Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][C@H:4]1[OH:16].[NH2:17][C:18]1[C:30]([Cl:31])=[CH:29][C:21]([C:22](N2C=CN=C2)=[O:23])=[C:20]([O:32][CH3:33])[C:19]=1[O:34][CH3:35]>C(#N)C>[NH2:17][C:18]1[C:30]([Cl:31])=[CH:29][C:21]([C:22]([NH:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][C@H:4]2[OH:16])=[O:23])=[C:20]([O:32][CH3:33])[C:19]=1[O:34][CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)[C@H](O)C1
Reactant: COc1c(C(=O)n2ccnc2)cc(Cl)c(N)c1OC
Solvent: CC#N
Product: COc1c(C(=O)NC[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc(Cl)c(N)c1OC
Yield: 78.5 %

Procedure:
A mixture of intermediate (1-e) (0.087 mol) and intermediate (3-a) (0.087 mol) in acetonitrile (600 ml) was stirred and refluxed for 90 min. The reaction mixture was cooled, and the solvent was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE with a drop of ACN, filtered off and dried (vacuum, 40° C.), yielding 30.3 g (80%) of (±)-1,1-dimethylethyl trans-4-[[(4-amino-5-chloro-2,3-dimethoxybenzoyl)amino]methyl]-3-hydroxy-1-piperidinecarboxylate (interm. 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([CH2:29][NH2:30])[OH:28].C(N(C(C)C)CC)(C)C.Cl>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([NH:30][CH2:29][CH2:27][OH:28])=[O:23])=[CH:19][CH:20]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Cc2ccc(CC(=O)Cl)cc2)nc(-c2cccc(Cl)c2)n1
Reactant: NCCO
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(Cc2ccc(CC(=O)NCCO)cc2)nc(-c2cccc(Cl)c2)n1
Reaction time: 3 h
Yield: 43.9 %

Procedure:
To a stirred solution of crude 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetyl chloride (˜0.20 mmol) in dichloromethane (8 mL) at 0° C. was added ethanolamine (0.060 mL, 1.00 mmol) followed by diisopropylethylamine (0.17 mL, 1.00 mmol). After stirring for 3 h, the reaction mixture was diluted with dichloromethane (50 mL) and water (5 mL). The mixture was acidified with 2N aqueous HCl until pH˜5. The organic layer was washed with saturated sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.036 g, 45%) as a white solid. MW=409.91. M.p. 136-138° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.37-8.31 (m, 2H), 8.02-7.96 (m, 1H), 7.59 (dt, J=6.5, 2.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 4.63 (t, J=5.0 Hz, 1H), 4.09 (s, 2H), 3.40-3.35 (m, 4H), 3.90 (q, J=6.0 Hz, 2H), 2.77 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H); APCI MS m/z 410 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15](=[O:19])[CH2:16][C:17]#[N:18])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.CSC.N.CO.C(Cl)Cl.BrC1N=C(C(O)=O)C=CC=1>>[NH2:18][CH2:17][CH2:16][CH:15]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:14]=[CH:13][N:12]=1)[OH:19]
Reactant: N#CCC(=O)c1cc(OCC2CCCCC2)ccn1
Agent: B
Agent: N
Agent: O=C(O)c1cccc(Br)n1
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: NCCC(O)c1cc(OCC2CCCCC2)ccn1

Procedure:
Reduction of 3-(4-(cyclohexylmethoxy)pyridin-2-yl)-3-oxopropanenitrile with borane-dimethylsulfide following the method used in Example 2 gave after flash chromatography purification (20%-30% 7N NH3/MeOH—CH2Cl2 gradient) Example 12 as a yellow oil. Yield (0.13 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J=4.5 Hz, 1H), 6.98 (d, J=2.3 Hz, 1H), 6.76 (dd, J=5.9, 2.8 Hz, 1H), 4.62-4.58 (m, 1H), 3.94 (d, J=5.8 Hz, 2H), 2.72-2.58 (m, 2H), 1.88-1.58 (m, 8H), 1.40-1.02 (m, 5H); RP-HPLC tR=5.91 min; ESI-MS m/z 265.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20](N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:20])=[O:15])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
A mixture of 16.2 g (64.5 mmol) of 4-(tert-butoxycarbonylaminomethyl)benzoic acid, 13.6 g (70.9 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.00 g of 4-dimethylaminopyridine and 200 ml of methanol was stirred at room temperature for 4 hours. Methanol was distilled off under reduced pressure and ice water was poured to the residue thus obtained. The mixture was extracted twice with ethyl acetate and the extract was washed with 10% citric acid aqueous solution and then with saturated sodium hydrogencarbonate aqueous solution and finally with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 14.3 g (83.6%) of methyl 4-(tert-butoxycarbonylaminomethyl)benzoate.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[N:12]=[C:11]([O:13][C@H:14]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)[CH:10]=[CH:9][CH:8]=2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:16]1[CH2:17][CH2:18][C@H:14]([O:13][C:11]2[N:12]=[C:7]([C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc(-c3n[nH]c(=O)[nH]3)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]nc(-c2cccc(O[C@H]3CCNC3)n2)[nH]1
Yield: 14 %

