Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:28][C:27]1[CH:29]=[CH:30][C:24]([O:23][C:21]2[CH:22]=[CH:17][N:18]=[C:19]([C:9]3[N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:12]=[CH:11][CH:10]=3)[CH:20]=2)=[CH:25][CH:26]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1cc(Oc2ccc(N)cc2)ccn1
Temperature: 72 °C

Procedure:
To a stirred mixture of N-Boc-pyrrole-2-boronic acid (114 mg, 0.54 mmol) and 4-((2-chloropyridin-4-yl)oxy)aniline (100 mg, 0.45 mmol) in 8 ml of 1,4-dioxane, was added PdCl2(PPh3)2 (10 mg, 0.014 mmol) and 1M Na2CO3 aqueous solution (0.5 ml, 1.0 mmol). The mixture was heated at 72° C. under N2 for one hour, cooled to room temperature and poured into 100 ml of water. The resulting mixture was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (50 ml), dried over Na2SO4, and evaporated to give a brown oil, which was purified by silica gel chromatography with a gradient of 20˜50% EtOAc/hexanes to give tert-butyl 2-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1-carboxylate as colorless oil. Yield: 110 mg, 70%.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:34]>C(Cl)Cl>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])[N:15]=[C:14]2[N:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:10]1
Reactant: CC(C)COC(=O)Cl
Reactant: N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)COC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
At −70° C., triethylamine (215 μL, 1.54 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (250 mg, 0.77 mmol) in CH2Cl2 (2.5 mL), followed by the dropwise addition of isobutyl chloroformate (100 μL, 0.77 mmol). The reaction was stirred for 30 minutes and warmed to RT. The mixture was quenched with H2O and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 2.5-10% EtOAc in a 1:1 mixture of CH2Cl2 and hexanes gave (R)-isobutyl 1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 15) (195 mg, 60%). 1H NMR (400 MHz, acetic acid-d4) δ 8.43 (m, 1H), 8.01 (m, 1H), 7.90 (m, 1H), 7.76 (m, 1H), 7.58 (d, J=5.6 Hz, 1H), 7.37 (m, 1H), 6.93 (m, 2H), 4.07 (m, 5H), 3.75 (d, J=6.2 Hz, 2H), 2.23 (m, 1H), 2.03 (m, 1H), 1.83 (m, 1H), 0.88 (d, J=6.5 Hz, 6H) ppm. LC/MS: m/z 425.3 (M+H)+ at 2.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[C:25]4[CH:26]=[CH:27][C:28]([CH2:30][C:31](O)=[O:32])=[CH:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[C:25]4[CH:26]=[CH:27][C:28]([CH2:30][C:31]([N:55]5[CH2:60][CH2:59][O:58][CH2:57][CH2:56]5)=[O:32])=[CH:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Cc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of (4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}[1]benzothieno[2,3-d]pyrimidin-7-yl)acetic acid (50 mg, 0.10 mmol, 1 eq, from example 94) in DCM (2 mL) were added HOBt (14 mg, 0.10 mmol, 1 equiv) and EDCI (24 mg, 0.13 mmol, 1.2 equiv) under nitrogen. After the mixture was stirred at rt for 5 min, morpholine was added. The resulting reaction mixture was stirred at rt for 15 h. The solvent was concentrated in vacuo. Methanol was added to the residue and a white solid was precipitated out from the solution. The solid was filtered, washed with methanol (2×3 mL) then dried in vacuo to obtain a white solid (27.8 mg, 0.05 mmol, 51%). 1H-NMR (DMSO-d6) δ 9.0 (broad s, 1H), 8.58 (d, J=4.6 Hz, 1H), 8.51 (s, 1H), 8.49 (d, J=8.5 Hz, 1H), 7.94 (s, 1H), 7.87 (t, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.53 (dd, J=2.6, 8.8 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.35 (m, 1H), 7.24 (d, J=8.7 Hz, 1H), 5.30 (s, 2H), 3.91 (s, 2H), 3.50 (m, 8H); LCMS RT=2.69 min, [M+H]+=546.20
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33]>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1ccccc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12e and 2-bromoanisole
Reaction SMILES: [CH:1]1[C:10]2[C@@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29])=[O:22].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1[C:10]2[C@@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH2:29])=[O:22])[CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Reactant: Nc1ccccc1C(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccccc1C(=O)CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCC3
Yield: 16.5 %

