Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([C:10]([N:12]([CH2:14][C:15]2([OH:22])[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH3:13])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[OH-].[Na+]>CS(C)=O>[CH3:21][N:18]1[CH2:19][CH2:20][C:15]2([CH2:14][N:12]([CH3:13])[C:10](=[O:11])[C:9]3[CH:8]=[CH:7][CH:6]=[N:5][C:4]=3[O:22]2)[CH2:16][CH2:17]1
Reactant: CN1CCC(O)(CN(C)C(=O)c2cccnc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN1CCC2(CC1)CN(C)C(=O)c1cccnc1O2
Temperature: 70 °C

Procedure:
To a stirred suspension of 6.7 g (0.168 mole) of 60% sodium hydride/mineral oil in 500 ml of dimethylsulfoxide was added 50 g (0.168 mole) of 2-chloro-N-(4-hydroxy-1-methyl-4-piperidinylmethyl)-N-methyl-3-pyridinecarboxamide and the mixture was heated to 70° C. for 20 hr. An equal volume of dilute sodium hydroxide was added and the solution was extracted twice with methylene chloride. The combined methylene chloride solution was extracted 3 times with water followed by 3 extractions with dilute hydrochloric acid. The acid layers were combined, made basic with concentrated sodium hydroxide, and extracted 3 times with methylene chloride. The combined methylene chloride extract was dried over sodium sulfate and concentrated. Yield of residue was 23 g (52%).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:26][CH2:27]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC2CCOCC2)[nH]n1
Yield: 43 %

Procedure:
As described for example 1b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using 4-aminotetrahydropyran instead of morpholine, to the title compound (52 mg, 43%), which was obtained as a colorless oil. MS: m/e=383.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26])(=[O:22])[CH3:21]>>[C:20]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:26])(=[O:22])[CH3:21]
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Product: CC(=O)OC(C)(C)C(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and 2-acetoxyisobutyryl chloride. m.p.: 162-165° C. 1H-NMR (CDCl3) δ: 10.78 (1H, br s), 8.36 (1H, d, J=9.2 Hz), 8.28 (1H, br s), 7.85-7.76 (2H, m), 7.68-7.53 (3H, m), 7.26 (1H, d, J=1.8 Hz), 7.08 (1H, dd, J=1.8, 9.2 Hz), 2.21 (3H, s), 1.75 (6H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:10][C@@H:11]2[C@@H:15]([OH:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[CH:5][CH:4]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:10][C@@H:11]2[C@@H:15]([O:16][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2OS(C)(=O)=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-(bis(4-methoxyphenyl)(phenyl)methoxy)-4-hydroxypyrrolidine-1-carboxylate (3.50 g, 6.92 mmol) and DMAP (4.23 g, 34.61 mmol) in dichloromethane (60 mL) at 0° C. in an ice bath was added methanesulfonyl chloride (2.69 mL, 34.61 mmol) dropwise. The resulting mixture was stirred at ambient temperature for 1 hour, cooled to 0° C. in an ice bath and quenched with water (15 mL). The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution (60 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give (3S,4S)-tert-butyl 3-(bis(4-methoxyphenyl)(phenyl)methoxy)-4-(methylsulfonyloxy)pyrrolidine-1-carboxylate (4.01 g, 99%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17][C:16]=1[N:22]([CH3:39])[C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:25]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17][C:16]=1[N:22]([CH3:39])[C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[C:26]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:25]=1
Reactant: Cc1cc(-c2ccccc2OCc2ccccc2)c(N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2O)c(N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Reaction time: 5 h

Procedure:
To a solution of N-(4-(2-(benzyloxy)phenyl)-6-methylpyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (1.63 g, 2.94 mmol) in MeOH (16 mL) and EtOAc (16 mL) was added Pd on carbon (10%, 200 mg, 2.94 mmol) under argon atmosphere. The reaction was evacuated and purged with hydrogen. The reaction was stirred for 5 hours at 1.7 bar under hydrogen atmosphere. The reaction mixture was filtered over dicalite. The filtrate was concentrated under vacuum and the compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (1.367 g, 100%). MS (ESI): m/z=465.109 [M+H]+.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([Zn]CC)[CH3:10]>>[C:2]1([C@H:1]([OH:8])[CH2:9][CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC[Zn]CC
