Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:61][C:62]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)([CH3:68])[C:63]([O:65][CH2:66][CH3:67])=[O:64].C(N(CC)C(C)C)(C)C>CS(C)=O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:61][C:62]([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)([CH3:68])[C:63]([O:65][CH2:66][CH3:67])=[O:64])=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CCOC(=O)C(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(NC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
The product of Example 385E (90 mg, 0.17 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate [TBTU] (60 mg, 0.19 mmol) and ethyl 2-amino-2-phenylpropanoate (39 mg., 0.20 mmol) in DMSO (0.9 mL) was reacted with N,N-diisopropylethylamine (0.060 mL, 0.34 mmol) dropwise at room temperature then stirred at room temperature for 18 hours under N2. The mixture was poured into water (10 mL) with stirring. The resulting precipitate was extracted with ethyl acetate (50 mL) and the organic layer was washed with water (3×), saturated aqueous NaHCO3, then brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate:chloroform 4:1) to give the title compound as a pale yellow amorphous solid (93 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[C:25]([OH:29])(=[O:28])[CH:26]=[CH2:27]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH2:27][CH2:26][C:25]([OH:29])=[O:28]
Reactant: Fc1cccc(CNCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Reactant: C=CC(=O)O
Solvent: c1ccccc1
Product: O=C(O)CCN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1