Procedure:
Crude (S)-tert-butyl 3-((6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)pyrrolidine-1-carboxylate was treated with DCM (4 mL) and TFA (2 mL) for 2 hours at RT and then concentrated. The crude product was purified by preparative HPLC eluting with a gradient of 1-25% ACN in water (acid mode) to give the title compound (125 mg, 14.0% over 3 steps).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>>[C:1]1([C:7]2[NH:12][C:11]3[C:13]([CH:8]=2)=[CH:14][CH:15]=[CH:16][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1I
Reactant: C#Cc1ccccc1
Product: c1ccc(-c2cc3ccccc3[nH]2)cc1

Procedure:
The general procedure was used to convert phenylacetylene and 2-iodoaniline to the title product. Purification by flash chromatography gave the analytically pure product as a white solid (92% yield). 1H NMR (300 MHz, DMSO) δ 11.54 (s, 1H), 7.86-7.84 (d, J=7.15, 2H), 7.53-7.50 (d, J=7.72, 1H), 7.45-7.40 (t, J=7.72, 3H), 7.30-7.25 (t, J=7.34, 1H), 7.01-6.96 (t, J=6.97, 1H), 6.87 (s, 1H). 13C NMR (75 MHz, DMSO) δ 138.48, 138.01, 133.09, 132.43, 132.30, 129.76, 129.25, 128.24, 125.84, 122.44, 120.93, 120.24, 112.18, 99.55. Anal. Calcd. for C14H11N: C, 87.01; H, 5.74; N, 7.25. Found C, 86.87; H, 5.72; N, 6.99. m.p.: 183-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.[F-].[Cs+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:32]=[CH:31][CH:30]=[C:29]([C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])[CH:28]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: O=C(N1CCc2ccc(Cl)c(-c3cccc(-c4ccccc4)c3)c2CC1)C(F)(F)F

Procedure:
Combine 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol), 3-biphenylboronic acid (280 mg, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.047 mmol) and cesium fluoride (144 mg, 0.94 mmol) in anhydrous DME (8 mL) and reflux the mixture for 3 h. Cool the reaction mixture and partition between brine and EtOAc. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 7:3 gradient) to obtain 6-(biphenyl-3-yl)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:29])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18](NC(C3CC3)=O)[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+].[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:29])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([C:36]([CH:35]3[CH2:33][CH2:34]3)=[O:32])[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)c(C(=O)n2ccc3c(C(=O)C4CC4)nccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To the stirred solution of methyl 3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoate (500 mg, 1.1 mmol) in tetrahydrofuran and water (1:1, 5 mL) was added sodium hydroxide (46 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for about 1 hour. The reaction mixture was then concentrated under vacuum and the aquoeus residue was neutralized using dilute hydrochloric acid. The precipitated solid was filtered, washed with water and dried to afford 3,5-dichloro-4-{[4-(cyclopropylcarbonyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoic acid (470 m g, 97%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[CH2:18][N:17]([C:19]4[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=4[CH3:28])[CH2:16][CH2:15][C:13]=3[N:14]=2)=[CH:4][CH:3]=1.C1COCC1>[Pd].CO>[NH2:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:28])=[C:19]([N:17]2[CH2:16][CH2:15][C:13]3[N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:10]=[CH:11][C:12]=3[CH2:18]2)[CH:24]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(Cl)cc3)ncc2C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(Cl)cc3)ncc2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (4-Chloro-phenyl)-[6-(2-methyl-5-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]amine (100 mg, 0.25 mmol) in the mixed solvent of THF (5 ml) and methanol (5 ml) was added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give [6-(5-Amino-2-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-(4-chloro-phenyl)amine [12]as a off white solid [Yield: 81.5 mg, 88.2%]
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:35]([NH:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]([O:26][CH3:25])=[O:37])=[O:36])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added methyl-2-isocyanatobenzoate (216 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 239 mg (69.5%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]([OH:20])=[CH:10][CH:9]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]([O:20][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]/[C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CCCCc1ccc(O)c(CCC(=O)OC)n1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Product: COC(=O)CCCCc1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(CCC(=O)OC)n1
Yield: 44.7 %

