Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[N:30]=2)=[O:28])[CH2:23][CH2:22]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.Cl.Cl[CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CC(C)=O.O>[CH3:1][N:2]([CH2:17][CH:18]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]([C:29]2[N:30]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[O:28])[CH2:23][CH2:22]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4[nH]3)CC2)c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4n3CCN3CCOCC3)CC2)c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Combine N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide (0.70 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (0.84 mmol), and potassium carbonate (3.36 mmol) in acetone (10 mL), water (4 mL), and dichloromethane (5 mL). Heat to reflux. After 20 hours, cool to ambient temperature and concentrate the reaction mixture invacuo and dilute with ethyl acetate. Extract with saturated aqueous ammonium chloride solution, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over MgSO., filter, and concentrate invacuo to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([NH:11][C:12]([N:14]1[C:18]2[CH2:19][CH2:20][O:21][CH2:22][C:17]=2[C:16]([C:23]2[CH:28]=[CH:27][C:26](F)=[C:25]([F:30])[CH:24]=2)=[N:15]1)=[O:13])[C:7]([CH3:10])([CH3:9])[CH3:8].[F:32]C1C=CC(F)=CC=1C(Cl)=O>>[F:32][C:28]1[CH:27]=[CH:26][C:25]([F:30])=[CH:24][C:23]=1[C:16]1[C:17]2[CH2:22][O:21][CH2:20][CH2:19][C:18]=2[N:14]([C:12]([NH:11][C@@H:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:31])=[O:13])[N:15]=1
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCO
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2cc(F)ccc2F)c2c1CCOC2)C(=O)NCCO

Procedure:
(S)-3-(2,5-difluorophenyl)-N-(1-(2-hydroxyethylamino)-3,3-dimethyl-1-oxobutan-2-yl)-6,7-dihydropyrano[4,3-c]pyrazole-1(4H)-carboxamide (87) Compound 87 was prepared according to the procedure for the synthesis of compound 36 by replacing 3,4-difluorobenzoyl chloride with 2,5-difluorobenzoyl chloride. LCMS (+ESI) m/z=437.4 [M+H]+. 1H NMR (CDCl3) δ 7.88 (d, J=9.0 Hz, 1H), 7.41-7.45 (m, 1H), 7.07-7.11 (m, 2H), 6.34 (br, 1H), 4.67 (s, 2H), 4.15 (d, J=9.0 Hz, 1H), 3.95 (t, J=5.6 Hz, 2H), 3.72-3.76 (m, 2H), 3.45-3.49 (m, 2H), 3.17 (br, 2H), 1.05 (s, 9H). Purity: 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:55][CH2:56][C:57]1[C:58](=[O:65])[NH:59][C:60]([CH3:64])=[CH:61][C:62]=1[CH3:63]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:55][CH2:56][C:57]1[C:58](=[O:65])[NH:59][C:60]([CH3:64])=[CH:61][C:62]=1[CH3:63])=[O:9]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCc1c(C(=O)O)cc(Cl)cc1N(CC)C1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1c(C(=O)NCc2c(C)cc(C)[nH]c2=O)cc(Cl)cc1N(CC)C1CCOCC1
Yield: 63.1 %

Procedure:
To a solution of 5-chloro-2-ethyl-3-[ethyl(oxan-4-yl)amino]benzoic acid (100 mg, 0.32 mmol) in DMF (2 ml) at room temperature under nitrogen was added HBTU (146 mg, 0.38 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (84 μl, 0.48 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 60.3 mg, 0.35 mmol). After stirring for 3 hours at room EtOAc (30 ml) was added to the reaction mixture and this was then washed with deionized water (5 ml) followed by saturated NaHCO3(aq) (3×5 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 100% EtOAc to 97:3 EtOAc:MeOH) to give 90 mg (63%) of the title compound as a white solid. LC-MS 97%, m/z=446.1/448.2, 1H NMR (500 MHz, Chloroform-d) δ ppm 11.93 (s, 1H), 7.14 (t, J=5.7 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 5.95 (s, 1H), 4.52 (d, J=5.8 Hz, 2H), 3.95 (d, J=11.2 Hz, 2H), 3.30 (td, J=11.3, 3.6 Hz, 2H), 3.01 (q, J=7.0 Hz, 2H), 2.93 (ddd, J=15.3, 10.0, 5.3 Hz, 1H), 2.83 (q, J=7.4 Hz, 2H), 2.38 (s, 3H), 2.22 (s, 3H), 1.71-1.63 (m, 4H), 1.02 (t, J=7.5 Hz, 3H), 0.86 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.C(N(C(C)C)C(C)C)C.[CH3:14][CH:15]([CH3:20])[C:16](=[CH2:19])[CH2:17][OH:18]>C1COCC1>[CH3:1][O:2][CH2:3][O:18][CH2:17][C:16]([CH:15]([CH3:20])[CH3:14])=[CH2:19]
Reactant: C=C(CO)C(C)C
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=C(COCOC)C(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.3 %

