Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]3=[N:14][C:15]([NH:18][C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[N:16][CH:17]=[C:12]3[CH:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:24][N:22]1[CH:23]=[C:19]([NH:18][C:15]2[N:14]=[C:13]3[N:9]([CH2:8][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[N:7]=4)[N:10]=[CH:11][C:12]3=[CH:17][N:16]=2)[CH:20]=[N:21]1
Reactant: C1CCNC1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(F)n4)c3n2)cn1
Solvent: C1COCCO1
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCCC5)n4)c3n2)cn1
Temperature: 160 °C
Yield: 33 %

Procedure:
1-((6-fluoropyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 170) (45 mg, 0.138 mmol) was dissolved in dioxane/pyrrolidine (0.6 mL, 1:1) in a microwave tube under nitrogen. This was sealed and heated at 160° C. for 1 h. The mixture was concentrated in vacuo and re-dissolved in MeOH (2 mL). A solid precipitated over 16 h and was collected by filtration, and triturated with more MeOH to give N-(1-methyl-1H-pyrazol-4-yl)-1-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine as a white solid (17 mg, 33% yield). 1H NMR (d6-Acetone) δ 8.86 (s and br s, 2H), 8.05 (s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.35 (t, 1H), 6.28 (d, 1H), 6.18 (d, 1H), 5.47 (s, 2H), 3.82 (s, 3H), 3.38 (m, 4H), 1.95 (m, 4H); LC-MS method B, (ES+) 376.2, RT=4.95 min.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([Cl:18])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-(Trifluoromethyl)phenyl]acetic acid (4.1 g, 20.1 mmol) was dissolved in tetrahydrofuran (20 mL), and oxalyl chloride (2.1 mL, 24.5 mmol) and N,N-dimethylformamide (5 μL) were added. The reaction mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure to give [3-(trifluoromethyl)phenyl]acetyl chloride. To a solution of 3-amino-4-fluorophenol (2.43 g, 19.1 mmol) in tetrahydrofuran (20 mL) was added a suspension of sodium hydrogen carbonate (2.41 g, 28.6 mmol) in water (30 mL), and the mixture was vigorously stirred at room temperature. A solution of [3-(trifluoromethyl)phenyl]acetyl chloride produced above in tetrahydrofuran (10 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 min. Ethyl acetate (100 mL) was added to the reaction mixture to separate the aqueous layer. The organic layer was washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the obtained solution was purified by silica gel chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (5.84 g, 98%) as a pale-brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCc2ccc(OCCCCBr)cc2N1
Yield: 73.8 %

Procedure:
7-hydroxy-3,4-dihydroquinolin-2(1H)-one (163 mg, 1.0 mmol), 1,4-dibromobutane (0.36 mL, 3.0 mmol) and anhydrous K2CO3 (138 mg, 1.0 mmol) were dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=2:1) to give 7-(4-bromobutoxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 4) (220 mg, 74%) as a white solid. mp: 106-109° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14]([O:16]C)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:24]([O:23][C:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14]([OH:16])=[O:15])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)c1cnc(OC)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(C(=O)O)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the methyl 5-[bis(tert-butoxycarbonyl)amino]-6-methoxynicotinate (1 g, 2.61 mmol) in THF (10 mL) at 0° C. was added LiOH.H2O (275 mg, 6.54 mmol) in water (2.5 mL) and the reaction allowed to stir at room temperature for 4 hours. The reaction was diluted with water (5 mL) and extracted into DCM twice (2×10 mL). The aqueous layer was acidified to pH=5 with 10% citric acid solution and extracted into DCM (4×20 mL). The organic layers were collected, washed with brine (10 mL), dried over sodium sulphate and concentrated in vacuo to afford the title compound that was used directly in the next step.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([CH:18]=O)[O:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NO.C([N:25](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([C:18]#[N:25])[O:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2oc(C=O)cc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NO
Product: CC(C)(C)[Si](C)(C)OC1CCCc2oc(C#N)cc21

