Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][C@@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[F:30][C:31]1[CH:65]=[CH:64][C:34]([C:35](/[N:37]=[C:38]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:36])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:32]=[CH:33][C:34]([C:35](/[N:37]=[C:38]2/[N:17]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([C:24](=[O:25])[NH:26][CH:27]([CH3:29])[CH3:28])[CH2:20][CH2:19]3)[C:3]3[CH:4]=[C:5]([NH:8][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[N:6]=[CH:7][C:2]=3[NH:1]/2)=[O:36])=[CH:64][CH:65]=1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(NCCN3CCOCC3)ncc2N)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(NCCN4CCOCC4)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(5-amino-2-(2-morpholinoethylamino)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used to prepare (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide. Isolated as an off-white solid (23 mg, 23% yield). M/Z calc'd for C29H38FN7O3: 551.66. found 552 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:25]2[CH3:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: C[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CCCN1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Yield: 74.8 %

Procedure:
A suspension of 3-(3S)-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.51 g, 13.2 mmol), (S)-(+)-2-methylpyrrolidine (1.35 g, 15.84 mmol), and K2CO3 (4.01 g, 29.04 mmol) in acetonitrile (44 mL) was heated to 80° C. for 20 h and then added additional (S)-(+)-2-Methylpyrrolidine (834 mg, 9.79 mmol), and continued heating for 20 h. Removed from heating and concentrated to provide a residue which was taken up with H2O (100 mL) and extracted with CH2Cl2 (2×100 mL). Dried the organics over K2CO3, filtered and concentrated to provide a crude oil which was purified by flash column chromatography (0 to 5% MeOH/CH2Cl2) to provide 2.51 g (75% yield) of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19](N(OC)C)=[O:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19](=[O:20])[CH3:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To 208 mg (0.51 mmol) 2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-N-methoxy-N-methyl-acetamide in 8 ml THF were added 0.51 ml 3M (1.53 mmol, 3 eq) methylmagnesiumbromide in THF at −75° C. The solution was slowly warmed to RT over night, a saturated aqueous solution of NH4Cl was added and the mixture stirred for 30 min. The phases were separated and the inorganic phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with EtOAc:hexane 1:4 yielded 109 mg (53%) 1-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propan-2-one as white solid, MS: 361 (M, 1Br).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[CH:10]([NH2:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([OH:14])[CH:10]([NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(N)C1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
3-Amino-4-(4-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.116 g, 0.35 mmol) was dissolved in CH2Cl2. Propionyl chloride (0.034 mL, 0.39 mmol) and triethylamine (0.109 mL, 0.78 mmol) were added and the solution was stirred for 24 h at room temperature. The reaction was concentrated in vacuo, then purified by Biotage flash chromatography (30% ethyl acetate/70% hexane to 50% ethyl acetate/50% hexane) to yield the title compound (0.133 g, 97%). 1H-NMR (CDCl3): δ 0.87 (t, 3H), 1.44 (s, 9H), 1.78–1.95 (m, 3H), 2.20 (dt, 1H), 3.24 (t, 1H), 3.50 (d, 1H), 3.90 (t, 1H), 4.08 (q, 2H), 4.28 (d, 1H), 5.48 (bd, 1H), 7.26 (d, 2H), 7.37 (d, 2H). ESI-MS m/z: 383 (M+1), retention time 2.21.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:3][CH:2]=1.C(OC([NH:28][C:29]1[N:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31][N:30]=1)=O)(C)(C)C.Cl>O1CCOCC1>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:35]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=3)=[O:36])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:5][CH:6]=1
Reactant: Cc1ccc(CCS(=O)(=O)N2CCC(CN)CC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(CCS(=O)(=O)N2CCC(CNC(=O)c3cnc(N)nc3)CC2)cc1

Procedure:
The title compound was prepared from C-[1-(2-p-tolyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-tert-butoxycarbonylamino-pyrimidine-5-carboxylic acid, followed by treatment with 4N HCl in dioxane as described in EXAMPLE 192.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[N+:15]([O-])=O.[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][CH:28]1[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])c1cccc2cc(C3=NCCS3)[nH]c12