Procedure:
Chloromethyl methyl ether (98 ml, 1292 mmol) and N-ethyldiisopropylamine (234 ml, 1344 mmol) were added to a solution of 3-methyl-2-methylenebutane-1-ol (61.5 g, 615 mmol) prepared in Reference Example 202 in THF (500 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, and the mixture was washed with water and brine, dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2-methoxymethoxymethyl-3-methyl-1-butene (89 g, quantitative) as a colorless oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH:29]1([CH2:32][NH2:33])[CH2:31][CH2:30]1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:33][CH2:32][CH:29]3[CH2:31][CH2:30]3)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Reactant: NCC1CC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCC2CC2)c1

Procedure:
Example 137 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and 1-cyclopropylmethanamine to give the title compound (0.008 g).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[O:14]=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.[Cl-].[NH4+]>O1CCCC1>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:15]1([OH:14])[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Fc1ccccc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2F)C1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
3.1 ml (6.1 mmol) of a 2M solution of isopropylmagnesium chloride in tetrahydrofuran are added to a solution of 1.1 g (6.2 mmol) of 1-bromo-2-fluorobenzene in 4 ml of tetrahydrofuran, cooled beforehand to −25° C. After stirring for 30 minutes at −25° C., a solution of 0.65 g (3.7 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 7.5 ml of tetrahydrofuran is added. The reaction medium is stirred for 30 min and then a saturated aqueous solution of ammonium chloride is added. The organic compounds are extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate and then filtered and evaporated. The crude product is purified by silica gel chromatography, elution being carried out with a 5/5 heptane/ethyl acetate mixture. 135 mg of 3-(2-fluorophenyl)-3-hydroxy-1-(tert-butoxycarbonyl)-azetidine are obtained in the form of a white solid with a yield of 14%.
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.I[C:17]1[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:19][O:20][C:21]=1[CH3:22].C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:17]2[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:19][O:20][C:21]=2[CH3:22])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1noc(C)c1I
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(C)c1-c1ccc(O)cc1
Temperature: 95 °C
Yield: 57.8 %