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1c) using 4-{[t-butyl(dimethyl)silyl]oxy}-4,5,6,7-tetrahydro-1-benzofuran-2-carboxaldehyde (4.3 g, 15.3 mmol) that was obtained in Example 7 (7b), hydroxylamine hydrochloride (1.2 g, 17 mmol), triethylamine (4.3 ml, 31 mmol), and N,N′-dicyclohexylcarbodiimide (3.5 g, 17 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (3.0 g) in a yield of 71% as a colourless oily product.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:26]([C:8]1[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[C:12]2[C:7]=1[CH:6]=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1)#[N:27]
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c2ccn(C3CC3)c2c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1cc(C#N)c2ccn(C3CC3)c2c1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
In a 300-mL egg plant-type flask, tetrakistriphenylphosphine palladium (2.31 g, 2.0 mmol) was added to a DMF (50 mL) solution of ethyl 1-cyclopropyl-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-indole-6-carboxylate (7.54 g, 20 mmol) and zinc cyanide (4.70 g, 40 mmol), then purged with nitrogen, and stirred at 90° C. for 1.5 hours. After left cooled, this was diluted with ethyl acetate (100 mL), and aqueous 25% ammonia (50 mL) and water (50 mL) were added thereto, stirred at room temperature for 30 minutes, extracted with ethyl acetate, and washed with water and saturated saline water in that order. The reaction solution was dried with sodium sulfate, filtered, concentrated, and purified through silica gel column chromatography (Biotage [SiO2, 40+M]) with a hexane/ethyl acetate developer system to obtain the title compound as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:20][NH2:21].O>ClCCl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:21][CH3:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
2,4-Difluoronitrobenzene (1.00 g, 6.29 mmol), potassium fluoride (0.365 g, 6.29 mmol), potassium carbonate (0.869 g, 6.29 mmol), and 40% methylamine in water (0.58 mL, 7.5 mmol) were added to a vial and heated in a microwave at 90° C. for 10 min. The reaction was then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, and concentrated to provide the title compound: 1H NMR (500 MHz, CDCl3) δ 8.22 (dd, J=9.4, 6.1 Hz, 1 H), 8.16 (br s, 1 H), 6.48 (dd, J=11.5, 2.6 Hz, 1 H), 6.40-6.36 (m, 1 H), 3.01 (d, J=5.0 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[NH2:13][C:14](N)=[O:15].N>O>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:14]([NH2:13])=[O:15])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=O
Reactant: COc1cccc2sc(N)nc12
Agent: N
Solvent: O
Product: COc1cccc2sc(NC(N)=O)nc12
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-methoxy-benzothiazole (330 mg, 1.83 mmol) and urea (1.1 g, 1.83 mmol) were heated together for 1 h at 170° C., with evolution of ammonia. After allowing to cool to r.t., water (10 ml) was added and the mixture was vigorously stirred. The solid was then filtered, washed with water (10 ml) followed by ethanol (10 ml) and dried at 60° C. under vaccum (0.05 mmHg). The title product was afforded as an off-white solid (300 mg, 73% yield), MS: m/e=223 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:7]=1.[CH2:21](O)[CH2:22][CH2:23][OH:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:21][CH2:22][CH2:23][OH:24])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cc(F)ccc2C)c1
Reactant: OCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(F)ccc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To 458 mg (1.49 mmol) 3-(5-fluoro-2-methylphenylsulfonyloxy)-5-methylphenol, as prepared in the preceding step, 1.08 mL (14.9 mmol) of 1,3-propanediol and 782 mg (2.98 mmol) of triphenylphosphine in 10 mL of anhydrous tetrahydrofuran was added 0.470 mL (2.98 mmol) of diethyl azodicarboxylate dropwise over 15 min. After stirring at ambient temperature for 2 h, the reaction mixture was concentrated to a semisolid. The resulting mixture was flash chromatographed on 50 g of silica gel with 8-10% ethyl acetate-dichloromethane. Impure fractions were re-chromatographed on 40 g of silica gel with 50-100% ethyl acetate-hexane. Material from the two purifications was combined to afford 530 mg (97% yield) of the title compound as a colorless oil: 1H-NMR (300 MHz; CDCl3) δ 7.59 (dd, 1H, J=8.3, 2.8 Hz), 7.38 (dd, 1H, J=8.4, 5.3 Hz), 7.25 (td, 1H, J=8.4, 2.8 Hz), 6.62 (m, 1H), 6.1 (m, 1H), 6.37 (t, 1H, J=2.1 Hz), 4.00 (t, 2H, J=6.0 Hz), 3.83 (dd, 2H, J=11.3, 5.8 Hz), 2.73 (s, 3H), 2.24 (s, 3H) and 1.99 (pentet, 2H, J=6.0 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H19FO5S: 377.1 (M+Na). Found: 377.0.
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(N(CC)CC)C>CS(C)=O>[F:1][C:2]1[C:22]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3cc2c1=O
Yield: 8.3 %