Procedure:
A mixture of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amine (see Example 6), (113 mg, 0.31 mmol), acrylic acid (23 mg, 0.33 mmol) and benzene (4 mL) was heated to reflux for 14 h. The solvent was evaporated in vacuo to afford crude 3-[[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amino]-propionic acid. To a mixture of this acid (135 mg, 0.31 mmol), isonipecotamide (44 mg, 0.35 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol) and CH2Cl2 (1 mL) at 0° C. was added a solution of dicyclohexylcarbodiimide (68 mg, 0.33 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred at ambient temperature for 14 h and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20:1 to 10:1 CH2Cl2/MeOH) to provide the title compound (86 mg, 51%) as a white solid: ESI MS m/z 546 [C27H30Cl2FN5O2+H]+.
Reaction SMILES: [Cl-].[Li+].[CH2:3]([O:10][C:11]1[C:16](=[O:17])[C:15](Br)=[CH:14][N:13]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:31][O:32][B:33](OC)[O:34][CH3:35]>C1COCC1>[CH3:31][O:32][B:33]([C:15]1[C:16](=[O:17])[C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:12][N:13]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH:14]=1)[O:34][CH3:35]
Reactant: COB(OC)OC
Reactant: O=c1c(Br)cn(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COB(OC)c1cn(-c2cccc(-c3ccccc3)c2)cc(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium chloride (515 mg, 12.1 mmol) in a 25 mL round bottom flask under high vacuum was heated with a heat gun until a free flowing granular solid was obtained (˜5 min). The flask was cooled to room temperature, purged with N2, and treated with isopropylmagnesium chloride (6.1 mL of a 2 M solution in THF). After stirring at room temperature for 1 h, the mixture was cooled to −10° C. and treated with 3-(benzyloxy)-1-(biphenyl-3-yl)-5-bromopyridin-4(1H)-one (1.05 g, 2.4 mmol) as a suspension in 3.5 mL of THF. After stirring for 0.5 h, trimethylborate (1.35 mL, 12.1 mmol) was added dropwise and the reaction mixture was stirred an additional 3.5 h, before being quenched with the addition of MeOH (12 mL) to provide a solution of crude dimethyl[5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridin-3-yl]boronate which was used directly in the subsequent step. LC/MS (M+H)+ 398. The solution of crude dimethyl[5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridin-3-yl]boronate (2.4 mmol) in THF/MeOH from the preceeding step and 10% Pd/C (52 mg, 0.49 mmol) was stirred under H2 (1 atm) for 18 h. The reaction mixture was diluted with MeOH (20 mL), filtered through a pad of Celite (MeOH wash), and concentrated under reduced pressure. The residue was diluted with DMF (10 mL) and 0.5 M aq, HCl (0.4 mL) and purified by reversed phase HPLC (2 cm×5 cm C18, acetonitrile-water gradient, 0.05% TFA added, fractions were lypholized) to provide [1-(biphenyl-3-yl)-5-hydroxy-4-oxo-1,4-dihydropyridin-3-yl]boronic acid. 1H NMR (599 MHz, DMSO, 75° C.): δ 8.19 (d, J=2.3 Hz, 1 H); 7.89 (d, J=2.3 Hz, 1 H); 7.83 (s, 1 H); 7.79-7.74 (m, 3 H); 7.67-7.61 (m, 1 H); 7.56 (d, J=8.1 Hz, 1 H); 7.49 (t, J=7.6 Hz, 2 H); 7.46-7.38 (m, 1 H). HRMS (ES) Calc (M+H)+ 308.1089. Found 308.1092.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(C(C)C)C(C)C)C.C[Si]([N:37]=[C:38]=[O:39])(C)C>CN(C)C=O>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:6]2[C:5](=[O:23])[CH2:4][CH:3]([NH:2][C:38]([NH2:37])=[O:39])[CH2:7]2)=[CH:13][CH:12]=1
Reactant: NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
A solution of 250 mg (0.74 mmol) of (RS)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 1f)] in 2 ml of N,N-dimethylformamide is cooled to 0° C. and successively treated with 386 μl (2.2 mmol) of N-ethyl-diisopropylamine and 307 μl (2.2 mmol) of trimethylsilylisocyanate. The mixture is left to warm to RT and stirred for 4 hours. For the working-up, the reaction mixture is evaporated under reduced pressure. The red residue is dissolved in dichloromethane and the organic phase washed with water. After separation of the organic layer and drying over sodium sulfate, it is evaporated to give a red oil. For purification, the crude product is chromatographed on silica gel using a gradient of a 95:5- to 90:10-mixture of dichloromethane and methanol as the eluent. After the chromatography, in addition, the product is triturated in ethyl acetate and sodium hydrogencarbonate at RT. There are obtained 153 mg (60% of theory) of (RS)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-urea as a white solid. MS: m/e=344 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([NH:17][C:18](=[O:20])[CH3:19])[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-]>C1COCC1.O.[Zn]>[NH2:14][C:12]1[CH:11]=[C:10]([NH:17][C:18](=[O:20])[CH3:19])[CH:9]=[C:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:13]=1
Reactant: CC(=O)Nc1cc(-c2ncccc2F)cc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(N)cc(-c2ncccc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of N-(3-(3-fluoropyridin-2-yl)-5-nitrophenyl)acetamide (5 g, 18.18 mmol) in THF (50 ml), Zn (11.8 g, 181.18 mmol) was added followed by slow addition of solution of NH4Cl (9.7 g, 181.18 mmol) in 20 ml water. The mixture was stirred at RT for 1 h. The mixture was filtered through celite and bed washed with ethyl acetate. The mixture was diluted with ethyl acetate and washed with water and brine solution, dried over sodium sulphate and distilled to give the product in 90% yield (4.2 g). LC-MS (ESI): Calculated mass: 245; Observed mass: 246.1 [M+H]+ (rt: 0.21 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19].S(=O)(=O)(O)O>C(O)C>[CH3:15][C:16]1[CH:17]=[C:18]([CH3:19])[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cc(C)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (5.0 g), 2,4-pentanedione (2.1 ml) and conc. sulphuric acid (0.8 ml) in ethanol (40 ml) was heated under reflux for 20 hours. The ethanol was evaporated under reduced pressure and the residue dissolved in dichloromethane. The extract was washed with sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to give 3,5-dimethyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[C:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:14]([NH2:16])=[O:15])=[CH:5][CH:4]=1)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[OH:33])[C:26]([NH:28][NH2:29])=[O:27]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[OH:33])[C:26]([NH:28][N:29]=[CH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[C:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:14]([NH2:16])=[O:15])=[CH:5][CH:4]=1)=[O:27]
Reactant: CCC(CC)=C(C(N)=O)c1ccc(C=O)c2ccccc12
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Product: CCC(CC)=C(C(N)=O)c1ccc(C=NNC(=O)c2ccc(O)c(Cl)c2)c2ccccc12

Procedure:
The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-formyl-1-naphthyl diethylacrylamide (from step D) and 3-chloro-4-hydroxy benzoic acid hydrazide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([CH3:15])[C:10](OCC)=[O:11]>C(O)C>[CH3:15][C:9]1[C:10](=[O:11])[NH:1][C:2]2[C:3]([CH:8]=1)=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCOC(=O)C(C)=Cc1ccccc1N
Solvent: CCO
Product: Cc1cc2ccccc2[nH]c1=O

Procedure:
Into 10 ml of ethanol, 0.5 g of (E) ethyl 3-(2-aminophenyl)-2-methyl-2-propenate was dissolved; and, while being stirred, the mixture was irradiated with ultraviolet rays at 256 nm for 48 hours. The reaction liquid was concentrated under a reduced pressure, and the resulting crude crystal was recrystallized from ethanol, whereby the aimed compound was obtained.
Reaction SMILES: [F:1][CH2:2][C:3](OCC)=O.[H-].C([Al+]CC(C)C)C(C)C.[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[F:1][CH2:2][CH:3]=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CF
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCOC(=O)C=CCF
Reaction time: 0.5 h

