Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@H:5]([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[C:12](N1CCOCC1)=[O:13].C([Mg]Cl)(C)C.[Br:25][C:26]1[CH:42]=[CH:41][C:40](I)=[CH:39][C:27]=1[CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1>C1COCC1>[Br:25][C:26]1[CH:42]=[CH:41][C:40]([C:12]([C@@H:3]2[O:4][C@H:5]3[O:6][C:7]([CH3:10])([CH3:11])[O:8][C@H:9]3[C@@H:2]2[OH:1])=[O:13])=[CH:39][C:27]=1[CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1
Reactant: Brc1ccc(I)cc1Cc1ccc2c(c1)OCCO2
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2O[C@@H](C(=O)c3ccc(Br)c(Cc4ccc5c(c4)OCCO5)c3)[C@@H](O)[C@@H]2O1
Temperature: 0 °C
Yield: 6.6 %

Procedure:
Step-V: To a cooled solution of ((3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-morpholin-4-yl-methanone (11.05 g, 256 mmol) in THF (200 ml) was added 2.0 M solution of isopropylmagnesium chloride (12.78 ml, 256 mmol) under stirring at 0° C. and stirred for additional 1.5 h. To this was added a solution of 6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]dioxine (4.0 g, 146 mmol) in THF (50 ml) at 0° C. and then stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of aqueous saturated ammonium chloride solution and extracted with ethyl acetate (200 ml×3). Combined organic layers were washed with brine (500 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 4.7 g of [4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-methanone. 1H NMR (400 MHz, CDCl3): δ 1.35 (s, 3H), 1.53 (s, 3H), 2.92 (d, J=4.0 Hz, 1H), 4.04 (d, J=3.6 Hz, 2H), 4.23 (s, 4H), 4.54 (br s, 1H), 4.56 (d, J=3.6 Hz, 1H), 5.21 (d, J=2.8 Hz, 1H), 6.05 (d, J=3.2 Hz, 1H), 6.67 (s, 2H), 6.79 (d, J=9.2 Hz, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.75-7.77 (m, 2H). MS (ES) m/z 490.7 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH2:28][C:29](N)=[O:30]>C(O)(=O)C>[CH:13]1([NH:12][C:10](=[O:11])[C:9]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:7]([N:6]3[CH:5]=[N:4][C:3]4[C:2]3=[N:1][C:29]([OH:30])=[N:28][C:20]=4[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:8]=2)[CH2:15][CH2:14]1
Reactant: NC(N)=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2ccccc2)c1N
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccccc3)nc(O)nc21
Temperature: 180 °C
Yield: 23.9 %

Procedure:
To a stirred solution of 3-(5-amino-4-benzoyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (9.2 mg, 0.026 mmol) in 0.3 mL acetic acid was added urea (20 mg) and the mixture was heated at 180° C. for 20 min. in the microwave. The crude product was purified by HPLC to give a colorless solid (2.4 mg, 24%). HPLC tR=1.63 min; MS m/z 386 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].ClCCl.CCN(C(C)C)C(C)C.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Reactant: CN1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(N)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a suspension of 4-amino-3-(trifluoromethoxy)benzoic acid (900 mg, 4 mmol) in dichloromethane (60 ml) TBTU (1.9 g, 6 mmol) and DIPEA (1.04 ml, 6 mmol) were added. The mixture was stirred at room temperature for 30 minutes. Then 1-methylpiperidin-4-amine (513 mg, 4.5 mmol) was added and the reaction was stirred for an additional 3 h. The solution was washed with water and the organic phase was dried over anhydrous Na2SO4. The crude was purified by flash chromatography (DCM/MeOH/NH3aq, 9:1:0.5), to give the title compound (900 mg, 71%), as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21](I)=[CH:22][C:13]=12.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]#[CH:33])[CH2:27][CH2:26]1>C1C=CC=CC=1.C(N(CC)CC)C.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.[Cu](I)I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21]([C:33]#[C:32][CH2:31][N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[CH:22][C:13]=12
Reactant: C#CCN1CCN(C)CC1
Reactant: COc1cc(Nc2c(C#N)cnc3sc(I)cc23)c(Cl)cc1Cl
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(Nc2c(C#N)cnc3sc(C#CCN4CCN(C)CC4)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile (160 mg, 0.34 mmol), 1-methyl-4-prop-2-ynyl-piperazine (70 mg, 0.5 mmol), 15 mg of tetrakis(triphenylphosphine)palladium(0) and copper iodide (8 mg, 0.016 mmol) in 7 mL of benzene and 2 mL of triethylamine is heated at reflux for 7 hours. The reaction mixture is cooled to room temperature and partitioned between water and dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is triturated with ether and hexanes to provide 110 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]thieno[2,3-b]pyridine-5-carbonitrile as an off white solid, mp 175° C. (decomposition); 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 2.37 (bs, 4H), 2.54 (bs, 4H), 3.62 (s, 2H), 3.85 (s, 3H), 7.38 (s, 1H), 7.76 (s, 1H), 7.91 (s, 1H), 8.47 (bs, 1H), 9.83 (bs, 1H); MS 486.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[ClH:25].FC1C=C(N[C:51]([NH:53][C:54](=[O:62])[CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:52])C=CC=1OC1C=CN=C2C=C(C(N3CCCC3)=O)SC=12>>[ClH:25].[ClH:25].[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:51]([NH:53][C:54](=[O:62])[CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[O:52])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: Cl
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)c2s1
Yield: 15 %

