyl 4-fluoro-3-nitrophenylcarbamate (6.50 g, 30.35 mmol, from previous step) in 80% aqueous ethanol (100 mL) was added cyclopropanemethylamine (5.00 mL, 57,65 mmol) at room temperature. The reaction mixture was heated at 60° C. overnight. After the usual work up, the crude product, which precipitated out, was collected (8.21 g). MS (ESI) (M+H)+=266.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:13][C:14](=[O:29])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]=[N+]=[N-])[CH:17]=2)=[CH:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:13][C:14](=[O:29])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(OCCCN=[N+]=[N-])c3)C(=O)NC2=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3cccc(OCCCN)c3)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.2 %

Procedure:
To a solution of 3-(1-methylindol-3-yl)-4-[3-(3-azidopropyloxy)phenyl]-1H-pyrrole-2,5-dione (0.4 g, 1 mmol) in THF (20 mL) was added Ph3P (0.25 g, 1.1 eq.), followed by the H2O (0.017 mL). The resulting mixture was stirred at room temperature for 48 h and then concentrated in vacuo. The residue was purified on a silica gel column with 8% (10% NH4OH in methanol) in CH2Cl2 to give 3-(1-methylindol-3-yl)-4-[3-(3-aminopropyloxy)-phenyl]-1H-pyrrole-2,5-dione (0.35 g) which was converted to HCl salt and recrystalized to give 3-(1-methylindol-3-yl)-4-[3-(3-aminopropyloxy)phenyl]-1H-pyrrole-2,5-dione (0.21 g) as the HCl salt.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([F:36])=[C:32]([F:35])[CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[CH:20][N:19]=1>CN1C(=O)CCC1>[F:36][C:31]1[CH:30]=[C:29]2[C:34](=[CH:33][C:32]=1[F:35])[N:26]([C:24]([C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:23]=1)=[O:25])[CH2:27][CH2:28]2
Reactant: O=C(c1ccnc(Cl)c1)N1CCc2cc(F)c(F)cc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN1CCCC1=O
Product: O=C(c1ccnc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c1)N1CCc2cc(F)c(F)cc21

Procedure:
1.0 g (4.6 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.45 g (1.5 mmol) (2-chloro-pyridin-4-yl)-(5,6-difluoro-2,3-dihydro-indol-1-yl)-methanone were stirred in 4 mL of NMP for 4 h at 130° C. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]2[NH:21][CH2:20][C@@H:19]3[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:18]3[C:17]=2[CH:16]=1>>[CH3:26][O:25][C:23]1[C:22]2[NH:21][CH2:20][C@@H:19]3[CH2:27][NH:28][CH2:29][C@@H:18]3[C:17]=2[CH:16]=[C:15]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:13])([F:12])[F:1])[CH:24]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COc1cc(Br)cc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Product: COc1cc(-c2ccccc2C(F)(F)F)cc2c1NC[C@@H]1CNC[C@H]21

Procedure:
Following the procedures described in Example 12, except that 2-(trifluoromethyl)phenylboronic acid was used instead of phenylboronic acid, (±)-cis-tert-butyl 8-bromo-6-methoxy-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate from Example 11, Part A was converted into the title compound of Example 13. 1H NMR (CDCl3): δ 7.73 (d, 1H, J=7.7 Hz), 7.57-7.52 (m, 1H), 7.46-7.40 (m, 1H), 7.36 (d, 1H, J=7.4 Hz), 6.68 (s, 1H), 6.66 (s, 1H), 4.51 (broad s, 1H), 3.85 (s, 3H), 3.65-3.30 (overlapping m, 5H), 3.15-2.98 (m, 2H), 2.78-2.68 (m, 1H). LRMS (ES)+: 349.3 (M+H)+.