Product: CC[C@@H](O)c1ccccc1

Procedure:
Reaction of benzaldehyde with diethylzinc in the presence of the polymer of Example 1 to give (R)-1-phenyl-1-propanol. The polymer of Example 1 (28 mg, 0.05 mmol based on the 2,2'-substituted biphenyl subunit) and diethylzinc (0.14 mL, 1.3 mmol) were added to a Schlenk flask containing toluene (10 mL) (dried with Na and degassed with N2), under N2 and at room temperature, to form an organozinc species. After ca. 15 min, the flask was cooled to 0° C. and benzaldehyde (0.1 mL, 1 mmol) was added in a dropwise manner. Stirring was continued at this temperature for 10 h. The 1H NMR spectrum of the crude mixture showed 100% conversion with no side product. The reaction was then quenched at 0° C. with the addition of 1N HCl and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with brine until pH 7 and then dried over anhydrous Na2SO4. Concentration in vacuum gave a pale yellow oil, which upon treatment with MeOH (20 mL) precipitated the polymer. The filtrate was concentrated and purified by column chromatography on silica gel (eluent: EtOAc/hexanes 1/4) to afford (R)-1-phenyl-1-propanol as a colorless liquid (122 mg, 89%). 1H NMR (270 MHz, CDCl3) δ 0.91 (t, J=7.4, 3H), 1.78 (dq, J=7.3, 6.4, 2H), 1.89 (br, 1H), 4.58 (t, J=6.5, 1H), 7.25-7.37 (m, 5H) . [α]D =42.91 (c=2.44, CHCl3). The ee value was determined to be 92.2% on GC with a chiral column (β-Dex capillary column, Supelco Company). The recycled catalyst showed the similar reactivity and the same ee for the product.
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[CH3:12][O:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:15]=1[CH3:24].C(OCC)(=O)C>ClC1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:12][O:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:15]=1[CH2:24][Br:1]
Reactant: COc1c([N+](=O)[O-])ccc(Cl)c1C
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: COc1c([N+](=O)[O-])ccc(Cl)c1CBr
Reaction time: 1 h
Yield: 181.8 %

Procedure:
A mixture of 5.8 g (20.0 mmol) of 1,3-dibromo-5,5-dimethylhydantoin and 0.5 g of azobisisobutyronitrile was added in portions at 110° C. to a solution of 8.0 g (40.0 mmol) of 2-methoxy-6-chloro-3-nitrotoluene from Example 11aα) in 50 ml of chlorobenzene. After 1 h, a mixture of 3.0 g (10 mmol) of 1,3-dibromo-5,5-dimethylhydantoin and 0.2 g of azobisisobutyronitrile was again added. After a further 1.5 h, the mixture was allowed to cool, and 500 ml of ethyl acetate were added to the reaction solution. The resulting mixture was washed once each with satd Na2SO3 solution, Na2CO3 solution, and NaCl solution, dried (MgSO4), and concentrated. 10.2 g of the title compound resulted in the form of an amorphous powder.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:8]1[CH:29]=[CH:28][C:11]([O:12][CH2:13][C:14]2([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:16][CH2:15]2)=[C:10]([O:30][CH3:31])[CH:9]=1)(=[O:7])[CH3:6]>CC(OC(C)=O)=O>[C:5]([C:8]1[C:29]([N+:1]([O-:4])=[O:2])=[CH:28][C:11]([O:12][CH2:13][C:14]2([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:16][CH2:15]2)=[C:10]([O:30][CH3:31])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(C)=O)ccc1OCC1(NC(=O)OCc2ccccc2)CC1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A solution of HNO3 (65%, 3 mL) in Ac2O (2 mL) at 0° C. was slowly added with a suspension of the compound of Example 1 (1.1 g, 2.9 mmol) in Ac2O (3 mL). After stirring at 0° C. for 2 h, the reaction mixture was poured into 50 mL of ice/water and the precipitate was recovered by filtration. The resulting yellow solid was recrystallized with 95% EtOH (5 mL) to give 1-[(4-acetyl-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane (0.69 g, yield: 56%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][C@@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[C@@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=1
Reactant: Cc1ccc(-c2nccs2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-c2nccs2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(thiazol-2-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 475 [M+1]+.