Procedure:
To a 25 mL RB flask fitted with a magnetic stirrer was charged with DMF (2.5 mL). To the stirred solvent were added 4-hydroxyphenylboronic acid (0.2 g, 0.7 mmol), ethyl 4-iodo-5-methyl-1,2-oxazole-3-carboxylate (0.116 g, 0.8 mmol), sodium bicarbonate (0.18 g, 2.1 mmol) and water (0.08 mL) under argon atmosphere. After addition, the reaction mixture was purged with argon for 15 minutes. To this bis(triphenylphosphine)palladium (II) chloride (0.05 g, 0.07 mmol) was added and purged with argon for 10 minutes. After addition, the reaction mixture was heated at 95° C. for 5 h under argon atmosphere. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with water (5 mL) and brine solution (5 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude was purified through silica gel column chromatography using ethyl acetate and petroleum ether as elutants. The product was obtained as an off white solid (0.1 g, yield: 57%). 1H NMR (300 MHz, CDCl3): δ 7.10-7.13 (d, 2H), 6.80-6.82 (d, 2H), 5.14 (s, 1H), 4.25-4.32 (q, 2H), 2.36 (s, 3H), 1.23-1.28 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.C[O:15][C:16](=[O:45])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32]C3C=CC(C(F)(F)F)=CC=3Br)[CH:27]=2)=[CH:21][C:20]=1[CH3:44]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([O:32][C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=2)[O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:45])=[O:15])=[C:20]([CH3:44])[CH:21]=2)=[C:5]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:8]=2)[CH:4]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3cccc(C(F)(F)F)c3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 3-trifluoromethylphenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 112 mg (63%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H22O4F6 560, found 561 (M+1, 100%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1CCCO1.FC(F)(S(O[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42]3[CH:47]=[C:46]([N:48]4[CH:53]=[CH:52][C:51](=[O:54])[NH:50][C:49]4=[O:55])[CH:45]=[C:44]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:43]=3[O:60][CH3:61])[CH:38]=2)[CH:33]=1)(=O)=O)C(F)(F)OC(F)(F)C(F)(F)F.[CH3:63][S:64]([NH2:67])(=[O:66])=[O:65]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:56]([C:44]1[C:43]([O:60][CH3:61])=[C:42]([C:37]2[CH:38]=[C:39]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([NH:67][S:64]([CH3:63])(=[O:66])=[O:65])[CH:41]=[CH:40]3)[CH:47]=[C:46]([N:48]2[CH:53]=[CH:52][C:51](=[O:54])[NH:50][C:49]2=[O:55])[CH:45]=1)([CH3:58])([CH3:57])[CH3:59]
Reactant: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.0026 g, 2.80 μmol), di-tert-butyl (2′,4′, 6′-triisopropyl-3,6-dimnethoxybiphenyl-2-yl)phosphine (0.0033 g, 6.72 μmol) and milled potassium phosphate tribasic (0.131 g, 0.616 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (1.5 mL) was added, the vial was capped, and the contents were heated to 80 ° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2-tetrafluoro-2-(perfluoroethoxy)ethanesulfonate (0.4 g, 0.560 mmol, Example 3-7, compound (5f), methanesulfonamide (0.064 g, 0.672 mmol) and ethyl acetate (3 mL) were added to the 40-mL reaction vial. The temperature of the closed vial was raised to 90 ° C. and the contents were magnetically stirred for 16 hours. HPLC analysis of the reaction mixture showed that the product was formed in 97 area % at 210 nm.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][OH:13])([O-:3])=[O:2].CN(C=O)C.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(OCC)(=O)C>[Si:24]([O:13][CH2:12][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:9]([CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1c(CO)cccc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a clean, dry round-bottom flask was added 2-nitro-1,3-benzenedimethanol (818 mg, 4.47 mmol), anhydrous DMF (40 mL), and imidazole (304.2 mg, 4.47 mmol). The solution was maintained at 0° C. while tert-butyldimethylsilylchloride (337 mg, 2.24 mmol) was slowly added. The resulting pale yellow solution was allowed to warm to room temperature and stirred overnight under argon before being diluted with ethyl acetate (100 mL), washed with water (5×50 mL), dried over MgSO4, filtered, concentrated on a rotary evaporator, and purified by silica gel chromatography (30% EtOAc:hexanes) to yield 3-(tert-butyldimethylsilyloxymethyl)-2-nitro-hydroxymethylbenzene as a yellow oil which crystallized upon further solvent removal in vacuo. The excess 2-nitro-1,3-benzenedimethanol was recovered and re-subjected to the reaction conditions to yield Compound 9 in 80% yield after three iterations.
Reaction SMILES: COC(=O)C([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[C@@H:8]([O:14][CH3:15])[C:7]1=[O:16])=O>CO.C(Cl)Cl>[C:11]([S:10][C@H:9]1[NH:6][C:7](=[O:16])[C@@H:8]1[O:14][CH3:15])(=[O:13])[CH3:12]
Reactant: COC(=O)C(=O)N1C(=O)[C@H](OC)[C@H]1SC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CO[C@H]1C(=O)N[C@@H]1SC(C)=O

Procedure:
A solution of 71.20 mg of 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-oxoacetic acid methyl ester (crude product) in 10 ml of 1% aqueous methanol is stirred overnight at room temperature. The reaction mixture is diluted with methylene chloride, washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1) and yields the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]OC2C=CC=CC=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)[Br:24]>C(Cl)Cl>[Br:24][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1cccc(CCCCCCCOc2ccccc2)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(CCCCCCCBr)c1

