Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>C1(C)C=CC=CC=1>[CH3:20][C:3]([NH:2][C:28](=[O:31])[CH2:29][CH3:30])([CH:17]([CH3:18])[CH3:19])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2-Amino-2,3-dimethyl-N-(p-tolylsulfonyl)butyramide hydrochloride (1.2 g, 5.3 mol) is dissolved in 25 mL of toluene under N2. Then triethylamine (1.9 mL, 2.5 equivalents) is added, followed by immediate addition of propionyl chloride (0.55 mL, 6.36 mol). The reaction mixture is heated for one hour, and then solvents are removed under reduced pressure. The yellowish residue is recrystallized from EtOH/water, to yield the title product as a white solid having mp 166°-168° C.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.6 %

Procedure:
The suspension of 0.15 g (0.36 mmol) (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 146 mg (1.1 mmol) 4-methylphenylboronic acid, 0.13 g (0.72 mmol) copper(II) acetate and 0.12 mL (0.11 g, 1.43 mmol) pyridine in 5 mL dichloromethane was stirred for 3 days at room temperature. The volatile components were evaporated at a rotary evaporator and the residue was purified using flash chromatography on silica gel with dichloromethane:methanol (19:1 v/v) as eluant to give 89 mg (49%) of the desired compound as a colorless foam.
Reaction SMILES: CC(C)([O-:4])C.[K+].[CH2:7]([SH:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:14][O:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:17]>>[CH3:14][O:15][C:16]([CH:18]1[CH:22]([CH2:23][S:13][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:21][CH2:20][C:19]1=[O:4])=[O:17]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCS
Reactant: CCCCCCC(=O)OC
Agent: [K+]
Product: CCCCCCSCC1CCC(=O)C1C(=O)OC
Yield: 61.3 %

Procedure:
In accordance with the process of Example 17, potassium t-butoxide, (336 mg; 3 m mol), n-hexyl mercaptan (354 mg; 3 m mol) and 2-oxo-bicyclo 3.1.0!hexane-1-carboxylic acid methyl ester (463 mg; 3 m mol) were used to obtain 500 mg of 5-hexylthiomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:2]2[C:3]3[S:22][CH2:21][CH2:20][C:4]=3[N:5]=[C:6]([N:8]3[CH2:9][CH2:10][N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:12][CH2:13]3)[N:7]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(Nc2nc(N3CCN(c4ccccc4)CC3)nc3c2SCC3)c1

Procedure:
0.320 g (0.96 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V), 1.0 mL (9.5 mmol) of 3-chlorophenylamine, and 0.33 mL (1.92 mmol) of diisopropylethylamine are combined and the mixture is reacted for 0.5 hours at 130° C. in the microwave. Then the reaction mixture is combined with ethyl acetate and acidically extracted. The organic phase is dried and evaporated to dryness. The residue is combined with acetonitrile, water, and trifluoroacetic acid. The phase containing the product I is purified by chromatography through an RP column by HPLC (column: Microsorb, RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1% formic acid (A), water+0.13% formic acid (B)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].[CH2:23](O)[CH2:24][CH2:25][CH3:26].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:23]([O:22][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCO
Reactant: CCOC(=O)c1c(O)c2cc(F)ccc2c(=O)n1CC(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)OCC)n(CC(C)C)c(=O)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a solution of ethyl 6-fluoro-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (9.22 g, 30 mmol), 1-butanol (3.3 mL, 45 mmol) and tributylphosphine (14.9 mL, 60 mmol) in tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (15.14 g, 60 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give ethyl 4-butoxy-6-fluoro-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (9.25 g, 84.9%) as an oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O[CH:8]=[N:9][CH:10]1[C:14]([C:15]([O:17]CC)=O)=[CH:13][C:12](C)([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[S:11]1)C.[CH2:26](O)C>>[OH:2][CH2:1][CH2:3][N:4]1[C:15](=[O:17])[C:14]2[C:13]([CH3:26])=[C:12]([C:20](=[O:24])[N:21]([CH3:22])[CH3:23])[S:11][C:10]=2[N:9]=[CH:8]1
Reactant: NCCO
Reactant: CCO
Reactant: CCOC=NC1SC(C)(C(=O)N(C)C)C=C1C(=O)OCC
Product: Cc1c(C(=O)N(C)C)sc2ncn(CCO)c(=O)c12
Yield: 93 %