Procedure:
The title compound (0.031 g, 16%) was prepared by the general method of Example 402 from (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.11 g, 0.50 mmol), 4-chloro-2′-aminobutyrophenone (0.20 g, 1.0 mmol), KI (catalytic) and K2CO3 (0.14 g, 1.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ1.80-2.20 (m, 7H), 2.20-2.60 (m, 3H), 2.82-2.95 (m, 1H), 2.98 (t, J=7.4 Hz, 2H), 3.05-3.20 (m, 2H), 3.20-3.38 (m, 2H), 3.64 (t, J=6.6 Hz, 1H), 3.68-3.80 (m, 1H), 3.81 (t, J=6.0 Hz, 1H), 6.26 (br, 2H), 6.58-6.68 (m, 2H), 6.80-6.92 (m, 2H), 7.10-7.30 (m, 2H), 7.52-7.72 (m, 1H), 7.77 (dd, J=1.3, 8.4 Hz, 1H), 8.09 (td, J=1.6, 8.4 Hz, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.[NH2:12][OH:13].C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7](=[N:12][OH:13])[NH2:8]
Reactant: Cc1ccc(Cl)cc1C#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cl)cc1C(N)=NO
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 5-chloro-2-methylbenzonitrile (1.5 g, 9.89 mmol), hydroxylamine hydrochloride (1.38 g, 19.79 mmol) and sodium bicarbonate (3.33 g, 39.6 mmol) in methanol (100 mL) was heated to 70° C. for 6 h. The mixture was cooled to room temperature and diluted with methanol (100 mL). The mixture was filtered, and the filtrate was concentrated, diluted with water and extracted with EtOAc (100 mL, 3×). The EtOAc extract was dried over MgSO4, filtered and concentrated under reduced pressure to obtain crude 5-chloro-N′-hydroxy-2-methylbenzimidamide (1.8 g, 99% crude yield). LC/MS: m/e 185.0 (M+H)+. 1H NMR (400 MHz, CD3OD) δ ppm 7.30-7.29 (2 H, m), 7.23 (1 H, d), 2.36 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17]C(=O)OC(C)(C)C)=[N:15][CH:16]=3)=[CH:9][N:8]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:9][N:8]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.1 %

Procedure:
A solution of tert-butyl N-[5-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-pyridyl]carbamate (0.13 g, 0.315 mmol) in dichloromethane (5.5 ml) was cooled to 0° C. then treated with trifluoroacetic acid (0.6 ml). The solution was stirred at 0° C. for 5 minutes then warmed to ambient temperature and stirred for a further 18 hours. The solvents were evaporated under reduced pressure then the residue was partitioned between dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (10 ml). The organic solution was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give 5-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-pyridinamine (92 mg): RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=10.73 min; MS: MH+314.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH2:24])=[N:20]1>>[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ncn(Cc2cccc(F)c2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4cccc(F)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3-fluoro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25](SC)=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:53][NH2:54]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25]([NH:54][CH3:53])=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccccc3)c(F)cc1C)C2
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccccc3)c(F)cc1C)C2
Yield: 66 %

Procedure:
Using a procedure analogous to Example A2, the sulfide was oxidized with mCPBA to the sulfone and then treated with methylamine to provide 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea (0.163 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.85 (brs, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.52 (m, 3H), 7.42 (m, 1H), 7.18 (d, J=12 Hz, 1H), 7.02 (m, 1H), 6.38 (s, 1H), 4.53 (d, J=14 Hz, 1H), 4.33 (d, J=14 Hz, 1H), 3.25 (brs, 3H), 2.78 (d, J=5 Hz, 3H), 2.04 (s, 3H), 1.25 (s, 9H); MS (ESI) m/z: 558.3 (M+H+).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][N:4]=1.[ClH:19]>O1CCOCC1>[ClH:19].[O:2]=[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][NH:4]1
Reactant: COc1ncc(-c2cccnc2C#N)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ncccc1-c1c[nH]c(=O)[nH]c1=O
Yield: 97 %

Procedure:
3-(2,4-Dimethoxy-pyrimidin-5-yl)-pyridine-2-carbonitrile (Prep102, 1 g, 4.13 mmol) was dissolved in a solution of 4N HCl in dioxane (20 ml). The mixture was refluxed for 45 minutes. The solvent was removed under vacuum to give 1 g of the title compound (97% yield).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:19]O>>[C:1]([CH2:9][CH2:10][C:11]([O:13][CH3:19])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccccc1
Yield: 100 %