Reaction SMILES: C1C=CC=CC=1.II.[C:9]1([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22][CH2:21]3)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH:30](C)[C:31]([O:33][CH2:34]C)=[O:32]>O.[Zn]>[CH3:34][O:33][C:31](=[O:32])[CH2:30][C:24]1([OH:28])[C:25]2[C:20](=[CH:19][C:18]([S:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)(=[O:17])=[O:16])=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: II
Agent: [Zn]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)CC1(O)CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution/suspension of anhydrous benzene (25 mL), powdered Zinc metal (0.505 g, 7.72 mmol), I2 (0.01 g) and 6-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one was stirred for 10 minutes at room temperature. Ethyl bromopropionate (0.784 mL, 1.18 g, 7.07 mmol) was added and the reaction mixture was heated to reflux for 2.5 hours. The reaction mixture was allowed to cool, diluted with 300 mL of water and extracted twice with 250 mL of EtOAc. The combined organic layers were washed with water and saturated brine, dried (MgSO4) and evaporated under reduced pressure to yield (6-benzenesulfonyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid methyl ester. MS: 375 (M+H)+.
Reaction SMILES: [N:1]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].[Cl:18][CH2:19][C@H:20]([OH:22])[CH3:21].B(F)(F)F.CCOCC>ClCCl>[CH2:11]([O:10][C:8]([NH:1][C@H:2]([CH2:3][O:22][CH:20]([CH3:21])[CH2:19][Cl:18])[C:4]([O:6][CH3:7])=[O:5])=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@@H](O)CCl
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H](COC(C)CCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
To a 100 mL flask was added 1-benzyl 2-methyl aziridine-1,2-dicarboxylate (1 g, 4.25 mmol), dichloromethane (12 mL), (R)-1-Chloro-2-propanol (0.76 mL, 8.50 mmol), and boron trifluoride diethyl etherate (0.05 mL, 0.398 mmol). The mixture was stirred at room temperature for 15 minutes Solvent was removed in vacuo and the residue purified on silica gel eluting with Hexanes-EtOAc (0-50%) to give (R)-methyl 2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoate (583 mg, 41%). MS [M+H] found 330.2.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27]C=C)([CH3:20])[C@@H:18]([O:30]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.[F:38][C:39]([F:60])([C:56]([F:59])([F:58])[F:57])[CH2:40][CH2:41][CH2:42][CH:43]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]=[CH2:55])[C:44]([O:46]CC)=[O:45]>>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:43]([CH2:42][CH2:41][CH2:40][C:39]([F:38])([F:60])[C:56]([F:57])([F:58])[F:59])[C:44]([OH:46])=[O:45])([CH3:20])[C@@H:18]([OH:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: C[C@]12C[C@H](CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10), 9(11)-tetraene prepared in Example 20 and ethyl 2-(4,4,5,5,5-pentafluoro-pentyl)-8-nonenoate prepared separately, the same procedure as shown in Example 20 was repeated to give 10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9][N:8]=1.Br.O>C(O)(=O)C>[C:17]1([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH2:6])=[N:8][N:9]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(CNc2nnc(-c3ccccc3)c3ccccc23)c(OC)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Nc1nnc(-c2ccccc2)c2ccccc12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In a 150 mL sealed tube, dissolved N-(2,4-dimethoxybenzyl)-4-phenylphthalazin-1-amine (3.00 g, 8.1 mmol) in acetic acid (40 mL). Hydrobromic acid (48% aqueous) (2.6 mL, 24 mmol) was added and the tube was stirred at 90° C. for 3 h. The solution was cooled to RT, and slowly poured into water, which caused a pink solid to crash