Procedure:
Ethyl 2-fluoroacetate (21.0 g) in CH2Cl2 (200 mL) at −78° C. was treated dropwise over 45 min with a 1.0 M solution of diisobutylaluminum hydride in CH2Cl2 (200 mL) maintaining the internal temperature below −70° C. Stirring was continued at −78° C. for 30 minutes and then (carbethoxymethylene)triphenylphosphorane (70.0 g) was added in one portion. The reaction mixture was allowed to slowly reach room temperature while stirring overnight. It was then quenched with methanol, filtered and concentrated to give the product as a mixture of isomers (E/Z=3:1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([O:26][CH2:27][CH:28]=[C:29]([Cl:31])[Cl:30])[CH:23]=[C:22]([Cl:32])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][C:17](=O)[CH2:16]2)=[CH:11][CH:10]=1.Cl.[CH3:34][O:35][NH2:36]>N1C=CC=CC=1>[CH3:34][O:35][N:36]=[C:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[C:22]([Cl:32])=[CH:23][C:24]([O:26][CH2:27][CH:28]=[C:29]([Cl:30])[Cl:31])=[CH:25][C:2]=3[Cl:1])=[CH:14][CH:13]=2)[CH2:16]1
Reactant: CON
Reactant: O=C1CCCC(c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)C1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCCC(c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)C1

Procedure:
109 mg of 3-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-cyclohexanone and 21 mg of O-methylhydroxylamine hydrochloride are stirred in 5 ml of pyridine at 85° C. for 3 hours. The reaction mixture is concentrated and the residue is stirred with tert-butyl methyl ether and 0.5N hydrochloric acid. After concentration of the organic phase and purification over silica gel, the title compound is obtained in the form of a colourless oil.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[N:11]=[C:10]([CH2:12][O:13][N:14]=[C:15]([C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:8][CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.O.CCOC(C)=O>[CH3:27][N:26]1[C:22]([C:15](=[N:14][O:13][CH2:12][C:10]2[N:11]=[C:6]([CH:2]=[O:1])[CH:7]=[CH:8][CH:9]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:23][N:24]=[N:25]1
Reactant: Cn1nnnc1C(=NOCc1cccc(C2OCCO2)n1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cn1nnnc1C(=NOCc1cccc(C=O)n1)c1ccccc1
Temperature: 100 °C
Yield: 106.9 %

Procedure:
To a solution of N-{[6-(1,3-dioxolan-2-yl)pyridin-2-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (3.3 g, 9 mmol, 1 eq.) in 75 ml of DMSO and 15 ml of water was added p-TSA (1.79 g, 9.45 mmol, 1.05 eq.). The reaction was heated to 100° C. for 1.5 hrs. After cooling to room temperature, the mixture was diluted with 400 ml of EtOAc, washed with sat. aqueous NaHCO3, followed by water (×2). The organic layer was separated, dried over MgSO4 and concentrated to give 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridine-2-carbaldehyde (3.1 g, 96% yield) as a viscous yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH:9]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:22]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:23][CH:21]=[O:22])[CH2:10][CH:9]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CC(C=O)CCN1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC(C=CC=O)CCN1C(=O)OC(C)(C)C

Procedure:
A solution of 1 g of 1-(tert-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-carboxaldehyde and 2 g of formylmethylene-triphenylphosphoran in 16 ml of toluene is heated to 100° (bath) for 2 hours. The solution is cooled and purified by flash chromatography using ethyl acetate/hexane (25:75) to yield 1-(tert-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-acrylaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-])=O)=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][C:15]=2[F:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)c(N)cc2F)CC1
Yield: 109.7 %

Procedure:
1.4 g of 4-(5-amino-2-fluoro-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester in solution in 20 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 139 mg of palladium-on-charcoal at 22° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 1.4 g of 4-(4,5-diamino-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester are isolated in the form of a brown resin. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.41 (s, 9H); 2.73 (m, 4H); 3.40 (m, 4H); 4.23 (broad s, 2H); 4.37 (broad s, 2H); 6.27 (d, J=8.5 Hz, 1H); 6.31 (d, J=13.5 Hz, 1H). EI mass spectrum: m/z=310 M+. (base peak), m/z=254 (M-C4H)+, m/z=57 C4H+.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.O>C1C=CC=CC=1>[N:8]1([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCCCC1
Reactant: C1CCNC1
Solvent: O
Solvent: c1ccccc1
Product: C1=C(N2CCCC2)CCCC1
Yield: 95.9 %