Procedure:
Under the conditions of example 1 D, 490 mg of 5-[3-hydroxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-pentanoic acid methyl ester is reacted with 365 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 293 mg of 5-{2-(2-methoxycarbonylethyl)-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-pyridyl}-pentanoic acid methyl ester is obtained as oil.
Reaction SMILES: [Br-].[CH2:2]([N+:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].BrCC(C1C=CC=CC=1)=O.[N:31]1C2CCCCC=2[CH:34]=[CH:33][CH:32]=1>C(#N)C>[C:3]([C:2]1[N:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][C:12]2=[C:33]([C:32]#[N:31])[CH:34]=1)(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(C[n+]1cccc2c1CCCC2)c1ccccc1
Reactant: c1cnc2c(c1)CCCC2
Agent: O=C(CBr)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: N#Cc1cc(C(=O)c2ccccc2)n2c3c(ccc12)CCCC3

Procedure:
1-(Phenacyl)-5,6,7,8-tetrahydro-quinolinium bromide: The title compound was prepared from 2-bromo-1-phenyl-ethanone (507.7 mg, 2.55 mmol), 5,6,7,8-tetrahydro-quinoline (275 μL, 2.13 mmol) and acetonitrile (4.2 mL), similar to Example 1a, and yielded 694 mg (98%) as a light tan solid. 1H NMR (DMSO-d6): 8.80 (d, J=6.05 Hz, 1H), 8.45 (d, J=7.70 Hz, 1H), 8.11 (d, J=7.97 Hz, 2H), 8.00 (dd, J=7.69, 6.31 Hz, 1H), 7.82 (t, J=7.42 Hz, 1H), 7.68 (t, J=7.56 Hz, 1H), 6.52 (s, 2H), 3.02 (t, J=6.18 Hz, 2H), 2.92 (t, J=6.18 Hz, 2H), 1.85 (m, 2H), 1.77 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:26][O:25][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:27]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(I)cc2)cc1)OC
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccncc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 270, Step A) and 4-pyridyl boronic acid by following the procedure described for Example 270 (Steps B and C). 1H-NMR (CDCl3, 200.15 MHz): δ 8.67–8.65 (m, 2H), 8.16 (d, 2H, J=6.6), 7.90 (d, 2H, J=8.8), 7.16–7.09 (m, 4H), 6.82 (d, 2H, J=8.8), 4.26 (t, 2H, J=6.2), 4.13 (t, 2H, J=6.2), 3.90 (dd, 1H, J=7.7, 4.8), 2.97 (dd, 1H, J=14.3, 5.1), 2.83 (dd, 1H, J=14.3, 7.7), 2.24 (qn, 2H, J=5.9).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=[O:21])[C:11]2[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=2[N:13]=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>>[Cl:22][S:23]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:4]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(O)Cl
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3O)nc12
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3O)nc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
5-(2-Hydroxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.239 g, 0.00084 mol) was added, in portions, to stirred chlorosulphonic acid (3 ml) cooled to 0° C. under a nitrogen atmosphere, and the resulting deep red solution stirred at room temperature for 18 hours. The reaction mixture was then added dropwise, with care, to stirred ice/water to give a brown solid. The latter mixture was extracted with dichloromethane (3×30 ml), the combined extracts dried (Na2SO4) and filtered, and the filtrate evaporated under vacuum to give a brown solid (0.24 g, 75%), used in the next step without further purification; Rf 0.3 (silica; dichloromethane, methanol; 95:5).
Reaction SMILES: [Mg].[Br:2][CH:3]1[CH2:5][CH2:4]1.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=O)=[CH:10][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[Br:2][CH2:3][CH2:4][CH2:5][C:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[CH:17]=2)[CH2:12][CH2:13][CH:14]=1
