Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](Br)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]1[NH:27][CH2:26][CH2:25][NH:24][CH2:23]1>CN1CCCC1=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:24]4[CH2:25][CH2:26][NH:27][CH:22]([CH3:21])[CH2:23]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1CNCCN1
Reactant: Cc1c(F)c(Br)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN1CCCC1=O
Product: Cc1c(F)c(N2CCNC(C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 90 °C
Yield: 50.6 %

Procedure:
To a solution of 1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.58 g) in N-methyl-2-pyrrolidone (5 ml) is added 3-methylpiperazine (0.65 g), and the mixture is heated at 90° C. for 20 minutes. After the solvent is distilled off under reduced pressure, ethanol is added to the residue, and the crystals are separated by filtration and are recrystallized from ethyl acetate-ethanol to give 1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (310 mg), as white powdery crystals, m.p. 206°-208° C.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20](=O)[CH3:21])[C:15]=2[OH:23])[CH:10]=[CH:11][C:12]=1[Cl:13].[NH:24]([C:26]([NH:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([N+:39]([O-:41])=[O:40])[CH:30]=1)=[S:27])[NH2:25]>Cl.O>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20](=[N:25][NH:24][C:26]([NH:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([N+:39]([O-:41])=[O:40])[CH:30]=3)=[S:27])[CH3:21])[C:15]=2[OH:23])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)c1ccc(NC(=S)NN)cc1[N+](=O)[O-]
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(=S)NN=C(C)c2nn(C)c(-c3ccc(Cl)c(Cl)c3)c2O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 92.2 %

Procedure:
Dimethylformamide (1 ml) and conc. hydrochloric acid (1 drop) were added to 1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (60 mg, 0.21 mmol) synthesized in Synthetic Example 1 and methyl 4-hydrazinocarbonothioylamino-2-nitrobenzoate (57 mg, 0.21 mmol) synthesized in Reference Synthetic Example 56, and the mixture was stirred at room temperature for 21 hours. Water was added, and the precipitated solid was filtered, purified with a silica gel column chromatography (n-hexane/ethyl acetate=1/1 then chloroform/methanol=95/5). The obtained solid was extracted with ethyl acetate, washed with a saturated ammonium chloride aqueous solution, saturated sodium chloride aqueous solution. The organic layer was concentrated to obtain the desired product as a pale yellow solid (104 mg, yield 92%).
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH3:9])=[O:6])[CH3:4].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[C:19]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:10]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11])[CH3:9])=[O:6])[CH3:4])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)Nc1ccccc1
Agent: Br
Solvent: O
Solvent: c1ccncc1
Product: C[C@H](NC(=O)c1ccccc1)C(=O)N[C@@H](C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
4.1 g (0.013 mol) of L-alanyl-L-alanine anilide hydrobromide were dissolved in 120 ml of dry pyridine and 3 ml (0.026 mol) of benzoyl chloride were added. The solution was stirred at room temperature for 3 hours and was then evaporated to yield a solid. 50 ml of water were added, the solid was filtered off, washed with 50 ml of water and then recrystallise from ethanol to yield 3.15 g (72%) of N-benzoyl-L-alanyl-L-alanine anilide of melting point 245°-248° C.; [α]D20 =+66.6° (c=1.086% in dimethylformamide).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH2:30][OH:31]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][CH2:29][CH2:30][OH:31])=[O:23])[C:4]1=[O:27])[CH3:2]
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Product: CCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 58 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.081 mmol) and 2-aminoethanol (0.05 mL) was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (18 mg, 58% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.47 (br s, 1 H), 8.53 (s, 1 H), 7.35 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 4.20-4.13 (m, 4 H), 3.85 (m, 2 H), 3.63 (m, 2 H), 1.22 (m, 3 H); HRMS m/z calcd for C20H21FN3O4: 386.1510. Found: 386.1517.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.N[C:26](N)=[O:27]>O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:26](=[O:27])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Reactant: NC(N)=O
Solvent: O
Product: COC(=O)CCCCCOc1ccc2[nH]c(=O)n(-c3ccccc3)c2c1
Temperature: 140 °C