Procedure:
Starting from the compound 219 (scheme 47) and following the procedure described above for the synthesis of compound 305a, title compound 305b was obtained in 15% yield as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.07(s, 1H), 10.66(s, 1H), 8.67(d, 1H, J=5.5 Hz), 8.27(s, 1H), 7.85-7.80(m, 2H), 7.65(s, 1H), 7.51(t, 1H, J=8.6 Hz), 7.46(d, 1H), 7.34-7.28(m, 5H), 6.85(d, 1H, J=5.3 Hz), 4.03(s, 3H), 3.74(s, 2H). MS (m/z): 502.2(M+H) (found).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=2)=O)=[CH:3][CH:2]=1.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])C=CC=CC=1>>[CH3:32][N:31]([CH3:33])[CH2:30]/[CH:29]=[C:7](/[C:9]1[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=1)\[C:4]1[CH:5]=[CH:6][C:1]([CH3:20])=[CH:2][CH:3]=1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(=O)c2cccc(/C=C/C(=O)O)n2)cc1
Agent: [Br-]
Product: Cc1ccc(/C(=C\CN(C)C)c2cccc(/C=C/C(=O)O)n2)cc1

Procedure:
Treatment of (E)-3-[6-(4-toluoyl)-2-pyridyl]acrylic acid, vide supra, with the Wittig reagent derived from triphenyldimethylaminoethylphosphonium bromide by the method of example 1 gave a mixture of isomeric acids which were separated by fractional crystallization from ethyl acetate. The less-soluble E-isomer, (E)-3-{6-[3-dimethylamino-1-(4-tolyl)prop-1E-enyl]-2-pyridyl}acrylic acid was puried by crystallization from isopropanol, m.p. 222°-225° (decomp.)
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:20][C:19]2[CH:21]=[CH:22][C:16]([CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=Cc1ccc(OC(F)F)cc1
Product: CC(C)c1ccc(NCc2ccc(OC(F)F)cc2)cc1

Procedure:
Following the procedure described in Example 1A, step 1, 4-(difluoromethoxy)benzaldehyde and 4-isopropylaniline gave the title compound as a pale yellow oil.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>C(Cl)Cl>[C:1]1([S:7][CH2:17][CH2:16][C:15]([O:19][CH3:20])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)OC
Reactant: Sc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thiophenol (440 mg, 4 mmol) and Et3N (70 μl, 0.5 mmol) were dissolved in CH2Cl2 (5 ml). Methyl acrylate (412 mg, 4.8 mmol) was added dropwise. The reaction was exothermic. After stirring at room temperature for 30 minutes, the excess methyl acrylate was removed in vacuo. TLC: silica gel, Et2O-hexane 1:2, UV Rf =0.58. The crude title ester was used without further purification.
Reaction SMILES: [Br:1][CH:2]([C:6]1[N:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:10]=1)[C:3]([OH:5])=O.[CH:23]([C:26]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH2:28])([CH3:25])[CH3:24].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:26]([CH:23]([CH3:25])[CH3:24])[C:27]=1[NH:28][C:3](=[O:5])[CH:2]([C:6]1[N:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:10]=1)[Br:1])([CH3:35])[CH3:34]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCCCCCCCCCCCn1nnc(C(Br)C(=O)O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCn1nnc(C(Br)C(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.6 %

