Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:19][S:20]([O:18][CH2:17][CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)(=[O:22])=[O:21]
Reactant: OCCCc1cccc(OCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCc1cccc(OCc2ccccc2)c1

Procedure:
In substantially the same manner as in Reference Example 85, 3-(3-benzyloxyphenyl)propanol was allowed to react with methanesulfonyl chloride to give 3-(3-benzyloxyphenyl)propyl methanesulfonate. The yield was quantative. Oily substance.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCCS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1

Procedure:
Compound A28 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), propane-1-sulfonyl chloride (8 mg, 0.056 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 1.09 (t,3H), 1.90 (m,2H), 2.07 (m,4H), 2.95 (m, 2H), 3.08 (s, 3H), 3.40 (m, 2H), 3.57 (m, 2H), 5.67 (m, 1H), 7.87 (d, 2H), 7.98 (d, 2H), 8.41 (s, 1H), 10.21 (s, 1H). Exact mass calculated for C19H25N5O7S2 499.12, found 500.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=[C:4]2[CH:3]=1.[F:22][C@H:23]1[C@H:29](OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:28][CH2:27][N:26]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:25][CH2:24]1.C(N=C(N(C)C)N(C)C)(C)(C)C>CC#N>[F:22][C@H:23]1[C@@H:29]([O:21][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([C:8]2[N:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]4=[N:10][N:9]=2)[CH:20]=[CH:19]3)[CH2:28][CH2:27][N:26]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: Cc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: Cc1ccn2c(-c3ccc4cccc(O[C@H]5CCN(C(=O)OC(C)(C)C)CC[C@H]5F)c4n3)nnc2c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (300 mg, 1.09 mmol) was suspended in CH3CN (5 mL) at ambient temperature, and trans-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate (454 mg, 1.09 mmol) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (263 μL, 1.30 mmol) were added. The dark solution was stirred at 40° C. overnight, then concentrated to a grey solid which was slurried in water for 10 minutes. The solid was filtered, washed and dried in vacuo to provide the desired product. MS ESI (+) m/z 492.3 (M+1) detected.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[C@H:6]([OH:12])[CH2:5]1.Cl[C:14]1[C:19]([CH3:20])=[N:18][CH:17]=[CH:16][N:15]=1.[O-2].[Ca+2]>C(Cl)Cl.CO>[CH3:20][C:19]1[C:14]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[C@H:6]([OH:12])[CH2:5]2)=[N:15][CH:16]=[CH:17][N:18]=1
Reactant: Cc1nccnc1Cl
Reactant: NCCN1CC[C@H](CO)[C@H](O)C1
Agent: [Ca+2]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Product: Cc1nccnc1NCCN1CC[C@H](CO)[C@H](O)C1
Temperature: 120 °C
Reaction time: 5 h
Yield: 23.5 %

Procedure:
A mixture of (±)-cis-1-(2-aminoethyl)-3-hydroxy-4-piperidinemethanol (0.064 mol), 2-chloro-3-methylpyrazine (0.068 mol) and calcium oxide (0.145 mol) was stirred for 5 hours at 120° C. The reaction mixture was cooled. The mixture was dissolved in CH2Cl2 /CH3OH and filtered over dicalite. The filtrate was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 90/10). The desired fractions were collected and the solvent was evaporated. The oily residue was triturated in CH3CN. The precipitate was filtered off and dried, yielding 4 g (23.5%) of (±)-cis-1-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-3-hydroxy-4-piperidinemethanol (interm. 5a).
Reaction SMILES: NC1C=CC=CC=1.Cl.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+].Cl[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C(#N)C.O>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([NH:24][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(COc2cccc(N)c2)cc1
Reactant: COC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: Nc1ccccc1
Product: COC(=O)CNc1cccc(OCc2ccc(C)cc2)c1

