Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li][CH3:36]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)([OH:13])[CH3:36])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=1
Reactant: COc1nc2ccc(C(=O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: COc1nc2ccc(C(C)(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.67 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (220 mg, 0.45 mmol, Intermediate 10: step b) was added THF (15 mL). The solution was cooled in a dry ice bath and then MeLi (1.6 M in Et2O, 0.33 mL, 0.53 mmol) was introduced. After 40 minutes, the reaction was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (4×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness to afford an amber gum. Chromatography on silica gel (3% MeOH-DCM increasing to 5% MeOH) provided the title compound as a white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=2.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.45-7.35 (m, 3H), 7.07 (d, J=8.0 Hz, 1H), 4.34 (s, 2H), 4.06 (s, 3H), 2.54 (s, 3H), 2.24 (s, 1H), 2.17 (s, 3H), 2.01 (s, 3H); MS (ESI): mass calcd. for C27H24ClF3N2O2, 500.2, m/z found 501.1 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(2,6-dimethylpyridin-3-yl)ethanol was purified by chiral SFC (Stationary phase: Chiracel OD column (50×250 mm, 5 micron), Mobile phase: 12% EtOH-hexane with 0.2% Et3N), to give 2 enantiomers. The first eluting enantiomer was Example 13b and the second eluting enantiomer was Example 13c.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][S:6][CH2:5][CH:4]1[CH2:9][CH:10]([CH3:12])[CH3:11])=O.[P:13]([OH:16])([OH:15])[OH:14].P(Cl)(Cl)Cl>O>[CH2:9]([CH:4]1[CH2:5][S:6][CH2:7][CH2:8][N:3]1[CH:1]([P:13](=[O:14])([OH:16])[OH:15])[P:13](=[O:16])([OH:15])[OH:14])[CH:10]([CH3:12])[CH3:11]
Reactant: OP(O)O
Reactant: CC(C)CC1CSCCN1C=O
Solvent: O
Solvent: ClP(Cl)Cl
Product: CC(C)CC1CSCCN1C(P(=O)(O)O)P(=O)(O)O
Temperature: 100 °C