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cc(C4=NCCS4)[nH]c23)CC1

Procedure:
2-(4,5-Dihydro-thiazol-2-yl)-7-nitro-1H-indole prepared in Preparation 101 and 1-BOC-4-piperidone were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][CH:4]=1)=O.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[CH3:26].[OH-].[K+].Cl>CO.O>[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])/[CH:24]=[CH:1]/[C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:14][CH:15]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: CCOC(=O)COc1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)/C=C/c2ccc(OCC(=O)O)cc2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Commercially available ethyl 2-(4-formylphenoxy)acetate (20.0 g, 0.1 mol) and commercially available 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol) were dissolved in 200 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (22.0 g, 0.392 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, and extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with water and brine (200 mL each), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained yellow oil was dried under high-vacuum, 10 g (33%) of yellowish solid was obtained. MS (EI): 313 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[CH3:12][S+](C)(C)=O.[H-].[Na+].O>CS(C)=O>[O:10]1[CH:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12]1
Reactant: O=CCCc1ccccc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CCC2CO2)cc1
Reaction time: 1 h

Procedure:
3-Phenylpropionaldehyde (26.8 g) is added under nitrogen to the ylide prepared from trimethylsulfoxonium iodide (48.4 g) and sodium hydride (55% dispersion in oil; 9.6 g) in dry dimethylsulfoxide (200 ml), according to the procedure in J. Am. Chem. Soc., 84, 867 (1962) and ibid., 87, 1353 (1965). After one hour, the solution was poured into 1 liter of water and the product extracted with ether (3×300 ml.). The, extract was washed with water (2×150 ml.) dried (MgSO4) and evaporated to give an oil 1,2-epoxy-4-phenylbutane, used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:18]([O-:20])=[O:19])[CH:8]=2)[N:3]=1.O.[NH2:22][NH2:23]>>[N+:18]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][NH2:23])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)cc(-c3ccccc3)c2c1
Reactant: NN
Solvent: O
Product: NNc1cc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-6-nitro-4-phenylquinoline is reacted at reflux with hydrazine hydrate to give 6-nitro-4-phenyl-2-hydrazinoquinoline.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+].C(OCC)C.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[O:26]=[C:17]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@H](NC(=O)CCc1ccccc1)C(=O)O
Yield: 84.6 %

Procedure:
L-Leucine (7.87 g, 60 mmol) was dissolved in a solution of sodium hydroxide (4.8 g, 120 mmol) in water (40 ml, 1.5M). Diethyl ether (40 ml) was added. The mixture was cooled in an ice bath and while stirring rapidly, hydrocinnamoyl chloride (10.1 g, 8.92 ml, 60 mmol) was added dropwise over a period of 30 minutes. The ice bath was removed and the mixture was stirred at room temperature 2 hours, maintaining a slightly basic pH by periodic addition of small amounts of 1N sodium hydroxide solution. The layers were separated. The ether layer was reextracted with 1N sodium hydroxide solution. The combined aqueous layers were washed once with ether and then acidified with concentrated hydrochloric acid. The product was extracted into chloroform, dried over magnesium sulfate, and freed of solvent in vacuo leaving a white solid (13.36 g). This material was recrystallized from ethyl acetate (65 ml) to give 8.37 g of the title B compound (53%), m.p. 129°-130° C. [α]D =-41.3° (c=1.3, MeOH).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:27][CH:26]=2)=[N:4]1)[CH3:2].[CH3:37][NH:38][CH3:39].C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:37][N:38]([CH2:23][C:19]1[CH:18]=[C:17]([C:15]2[NH:14][C:10]3=[N:11][CH:12]=[CH:13][C:8]([C:6]4[C:5]([C:25]5[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:29][CH:30]=5)=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=4)=[C:9]3[CH:16]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:39]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(C=O)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To N′-(4-{1-ethyl-4-[2-(3-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea (11.45 g, 23.9 mMol) was added a solution of 2 M dimethylamine in THF (24 mL, 48 mMol). The slurry was rinsed down with THF (150 mL) and treated with NaBH(OAc)3 (8.6 g, 40.6 mMol). (Gentle gas evolution was seen and the reaction got slightly warm to the touch.) The reaction was stirred at RT for 1 h (started out as a thick suspension that slowly became a homogeneous fine suspension) and concentrated to dryness under vacuum. The residue that remained was basified with aq. 1 N Na2CO3, (200 mL) and aq. 1 N NaOH (25 mL), extracted with CHCl3 (300 mL) washed with brine, dried (Na2SO4), filtered, and evaporated to dryness under vacuum. Trituration with (1:1) Et2O/pet. ether, filtration, and drying under vacuum gave the title compound (11.20 g, 92%) as a yellow solid (>95% pure by HPLC): MS (ES) m/e 508.