Procedure:
A mixture of the aniline (Intermediate 82, 20 g, 94 mmol), sodium bicarbonate (11.8 g, 141 mmol) and methyl chloroacetate (9.1 ml, 103 mmol) in acetonitrile (30 ml) was heated at 90°-100° for 24 h. Water (200 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were washed with 2N hydrochloric acid (2×100 ml), water (2×100 ml) and brine (100 ml) before drying (Na2SO4) and evaporating to an orange solid. Trituration with ether, followed by evaporation of the triturate gave the title compound (Intermediate 83) as a pale grey solid (16 g; 60%), m.p. 78°-80°.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[C:18]4[CH:19]=[C:20]([OH:25])[C:21]([Br:24])=[C:22]([Br:23])[C:17]=4[O:16][CH:15]=3)=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+]([O-])(O)=[O:27].O>CC(O)=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[C:18]4[C:19](=[O:27])[C:20](=[O:25])[C:21]([Br:24])=[C:22]([Br:23])[C:17]=4[O:16][CH:15]=3)=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccc(-n2ccnc2)cc1)c1coc2c(Br)c(Br)c(O)cc12
Solvent: O
Solvent: CC(=O)O
Product: O=C1C(=O)c2c(C(=O)c3ccc(-n4ccnc4)cc3)coc2C(Br)=C1Br
Temperature: 60 °C
Yield: 74.1 %

Procedure:
To a solution of (4-(1H-imidazol-1-yl)phenyl)(6,7-dibromo-5-hydroxybenzofuran-3-yl)methanone (55 mg, 0.119 mmol) in AcOH (1 mL) was added nitric acid—69% (36.7 μl, 0.595 mmol) at room temperature. The mixture was heated to 60° C. for 1 hour then cooled to room temperature, poured onto iced water (3 mL) and the suspension filtered under vacuum to furnish 42 mg of a red/orange solid. 1H NMR (DMSO-d6) was consistent with two species—product and starting material. The material was re-subjected to the above conditions for a further hour and then worked up as before to afford compound x (25 mg, 44%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Br:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.CN(C=O)C>CCOC(C)=O>[Br:11][C:12]1[CH:13]=[N:14][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH:16]=1
Reactant: Brc1cn[nH]c1
Reactant: Brc1ccnc2[nH]ccc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cnn(-c2ccnc3[nH]ccc23)c1
Temperature: 150 °C

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.10 g, 0.00558 mol) and 4-bromo-1H-pyrazole (1.2 g, 0.0084 mol) was heated neat to 150° C. for 2 h. DMF was added to dissolve the crude residue. This residue was taken up in EtOAc and washed with 1N NaOH. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a crude 4-(4-bromo-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine residue, LC/MS (M+H)+: 263,265.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:6](=[O:8])[CH:5]([O:4][C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[Cl:1])[CH3:9])[N+:19]([O-:21])=[O:20]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(Oc1ccccc1Cl)C(=O)O
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CC(Oc1ccccc1Cl)C(=O)NCCO[N+](=O)[O-]
Yield: 42.1 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 2-(2-chlorophenoxy)propionic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.43 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][NH:6][NH2:7].C([O:16][C:17](=O)[CH:18]=[C:19]([NH2:23])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:23][C:19]1[NH:7][N:6]([CH2:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:12])([F:13])[F:1])[C:17](=[O:16])[CH:18]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccccc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccccc2C(F)(F)F)[nH]1
Reaction time: 8 h

Procedure:
46 g of 2-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 38.2 g of β-amino-β-ethoxyacrylic acid ethyl ester and 2 g of p-toluenesulphonic acid in 250 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the residue was recrystallised from ethanol. The product was the compound identified above. Melting point: 184°, 22 g (34%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:7]3[C:6](=[O:19])[C:5]=2[CH:4]=1>Br.C(O)(=O)C.O>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:7]3[C:6](=[O:19])[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc2[nH]c3ccc(O)cc3c(=O)n2n1

Procedure:
A suspension of 4,9-dihydro-7-methoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (2.0 g; 0.0077 mole) in 48% hydrobromic acid (30 ml) and glacial acetic acid (50 ml) is refluxed for 23 hrs. The mixture is cooled and then diluted with water (25 ml). The product, which precipitates out, is collected by filtration and recrystallized from DMF-Ether (1:1, 90 ml). Yield 1.1 g; mp 285°-286° C. (d).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[CH3:20][C:21]1([CH3:39])[CH2:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([S:30]([NH:33][C:34](=[O:38])[CH:35](Br)[CH3:36])(=[O:32])=[O:31])[C:23]=2[O:22]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:39][C:21]1([CH3:20])[CH2:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([S:30]([NH:33][C:34](=[O:38])[CH:35]([O:8][C:7]3[CH:6]=[C:5]([N:9]4[C:13](=[O:14])[N:12]([CH:15]([F:16])[F:17])[C:11]([CH3:18])=[N:10]4)[C:4]([F:19])=[CH:3][C:2]=3[Cl:1])[CH3:36])(=[O:32])=[O:31])[C:23]=2[O:22]1
Reactant: CC(Br)C(=O)NS(=O)(=O)c1cccc2c1OC(C)(C)C2
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nn(-c2cc(OC(C)C(=O)NS(=O)(=O)c3cccc4c3OC(C)(C)C4)c(Cl)cc2F)c(=O)n1C(F)F