Procedure:
A mixture of N-formyl-3-isobutyl-thiomorpholine (18.7 g) and phosphorous acid (16.4 g) was heated at 100° C. for 2 hours. Phosphorus trichloride (30 ml) was added dropwise with stirring, and after reflux for 3 hours water (180 ml) was added slowly. The mixture was refluxed for 1 hour and filtered. Evaporation of the filtrate gave a residue which was triturated with ethanol to yield a crystalline compound which was isolated by filtration. M.p.: 237°-238° C. (dec.).
Reaction SMILES: [C@H:1]12[N:8]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.Cl[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:3]2[CH2:4][CH2:5][C@H:6]3[C@H:1]([N:8]([C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:10])[CH2:7]3)[CH2:2]2)[N:21]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H]2CCNC[C@H]21
Reactant: Cc1cc(C)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC[C@@H]3CN(C(=O)OCc4ccccc4)[C@@H]3C2)n1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
To (1S,6R)-benzyl 3,8-diazabicyclo[4.2.0]octane-8-carboxylate (2.5 g, 6.9 mmol) and 2-chloro-4,6-dimethylpyrimidine (980 mg, 6.9 mmol) in DMF (35 mL) was added Cs2CO3 (9.0 g, 27.6 mmol). The reaction flask was heated to 100° C. until starting materials were consumed, cooled to rt, diluted with EtOAc and washed with H2O. The aqueous layer was back-extracted with EtOAc (1×). The combined organics were washed with brine and dried (Na2SO4) to give an oil. Purification via silica gel (15-75% EtOAc in hexanes) gave 1.6 g (63%) of the title compound as a clear oil. MS (ESI) mass calcd. C20H24N4O2, 352.44; m/z found 353.2 [M+H]+.
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH2:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([O:45][C:46]3[C:47]([F:56])=[C:48]4[C:52](=[CH:53][CH:54]=3)[NH:51][C:50]([CH3:55])=[CH:49]4)=[N:40][CH:41]=[N:42]2)=[CH:37][C:36]=1[O:57][CH3:58]>CC(N(C)C)=O>[F:56][C:47]1[C:46]([O:45][C:39]2[C:38]3[C:43](=[CH:44][C:35]([O:34][CH2:33][CH2:32][CH2:31][N:21]4[CH2:22][CH2:23][N:18]([CH2:15][C:16]#[CH:17])[CH2:19][CH2:20]4)=[C:36]([O:57][CH3:58])[CH:37]=3)[N:42]=[CH:41][N:40]=2)=[CH:54][CH:53]=[C:52]2[C:48]=1[CH:49]=[C:50]([CH3:55])[NH:51]2
Reactant: C#CCN1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1CCN(CCCOc2cc3ncnc(Oc4ccc5[nH]c(C)cc5c4F)c3cc2OC)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
1-Prop-2-ynylpiperazine diTFA salt (329 mg, 0.94 mmol) and potassium carbonate (258 mg, 1.87 mmol) were added to a solution of 7-(3-bromopropoxy)-4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxyquinazoline (144 mg, 0.31 mmol), (prepared as described for the starting material in Example 7), in DMA (3.6 ml). The reaction mixture was stirred at 85° C. overnight before being filtered. The filtrate was concentrated under vacuum and the crude product was purified by column chromatography eluting with increasingly polar mixtures of ammonia/methanol in methylene chloride (1 to 7%). A second purification by column chromatography eluting with a mixture of methanol in methylene chloride (1/9) gave 4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-(3-[4-(2-propynyl)piperazin-1-yl]propoxy}quinazoline as a white solid (115 mg, 73%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][C:3]=1[NH2:4].FC(F)(F)S(O[C:25]1[C:36]([CH3:37])=[N:35][C:28]2[N:29]=[C:30]([S:33][CH3:34])[N:31]=[CH:32][C:27]=2[CH:26]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.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>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([C:25]2[C:36]([CH3:37])=[N:35][C:28]3[N:29]=[C:30]([S:33][CH3:34])[N:31]=[CH:32][C:27]=3[CH:26]=2)=[CH:5][C:3]=1[NH2:4]
Reactant: CSc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
Reactant: Cc1cc(F)c(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
Combine 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (370 mg, 1.474 mmol), 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (500 mg, 1.474 mmol) and K2CO3 (611 mg, 4.42 mmol) in dioxane (12 mL) and H2O (3 mL), sparge with argon, treat with Pd(PPh3)4 (85 mg, 0.074 mmol) and heat to 60° C. for 3 h. Cool the mixture to RT, stir overnight, treat with EtOAc and wash with brine. Filter the mixture, wash the organic layer again with brine, dry over Na2SO4, concentrate to dryness and purify via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). Combine fractions, remove the organics under reduced pressure and neutralize the aqueous residue with saturated. NaHCO3. Extract the mixture with EtOAc (2×), wash the combined organics with brine, dry over Na2SO4 and concentrate to dryness to afford the title compound as an amorphous solid (373 mg, 81%). MS (m/z): 315.1 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:14][N:5]2[C:6]3[C:11]([NH:12][CH2:13][C@@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:15]1([CH3:39])[CH:20]=[CH:19][C:18]([C:21]2[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=2[C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[O:24])=[CH:17][CH:16]=1>>[OH:1][C@H:2]1[CH2:14][N:5]2[C:6]3[C:11]([N:12]([C:30](=[O:31])[C:29]4[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[C:22]5[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=5[C:18]5[CH:17]=[CH:16][C:15]([CH3:39])=[CH:20][CH:19]=5)=[CH:34][CH:33]=4)[CH2:13][C@@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: O[C@@H]1C[C@H]2CNc3ccccc3N2C1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)O)cc2)cc1
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3C[C@@H]4C[C@@H](O)CN4c4ccccc43)cc2)cc1
Yield: 55 %