Reactant: BrC1CC1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCCBr)=CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To tetrahydrofuran (100 ml), in which magnesium (2.9 g) was suspended, was gradually added dropwise under ice-cooling bromocyclopropane (14.4 g, 119 mmol.) under argon atmosphere. The mixture was stirred for 30 minutes at room temperature, to which was added dropwise a tetrahydrofuran (50 ml) solution of 7-methoxy-1-tetralone (15 g, 85.1 mmol.), which was heated for 2 hours under reflux. The reaction mixture was cooled to room temperature, to which was poured a saturated aqueous solution of ammonium chloride, followed by extracting the organic substance with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was dissolved in acetic acid (100 ml), to which was added 20% hydrobromic acid (75 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, which was poured into a saturated aqueous solution of sodium hydrogencarbonate, and the organic substance was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (ethyl acetate hexane=1:9) to afford the titled compound (20 g, yield 84%, oily).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH:12]=O)=[CH:8][CH:7]=1)[CH2:3][CH3:4].N1C=CC=CC=1.Cl.[CH2:23]([O:25][NH2:26])[CH3:24].O>O1CCOCC1>[CH2:23]([O:25][N:26]=[CH:12][CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:15][CH:14]=1)[CH3:24]
Reactant: CCC(C)Oc1ccc(OCC=O)cc1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: CCON=CCOc1ccc(OC(C)CC)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-(1-methylpropoxy)phenoxyacetaldehyde (0.68 g, 3.3 mmol) and pyridine (0.50 g, 6.3 mmol) in 5 ml of p-dioxane is added a solution of ethoxyamine hydrochloride (0.60 g, 6.2 mmol) in a minimum amount of water. The reaction mixture is stirred at RT for 6 hours, after which the dioxane is removed in vacuo. The residue is taken up in ether and the organic layer is washed with water. The aqueous phase is extracted with ether, and the combined organic phases are dried, the solvent is removed in vacuo and the product is purified by column chromatography to give 4-(1-methylpropoxy)phenoxyacetaldehyde O-ethyloxime as a mixture of syn and anti stereo isomers. MS m/e 251 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][S:19]([C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[F:11])(=[O:21])=[O:20])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Product: COc1ncc(Br)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
To a cooled (0° C.) solution of 5-bromo-2-(methyloxy)-3-pyridinamine (20.3 g, 100 mmol) in pyridine (200 mL) was added slowly 2,4-difluorobenzenesulfonyl chloride (21.3 g, 100 mmol) over 15 min (reaction became heterogeneous). The ice bath was removed and the reaction was stirred at ambient temperature for 16 h, at which time the reaction was diluted with water (500 mL) and the solids filtered off and washed with copious amounts of water. The precipitate was dried in a vacuum oven at 50° C. to give N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (12 g, 31.6 mmol, 31.7% yield) MS(ES)+ m/e 379.0, 380.9 [M+H]+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:33]=[CH:32][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:11]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[C:10]=2[CH3:31])=[CH:6][CH:5]=1.O>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[N:11]([CH2:23][C:24]([OH:26])=[O:25])[C:10]=2[CH3:31])=[CH:32][CH:33]=1
Reactant: Cc1c(Oc2ccc(Cl)cc2)c2c(NS(C)(=O)=O)cccc2n1CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Oc2ccc(Cl)cc2)c2c(NS(C)(=O)=O)cccc2n1CC(=O)O
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A solution of 1M sodium hydroxide (0.5 ml) was added to a stirred mixture of the product from step (v) (40 mg) in THF (1 ml). After 3 h, further 1M sodium hydroxide (1 ml) was added and the reaction heated at 55° C. for 16 h. Water (10 ml) was added and the THF evaporated under reduced pressure. The solution was acidified with 2M hydrochloric acid and the resulting solid filtered off and dried. Yield 24 mg
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[C:5]([CH3:15])[CH:4]=1.S(Cl)([Cl:18])=O.O>ClCCl>[Cl:18][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[C:5]([CH3:15])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)NCc1c(C)cc(CO)cc1C
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCc1c(C)cc(CCl)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-((4-hydroxymethyl-2,6-dimethylphenyl)methyl)acetamide (1.0 g) in dichloromethane (12 ml) was added thionyl chloride (0.88 ml). This mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from ethyl acetate-isopropyl ether to give the title compound (1.0 g) as white crystals.