Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:23])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[C:9]1[CH3:22].[S]>CN(C)C=O>[CH3:1][C:2]1[NH:3][C:4](=[O:23])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH3:22]
Reactant: CC1=CN(C(=O)OCC(Cl)(Cl)Cl)C=CC1C1=C(C)NC(=O)CS1
Agent: [S]
Solvent: CN(C)C=O
Product: CC1=C(c2ccncc2C)SCC(=O)N1
Temperature: 160 °C
Yield: 85.2 %

Procedure:
The mixture of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-methyl-1,4dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (250 mg) and sulfur (125 mg) in N,N-dimethylformamide (2 ml) was heated at 160° C. for 1 hour. N,N-dimethylformamide was removed under reduced pressure and residue was extracted with 2N hydrochloric acid. The insoluble solid was removed by filtration and filtrate was washed with ether. The aqueous solution was adjusted to pH 7.2 by 2N aqueous sodium hydroxide. The precipitates were extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. Chloroform was removed under reduced pressure and residue was purified by silica gel column chromatography (Wakogel C-200, chloroform/methanol=20/1) to give 118 mg of 5-methyl-6-(3-methyl-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one as pale-brown crystal.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:26]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1cccc(OC(C)(C)C(=O)O)c1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-{3-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the desired product. mp 67-71° C.; Rf=0.09 in 60% ethyl acetate/hexanes; 1H NMR (400 MHz, CDCl3) δ8.22 (s, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.65-7.63 (m, 3H), 7.51-7.41 (m, 3H), 7.35 (t, J=7.2 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.72 (s, 1H), 6.38 (d, J=8.0 Hz, 1H), 6.53 (d, J=8.0 Hz), 4.19 (t, J=7.4 Hz, 2H), 2.92 (t, J=7.4 Hz, 2H), 2.36 (s, 3H), 1.58 (s, 6H); MS (EI) 479.9 (M+Na)+, 457.9 (M+H)+.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([NH:16][C@H:17]3[CH2:22][N:21](C(OC(C)(C)C)=O)[C@@H:20]([CH2:30][C:31]4([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:19][CH2:18]3)=[O:15])=[N:6]2)[CH2:4][CH2:3][CH2:2]1.Cl>CO>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([NH:16][C@H:17]3[CH2:18][CH2:19][C@@H:20]([CH2:30][C:31]4([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[NH:21][CH2:22]3)=[O:15])=[N:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2nn(C3CCC3)c3ccccc23)CC[C@@H]1CC1(O)CCOCC1
Agent: Cl
Solvent: CO
Product: O=C(N[C@H]1CC[C@@H](CC2(O)CCOCC2)NC1)c1nn(C2CCC2)c2ccccc12
Temperature: 25 °C
Yield: 80.4 %

Procedure:
The mixture of tert-butyl cis-5-{[(1-cyclobutyl-1H-indazol-3-yl)carbonyl]amino}-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (112 mg, 0.22 mmol, step 3 of Example 4) and 10% hydrochloric acid in methanol (15 mL) was stirred at room temperature. After stirring for 1 h, the solvent was removed under reduced pressure. The residue was dissolved in methanol (2 mL), and this was poured onto saturated aqueous sodium hydrogencarbonate solution (50 mL). The aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a column of NH-silica gel eluting with ethyl acetate/n-hexane (5:1) to give 73 mg (81%) of the title compound as a colorless oil. This was treated with oxalic acid monohydrate (22 mg) in methanol (5 mL). The solvent was removed under reduced pressure to give 42 mg of the title compound as an ethanedioate salt as a white solid.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH:22]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:28][CH2:27][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: NCC1CCCC1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCC3CCCC3)c2)N1C

Procedure:
8.8 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were introduced portionwise at 20° C. in a stirred mixture of 4 g of cyclopentylmethyl amine, 8 g of triethyl amine and 100 ml of ethanol and the reaction mixture was allowed to stand over night. The solvent was distilled off under reduced pressure and the amorphous end product was crystallized under 80 ml of water. Colorless solid body, decomposition beginning at 80° C., γ C=N 1620 cm-1.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:24][C:23]([C:25]5[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=5)=[N:22][N:21]=4)=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:32]([O:37][CH2:38][CH2:39]Br)(=[O:36])[C:33]([CH3:35])=[CH2:34].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:32]([O:37][CH2:38][CH2:39][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:23]2[O:24][C:20]([C:17]3[CH:18]=[CH:19][C:14]([N:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)=[CH:15][CH:16]=3)=[N:21][N:22]=2)[CH:26]=1)(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: C=C(C)C(=O)OCCBr
Reactant: Oc1cccc(-c2nnc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)OCCOc1cccc(-c2nnc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)o2)c1
Reaction time: 23.5 h