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 12.14 (d, J=1.8 Hz, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 8.07 (d, J=4.8 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.77 (s, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.1 Hz, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.27 (dd, 1H), 6.79 (d, J=5.1 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 4.27 (q, J=7.3 Hz, 2H), 3.43 (s, 2H), 2.18 (s, 6H), 1.51 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1)[CH2:2][CH2:3][CH3:4].C(OO)(=[O:18])C.O>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]2[CH:12]([O:18]2)[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OO
Reactant: CCCCOCCOCC1C=CCCC1
Solvent: O
Solvent: ClCCl
Product: CCCCOCCOCC1CCC2OC2C1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 13.78 g (0.065 mol) 3-butoxyethoxymethylcyclohexene, and 100 niL of methylene chloride. Peracetic acid (15.5 g, 35 wt. % in acetic acid; 0.065 mol) in methylene chloride (80 mL) was added dropwise to above mixture over 30 min. in an ice bath. After the above mixture was reacted at room temperature overnight, 250 mL of water was added to above reaction mixture, the water layer was extracted with methylene chloride (2×150 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×150 mL), then with water (2×150 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[CH2:12][CH2:13][O:14][C:9]3=[CH:8][C:6]=2[N:7]=1.[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH2:21])[CH3:17]>COCCOC>[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH:21][C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[CH2:12][CH2:13][O:14][C:9]3=[CH:8][C:6]=2[N:7]=1)[CH3:17]
Reactant: CCN(CC)CCN
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCO3
Solvent: COCCOC
Product: CCN(CC)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Yield: 75.1 %

Procedure:
A solution of chloride 206 (250 mg, 1.12 mmol) and N1,N1-diethylethane-1,2-diamine (0.63 mL, 4.48 mmol) in DME (25 mL) was stirred at reflux temperature for 2 h, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (5-10%) of MeOH/DCM to give the 1-oxide 209 (255 mg, 75%) as a yellow solid: mp 150-151° C.; 1H NMR δ 8.09 (t, J=1.6 Hz, 1H, H-9), 6.79 (s, 1H, H-5), 5.90 (br s, 1H, NH), 4.72 (t, J=8.3 Hz, 2H, H-7), 3.48-3.54 (m, 2H, CH2N), 3.30 (dt, J=8.3, 1.4 Hz, 2H, H-8), 2.69-2.72 (m, 2H, CH2N), 2.59 (q, J=7.1 Hz, 4H, 2×CH2), 1.05 (t, J=7.1 Hz, 6H, 2×CH3); 13C NMR δ 166.5, 159.3, 151.8, 129.3, 126.3, 116.6, 102.1, 72.9, 51.3, 46.7 (2), 38.7, 28.6, 11.7 (2). Anal. calcd for C15H21N5O2.¼CH3OH: C, 58.8; H, 7.1; N, 22.5. Found: C, 58.8; H, 6.7; N, 22.8%.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:24][C:23]2=[O:36])[C:9]([NH:11]C2C=CN(CC(O)(C)C)N=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:70][O:71][C:72](=[O:80])[C:73]1[CH:78]=[CH:77][C:76](N)=[N:75][CH:74]=1>ClCCl>[CH3:70][O:71][C:72](=[O:80])[C:73]1[CH:78]=[CH:77][C:76]([NH:11][C:9](=[O:10])[C@@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=3[F:34])=[CH:24][C:23]2=[O:36])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:75][CH:74]=1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Reactant: COC(=O)c1ccc(N)nc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.2 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (prepared in Example 36, 90 mg, 0.25 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (138 mg, 0.30 mmol), N,N-diisopropylethylamine (95 mg, 0.74 mmol) and 6-aminonicotinic acid methyl ester (45 mg, 0.30 mmol). The reaction mixture was stirred at 25° C. for 18 h under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 6-{(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionylamino}-nicotinic acid methyl ester (49 mg, 40%) as a white solid: LR-ES-MS m/z calculated for C26H27F2N3O5 [M]+ 499, observed [M+H]+ 500; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85-1.35 (m, 6H) 1.49-1.88 (m, 7H) 3.86 (s, 3H) 4.31 (d, J=18.3 Hz, 1H) 4.63 (d, J=18.3 Hz, 1H) 5.03 (m, 1H) 5.07 (s, 1H) 7.30-7.52 (m, 3H) 8.16 (d, J=9.1 Hz, 1H) 8.28 (dd, J=9.1, 2.4 Hz, 1H) 8.87 (d, J=2.4 Hz, 1H) 11.32 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([N:27]([CH3:44])[C:28]([NH:30][CH:31]4[C:36]([Cl:38])(C)[C:35]([O:39][CH3:40])=[CH:34][C:33]([O:41][CH3:42])=[C:32]4[Cl:43])=[O:29])[CH:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>[Pd].CO>[Cl:38][C:36]1[C:35]([O:39][CH3:40])=[CH:34][C:33]([O:41][CH3:42])=[C:32]([Cl:43])[C:31]=1[NH:30][C:28](=[O:29])[N:27]([CH3:44])[C:23]1[CH:22]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15][CH:16]=2)[N:26]=[CH:25][N:24]=1