Procedure:
The same procedures used in Example 1 were repeated using (2R, 3aS)-2-hydroxy-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline prepared in Reference Example 16 and 4-[[2-(4-tolyl)benzoyl]amino]benzoic acid to give the title compound after recrystallization from ethyl acetate-hexane. m.p.: 163-164.5° C.; Yield 55.0%.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH3:5])[CH2:2]1.[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1>C(#N)C>[N:6]1([CH2:2][CH:3]([OH:1])[CH2:4][CH3:5])[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: CCC1CO1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CCC(O)Cn1ccnc1
Yield: 48.7 %

Procedure:
A solution of 1,2-epoxybutane (2.0 mL, 23 mmol) and imidazole (2.37 g, 35 mmol) in acetonitrile (20 mL) was stirred at reflux for 24 h. The mixture was concentrated, taken up in water (30 mL) and extracted with ethyl acetate (9×10 mL). The combined extracts were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (SiO2, CH2Cl2-methanol-ammonium hydroxide 80:20:1) to give 1-(1H-imidazol-1-yl)-2-butanol (1.57 g, 48%) as a colorless oil. NMR spectrum was consistent with structure. MS EI: M+• 140.0948 (M+• 140.0950).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3(OCC[O:15]3)[C:7]3[N:8]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:9]=2[CH:10]=1.S(=O)(=O)(O)O.N>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:9]=2[CH:10]=1
Reactant: Clc1ccc2c(c1)N1CCCN=C1C21OCCO1
Agent: N
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: O=C1C2=NCCCN2c2cc(Cl)ccc21
Temperature: 0 °C
Yield: 64.3 %

Procedure:
7'-Chloro-2',3',4',10'-tetrahydrospiro[1,3-dioxolane-2,10'-pyrimido(1,2-a)indole] (5.71 g) was added to cooled 98% sulphuric acid (30 ml) with stirring. The solution was then poured on to ice (300 ml) and basified to pH9 with conc. ammonia solution. The resulting suspension was stirred with chloroform (100 ml) and, after separation, the aqueous phase was exhaustively extracted with further chloroform. Evaporation of the combined, dried (MgSO4) extracts left a brownish orange solid which was crystallised from benzene-cyclohexane, giving 7-chloro-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one as orange crystals (3.06 g), darkening above 160° and melting from 168°-170° with decomposition.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[NH2:16][C:4]1[N:3]=[C:2]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C#N)cc2)nc(N)n1
Yield: 71 %

Procedure:
Following the method described in Example 26, 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine and 4-amino-benzonitrile provided the title compound (71% yield). 1H NMR (DMSO-d6) δ 2.36 (s, 3H, CH3), 6.19 (s, 1H, Ar), 6.61 (s, 2H, NH2), 7.32 (d, 1H, J=8.2 Hz, Ar), 7.38 (dd, 1H, J=8.2 Hz, J=2.3 Hz, Ar), 7.43 (d, 1H, J-2.3 Hz, Ar), 7.72 (d, 2H, J=8.8 Hz, Ar), 8.00 (d, 2H, J=8.8 Hz, Ar), 9.73 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:11][O:9][C:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Cc1cccnc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ncccc1C
Yield: 57.1 %

Procedure:
Heat a mixture of 3-methylpicolinic acid (1.0 g, 7.3 mmol), potassium carbonate (4.1 g, 29.7 mmol), and iodomethane (4.4 g, 31.0 mmol) in acetone (35 mL) overnight under reflux. Filter, wash the residue with EtOAc, and concentrate in vacuo. Pass through a short plug of silica gel eluting with hexane/EtOAc (1:1) to provide 2-methoxycarbonyl-3-methylpyridine as a pale yellow liquid (630 mg, 57%). To a solution of 2-methoxycarbonyl-3-methylpyridine in anhydrous THF (10 mL) at 0° C., add with stirring a solution of 1M lithium aluminum hydride in THF (5 mL, 5 mmol), and continue stirring for 30 min at 0° C. Allow the mixture to warm to ambient temperature and quench cautiously with 0.5M aqueous NaOH. Heat the mixture at 60° C. for 40 min, cool to ambient temperature, extract with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:3) to give the desired intermediate (90 mg, 18%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cnn(C)c3)cccc2c1N
Yield: 81.7 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (212 mg, 1.020 mmol) were reacted to afford the title compound (123 mg, 82% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]([O:13][CH3:14])[O:4]1.[H][H]>CO.[Ni]>[CH3:1][O:2][CH:3]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH:5]([O:13][CH3:14])[O:4]1
Reactant: [H][H]
Reactant: CCOC(=O)C1=CC(OC)OC1OC
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)C1CC(OC)OC1OC
Yield: 90.7 %