Procedure:
To a 1.0 L round bottom flask was added 89 g (0.5 mol) of 3-benzoylpropionic acid and 200 mL of methanol. The solution was stirred until all of the acid had dissolved. To this solution was added approximately 2.0 mL of conc. H2SO4 and the reaction refluxed for 2.5 hours. After the reaction was determined to be complete, the methanol was removed on the rotoevaporator and to the residual oil was added ethyl acetate (˜500 mL). To the ethyl acetate layer was then added 150 mL of a saturated sodium carbonate solution. The layers were extracted and allowed to separate. The organic layer was then dried (MgSO4), filtered, and concentrated to yield methyl 3-benzoylpropionate (1) as a light yellow oil. Yield 96 g; yield 100%; >97% cp. Lit bp 172–174° C. at 10 mm Hg.; 1H NMR ppm (δ), CDCl3 7.98 (dd, 2H), 7.54 (m, 1H), 7.45 (m, 2H), 3.70 (s, 3H, OCH3), 3.32 (t, 2H), 2.76 (t, 2H). 13C NMR ppm (δ), CDCl3 198.0 (C═O), 173.3 (CO2), 136.5 (q), 133.2, 128.6, 128.0, 51.7 (OCH3), 33.3, 28.0. IR oil cm−1 2952, 1737, 1687, 1596, 1449, 1358, 1221, 1168 1001, 750, 691.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:14][NH2:15]>C1COCC1>[CH3:14][NH:15][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 154a from 6-chloro-5-nitro-nicotinic acid and 2 M methylamine solution in THF.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].Cl[C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1>O1CCCC1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-]CCCN1CCCCC1
Reactant: Clc1nc2ccccc2s1
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc2sc(OCCCN3CCCCC3)nc2c1

Procedure:
Sodium 3-piperidinopropanolate (5 mmol) and 5 mmol of 2-chlorobenzothiazole in 20 ml of dry tetrahydrofurane were refluxed for 12 hours. The suspension was filtered and the solvent evaporated under reduced pressure. The product was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.C([N:22](CC)CC)C>ClCCl>[NH2:22][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (9.56 mL, 124 mmol) was added dropwise over 10 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-hydroxypiperidine-1-carboxylate (20.7 g, 103 mmol) and triethylamine (21.5 mL, 154 mmol) in dichloromethane (300 mL) at 0° C. After stirring for 3 hour at 0° C., the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20:80 to 50:50), to give the title compound as an oil.
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10]2)=[CH:20][CH:21]=1
Reactant: c1ccc(CC[C@H]2CCCNC2)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCC[C@H](CCc2ccccc2)C1)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 0 %

Procedure:
A solution of (S)-3-phenethyl-piperidine (4.23 mmol, 801 mg), 2-bromo-4′-chloroacetophenone (1.5 equiv, 6.35 mmol, 1.48 g) and K2CO3 (2.0 equiv, 8.46 mmol, 1.17 g) in CH3CN (10 mL) was heated to 60° C. and stirred for 12 h. The reaction mixture was quenched with H2O (25 mL) and then extracted with EtOAc (2×50 mL). The combined organics were dried with NaCl(sat) and Na2SO4(s). The solvents were removed in vacuo and chromatography (Isco Combi-Flash, 110 g cartridge, 9:1 Hexane-EtOAc) provided the desired product (0.556 mg, 1.45 mg theoretical, 38%) as a colorless oil: Rf 0.37 (SiO2, 5:1 hexane-EtOAc); LRMS m/z 342 (M++1, C21H24ClNO, requires 342).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C:12]([CH3:27])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])[CH2:13][OH:14]>N1C=CC=CC=1>[C:2]([O:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]([CH3:27])([CH3:11])[CH2:13][O:14][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(CO)CCCCCCCC(C)(C)CO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(CCCCCCCC(C)(C)COC(=O)c1cccnc1)COC(=O)c1cccnc1
Reaction time: 36 h
Yield: 51.9 %