Procedure:
7.5 g of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was mixed with 8.23 g of urea, and the mixture was heated to 140° C. for 4 hours. After cooling, it was mixed with water, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was crystallized from diisopropyl ether. 4.27 g was obtained.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[O:9])[CH2:3]1.[CH3:22][O:23][C:24]1[N:29]=[C:28]([C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][O:23][C:24]1[N:29]=[C:28]([C:30]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([C:10]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)[N:11]=3)=[O:9])[CH2:3][C@H:2]2[CH3:1])=[O:31])[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(C(=O)O)n1
Reactant: Cc1cccc(-n2cnc(C(=O)N3CCN[C@H](C)C3)n2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4cccc(C)c4)n3)C[C@H]2C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 86 mg (0.30 mmol) ((R)-3-methyl-piperazin-1-yl)-(1-m-tolyl-1H-[1,2,4]-triazol-3-yl)-methanone, 46 mg (0.30 mmol) 6-methoxy-pyridine-2-carboxylic acid, 0.11 g (0.33 mmol) TBTU and 80 μL (0.45 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2>>[NH:19]1[C:20]2[C:16](=[CH:15][C:14]([N:13]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: Nc1ccc2[nH]ncc2c1
Product: Cc1ccc2c(c1)C(=Nc1ccc3[nH]ncc3c1)C(=O)N2
Yield: 60.1 %

Procedure:
The title compound (83 mg, 60%) was synthesized as a brown solid according to the method described for Example A74 using 5-methylisatin (80.5 mg, 0.5 mmol), 5-aminoindazole (66.5 mg, 0.5 mmol). 1H NMR indicated a 78:22 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H, NH), 10.86 (s, 1H, NH), 8.08 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.07 (dd, J=8.8 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H) 6.33 (s, 1H), 1.89 (s, 3H); MS ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.1.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]([O:13][C:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH:15]=1)[CH3:12].CN1CCCN(C)C1=O.[CH3:30][O:31][C:32]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:33]=1[CH2:34][NH:35][C:36](=[O:39])[CH2:37]I>C1COCC1>[CH3:30][O:31][C:32]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:33]=1[CH2:34][NH:35][C:36](=[O:39])[CH2:37][CH:17]1[CH2:18][CH2:19][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]1=[O:20]
Reactant: CCOC1=CC(=O)CCC1
Reactant: COc1ccc(CNC(=O)CI)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC1=CC(=O)C(CC(=O)NCc2ccc(OC)cc2OC)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 55.9 %

Procedure:
To a −78° C. solution of 1.0 M lithium hexamethyldisilazide in THF (0.90 mL) in 4.0 mL THF was added 3-ethoxy-2-cyclohexen-1-one (0.100 mL, 0.687 mmol). After stirring at −78° C. for 40 minutes, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.0 mL, 8.3 mmol) was added. After 5 minutes, N-(2,4-Dimethoxy-benzyl)-2-iodo-acetamide (0.342 g, 1.02 mmol) was added as a solution in 2.0 mL THF. The reaction was kept at −78° C. for one hour, and then quenched with water and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. Purification by column chromatography on silica gel (gradient: 0 to 100% ethyl acetate in dichloromethane) yielded 133.5 mg (56%) of N-(2,4-dimethoxy-benzyl)-2-(4-ethoxy-2-oxo-cyclohex-3-enyl)-acetamide. LCMS (Method E, ESI): RT=1.57 min, m+H=336.2; 1H NMR (400 MHz, CDCl3) δ: 7.17 (d, J=8.1 Hz, 1H), 6.47-6.39 (m, 2H), 6.35 (s, 1H), 5.32 (s, 1H), 4.38-4.30 (m, 2H), 3.90 (dd, J=13.5, 6.5 Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 2.77 (dd, J=14.3, 5.6 Hz, 1H), 2.68 (dt, J=10.6, 5.5 Hz, 1H), 2.59-2.48 (m, 1H), 2.37 (ddd, J=12.0, 6.3, 2.9 Hz, 1H), 2.17 (ddd, J=13.1, 11.2, 4.6 Hz, 2H), 1.72 (ddd, J=25.0, 12.6, 4.9 Hz, 1H), 1.36 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.[N:18]([C@H:21]1[CH2:23][C@@H:22]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:19]=[O:20]>C(Cl)Cl>[C:24]1([C@H:22]2[CH2:23][C@@H:21]2[NH:18][C:19]([N:4]2[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C@H:3]2[C:7]([O:9][CH3:10])=[O:8])=[O:20])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C=N[C@H]1C[C@@H]1c1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)N[C@H]1C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-tert-butyl 3-methyl (3S)-1,3-piperazinedicarboxylate (AA3) in DCM (0.17 M) was added to a stirred solution of [(1R,2S)-2-isocyanatocyclopropyl]benzene (1.0 eq.) in DCM (0.17 M) and the mixture was stirred at RT for 1 h. Solvents were evaporated under reduced pressure to give the title compound that was used as such in next step. MS (ES+) C21H29N3O5 requires 403, found: 404 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5](Cl)=[N:4][CH:3]=1.CO.[CH3:19][NH2:20]>>[Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5]([NH:20][CH3:19])=[N:4][CH:3]=1
Reactant: CN
Reactant: Fc1ccc2[nH]c3c(Br)cnc(Cl)c3c2c1
Solvent: CO
Product: CNc1ncc(Br)c2[nH]c3ccc(F)cc3c12
Temperature: 140 °C