Procedure:
A stirred mixture of 0.2 gram (0.0007 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.3 gram (0.0007 mole) of N-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)sulfonyl-2-bromopropionamide, 0.3 gram (0.002 mole) of potassium carbonate in 20 ml of acetone was heated under reflux for 18 hours. The reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was dissolved in 100 ml of water and the solution acidified by the dropwise addition of concentrated hydrochloric acid. The resultant precipitate was collected by filtration, washed with water, and dried to yield N-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)sulfonyl-2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionamide; m.p. 198°-201° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([C:12](OCCCC)=[O:13])[CH:9]=[CH:8][C:7]=1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[F:27])[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[F:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ccc(-c2cc(OC)ccc2F)c(OCCCC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1cc(CO)ccc1-c1cc(OC)ccc1F
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To 5.2 (1.1530 g, 3.079 mmol) in THF (10 mL) at 0° C. was added LAH (1.0 M solution in THF (4.619 mL, 4.619 mmol)). The reaction was stirred for one hour and then carefully diluted with water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to provide 5.3 (0.9050 g, 96.57% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[Cl:17])[NH:13][CH:12]=[C:11]2[CH2:18][C:19]([O:21]CCCC)=[O:20]>O.CO>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[Cl:17])[NH:13][CH:12]=[C:11]2[CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCCCOC(=O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Yield: 33.2 %

Procedure:
An aqueous solution prepared by dissolving 280 mg of potassium carbonate in 2.5 ml of water was added to a solution of 100 mg of n-butyl 5,6-dichloroindole-3-acetate in 10 ml of methanol. After 1.5 hours of refluxing, the methanol was removed from the reaction solution under reduced pressure, and the aqueous solution thus obtained was extracted with ethyl acetate. The aqueous phase was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase was washed with distilled water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was purified by a silica gel thin-layer chromatography to obtain 27 mg of 5,6-dichloroindole-3-acetic acid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:11][C:12]1([CH3:21])[O:16][CH:15]([CH2:17][CH2:18]CO)[CH2:14][O:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][CH2:17][CH:15]2[CH2:14][O:13][C:12]([CH3:21])([CH3:11])[O:16]2)[CH:3]=1
Reactant: CC1(C)OCC(CCCO)O1
Reactant: Brc1c[nH]c2cnccc12
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(CCn2cc(Br)c3ccncc32)O1
Yield: 199.9 %

Procedure:
A mixture of Example 695J (118 mg, 0.6 mmol), 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-propan-1-ol (131.6 mg, 0.9 mmol), polymer-supported PPh3 (400 mg, 1.2 mmol), and DBAD (0.268 mg, 1.2 mmol) in THF (3 mL) was stirred at room temperature for 8 hours. The reaction mixture was loaded onto the silica gel column and eluted with 100% EtOActo give 0.39 g of the desired product (67%). MS (DCI) m/e 326 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 8.94 (s, 1H), 8.23 (d, J=5.49 Hz, 1H), 7.88 (s, 1H), 7.41 (d, J=5.49 Hz, 1H), 4.37-4.40 (m, 2H), 3.91-3.97 (m, 2H), 3.47 (dd, J=7.63, 6.41 Hz, 1H), 2.07 (m, 1H), 1.98 (m, 1H), 1.34 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)CC
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)C(C)(C)C)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-chlorophenoxy)acetic acid methyl ester and 2-[4-(2,2-dimethylpropionyl)benzyl]-3-oxopentanoic acid ethyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1.[H][H]>[Pd].O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC(C)=CCC#CCC#CCCCCCCCl
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC(C)=CCC=CCC=CCCCCCCCl