Procedure:
A suspension of 53.10 grams (0.3 mole) of nicotinoyl chloride hydrochloride in 150 ml of anhydrous pyridine was added in 2 hours under stirring with a solution of 12.2 grams (0.05 mole) of 2,2,10,10-tetramethyl-1,11-undecanediol in 30 ml of anhydrous pyridine while keeping the temperature at about 70° C. The reaction was refluxed and stirred for 36 hours then, after cooling, the formed precipitate was removed by filtration. The filtrate was evaporated under vacuum and the obtained residue was treated with a mixture of 200 ml of diethyl ether and 100 ml of an 8% aqueous solution of sodium bicarbonate. The organic layer was separated and washed first with 100 of a 3% aqueous solution of sodium bicarbonate and then with 100 ml of water. After evaporating the diethyl ether in vacuo the obtained residue was dissolved in 50 ml of methylene chloride, the organic solution was twice washed with 30 ml of 1N hydrochloric acid and twice with 50 of water, dried over sodium sulphate and finally brought to dryness. The residue was crystallized from ethanol thus obtaining 11.80 grams of the title product, having m.p. 70°-71° C. Yield: 52% of theoretical.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14](=O)[C:15]([F:18])([F:17])[F:16].Cl.[NH2:28][OH:29].Cl.O>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]1[O:29][N:28]=[C:14]([C:15]([F:18])([F:17])[F:16])[CH:13]=1
Reactant: NO
Reactant: Cc1nc(-c2cc(C)c(OCCCC#CC(=O)C(F)(F)F)c(C)c2)no1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(-c2cc(C)c(OCCCc3cc(C(F)(F)F)no3)c(C)c2)no1
Reaction time: 120 h
Yield: 18.5 %

Procedure:
To 479 mg of 3-{3,5-dimethyl-4-[3-(trifluoroacetylethinyl)propoxy]phenyl}-5-methyl-1,2,4-oxadiazole from part (a) above and 509 mg hydroxylamine hydrochloride in 10 mls of acetic acid at ambient room temperature was added with stirring 1 ml 1M hydrochloric acid. After twenty hours an additional 1 ml 1M aqueous hydrochloric acid and 1.00 g hydroxylamine hydrochloride were added and stirring was continued for five days. The reaction mixture was poured into 200 mls water and extracted with ethyl ether. The ethyl ether extracts were washed with water, dried (Na2SO4) and concentrated. A solution of the residue (470 mg) in benzene was heated at reflux overnight, cooled, diluted with methylene chloride, washed with aqueous 1.5M potassium bicarbonate and water, filtered through silica gel and concentrated. The oily residue was subjected to preparative TLC (silica gel; methylene dichloride) to yield 92 mg of the title compound, m.p. 62°-64.5° C.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.Cl>C(O)(=O)C>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][C:13]2[CH:3]=[CH:4][NH:5][C:6](=[O:16])[CH2:7][C:8]=2[CH:9]=1
Reactant: COc1cccc(CC(=O)NCC(OC)OC)c1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(=O)NC=C2
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of the benzeneacetamide (70 g, 0.277 m) in acetic acid (180 ml) was added with stirring to concentrated hydrochloric acid (120 ml). The mixture was stirred for 16 hours, diluted with ice/water and filtered. The filter cake was dissolved in methylene chloride which was washed with water, dried with magnesium sulfate and concentrated in vacuo to give 2,3-dihydro-8-methoxy-2-oxo-1H-3-benzazepine.
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])C.ClC1[N:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[S:34][C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=3)=[CH:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1>C1COCC1>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:6]1[CH:17]=[CH:18][C:19]2[C:24](=[N:23][CH:22]=[CH:21][C:20]=2[NH:26][C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=2[S:34][C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)[N:25]=1)[CH3:13])[CH3:12]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(Cl)ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a slurry of sodium hydride (95%, 0.025 g, 1.0 mmol) in 5 mL anhydrous THF at 0° C. under an atmosphere of N2 was added 2-methyl-malonic acid diethyl ester (0.174 g, 1.0 mmol) dropwise. The mixture was stirred for 30 minutes at ambient temperature, treated with the product from Example 24a (0.047 g, 1.0 mmol), microwave at 120° C. for 1 hour, cooled, partitioned between ethyl acetate and water and neutralized with 1M HCl. The aqueous layer was extracted by ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound. The residue was purified by chromatography on silica eluting with 1% methanol in dichloromethane to give the title compound (0.031 g, 62%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.14 (t, J=7.17 Hz, 3 H) 1.52 (d, J=7.35 Hz, 3 H) 2.04 (s, 3 H) 2.30 (s, 3 H) 4.10 (m, 3 H) 6.17 (s, br, 1 H) 7.04 (m, 3 H) 7.26 (d, J=8.82 Hz, 2 H) 7.48 (d, J=7.35 Hz, 1 H) 7.57 (d, J=8.46 Hz, 2 H) 8.45 (d, J=8.46 Hz, 1 H) 8.78 (d, J=8.82 Hz, 1 H) 9.11 (s, 1 H) 10.05 (s, 1H); (ESI+) m/z 501 (M+H)+.