Procedure:
4-Bromo-1-chloro-8-fluoro-5H-pyrido[4,3-b]indole (150 mg, 0.501 mmol) was dissolved in methylamine in methanol (3 mL, 6.00 mmol) and heated to 140° C. in the microwave for six hours. The reaction mixture was concentrated in vacuo and purified on silica gel (0-20% ethyl acetate/hexanes gradient elution).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:31][CH2:32][O:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])C(OC(C)(C)C)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:31][CH2:32][O:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(CCCCN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1

Procedure:
A solution of 2.9 g (5 mmol) of ethyl 8-[N-(p-chlorophenylsulfonyl)-N-(t-butoxycarbonyl)-amino]-4-[2-(3-pyridyloxy)ethyl]-octanoate in 30 ml trifluoroacetic acid is stirred at room temperature. After 18 h the reaction mixture is evaporated to dryness. The residue is dissolved in methylene chloride and the solution is washed with saturated NaHCO3 solution, dried and evaporated. The residue is chromatographed on silica gel using 1:1 ethyl acetate/methylene chloride as eluent to yield ethyl 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl]-octanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=[C:16]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[N:17]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: CC(C)(N)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(C)(C)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 72 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and 95% 2-amino-2-methyl-1-propanol (94 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 50° for 3 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as a off-white amorphous solid. mp 99-105° C., LC MS m/z=455 (MH+) Retention time=2.19 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.O.[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccccc1

Procedure:
The reaction Was carried out in the same reactor as that described above in Examples 3 and 4 which are representative of the present invention. Benzene in 7% stoichiometric excess is metered into a nitrating acid consisting of 2.3 wt. % of nitric acid, 68.0 wt. % of sulfuric acid and 29.7 wt. % of water. The amount of benzene was chosen so as to give a space-time yield of nitrobenzene of 4.3 t/m3h, based on the reactor volume. The mixture obtained was introduced into a reactor at a start temperature of 99.8° C. After 13.4 vol. % of the reaction space, the temperature of the reaction mixture was 113.6° C. The reaction end temperature was 123.6° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.P(O)(O)(O)=O.[NH2:16][OH:17].[OH-].[NH4+]>O>[CH3:1][C:2]([NH:16][OH:17])=[C:4]1[CH:5]=[CH:6][C:7](=[O:10])[CH:8]=[CH:9]1
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(NO)=C1C=CC(=O)C=C1
Yield: 211.8 %

Procedure:
A solution was prepared by adding 20.4 g (0.15 mol) of 4-hydroxyacetophenone and 12.9 g (65.6 mmol) of hydroxylamine phosphate to 100 mL of water at 70° C. To the solution was added 16.3 mL of 30% ammonium hydroxide which was then heated at reflux for 0.5 h. White crystals formed upon cooling yielding 21.0 g (92.6%) of 4-hydroxyacetophenone oxime.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])(=[O:4])=[O:3].[CH3:14][C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O>>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][C:10]([C:15]([CH3:20])([CH3:14])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][C:6]=1[O:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CC(C)=CC(=O)O
Reactant: COc1ccccc1OS(C)(=O)=O
Agent: O=S(=O)(O)O
Product: COc1ccc(C(C)(C)CC(=O)O)cc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
To a mixture of 2-methoxyphenyl methanesulfonate (Example 50b) (82 g, 406.4 mmol) and 3-methylbut-2-enoic acid (20.3 g, 203.2 mmol), was added concentrate sulfuric acid (11 mL, 96%, 206.3 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min, then heated to 70° C. and stirred under nitrogen overnight. Upon completion, the reaction was cooled to room temperature, quenched with ice water (500 mL) and extracted with ether (1×). The phases were separated, and the organic layer was washed with 2N NaOH (1×). The combined aqueous layers were acidified to pH 1 with 12N HCl at 0° C. and extracted with ether (1×). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a red-brown oil (14.4 g, contained <20% 3-methylbut-2-enoic acid) 1H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 6H), 2.53 (s, 2H), 3.31 (s, 3H), 3.79 (s, 3H), 7.08-7.31 (m, 3H), 11.87 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[N:16]=[C:15](Cl)[C:14]([F:18])=[CH:13][N:12]=1>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:11]2[N:16]=[C:15]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[C:14]([F:18])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(Nc2ncc(F)c(Nc3ccc(C#N)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine, 4-aminobenzonitrile and 2,4-dichloro-5-fluoropyrimidine gave N2,N4-bis(4-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 7.26 (d, J=8.7 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.86 (d, J=3.6 Hz, 1H), 9.49 (br, 1H, NH), 9.51 (br, 1H, NH); 19F NMR (282 MHz, DMSO-d6): δ −161.48; LC: 27.15 min.; 100%; MS (m/e): 331.00 (MH+).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]([CH3:16])[C:4]=1[CH2:17][CH3:18].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=1>>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]([CH3:16])[C:4]([CH2:17][CH3:18])=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: CCc1c(Cl)cc(-c2cccc(Cl)c2)nc1C
Agent: Cl
Product: CCc1c(Nc2ccc(CC(=O)OC)cc2)cc(-c2cccc(Cl)c2)nc1C
Temperature: 150 °C
Yield: 40.5 %