Procedure:
Ethyl 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was prepared by analogy to the method described in Example 1, from 3.2 g of ethyl 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate, 2.16 g of 4-(4-fluorophenyl)piperazine and 3.35 cm of triethylamine in 40 cm3 of dimethyl sulphoxide. After filtering off with 2 times 15 cm3 of water and 2 times 15 cm3 of ethanol, 0.4 g of ethyl 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was obtained in the form of a yellow solid melting at about 310° C.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.[NH:24](C(OCC1C=CC=CC=1)=O)[C@H:25]([C:36]([NH:38][C@H:39]([C:43](O)=[O:44])[CH:40]([CH3:42])[CH3:41])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1>>[NH2:24][C@@H:25]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[C:36]([NH:38][C@@H:39]([CH:40]([CH3:41])[CH3:42])[C:43]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:44])=[O:37]
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Method B, Example 12, and employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-Trp-Val-OH as the staring materials, which yielded the title compound as a white powder. 1H NMR (CD3OD, 300 MHz): δ 7.65-7.62 (d, 1H), 7.38-7.35 (d, 1H), 7.17-7.01 (m, 3H), 4.26-4.20 (m, 1H), 4.17-4.14 (d, 1H), 4.05 (m, 1H), 3.46-3.20 (m, 4H), 2.00 (m, 1H), 1.9-1.88 (m, 2H), 1.77-1.54 (m, 8H), 1.34-1.16 (m, 3H), 1.05-0.94 (m, 8H). 31P NMR (CD3OD, 300 MHz): δ 42.89. LCMS m/z: [M+H]+=521.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]=[C:9]([Cl:30])[C:10]=1[NH:11][C:12]1[N:22]=[C:21]2[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]2[CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:14][N:13]=1)[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][CH:57]1[CH2:62][CH2:61][N:60]([CH3:63])[CH2:59][CH2:58]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]=[C:9]([Cl:30])[C:10]=1[NH:11][C:12]1[N:22]=[C:21]2[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]2[CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:14][N:13]=1)[C:5]([NH:56][CH:57]1[CH2:62][CH2:61][N:60]([CH3:63])[CH2:59][CH2:58]1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3c(Cl)cc(C(=O)O)c(F)c3Cl)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2cc(Cl)c(Nc3ncc4c(n3)N(C3CCCC3)CCC(=O)N4C)c(Cl)c2F)CC1
Reaction time: 2 h
Yield: 65.9 %

Procedure:
3,5-dichloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2-fluoro-benzoic acid (Intermediate 221; 85 mg, 0.18 mmol), HATU (104 mg, 0.27 mmol) and 4-amino-1-methylpiperidine (32 mg, 0.27 mmol) were stirred in DMF (3 mL) and diisopropylethylamine (95 μl, 0.54 mmol) added. The mixture was stirred for 2 hours and absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the residue purified by column chromatography (4% ammonia in methanol/DCM) to yield the title compound as a white solid (67 mg, 66%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][O:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(Oc2ccccc2)cnc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 62 %

Procedure:
5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine (0.68 mmol) is dissolved in DMF (7 ml), phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction mixture is heated to 100° C. in the microwave for 30 min. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-ethoxy)-2-nitro-5-phenoxy-pyridine is obtained after column chromatography (heptane ethyl acetate) as yellow oil in a yield of 62%; HPLC (method C): 1.93 min; LC-MS (method A): 1.80 min, 291.15 (M+H+).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:23][CH2:22][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]1>>[CH2:20]([O:19][C:17]([CH:16]1[CH2:22][CH2:23][N:13]([C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCC(C(=O)OCC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and ethyl isonipecotate as starting raw materials, to produce an intended compound.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][OH:5].O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:16])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:16])=[O:15]
Reactant: NC(=O)Nc1ccccc1O
Reactant: OC[C@H]1CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC(=O)Nc1ccccc1OC[C@H]1CO1
Temperature: 25 °C
Yield: 40.3 %