Procedure:
To a solution of 3-(5-(4-carbazol-9-ylphenyl)-1,3,4-oxadiazol-2-yl)phenol (1.0 g, 2.48 mmol) and 2-bromoethyl methacrylate (0.5 g, 2.59 mmol) in DMF (20.0 ml) was added K2CO3 (4.0 g, 28.94 mmol) at room temperature under stirring. The reaction was carried out at room temperature for 23.5 h. Water (100.0 ml) was added. Brown solid product was obtained by filtration. The crude product was purified by silica gel column chromatography using dichloromethane/ethyl acetate (9.7:0.3) as eluent. After removal of solvent, white glass-like solid product was dissolved in acetone. The acetone solution was slowly dropped into methanol (60.0 ml) under stirring. After addition of acetone solution, water (30.0 ml) was added into this solution. White solid product was obtained and collected by filtration. After vacuum dry, the product as white solid in 0.98 g (76.6%) was obtained. 1H NMR (400 MHz, CDCl3, δ): 8.37 (d, J=8.0 Hz, 2H), 8.14 (dd, J1=8.0 Hz, J2=0.8 Hz, 2 Hz), 7.78-7.72 (m, 4H), 7.50-7.41 (m, 5H), 7.31 (m, 2H), 7.12 (dd, J1=8.0 Hz, J2=2.4 Hz, 1H), 6.16 (d, J=0.4 Hz, 1H, C═C—H), 5.59 (t, J=0.8 Hz, 1H, C═C—H), 4.55 (t, J=4.8 Hz, 2H, OCH2), 4.33 (t, J=4.8 Hz, 2H, OCH2), 1.96 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ): 167.28, 164.57, 164.06, 140.94, 140.22, 135.89, 130.40, 128.59, 127.21, 126.21, 124.97, 123.78, 122.34, 120.58, 120.47, 119.79, 118.74, 112.47, 109.87, 66.22, 62.86, 18.30. [M]+ calcd for C32H25N3O4, 515.2. found 515.2. Anal. Calcd for C32H25N3O4: C, 74.55; H, 4.89; N, 8.15. Found: C, 74.29; H, 4.79; N, 8.13.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17](C)(C)[CH3:18])=[O:15])[C:3]1=[O:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(O)C>C1(C)C=CC=CC=1>[NH2:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:21]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Yield: 79.7 %

Procedure:
5.0 g of tert-butyl (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-1-acetate (preparation see Example 3E)) and 3.75 g of p-toluenesulfonic acid were boiled in a water separator for 2.5 hours in 80 ml of toluene. A total of 200 ml of ethanol was then added in portions, and the resulting reaction mixture was refluxed for 3.5 hours. The mixture was then concentrated in vacuo, and the residue was taken up with dichloromethane. The mixture was shaken with ice-cold sodium carbonate solution, and the organic phase was washed with water until neutral. The organic phase was dried over sodium sulfate, evaporated in vacuo and the residue which remained was dried. 3.6 g of ethyl (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate were obtained, m.p.=106.5°-108° C.; IR: 3350, 3300, 2930, 1735, 1660 cm-1 (film); [α]D20 =-288.4° (c=0.5 in methanol).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1.CN1CCCC1=O.[OH-].[Na+]>ClCCl>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][C:12]([NH:11][C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=2)=[CH:13][CH:14]=1)[CH3:20]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cn1cc(Br)nc(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (21.3 g; 79.5 mmol), ethyl 4-aminobenzoate (13.1 g; 79.5 mmol), and 1-methyl-2-pyrrolidinone (10 mL) was heated at 130 degrees for 1 hr. The mixture was cooled to room temperature, diluted with dichloromethane and filtered to give a dull brown solid. This was slurried with 0.5N NaOH, filtered, washed with water and diethyl ether to give 4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acid ethyl ester (1) as a light brown solid (21.3 g)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([OH:3])=O.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[CH2:44]([S:49]([NH2:52])(=[O:51])=[O:50])[CH2:45][CH2:46][CH2:47][CH3:48].Cl>O.CN(C)C=O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:3])[NH:52][S:49]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:51])=[O:50])[CH:5]=2)[NH:9][CH:8]=1
Reactant: CCCCCS(N)(=O)=O
Reactant: O=C(O)c1ccc2[nH]cc(Cc3ccc(Cl)cc3Cl)c2c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2[nH]cc(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
N,N′-Carbonyldiimidazole (0.282 g) is added to an N,N-dimethylformamide (4.3 ml) solution of 5-carboxy-3-(2,4-dichlorobenzyl)indole (0.429 g), and stirred at room temperature for 1 hour. Diazabicycloundecene (0.306 g) and 1-pentanesulfonamide (0.304 g) are added thereto, and stirred at 100° C. for 40 hours. The reaction mixture is cooled, and then made acidic with water and 1M HCl added thereto. Then, the gummy residue formed is collected. This is dissolved in ethyl acetate, washed with water, and died. The solvent is evaporated away, and the resulting residue is crystallized from ether. The crystal formed is collected and dried to obtain 3-(2,4-dichlorobenzyl)-5-(1-pentanesulfonylcarbamoyl)indole (88) (0.258 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester (2.0 g, 9.66 mmol, 1.0 equiv; commercially available from Peakdale Molecular, UK) in ethanol (50 mL) was added palladium on activated charcoal 5% (0.10 g, 0.048 mmol, 0.5 equiv) and the reaction vessel filled with hydrogen (2.5 bar). After stirring at rt for 18 h, the reaction mixture was filtered over celite, concentrated under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.19 g (11%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 3.97 (s, 3H), 7.89 (d, J=4.9 Hz, 1H), 8.81 (d, J=4.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 52.67, 118.22, 156.45, 160.62, 161.18, 162.31. MS (ISP): 172.5 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][CH3:16])[C:12]([OH:14])=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([O:34][CH3:35])[C:28]([N:30]([O:32][CH3:33])[CH3:31])=[O:29])=[CH:23][CH:22]=1)([CH3:19])[CH3:18].[Br:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][C:40]([C:45]2[N:46]=[CH:47][O:48][CH:49]=2)=[CH:39][C:38]=1[O:50][CH3:51]>>[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([O:34][CH3:35])[C:28]([N:30]([O:32][CH3:33])[CH3:31])=[O:29])=[CH:23][CH:22]=1)([CH3:19])[CH3:18].[Br:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][C:40]([C:45]2[N:46]=[C:47]([C:12](=[O:14])[CH:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=3)[O:15][CH3:16])[O:48][CH:49]=2)=[CH:39][C:38]=1[O:50][CH3:51]
Reactant: COC(C(=O)O)c1ccc(OC(C)C)cc1
Reactant: COc1cc(-c2cocn2)cc(OC)c1Br
Agent: COC(C(=O)N(C)OC)c1ccc(OC(C)C)cc1
Product: COc1cc(-c2coc(C(=O)C(OC)c3ccc(OC(C)C)cc3)n2)cc(OC)c1Br