Procedure:
Cyclohexanone (196.3 g) and pyrrolidine (214 g) in benzene (500 ml) were refluxed under nitrogen with a Dean-Stark apparatus, until no more water separated out. The solvents were then evaporated off under nitrogen, and the residual oil was distilled to give 1-(1-pyrrolidinyl)cyclohexene (290 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=O)[CH2:15][CH2:16][CH:17]1[CH2:20][CH:19]([N:21]([CH2:25][C@@H:26]2[C@@H:33]3[C@@H:29]([O:30][C:31]([CH3:35])([CH3:34])[O:32]3)[C@H:28]([N:36]3[C:40]4[N:41]=[CH:42][N:43]=[C:44]([NH:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=5[O:55][CH3:56])[C:39]=4[CH:38]=[CH:37]3)[CH2:27]2)[CH:22]([CH3:24])[CH3:23])[CH2:18]1>CC(O)=O>[CH3:56][O:55][C:48]1[CH:49]=[C:50]([O:53][CH3:54])[CH:51]=[CH:52][C:47]=1[CH2:46][NH:45][C:44]1[C:39]2[CH:38]=[CH:37][N:36]([C@H:28]3[C@H:29]4[C@H:33]([O:32][C:31]([CH3:34])([CH3:35])[O:30]4)[C@@H:26]([CH2:25][N:21]([CH:22]([CH3:23])[CH3:24])[CH:19]4[CH2:20][CH:17]([CH2:16][CH2:15][C:14]5[NH:13][C:3]6[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:10])[F:12])=[CH:7][C:2]=6[N:1]=5)[CH2:18]4)[CH2:27]3)[C:40]=2[N:41]=[CH:42][N:43]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(OC(F)(F)F)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(OC(F)(F)F)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1

Procedure:
N-(2-amino-4-(trifluoromethoxy)phenyl)-3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanamide (1.4 g, 1.8 mmol) was heated in AcOH at 60° C. overnight. The reaction mixture was concentrated in vacuo giving the crude product.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[N:43][CH:44]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:38][C:39]5[CH:44]=[N:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=5)=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c([N+](=O)[O-])c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
A solution of the product of Example 19C (290 mg, 0.546 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with 5-amino-2-methoxypyridine (78.5 mg, 0.601 mmol) and diisopropylethylamine (0.143 mL, 0.819 mmol), and stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (25 mL), water (2×25 mL), and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with 3% methanol/methylene chloride provided the title compound as a dark yellow solid (202 mg, 60%).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.S(OC)(OC)(=O)=O.[CH2:13]([NH2:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:5])[CH:3]=[N:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCN
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCN=CN(C)C
Temperature: 25 °C

Procedure:
Dimethylformamide (8.8 g, 0.12 mole), dimethyl sulfate (19.3 g, 0.15 mole) and toluene (20 ml) were placed in a 100 ml round bottom flask and heated at reflux for 30 minutes. During this time a light brown oil separated. The reaction was cooled to room temperature and the toluene was decanted. The dimethylformamide/dimethyl sulfate complex was washed with dry toluene (2×20 ml) and the toluene was decanted. n-Octylamine (15.5 g, 0.12 mole) in toluene (20 ml) was added rapidly with stirring. The reaction temperature rose briefly to 60° C. The reaction was stirred for 90 minutes, then extracted with a solution of sodium hydroxide (7.2 g, 0.18 mole) in water (40 ml). The organic phase was washed with brine (40 ml), dried over anhydrous Na2SO4, and filtered. GLC showed the product to be about 72% pure after concentration.
Reaction SMILES: O1CCCC1.[CH2:6]([NH2:8])[CH3:7].[CH2:9]([C:11]1[CH:12]=[C:13]([O:29][C:30]2[CH:31]=[N:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)[CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](O)=[O:27])[CH2:23][N:24]=1)=[CH:16]2)[CH3:10].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:6]([NH:8][C:26](=[O:27])[CH2:25][CH:22]1[S:21][C:20]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:29][C:30]2[CH:31]=[N:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)=[CH:12][C:11]=3[CH2:9][CH3:10])=[N:24][CH2:23]1)[CH3:7]
Reactant: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(CC)c3[nH]2)S1
Reaction time: 15 h
Yield: 44 %

Procedure:
To a mixed solution of 2.0M-ethylamine tetrahydrofuran solution (0.33 mL), [2-(7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), and N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole (89 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio), and the obtained pale-yellow oil was recrystallized from ethyl acetate-hexane to give the title compound (92 mg, yield 44%) as colorless crystals.