Procedure:
To a solution of α-bromo-2-dodecyltetrazoleacetic acid (5.0 g, 13.3 mmol) in dichloromethane (75 mL), cooled to -10° C., were added 2,6-diisopropylaniline (2.3 g, 12.9 mmol) and DCC (2.7 g, 13 mmol), respectively. The suspension was gradually warmed to room temperature and was stirred for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuo leaving a yellow liquid. The crude product was purified using silica gel chromatography (elution with 10% ethyl acetate/90% hexane) to give (±)-N-(2,6-diisopropylphenyl) -2-(2-dodecyl-2H-tetrazol-5-yl)-2-bromo-acetamide (4.8 g, 65% ) as a colorless liquid which crystallized on standing;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[CH:7]2
Reactant: Brc1cccc2cn[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2cccc(Br)c21
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
To a solution of 7-bromo-1H-indazole (1 g, 5.1 mmol) in dry tetrahydrofuran (20 mL) was added NaH (305 mg, 60%, 7.65 mmol) at −20° C. under N2 atmosphere. After 20 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (1 g, 6.1 mmol) was added and the mixture was warmed to 20° C. and stirred for 1 hour. Water (2 mL) was added and product extracted with dichloromethane (100 mL), organic phase washed with water (2×10 mL) and brine (2×10 mL) then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with ethyl acetate:petroleum ether=1:20) to afford 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.27 g, 77%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.03 (s, 1H), 7.69 (d, 1H, J=8.7 Hz), 7.60 (d, 1H, J=8.1 Hz), 7.06-7.01 (m, 1H), 6.08 (s, 2H), 3.60 (t, 2H, J=7.8 Hz), 0.90 (d, 2H, J=8.1 Hz), 0.01 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc(C)cc(C)c1C

Procedure:
Using 2,3,5-trimethylphenol and ethyl bromoacetate, the title compound was synthesized in the same manner as in Reference Example 153. Yield: quantitative. Oily matter.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:21]1
Reactant: O=C1CN(Cc2c(O)ccc3c2OCC3=O)CCN1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1CN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CCN1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A solution of 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazin-2-one (0.131 g, 0.500 mmol) in methanol (2 mL) was added with indazole-3-carbaldehyde (0.0731 g, 0.500 mmol), and piperidine (0.00426 g, 0.0500 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (6 mL), suspended in methanol and thereby washed, and the solid was collected by filtration to obtain (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazin-2-one (0.122 g, 62%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:9]([CH2:14][NH:15][CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29](=[O:40])[C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][C:31]=1[CH2:38]Br.CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29](=[O:40])[C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][C:31]=1[CH2:38][N:15]([CH2:14][C:9]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:26])=[CH:13][CH:12]=[CH:11][N:10]=1)[CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: CC(C)(C)OC(=O)Nc1cccnc1CNC1CCCc2cccnc21
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1NC(=O)OC(C)(C)C)C1CCCc2cccnc21

Procedure:
Using General Procedure A: Reaction of {2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-pyridin-3-yl}-carbamic acid tert-butyl ester in CH3CN with 2-bromomethyl-5-cyano-benzoic acid methyl ester, DIPEA, KI, and DMAP gave 2-{[(3-tert-butoxycarbonylamino-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a beige solid. 1H NMR (CDCl3) δ 1.65 (s, 9H), 1.68-1.71 (m, 1H), 1.85-1.93 (m, 1H), 2.08-2.12 (m, 1H), 2.27-2.28 (m, 1H), 2.81-2.86 (m, 2H), 3.79-3.91 (m, 7H), 4.02-4.07 (m, 1H), 4.50 (d, 1H, J=18.0 Hz), 7.02-7.06 (m, 1H), 7.12-7.18 (m, 1H), 7.43 (d, 1H, J=6.8 Hz), 7.54-7.59 (m, 1H), 8.00-8.09 (m, 3H), 8.41 (d, 1H, J=9.0 Hz), 8.67-8.71 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=[CH:5][CH:4]=1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[C:9]([O:11][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19])=[O:10]
Reactant: COc1ccccc1C(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
O-anisic acid (1.0 g), N-hydroxysuccinimide (0.76 g) and water-soluble carbodiimide hydrochloride (1.39 g) were dissolved in methylene chloride (15 ml), and the solution was stirred overnight at room temperature. The precipitate was removed by filtration. The mother liquor was concentrated under reduced pressure, and the residue was crystallized from isopropanol to give 1.47 g of N-(2-methoxybenzoyloxy)succinimide (mp. 180°-182° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.Cl.[NH2:20][OH:21].[OH-].[Na+]>O>[CH3:1][C:2]([CH3:17])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH:3]=[N:20][OH:21]
Reactant: NO
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 92 %

Procedure:
233.4 g (1 mol) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene is added dropwise to 100 g of 37% hydrochloric acid and 200 ml of water in the course of 1 hour, in a manner ensuring that the temperature does not exceed 80° C. The mixture is then cooled to 20°-25° C., and 69.5 g (1.0 mol) of hydroxylamine hydrochloride is added. There is subsequently added during one hour, with water-bath cooling, about 92 g (2.3 mols) of solid sodium hydroxide until the pH value of the aqueous solution is 10-11. The organic phase which precipitates is separated, and washed free from salt with water. Distillation yields 245 g (0.92 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal-oxime; b.p. 158°-162° C./4 Pa; nD20 =1.4930.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[O:8][CH2:9][CH2:10][O:11][C:4]=2[CH:3]=1.[CH2:12]([CH2:15]OC)OC>>[CH:12]([C:2]1[N:7]=[N:6][C:5]2[O:8][CH2:9][CH2:10][O:11][C:4]=2[CH:3]=1)=[CH2:15]
Reactant: COCCOC
Reactant: Clc1cc2c(nn1)OCCO2
Product: C=Cc1cc2c(nn1)OCCO2
Temperature: 95 °C
Yield: 50 %