Procedure:
Ethyl 2,5-dimethoxy-2,5-dihydrofuran-3-carboxylate (615 mg, 3.044 mmol) was dissolved in methanol (10 mL) and treated with hydrogen (10 bar) over Raney nickel at 40° C. for 2 h. The reaction mixture was evaporated to dryness to give ethyl 2,5-dimethoxy-tetrahydrofuran-3-carboxylate (564 mg, 91%) which was used directly in the next step.
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(OCC)C>CN(C)C=O>[CH:29]1([C:27](=[O:28])[CH2:26][CH:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[N:5]2[C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=3)[N:15]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(=O)C1CCCCC1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)C3CCCCC3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
An oily suspension (50% by weight; 3.1 g) of sodium hydride is added at a temperature in the region of -5° C. to a solution, maintained under a nitrogen atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g) in anhydrous dimethylformamide (180 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. A solution of cyclohexyl methyl ketone (8.2 g) in anhydrous dimethylformamide (20 cc) is then added and stirring is continued for 6 hours at a temperature in the region of 0° C. and then for 16 hours at a temperature in the region of 20° C. The reaction mixture is then poured into distilled water (800 cc). The solid obtained is separated by filtration, washed with water, dried in the air, and then recrystallized in acetonitrile and finally purified by chromatography under pressure (50 kPa) on silica gel (0.04-0.063 mm; 140 g) contained in a column 2.8 cm in diameter. Elution is performed with methylene chloride, collecting 20-cc fractions. Fractions 25 to 62 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is taken up with ethyl ether (100 cc) and separated by filtration. 3-(2-Cyclohexyl-2- oxoethyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (4.8 g), m.p. 140° C., is obtained.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:4])=[O:5])=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N(C)S(C)(=O)=O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CN(c1ccc(CBr)cc1)S(C)(=O)=O
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of N-methyl-N-(4-tolyl)methanesulphonamide (0.31 g, 1.54 mmol), N-bromosuccinimide (0.28 g, 1.55 mmol) and 2,2'-azobisisobutyronitrile (20 mg) in carbon tetrachloride (20 ml) was refluxed for 2 hours. The mixture was then cooled to ambient temperature and filtered. The solvent was evaporated and the residue partitioned between ethyl acetate (50 ml) and water (50 ml), washed with brine (50 ml) and dried (MgSO4). The solvent was evaporated yielding N-(4-bromomethylphenyl)-N-methylmethanesulphonamide (0.24 g, 54%) which was used without further purification.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:33])=[C:15]([CH:32]=3)[C:16]([NH:18][C:19]3[C:29]([CH3:30])=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=3[CH3:31])=[O:17])[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O.O.[OH-].[Na+]>[CH3:31][C:20]1[CH:21]=[C:22]([CH:28]=[C:29]([CH3:30])[C:19]=1[NH:18][C:16](=[O:17])[C:15]1[CH:32]=[C:11]([N:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:12]=[CH:13][C:14]=1[CH3:33])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC4(CC3)OCCO4)ccc2C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(=O)CC3)ccc2C)c(C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 59.4 %

Procedure:
To a solution of ethyl 4-[[5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-methyl-benzoyl]amino]-3,5-dimethyl-benzoate (205 mg, 452.99 μmoles) in acetone (5 ml) is added a mixture of 5M HCl (1 mL) in H2O (1 mL) and heated to 60° C. After 12 hours, the mixture is cooled to ambient temperature, diluted with 2M NaOH to pH 6 and extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 0-40% ethyl acetate in hexane to afford the title compound as an off-white foam (0.11 g, 61%). Mass spectrum (m/z): 409.2 (M+1).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[CH3:9][C:10]([NH:18][C:19]([C:21]1[N:22]=[C:23]([S:29][CH3:30])[S:24][C:25]=1[C:26]([OH:28])=[O:27])=[O:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11]>CN(C=O)C>[CH3:11][C:10]([NH:18][C:19]([C:21]1[N:22]=[C:23]([S:29][CH3:30])[S:24][C:25]=1[C:26]([O:28][CH3:1])=[O:27])=[O:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:9]
Reactant: CSc1nc(C(=O)NC(C)(C)c2ccccc2)c(C(=O)O)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1sc(SC)nc1C(=O)NC(C)(C)c1ccccc1
Temperature: 85 °C