Procedure:
2-(4-Isopropoxyphenyl)-N,2-dimethoxy-N-methylacetamide was synthesized from 2-(4-isopropoxyphenyl)-2-methoxyacetic acid following the method used for the synthesis of Example 1. 1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-(4-isopropoxyphenyl)-2-methoxyethanone was synthesized from 2-(4-isopropoxyphenyl)-N,2-dimethoxy-N-methylacetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole following the method used for the synthesis of Example 7. MS: m/z 490.1 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)[F:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.FC(F)(F)C(O)=O.[CH:31]([C:34]1[S:35][CH:36]=[C:37]([C:39]([N:41]2[CH2:46][C:45]3([CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[O:44][CH2:43][CH2:42]2)=[O:40])[N:38]=1)([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][N:49]1[CH2:50][CH2:51][C:45]2([O:44][CH2:43][CH2:42][N:41]([C:39]([C:37]3[N:38]=[C:34]([CH:31]([CH3:32])[CH3:33])[S:35][CH:36]=3)=[O:40])[CH2:46]2)[CH2:47][CH2:48]1)[F:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(F)c1cccc(C=O)c1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C(F)CO[Si](C)(C)C(C)(C)C)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 3-(2-(tert-butyldimethylsilyloxy)-1-fluoroethyl)benzaldehyde (example 39, step d) (0.329 g) in MeOH (4 mL) was treated with acetic acid (0.055 mL) followed by (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.408 g) and stirred at room temperature for 5 minutes. The solution was cooled in an ice-water bath, treated with sodium triacetoxyborohydride (0.309 g), stirred in ice-water for 135 minutes, then removed from the cooling bath and stirred at room temperature for a further 65 minutes. The solution was cooled back down in ice-water, treated with more sodium triacetoxyborohydride (0.310 g) and stirred in ice-water for 75 minutes. More sodium triacetoxyborohydride (0.312 g) was added and the mixture was stirred for 70 minutes. More sodium triacetoxyborohydride (0.619 g) was added and the mixture was stirred overnight, allowing the cooling bath to slowly expire. The next day, more sodium triacetoxyborohydride (0.307 g) was added and the mixture was stirred for 70 minutes. More acetic acid (0.055 mL) was added and the mixture was stirred for 80 minutes. The mixture was warmed to 40° C. and stirred at that temperature for 25 minutes, then it was concentrated onto flash silica in vacuo. The residue was purified by flash chromatography on silica eluted with 5% methanol in dichloromethane to afford the subtitled compound as a sticky white solid. Yield 0.344 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH2:21][C:22]1[C:23]([C:29]([NH:31][CH3:32])=[O:30])=[N:24][C:25](Br)=[CH:26][N:27]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:21][C:22]1[N:27]=[CH:26][C:25]([C:9]2[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])=[N:24][C:23]=1[C:29]([NH:31][CH3:32])=[O:30]
Reactant: CNC(=O)c1nc(Br)cnc1N
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNC(=O)c1nc(-c2ccc(Cl)c(C(=O)OC)c2)cnc1N
Temperature: 95 °C
Yield: 54.4 %