Procedure:
8.0 ml (133 mmol) of ethanolamine were added to 35.6 g (114 mmol) of 2-ethoxymethyleneamino-3-carboethoxy-5-methyl-5-dimethylcarbamoylthiophene in 200 ml of ethanol, and the mixture was boiled at reflux for 2 h. The mixture was then evaporated under reduced pressure. 29.9 g (93%) of a dark viscous oil were isolated.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.Cl[C:35]1[N:40]=[C:39]([NH:41][C@H:42]2[C@H:47]3[CH2:48][C@H:44]([CH2:45][CH2:46]3)[C@H:43]2[C:49]([NH2:51])=[O:50])[C:38]([Cl:52])=[CH:37][N:36]=1>>[Cl:52][C:38]1[C:39]([NH:41][C@H:42]2[C@H:47]3[CH2:48][C@H:44]([CH2:45][CH2:46]3)[C@H:43]2[C:49]([NH2:51])=[O:50])=[N:40][C:35]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:36][CH:37]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Reactant: NC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Product: NC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 29.7 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2,2-Trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine (75 mg, 0.290 mmol) was combined with DL-10-camphorsulfonic acid (101 mg, 0.436 mmol) and (1S,2R,3S,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid amide (86.9 mg, 0.290 mmol) to prepare (1S,2R,3S,4R)-3-{5-Chloro-2-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]heptane-2-carboxylic acid amide (45.07 mg, 30% yield) as a white powder. Product was purified on a 12 g Isco cartridge using methelene chloride/methanol as the eleuent. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.28 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.84 (m, 2H), 6.33 (m, 2H), 5.54 (br s, 1H), 5.32 (br s, 1H), 4.36 (t, J=7.8 Hz, 1H), 3.24 (q, J=18.9, 9.5 Hz, 2H), 3.06 (s, 1 h), 2.80 (m, 4H), 2.68 (m, 2H), 2.47 (d, J=8.5 Hz, 1H), 2.22 (d, J=9.5 Hz, 1H), 2.08 (m, 2H), 1.64 (m, 1H), 1.34 (m, 2H), 0.88 (m, 1H). LC/MS (ESI+)=521 (M+H). MP=217.5-218.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[C@H:47]([CH3:48])[CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:49])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[C@H:47]([CH3:48])[CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:49])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17][S:60]([CH3:59])(=[O:62])=[O:61])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 130a (175 mg, 0.26 mmol) in DCM (2.5 mL) was added DIPEA (184 μL, 1.0 mmol) followed by methanesulfonyl chloride (41 μL, 0.52 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.72 min, m/z 741 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:36](I)[CH3:37]>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:36][CH3:37])=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)C)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 247 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (12.9 mg, 322 μmol) was added and the mixture was allowed to stir for 30 min at 0° C. Ethyl iodide (57.9 mg, 30.0 μL, 371 μmol) was added and the mixture was warmed to 20° C. After 15 h the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix pre-packed column, 20-50% ethyl acetate in hexanes, 15 minute gradient) to give 2-(6-chloro-1-ethyl-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 152 μmol, 61%) as a yellow powder. MS (M+Na)+=535; 1H NMR (CDCl3) δ: 9.26 (s, 1H), 8.44-8.49 (m, 1H), 8.39-8.42 (m, 1H), 8.20-8.28 (m, 1H), 7.47-7.56 (m, 1H), 7.23 (d, J=1.5 Hz, 1H), 5.67-5.77 (m, 2H), 4.43-4.59 (m, 1H), 4.13 (q, J=7.2 Hz, 1H), 3.52-3.67 (m, 1H), 1.57-1.65 (m, 4H), 1.42 (d, J=6.4 Hz, 4H), 0.88-1.01 (m, 2H)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:14]([CH:16]=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: Ic1ccccc1
Reactant: O=Cc1cn2nccc(N3CCOCC3)c2n1
Product: O=Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccccc1