Procedure:
An 18-mL test tube was charged with 4-Chloro-6-(3-chlorophenyl)-3-ethyl-2-methyl-pyridine HCl salt (15 mg, 0.05 mmol, 1 eq.) and methyl 2-(4-aminophenyl)acetate (20 mg, 0.12 mmol, 2.4 eq.). The resulting mixture was heated at 150° C. under Ar for 1 hr. After cooling to room temperature, the mixture was partitioned between NaHCO3 aq. (10 ml) and dichloromethane (10 ml). The organic layer was collected and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel using dichloromethane/ethyl acetate (9:1 then 3:1) as eluent to methyl 2-[4-[[6-(3-chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]acetate (8 mg, 41% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([C@H:15]1[CH2:20][CH2:19][C@@H:18]([C:21](OC)=[O:22])[CH2:17][CH2:16]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:26]>>[CH2:8]([N:7]([C@H:15]1[CH2:20][CH2:19][C@@H:18]([C:21](=[O:22])[NH2:26])[CH2:17][CH2:16]1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N
Reactant: COC(=O)[C@H]1CC[C@@H](N(Cc2ccccc2)C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H]1CC[C@@H](C(N)=O)CC1
Temperature: 100 °C

Procedure:
tert-Butyl-cis-4-(methoxycarbonyl)cyclohexylbenzylcarbamate (0.25 g, 0.72 mmol) was dissolved in methanolic ammonia (15 ml) in a pressure bomb and heated at 100° C. for three days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford 200 mg of tert-butyl benzyl-cis-4-carbamoylcyclohexylcarbamate as crude compound. The crude compound (LC-MS shows 30% amide) was directly taken for next step.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[CH2:15][N:16]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[CH:31][CH:30]=[N:29][C:28]=34)=[O:23])[C:18]([C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[O:40][CH:41]([F:43])[F:42])=[N:17]2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([O:40][CH:41]([F:42])[F:43])=[C:33]([C:18]2[C:19]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[CH:31][CH:30]=[N:29][C:28]=34)=[O:23])=[CH:20][N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][CH:8]([NH:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:13][CH2:12]3)=[O:44])[N:17]=2)[CH:38]=1
Reactant: NC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-bromoacetate (30.74 mg, 0.20 mmol) was added to a mixture of N-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.18 mmol) in DMF (5 mL) and potassium carbonate (38.1 mg, 0.28 mmol). The resulting mixture was stirred at room temperature overnight. Additional amount of methyl 2-bromoacetate (30.74 mg, 0.20 mmol) was added and the resulting solution was stirred at 60° C. for 2 h. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (25.0% MeCN up to 32.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 25.0% in 2 min); Detector, UV 254/220 nm. This resulted in 68.9 mg (57%) of the formic acid salt of methyl 2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]-acetate as an off-white solid. LCMS (Method 24) [M+H]+=617.2, RT=1.53 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23-5.20 (m, 2H), 4.11-4.07 (m, 1H), 3.83-3.80 (m, 1H), 3.63 (s, 3H), 3.39-3.31 (m, 2H), 3.15-3.12 (m, 1H), 2.87-2.83 (m, 1H), 2.71-2.67 (m, 1H), 1.83-1.77 (m, 2H), 1.29-1.14 (m, 2H).