Reactant: COC1=CC(OC)=C(Cl)C(NC(=O)N(C)c2cc(Nc3ccc(N4CCN(Cc5ccccc5)CC4)cc3)ncn2)C1(C)Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(N4CCNCC4)cc3)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A suspension of 1-{6-[4-(4-benzyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(2,6-dichloro-3,5-dimethoxy-6-methyl-phenyl)-1-methyl-urea (100 mg, 0.161 mmol) (Example 13), palladium on carbon (30 mg), MeOH (6 mL), and HCl (37%, 16 μL) is stirred for 5 days at RT, under a hydrogen atmosphere. The reaction mixture is filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/2N NH3 in MeOH, 95:5) affords the title compound as a beige solid: ESI-MS: 532.0/534.0 [MH]+; tR=3.39 min (purity: 100%, system 1).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:73])([F:72])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:71])[C@@H:20]([NH:53]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:21][S:22][CH2:23][C@H:24]([NH:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1CCCCC1>C(#N)C>[NH2:53][C@@H:20]([CH2:21][S:22][CH2:23][C@H:24]([NH:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:19](=[O:71])[NH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])([F:72])[F:73]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution of (12R,16R)-12-(((9H-fluoren-9-yl)methoxy)carbonylamino)-16-dodecanamido-1,1-difluoro-11-oxo-4,7,18-trioxa-14-thia-10-azatriacontylphosphonic acid diethyl ester in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 minutes. After concentration, the crude material was by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% EtOAc/Hex, then 0-10% MeOH/DCM to give the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([C:7]([OH:33])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:10][CH2:11][C:12]#[C:13][CH2:14][N:15](CC2C=CC(OC)=CC=2)[CH2:16][CH3:17])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)OC(Cl)C.CO>ClC(Cl)C>[CH:27]1([C:7]([OH:33])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][C:12]#[C:13][CH2:14][NH:15][CH2:16][CH3:17])=[O:9])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCN(CC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1)Cc1ccc(OC)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: CC(Cl)Cl
Product: CCNCC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
reacting said 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butynyl α-cyclohexyl-α-hydroxybenzeneacetate sequentially with α-chloroethyl carbonochloridate in dichloroethane, followed by methanol to produce 4-(ethylamino)-2-butynyl α-cyclohexyl-α-hydroxybenzeneacetate (desethyloxybutyin).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][NH:6][C:7]2[CH:33]=[C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH:31]=[CH:30][C:8]=2[C:9]([NH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=4)[CH:19]=3)[NH:14][N:13]=2)=[O:10])[CH2:2]1.C=O.O.[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([F:29])[CH:25]=1)[CH2:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH:11][C:9](=[O:10])[C:8]1[CH:30]=[CH:31][C:32]([N:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]2)=[CH:33][C:7]=1[NH:6][CH2:5][CH:3]1[CH2:2][N:1]([CH3:44])[CH2:4]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CNC3)c2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CN(C)C3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
To a solution of 2-[(azetidin-3-ylmethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide (100 mg, 0.14 mmol) in dichloromethane (2 mL) were added formaldehyde 37 wt. % in water (0.014 mL, 0.168 mmol), TEA (0.4 mmol) and sodium triacetoxyborohydride (45 mg, 0.21 mmol). The mixture was stirred at room temperature overnight, diluted with dichloromethane, washed with aqueous NaHCO3 sat. sol., water and brine. Organic phase was dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol/NH3 5N in MeOH 100:10:1 as the eluant, affording 5 mg of the title compound.