Procedure:
Compound 5e (300 mg, 1.3 mmol) was coupled with iodobenzene (0.21 mL, 1.9 mmol) according to the procedures described in Example 20, Step A to afford compound 74a. 1H NMR (400 MHz, CDCl3) δ (ppm): 10.11 (s, 1H), 8.09 (d, J=5.6 Hz, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.44-7.63 (m, 3H), 6.13 (d, J=5.6 Hz, 1H), 4.04-4.16 (m, 4H), 3.80-4.02 (m, 4H).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[C:26]#[CH:27]>CC(C)=O>[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][N:14]([CH2:27][C:26]#[CH:25])[CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O=[N+]([O-])O
Product: C#CCN1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitric acid salt (1.0 g, 3.94 mmol) was dissolved in acetone (100 mL) followed by addition of Cs2CO3 (3.84 g, 11.82 mmol, 3.0 eq) and propargyl bromide (80% in toluene) (463 μL, 4.33 mmol, 1.1 eq). The reaction was stirred at room temperature for 24 hours. The solution was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (100 mL) and washed with water (100 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain 7-nitro-3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid (756 mg, 83%). m.p.=122-125° C.; LCMS (m/e) 231 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.05-7.98 (m, 2H), 7.30-7.23 (m, 1H), 3.49-3.43 (m, 2H), 3.13-3.02 (m, 4H), 2.84-2.71 (m, 4H), 2.26-2.22 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[CH3:15][O:16][NH2:17]>>[CH3:15][O:16][N:17]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11]
Reactant: CON
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Agent: Cl
Product: CON=C(C(=O)O)c1ccc(O)c(Cl)c1

Procedure:
2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (6.45 g.) and O-methylhydroxylamine hydrochloride (2.74 g.) were reacted according to a similar manner to that of Preparation (5-3)(a) to give oil of 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(=O)C.[Br:18]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:18])=[C:10]([OH:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(O)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2cc(Br)c(O)cc21
Temperature: 12.5 °C
Reaction time: 0.75 h
Yield: 73.6 %

Procedure:
A stirred suspension of finely powdered 1-acetyl-6-hydroxyindoline (D63, 2.4 g, 0.013 mole) in a mixture of DMF (25 ml) and glacial acetic acid (125 ml) at 15° C. was treated portionwise over 5 minutes with N-bromosuccinimide (2.65 g, 0.015 mole). The reaction mixture changed from yellow to grey-green in colour. The mixture was stirred at 1 5-20° C. for 45 minutes, then cooled to 5° C. and the solid filtered off, washed with acetic acid and dried to give the title compound as a grey solid (2.45 g, 71%).
Reaction SMILES: [ClH:1].[OH:2][CH2:3][C:4]([NH2:12])([CH2:8][CH2:9][CH2:10][NH2:11])[C:5]([OH:7])=[O:6].Cl.[CH3:14]O>>[ClH:1].[ClH:1].[OH:2][CH2:3][C:4]([NH2:12])([CH2:8][CH2:9][CH2:10][NH2:11])[C:5]([O:7][CH3:14])=[O:6]
Reactant: NCCCC(N)(CO)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)(CO)CCCN

Procedure:
2-Hydroxymethyl-2,5-diaminopentanoic acid hydrochloride (5 g or 2.5×10-2 mol) is suspended in 75 ml of absolute methanol and the solution is saturated with dry hydrogen chloride. The homogenous solution is then heated under reflux for 48 hours. The reaction mixture is regularly saturated with dry hydrogen chloride. The solvent is evaporated under reduced pressure and the hygroscopic residue is dried under high vacuo (6.2 g) to give methyl 2-hydroxymethyl-2,5-diaminopentanoate dihydrochloride. The ester (6.2 g) is dissolved in 100 ml of absolute methanol, and 175 ml of a methanolic solution of sodium methylate (1.15 g of Na or 5×10-2 mol) is added. The reaction mixture is stirred at room temperature under nitrogen for 24 hours. The solvent is evaporated under reduced pressure and the residue is extracted many times with hot chloroform to yield analytically pure 3-hydroxymethyl-3-amino-2-piperidone (2.9 g): m.p. 145° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:13][NH2:14])=[O:12])[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24]([C:26](=O)[CH3:27])[CH:25]=1>CO.C(O)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24](/[C:26](=[N:14]/[NH:13][C:11](=[O:12])[C:10]2[CH:15]=[CH:16][CH:17]=[C:8]([N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:18])[CH2:3][CH2:4]3)[CH:9]=2)/[CH3:27])[CH:25]=1
Reactant: NNC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.5 %