Procedure:
A mixture of 11.0 g. of 1-chloro-14-methyl-nonadeca-7,10-diyn-13-ene, 1.5 g. of 5% palladium on barium sulfate, and 80 ml. of pyridine was shaken in a Parr rocker under 40 lb. of hydrogen pressure for about 1.3 hrs., at which time two moles of hydrogen had been absorbed. The reaction mixture was then poured into water and extracted with ether. The extract was washed with water, dilute hydrochloric acid, saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated leaving a residue comprising 1-chloro-14-methyl-7,10,13-nonadecatriene. The residue was distilled in a rocking short-path distillation apparatus, collecting 7.6 g. of a mixture comprising 1-chloro-14-methyl-7,10,13-nonadecatriene at a bath temperature of 180°C. and a pressure of 0.005 mm.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH3:28][O:29][CH2:30][CH2:31][CH2:32][NH2:33].CCCP(=O)=O>O1CCCC1>[CH3:28][O:29][CH2:30][CH2:31][CH2:32][NH:33][C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26]
Reactant: COCCCN
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Product: COCCCNC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 3-methoxypropan-1-amine (169 μl, 1.66 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording N4-(3-Methoxypropyl)-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (113 mg, 94.3%) as a white solid. mp.: 191-3° C. MS: m/z=434.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[CH3:13][N:14]=[C:15]=[O:16]>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:13][NH:14][C:15](=[O:16])[O:11][C:10]1[C:4]2[O:3][C:2]([CH3:12])([CH3:1])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)Oc2cccc(O)c2O1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)Oc1cccc2c1OC(C)(C)O2
Reaction time: 0.5 h
Yield: 85 %

Procedure:
2,2-Dimethyl-4-hydroxy-1,3-benzodioxole (14 parts) in benzene (25 parts) was treated with methyl isocyanate (6 parts) and a few drops of triethylamine with cooling. After standing for 30 minutes, the crystals of 2,2-dimethyl-1,3-benzodioxol-4-yl N-methylcarbamate which formed were filtered off and washed with benzene then with petroleum (boiling point below 40° C.) to yield the pure compound as a white solid, melting point 129°-130° C. (16 parts, 85% yield).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:44])[O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[C:17]1([C:16]([NH:15][CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:1])[F:25])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:33]([O:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:44])[CH2:12]2)=[O:23])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC1CNCC(c2ccc(C(F)(F)F)cc2)C1)c1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 1.5 g (4.3 mmol) of N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide and 1.2 ml (1.1 mmol) of triethylamine were initially charged in 131 ml of dichloromethane, and 868 mg (4.3 mmol) of 4-nitrophenyl chlorocarbonate were added slowly. The mixture was stirred at 0° C. for 2 h and then warmed to RT. Water and saturated aqueous sodium bicarbonate solution were added, and the reaction mixture was extracted. The organic phase was concentrated under reduced pressure and purified by column chromatography (cyclohexane/ethyl acetate 1:2). Yield: 1.95 g (88% of theory)
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[C@@H:32]([CH3:33])[CH2:31][O:30][CH2:29][C@H:28]3[CH3:34])=[O:26])=[CH:21][N:20]=2)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=1)(=O)C.[OH-].[Li+].O>C1COCC1.C(O)(C)C.O>[CH3:34][C@H:28]1[CH2:29][O:30][CH2:31][C@@H:32]([CH3:33])[N:27]1[C:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=[C:12]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:37]4[CH2:49][CH2:48][N:40]5[C:41]6[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=6[CH:47]=[C:39]5[C:38]4=[O:50])[C:6]=3[CH2:5][OH:4])[CH:17]=2)=[N:20][CH:21]=1)=[O:26]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4[C@H](C)COC[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1COC[C@H](C)N1C(=O)c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a solution of 322a (136 mg, 0.20 mmol) in THF/i-propanol/water (4/2/1 mL) was added lithium hydroxide (48 mg, 2.0 mmol) at room temperature. After the reaction was stirred for 2 h, LCMS indicated the reaction was complete. Then the mixture was poured into water (15 mL) and extracted with dichloromethane (3×15 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC (A: 1% NH4HCO3/water, B: acetonitrile) to afford 322 (50 mg, 40%) as a white solid. MS-ESI: [M+H]+ 638.3. 1HNMR (500 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.77 (d, J=5.5 Hz, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.64-7.62 (m, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.37-7.35 (m, 2H), 6.57 (s, 1H), 4.95 (t, J=4.5 Hz, 1H), 4.47-4.38 (m, 2H), 4.23-3.99 (m, 5H), 3.88-3.87 (m, 1H), 3.65-3.61 (m, overlap, 5H), 3.56-3.53 (m, 2H), 2.66-2.56 (m, 2H), 2.47-2.44 (m, 2H), 1.80-1.79 (m, 2H), 1.70-1.66 (m, 2H), 1.25 (d, J=6.0 Hz, 6H)