Procedure:
7-Bromo-1-(3-hydroxy-phenyl)-heptane (9.2) was synthesized as in 9.1 using 8.2 (0.50 g, 1.68 mmol), in anhydrous CH2Cl2 (16 mL), and BBr3 (1M solution in CH2Cl2, 3.7 mL, 3.7 mmol). The title compound (9.2) was isolated as a viscous liquid after purification by flash column chromatography (0.420 g, 92% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=[O:13])[CH:11]=[CH2:12])=[N:7][CH:8]=1.C(O)C.O1CCCC1.[Si:29]([O:36][CH:37]([C:39]1[CH:40]=[CH:41][C:42]([CH:45]=[O:46])=[N:43][CH:44]=1)[CH3:38])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[Si:29]([O:36][CH:37]([C:39]1[CH:40]=[CH:41][C:42]([C:45](=[O:46])[CH2:12][CH2:11][C:10](=[O:13])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[N:43][CH:44]=1)[CH3:38])([C:32]([CH3:35])([CH3:33])[CH3:34])([CH3:31])[CH3:30]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ccc(C=O)nc1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(C(C)O[Si](C)(C)C(C)(C)C)cn2)nc1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of 4-[5-(methylsulfanyl)pyridin-2-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (93.1 mg) in a mixed solvent of ethanol (1.5 mL) and tetrahydrofuran (1.5 mL) were added 5-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyridine-2-carbaldehyde (169 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (8.6 mg) and triethylamine (17.8 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (123 mg, yield 69%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([O:26]CC)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][CH2:31][F:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([OH:26])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][CH2:31][F:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCF)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OCCF)nc1Cl
Yield: 93.2 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(2-fluoroethoxy)piperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (124a) (0.24 g, 0.49 mmol), 2 N lithium hydroxide (4 mL, 8 mmol), methanol (6 mL) and THF (6 mL), to obtain 0.21 g of the title compound as a light brown solid (93%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[F:32].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>O.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.COCCOC>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[C:31]([F:32])[CH:30]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4ccc(F)c(F)c4)cnc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.4 g, 3.55 mmol), 3,4-difluorophenylboronic acid (1.12 g, 7.10 mmol), potassium carbonate (1.62 g, 11.7 mmol), 1,2-dimethyoxyethane (DME)(13 mL), and water (7 mL) was stirred under nitrogen. Dichlorobis(triphenylphosphine)palladium(II)(0.025 g, 0.036 mmol) was added, and the suspension was heated at reflux for five hours, allowed to cool to room temperature, diluted with water (20 mL), and extracted with dichloromethane (50 mL). An emulsion formed. Solid sodium chloride was added to saturate the aqueous layer. The organic layer was then removed under reduced pressure. The aqueous layer was extracted with dichloromethane (4×50 mL); the third extraction was allowed to stand overnight. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown solid (2.03 g) was dissolved in dichloromethane (45 mL), purified by automated flash chromatography (40+M silica cartridge, eluting with 3% to 10% methanol in ethyl acetate), and then triturated with acetonitrile. The resulting solid was isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 485 mg of 1-[4-amino-7-(3,4-difluorophenyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as an off-white solid, mp 193-195° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=[C:2]([F:1])[CH:3]=1
Reactant: Nc1c(F)ccc(O)c1F
Reactant: O=C(O)c1cc(F)cc(-c2cccc(F)c2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1c(F)ccc(O)c1F)c1cc(F)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a stirred solution of 3-fluoro-5-(3-fluorophenyl)benzoic acid (533 mg, 2.3 mmol, 1.1 eq) in DCM (10 mL) and DMF (3 drops) at 0° C. was added oxalylchloride (866 mg, 6.8 mmol, 3.3 eq) dropwise. The reaction was warmed to room temperature and stirred for 2 h, and then the solvent removed. The residue that remained was dissolved in THF (6 mL) and added to a solution of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (300 mg, 2.07 mmol, 1.0 eq) and NaHCO3 (868 mg, 10.34 mmol, 5.0 eq) in THF (6 mL) at 0° C. The reaction was warmed to room temperature and stirred for 1 h then quenched by addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with 5% Na2CO3, water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was recrystallised from DCM: petroleum ether (1:3) and collected by filtration to give the title compound as a solid (390 mg, 52%).