Procedure:
To a mixture of (2S)-oxiran-2-ylmethanol (296 mg, 4.0 mmol), N-(2-hydroxyphenyl)urea (609 mg, 4.0 mmol) and triphenylphosphine (1.05 g, 4.0 mmol) in THF (10 mL) was dropwise added DEAD (697 mg, 4.0 mmol) in THF (3 mL) at room temperature. After addition was completed the reaction mixture was stirred at room temperature over night. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-80% ethyl acetate in petroleum spirit) to give sub-title compound (336 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][O-:15].[Na+]>>[CH3:14][O:15][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C[O-]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Product: COc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
2-Chloro-5-nitro-benzoic acid (3 g, 14 mmol) was added to a solution of freshly prepared sodium methoxide (from sodium (1.36 g, 56 mmol) in dry methanol (15 ml)) and the reaction was heated to reflux for 12 hr. Methanol was evaporated and the reaction mass diluted with water (25 ml). Conc hydrochloric acid was added until the pH was ˜2. The reaction mixture was stirred at room temperature for 30 min, then the precipitate was filtered and washed with water. Drying at 60-70° C. yielded 2-methoxy-5-nitro benzoic acid (2.4 g, 81%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[CH2:5]1)(=[O:3])[CH3:2].[CH3:14][C:15]1([CH3:23])[CH2:20][C:19](=[O:21])[CH2:18][C:17](=[O:22])[CH2:16]1.C(N(CC)CC)C>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:18]2[C:19](=[O:21])[CH2:20][C:15]([CH3:23])([CH3:14])[CH2:16][C:17]2=[O:22])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(=O)c2ccccc21
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)n1cc(C2C(=O)CC(C)(C)CC2=O)c2ccccc21
Yield: 76 %

Procedure:
1-Acetyl-1,2-dihydroindol-3-one of Example 1d (131.3 g, 0.75 mol) and 5,5-dimethyl-cyclohexane-1,3-dione (105 g, 0.75 mol) were added to a mixture of acetic acid (700 mL) and triethylamine (105 mL, 0.75 mol) at room temperature under stirring. The reaction mixture was refluxed for 6 h. About ⅓ volume of solvents was removed in vacuum, and the mixture was cooled and diluted with water (50 mL). The precipitate was filtered off, washed with ethanol-water, 1:1 and dried to afford 169.4 g (76%) of colorless crystals; m.p. 225-227° C.
Reaction SMILES: [N:1]1([N:7]2[NH:11][CH:10]=[C:9]([C:12]3[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=3)[S:8]2)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH3:21][N:22]1CCNCC1.N1CCCCC1>>[CH3:21][N:22]1[CH2:5][CH2:6][N:1]([N:7]2[NH:11][CH:10]=[C:9]([C:12]3[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=3)[S:8]2)[CH2:2][CH2:3]1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCCCC2)S1
Reactant: CN1CCNCC1
Solvent: C1CCNCC1
Product: CN1CCN(N2NC=C(c3ncc([N+](=O)[O-])n3C)S2)CC1

Procedure:
The preparation of the above compound is carried out in the manner described for the 2-piperidino derivative (Example 28), an equivalent of 1-methylpiperazine replacing the piperidine. The crude product is purified by recrystallization from 2-methoxyethanol and melts at 242°-244° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:16]1([C:22]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[C:25]([C:31]([F:33])([F:32])[F:34])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])[CH2:17][CH2:18]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(c1c(F)cccc1C(F)(F)F)N1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3c(F)cccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(6-fluoro-2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (16.8% yield). 1H NMR (400 MHz, CDCl3) δ 8.06, 7.85, 7.57-7.55, 7.39-7.36, 7.01, 4.04-3.94, 3.86-3.79, 3.49, 3.44-3.36, 1.73-1.68, 1.52, 0.94.