Procedure:
A solution of 3-chloro-6,7-dihydro[1,4]dioxino[2,3-c]pyridazine (13.6 g, 0.079 mol) containing ca. 15% of a bromo species in dimethoxyethane (400 ml) was degassed under argon for 10 min then tetrakis(triphenylphosphine)palladium (0) (2 g), potassium carbonate (10.33 g), triethenylboroxin pyridine complex (11.32 g) and water (55 ml) were added. The mixture was heated at 95° C. for 48 h and cooled and evaporated to dryness. The mixture was treated with aqueous sodium bicarbonate solution and extracted (5×) with DCM. Extracts were dried (sodium sulphate), evaporated and the residue chromatographed on silica gel (500 g), eluting with 0-100% ethyl acetate-hexane, affording the product (6.43 g, 50%); [also some impure fractions (1.8 g)]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9](O)=[O:10])=[C:4]([F:27])[CH:3]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:41][O:42][NH2:43].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:23][CH2:24]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH:43][O:42][CH3:41])=[O:10])=[C:4]([F:27])[CH:3]=1
Reactant: CON
Reactant: O=C(O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CONC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 45 °C
Reaction time: 24 h
Yield: 41.8 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetic acid (0.453 mmol) in dichloromethane (1 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.680 mmol) and 4-(dimethylamino)pyridine (2.266 mmol) at room temperature. This mixture was stirred for 10 min at which point O-methylhydroxylamine hydrochloride (0.906 mmol) was added. The reaction vessel was sealed and the mixture was stirred at room temperature for 18 h and at 45° C. for 24 h. The reaction was then cooled to room temperature and was treated with pyridine (0.5 mL). The reaction vessel was resealed and stirred overnight in an oil bath at 45° C. At this point the reaction was cooled to room temperature and treated with additional portions of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.680 mmol) and O-methylhydroxylamine hydrochloride (0.906 mmol). The reaction vessel was resealed and stirred in an oil bath at 45° C. for 2 h. The reaction mixture was then concentrated to dryness in vacuo. The resulting orange residue was dissolved in dichloromethane (10 mL) and was concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-40% acetonitrile/water with 0.1% NH4OH) afforded the title compound as a clear oily solid (89 mg, 38% yield). MS(ES)+ m/e 470.1/472.1 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.Cl.[NH2:21][CH2:22][C:23]([NH2:25])=[O:24].C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:25][C:23]([CH2:22][N:21]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:24]
Reactant: NCC(N)=O
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)n1CC(N)=O

Procedure:
5.2 g (0.02 mol) of 6-phthalimido-2,5-hexanedione, 2,3 g (0.02 mol) of glycine amide hydrochloride and 1.7 g (0.02 mol) sodium acetate are stirred in 70 ml of acetic acid at 80° C. for 3 hours and the mixture is worked up as in Example 1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[CH:4]=[N:3]1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH2:10]([NH:12][CH2:8][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7])[CH3:11]
Reactant: CCN
Reactant: Cc1c(C=O)cnn1C
Solvent: C1CCOC1
Product: CCNCc1cnn(C)c1C

Procedure:
prepared by reaction of the commercially available 1,5-dimethyl-1H-pyrazole-4-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:21]4[CH:26]=[C:25]([NH2:27])[C:24]([F:28])=[CH:23][C:22]=4[F:29])[C:15](=[O:20])[N:16]3[CH3:19])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:25]1[C:24]([F:28])=[CH:23][C:22]([F:29])=[C:21]([C:14]2[C:15](=[O:20])[N:16]([CH3:19])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:26]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2F)c(=O)n3C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1F)c(=O)n2C
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.7 %

Procedure:
A solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 6.8 mmol) in DCM (100 mL) was treated with TFA (20 mL) and stirred at RT for 6 h. The mixture was extracted with water and the combined aqueous layers were neutralized with NH3H2O. The precipitate was collected by filtration and dried to give 3-(5-amino-2,4-difluorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (661 mg, 30% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.78 (s, 1H), 7.08-6.93 (m, 2H), 6.80 (dd, J=10.2, 8.1 Hz, 1H), 6.16 (s, 1H), 5.00 (s, 2H), 3.50 (s, 3H), 2.84 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 317.0 [M+H]+.