Procedure:
3-(1,1-dioxidothiomorpholino)benzohydrazide (30 mg, 0.111 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (19.00 mg, 0.111 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-(1,1-dioxidothiomorpholino)benzohydrazide (15 mg, 0.035 mmol, 31.3% yield) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.65 (d, 1H, J=2.0 Hz), 7.47 (m, 1H), 7.41 (t, 1H, J=7.6 Hz), 7.36-7.27 (m, 3H), 6.94 (d, 1H, J=8.8 Hz), 3.87 (m, 4H), 3.17 (m, 4H), 2.48 (s, 3H). Mass [M+H]+: 422.2
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.Cl.CC[N:22]([CH:26](C)C)C(C)C.[C:29]([C:31]1[CH:32]=[C:33]([C:37]2[N:38]([CH2:50][CH2:51][CH2:52][C:53]([O-])=[O:54])[CH:39]=[C:40]3[C:45]=2[C:44](=[O:46])[N:43]([CH3:47])[C:42](=[O:48])[N:41]3[CH3:49])[CH:34]=[CH:35][CH:36]=1)#[N:30].[Li+].CN([CH:60]=[O:61])C>>[C:29]([C:31]1[CH:32]=[C:33]([C:37]2[N:38]([CH2:50][CH2:51][CH2:52][C:53]([N:22]([O:61][CH3:60])[CH3:26])=[O:54])[CH:39]=[C:40]3[C:45]=2[C:44](=[O:46])[N:43]([CH3:47])[C:42](=[O:48])[N:41]3[CH3:49])[CH:34]=[CH:35][CH:36]=1)#[N:30]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCC(=O)[O-])cc2n(C)c1=O
Reactant: CN(C)C=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: [Li+]
Product: CON(C)C(=O)CCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
T3P® (31.3 ml, 52.6 mmol) was added dropwise to a solution of N,O-dimethyllhydroxylamine hydrochloride (2.70 g, 27.6 mmol), DIPEA (18.39 ml, 105 mmol) and lithium 4-(5-(3-cyanophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)butanoate (9.8 g, 26.3 mmol) in DMF (263 mL). The mixture was stirred at room temperature for 40 minutes and quenched with water (250 mL). The resultant precipitate was collected by filtration under reduced pressure to afford the title compound.
Reaction SMILES: [C:1]1([C:7](=[O:13])[C:8]([O:10]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1>C(O)C>[CH2:21]([N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:8](=[O:10])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:13])[CH2:16][CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: O=C(NC1CCN(Cc2ccccc2)CC1)C(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
Added to 4.28 g of ethyl phenylglyoxylate were 9.12 g of 4-amino-1-benzylpiperidine. The mixture was heated and stirred at 120° C. for 3 hours on an oil bath. Thereafter, ethanol formed was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel, thereby obtaining 6.3 g (yield: 81.4%) of N- (1-benzyl-4-piperidinyl)phenyl-glyoxylic acid amide.
Reaction SMILES: [F:1][C:2]([F:22])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[F:23][C:24]([F:30])([F:29])S([O-])(=O)=O.[Yb+3].[F:32][C:33]([F:39])([F:38])S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.O.C(OCC)C>[F:1][C:2]([F:22])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:33]([F:39])([F:38])[F:32])[CH:8]=3)[CH:16]=2)[CH2:3][C@@H:2]([OH:6])[C:24]([F:30])([F:29])[F:23])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: Oc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: O[C@H](CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(OCc2cccc(C(F)(F)F)c2)c1)C(F)(F)F
Temperature: 25 °C
Yield: 597.5 %

Procedure:
EX-20B) A solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol (5.1 g, 16.2 mmol) from EX-20A, R-(+)-1,1,1-trifluoro-2,3-epoxypropane (1.5 mL, 17.4 mmol), and ytterbium trifluoromethanesulfonate (1.0 g, 10 mol %) in 10 mL of acetonitrile was heated at 50° C. in a sealed glass tube for 4 h. The reaction mixture was cooled to room temperature, then diluted with water and diethyl ether and extracted. The ether layer was washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4, and concentrated in vacuo to give 5.64 g (81%) of the desired (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy]phenyl]methyl][3,3,3-trifluoro-2-hydroxy-propyl)amino]-phenol product as a yellow oil. 1H NMR (acetone-d6) δ 7.41 (t, 1H), 7.23 (d, 1H), 7.16–7.20 (m, 2H), 6.97 (t, 1H), 6.42 (tt, 1H), 6.18–6.24 (m, 3H), 4.77 (s, 2H), 4.43–4.48 (m, 1H), 3.58 (dd, 1H), 3.39 (dd, 1H).