Procedure:
To a solution of methyl 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.16 g, 0.55 mmol) in toluene (2 mL)) were added 3-amino-6-bromo-N-methyl-2-pyrazincarboxamide (0.13 g, 0.58 mmol), tetralds(triphenylphosphin)palladium(0) (64 mg, 0.06 mmol), ethanol (2 mL), and 2.0 N sodium carbonate (0.42 g, 4.00 mmol). The solution was degassed with nitrogen gas for 3-5 min and heated at 90-100° C. for 2 h. Reaction cooled to room temperature and diluted with ethyl acetate (200 mL). The organic layer was washed water (50 mL) and saturated aqueous sodium chloride (40 mL), dried over magnesium sulfate, filtered, and concentrated to afford crude product. Trituration with methanol (1 mL), filtration and drying gave methyl 5-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}-2-chlorobenzoate (96 mg, 56% yield) as yellow solid. 1H NMR (400 MHz, CDCl3): 8.62 (br s, 1H), 8.28 (d, 1H), 7.92 (dd, 2H), 7.52 (d, 1H), 4.02 (s, 3H), 3.02 (s, 3H); MS (EI) for C14H13N4O2Cl: 321 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([F:11])=[CH:9][C:8](F)=[CH:7][N:6]=1)=[O:4].[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:32]=[C:31]([OH:33])[C:25]3[CH2:26][C:27]([CH3:30])([CH3:29])[O:28][C:24]=3[CH:23]=2)=[O:21])=[N:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([O:33][C:31]2[C:25]3[CH2:26][C:27]([CH3:29])([CH3:30])[O:28][C:24]=3[CH:23]=[C:22]([C:20](=[O:21])[NH:19][C:16]3[CH:17]=[CH:18][N:14]([CH3:13])[N:15]=3)[CH:32]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(F)cc1F
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F
Temperature: 160 °C
Yield: 56.5 %

Procedure:
A mixture of 3,5-difluoro-pyridine-2-carboxylic acid methyl ester (175a) (422 mg, 2.44 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (700 mg, 2.44 mmol), and Cs2CO3 (1.59 g, 4.88 mmol) in DMF was heated to 160° C. in a microwave for 30 min, cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage column chromatography with 40-70% EtOAc in hexanes to give a white solid (607 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ 9.12 (br. s., 1 H) 8.31 (d, J=2.02 Hz, 1 H) 7.27 (d, J=2.27 Hz, 1 H) 7.12 (d, J=5.81 Hz, 2 H) 6.97-7.07 (m, 1 H) 6.78 (d, J=1.77 Hz, 1 H) 4.00 (s, 3 H) 3.73 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C22H21FN4O5 m/z 441.20 (M+H)+.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH2:10]1)=O)C.[C:20]([CH:25]=[C:26]1[NH:30][CH2:29][CH2:28][NH:27]1)([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:23]([O:22][C:20]([C:6]1[CH:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:25]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:26]2[NH:27][CH2:28][CH2:29][N:30]2[C:5]=1[CH3:4])=[O:21])[CH3:24]
Reactant: CCOC(=O)C=C1NCCN1
Reactant: CCOC(=O)CC(=O)C=C1CC=Cc2ccccc21
Solvent: CCO
Product: CCOC(=O)C1=C(C)N2CCNC2=C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 52 %

Procedure:
Heating a solution of 9.0 g of (naphth-1-ylidene)-acetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 60 ml of ethanol for 6 hours yields 5-methyl-7-(naphth-1-yl)-1,2,3,7-tetrahydroimidazolo[1,2-a] -pyridine-6,8-dicarboxylic acid diethyl ester of melting point 169° - 170° C (ethanol). Yield: 52% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:27]=[C:26]([CH3:28])[O:25][N:24]=3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:35])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([C:23]3[CH:27]=[C:26]([CH3:28])[O:25][N:24]=3)=[O:22])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cc(C)on2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: Cc1cc(C(=O)N2CCN(c3c(C(C)N)cc(Cl)c4cccnc34)CC2)no1
Temperature: 65 °C

Procedure:
A mixture of 1-(5-chloro-8-{4-[(5-methylisoxazol-3-yl)carbonyl]piperazin-1-yl}quinolin-7-yl)ethanone (0.032 g, 0.080 mmol) and ammonium acetate (0.0618 g, 0.802 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.20 mL, 0.20 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C20H23ClN5O2 (M+H)+: m/z=400.2; Found: 400.2.