Procedure:
Potassium carbonate (0.37 g) and iodomethane (0.17 ml) were added to a solution of 4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-2-(methylthio)-1,3-thiazole-5-carboxylic acid (Intermediate 14; 0.9 g) in DMF (20 ml) and heated in a sealed tube at an external temperature of 85° C. for 30 min. The reaction mixture was concentrated to remove DMF and partitioned with EtOAc and water. The combined organic extracts were washed with water, dried with MgSO4, and concentrated to an orange solid (0.63 g). NMR: 1.60-1.65 (m, 6H), 2.76 (s, 3H), 3.78-3.83 (m, 3H), 7.22 (d, J=7.16 Hz, 1H), 7.33 (t, J=7.63 Hz, 2H), 7.46 (d, J=7.35 Hz, 2H), 8.75 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]=[CH2:13])[CH:7]=[CH:6][C:5]=1[OH:14].[OH-].[Na+].Cl>CO>[OH:14][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=1[C:3]([OH:15])=[O:2]
Reactant: C=CCOc1ccc(O)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.2 %

Procedure:
5-allyloxy-2-hydroxy-benzoic acid methyl ester (6.10 g, 29.30 mmol) was dissolved in methanol (25.0 mL, 1.2 M). This solution was treated with aq NaOH (75 mL, 1.33 M, 100 mmol) and stirred at room temperature for 48 h. The reaction is acidified to pH 1–2 with conc. HCl and extracted with ethyl acetate (4×). The combined organic extracts are washed with H2O (2×), aq saturated NaCl, dried with Na2SO4, filtered and concentrated to give 2-hydroxy-5-propoxy-benzoic acid (5.30 g, 91%) as a pale yellow solid: Anal. calcd for C10H10O4: C, 61.85; H, 5.19. Found: C, 62.06; H, 5.27.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([NH:2][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[NH:6]2
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.6 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (0.2 g, 0.642 mmol) in anhydrous dichloromethane (15 ml) was added dry triethylamine (220 ml, 1.4 mmol) and the resulting mixture was stirred at room temperature under an atmosphere of nitrogen until dissolution was complete. To this solution was added benzoyl chloride (82 ml, 0.706 mmol) and stirring was continued for 17 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (100 ml) and dilute citric acid (150 ml). The organic layer was washed successively with saturated sodium bicarbonate solution (2×50 ml) and brine (50 ml) then dried (MgSO4) and evaporated to give the crude product (0.26 g) which was recrystallised from ethyl acetate/petroleum ether (bp 60°-80° C.) to give the pure title compound as colourless crystals (0.201 g, m.p. 258°-259° C.); δ (360 MHz, DMSO) 1.79 (1H, ddd, J= 13.3, 12.6 and 4.1 Hz, CHACHBHCCHD), 2.28 (1H, dm, J=13.3 Hz, CHACHBHCCHD), 3.73 (3H, s, --CO2CH3), 4.09 (1H, dm, J=12.6 Hz, CHACHBHCCHD), 5.28 (1H, m, CHACHBHCCHD), 6.70 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.91 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.93 (1H, s, NH), 7.42-7.55 (3H, m, ArH), 7.89 (2H, d, J=7.1 Hz, ArH), 8.72 (1H, d, J=7.6 Hz, PhCONH-); m/e (CI+) 379 (M+1)+, 122 (100%); Found: C, 56.95; H, 4.30; N, 7.37; C18H16Cl2N2O3 requires C, 57.01; H, 4.25; N, 7.39%.