out. The solid was filtered and rinsed with water. The product containing filtrate was slowly poured into saturated sodium carbonate. The aqueous phase was extracted with DCM, washed twice with water, dried with Na2SO4, filtered through fritted funnel, and concentrated to yield 4-phenylphthalazin-1-amine as light yellow solid. MS [M+H]=222; Calc'd 221.3 for C14H11N3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=2)[C:8]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>O1CCCC1.O>[CH2:31]([N:33]([CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=2)[C:8]1=[O:21])[CH2:34][CH3:35])[CH3:32]
Reactant: CCNCC
Reactant: COC(=O)c1ccc2ccn(Cc3cccc(CBr)c3)c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)Cc1cccc(Cn2ccc3ccc(C(=O)OC)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of methyl 2-[3-(bromomethyl)benzyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.10 g, 0.26 mmol) in tetrahydrofuran (7 mL) was added cesium carbonate (0.25 g, 0.78 mmol) and diethylamine (40 μL, 0.39 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% MeOH/DCM) to afford methyl 2-{3-[(diethylamino)methyl]benzyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (71 mg, 72%). LC-MS: (FA) ES+ 379.
Reaction SMILES: [F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[OH:11][C:12]1[N:17]=[C:16]([CH:18]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[C:26]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]4=[O:37])=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)[CH:15]=[CH:14][CH:13]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].O>C(#N)C>[F:1][CH:2]([F:10])[O:11][C:12]1[N:17]=[C:16]([CH:18]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[C:26]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]4=[O:37])=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCCN1c1ncccc1CCN1CCC(c2cccc(O)n2)C1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCCN1c1ncccc1CCN1CCC(c2cccc(OC(F)F)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
2,2-Difluoro-2-(fluorosulfonyl)acetic acid (9.72 mg, 0.054 mmol, 1 eq) is added slowly, under stirring, to a mixture of 1-(3-{2-[3-(6-hydroxypyridin-2-yl)pyrrolidin-1-yl]ethyl}pyridin-2-yl)piperidin-2-one a16-1 (20 mg, 0.054 mmol, 1 eq) and dry sodium sulfate (0.78 mg, 0.005 mmol, 0.1 eq) in dry acetonitrile (400 μl). The reaction is stirred for 2 h at room temperature, then water (100 μl) is added. The resulting solution is concentrated in vacuo. The residue is purified by basic reverse phase chromatography (gradient: H2O/acetonitrile/NH4OH from 50/50/0.1 to 20/80/0.1) to afford 9.4 mg of 1-[3-(2-{3-[6-(difluoromethoxy)pyridin-2-yl]pyrrolidin-1-yl}ethyl)pyridin-2-yl]piperidin-2-one 109.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([NH:19][N:20]=[C:21]([CH3:23])[CH3:22])=[O:18])=[N:9]2)=[N:6][CH:7]=1.[CH3:24][C:25](C)=[O:26].CCCCCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:14])[F:15])=[CH:11][C:10]([C:17]3[O:18][C:21]([CH3:23])([CH3:22])[N:20]([C:25](=[O:26])[CH3:24])[N:19]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: CC(C)=NNC(=O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Reactant: CC(C)=O
Solvent: CCCCCC
Product: CC(=O)N1N=C(c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)OC1(C)C
Temperature: 25 °C
Yield: 72 %

Procedure:
Step-2: 1-(5-Bromopyridin-2-yl)-N′-(propan-2-ylidene)-5-(trifluoromethyl)-1H-pyrazole-3-carbohydrazide: A solution of step-1 intermediate (1.0 g, 2.86 mmol) in acetone: hexane (1:1, 12 mL) was stirred at 70° C. for 3 h. The reaction was then cooled to room temperature and the solvent was evaporated under vacuum to afford 800 mg (72%) of the title compound as white solid. ESI-MS (m/z) 390, 392 [(MH)+, Br79,81].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)[CH:9]=[O:10].[CH3:12][O:13][C:14]([C:16]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](C(O)=O)[N:18]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[N:17]=1)=[O:15]>ClCCl>[C:9]([C:19]1[N:18]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[N:17]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[C:20]=1[N+:21]([O-:23])=[O:22])(=[O:10])[NH2:8]
Reactant: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.2 mL, 13.76 mmol) and N,N-dimethylformamide (39 μL) were added to a solution of the carboxylic acid of Step 2 (1.33 g, 4.63 mmol) in dichloromethane (20 mL) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped from dichloromethane (3×50 mL). The product was dissolved in tetrahydrofuran (50 mL), cooled in an ice bath, treated with 0.88 ammonia solution (10 mL) and stirred for 18 hours at room temperature. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (200 mL) and water (50 mL). The organics phase was dried over magnesium sulphate and concentrated in vacuo to yield the title product.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.CCN(CCCC(N[C:25]1[CH:26]=[C:27](/C=C/C2C=CC=CC=2Cl)[N:28]=[C:29]2[CH:34]=[C:33](Cl)[CH:32]=[CH:31][C:30]=12)C)CC.C([O-])=O.[NH4+]>CO.[Pd]>[N:28]1[C:29]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[C:26]([NH:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=2)[CH:27]=1
Reactant: CCN(CC)CCCC(C)Nc1cc(/C=C/c2ccccc2Cl)nc2cc(Cl)ccc12
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: FC(F)(F)c1ccc(CCNc2cnc3ccccc3c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of 10.4 mmol 4-(trifluoromethyl)phenylacetonitrile (commercially available) and 3.5 eq. aminoquinoline in MeOH (10 mL) was treated with ammonium formate (5 eq.) and 10% Pd/C (100 mg) and stirred at 80° C. for 2 h. Filtration, concentration and purification by chromatography (SiO2, CH2Cl2/MeOH) afforded the title compound (73%) as a yellow oil. MS m/e: 317.1 [M+H]+.
Reaction SMILES: CO[C:3](=[O:16])[C:4]([CH2:9][NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH2:7][CH3:8])[CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([N+:31]([O-])=O)=[CH:26][N:25]=1>CC(C)=O.C(O)(=O)C.[Fe]>[Cl:23][C:24]1[N:29]=[C:28]2[C:27]([NH:31][C:3](=[O:16])[C:4]([CH2:5][CH3:6])([CH2:7][CH3:8])[CH2:9][N:10]2[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:26][N:25]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCC(CC)(CNC1CCCC1)C(=O)OC
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCC1(CC)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
To a solution of methyl2-[(cyclopentylamino)methyl]-2-ethyl-butanoate (Intermediate 252; 7.1 g, 31.3 mmol) in acetone (150 mL) was added potassium carbonate (5.3 g, 38.0 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 6.1 g, 31.3 mmol). The black mixture was stirred at room temperature for 18 hours. The reaction was filtered and the solvent removed in vacuo to yield a black gum, which was dissolved in acetic acid (175 mL) and iron (7.0 g, 125 mmol) added and the reaction heated at 80° C. overnight. The resulting solution was filtered and the solvent removed in vacuo, the black solid/gum was quenched with water (75 mL) and to this was added sodium carbonate until basic, the resultant black emulsion was filtered through a pad of celite. The obtained mixture was extracted with DCM (3×150 mL), dried and the solvent removed in vacuo to yield a black solid. This was passed through a bond elute column (50 g) eluting with 0-1% MeOH in DCM to afford a brown solid, which was triturated with diethyl ether to yield the title compound as a white solid (3.05 g, 30%)