Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([CH:19]=O)=[CH:14][CH:13]=3)=[N:2]1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:19][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]([C:3]2[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=2)=[CH:18]3)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc2[nH]c(-c3n[nH]c4ccccc34)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc3[nH]c(-c4n[nH]c5ccccc45)cc3c2)CC1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
A mixture of the aldehyde (6-3, 50 mg, 0.19 mmol), N-methylpiperazine (191 mg, 1.91 mmol), acetic acid (0.06 mL) and sodium triacetoxyborohydride (406 mg, 1.91 mmol) in N,N-dimethyl formamide (3 mL) was stirred at the ambient temperature for 11 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Chromatography (SiO2, 30% methanol in ethyl acetate) afforded the desired product (6-4) as a light tan solid; 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 11.56 (s, 1H), 8.23 (d, 1H, J=8.0 Hz), 7.66 (d, 1H, J=8.4 Hz), 7.53 (s, 1H), 7.49 (t, 1H, J=7.6 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.31 (t, 1H, J=7.6 Hz), 7.12–7.11 (m, 2H), 3.57 (s, 2H), 2.52–2.26 (m, 8H), 2.21 (s, 3H).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH2:8][C@H:9]1[CH2:11][C@@H:10]1[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>CC(C)=O.O.O.[Ru](=O)=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C@H:10]1[CH2:11][C@@H:9]1[C:8]([OH:2])=[O:7])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(C[C@H]1C[C@@H]1CO)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(C[C@H]1C[C@@H]1C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 91.3 %

Procedure:
Sodium metaperiodate (1729 mg, 8.08 mmol) and ruthenium(IV) oxide hydrate (48.8 mg, 0.32 mmol) were added to a solution of benzyl 2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetate (712 mg, 3.23 mmol) in acetone (11.5 mL) and water (13 mL) at 0° C., and the mixture was stirred at 0° C. for 2.5 hr. The reaction mixture was poured into water (100 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give (1S,2R)-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (690 mg, 2.95 mmol, 91%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2)#[N:2]>CCCCCC>[OH:12][CH:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: N#Cc1ccc2c(c1)CCC2=O
Solvent: CCCCCC
Product: N#Cc1ccc2c(c1)CCC2O

Procedure:
The operation is carried out as in preparation 10, starting with 5-cyano-1-indanone (1.93 g), the extracted residue is taken up in 20 ml of hexane, with agitation for one hour. After filtering, the filtrate is dried at 45° C. under reduced pressure and 1.92 g is obtained,
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[BrH:21].BrBr>C(O)(=O)C>[Br:21][CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:20]
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred slurry of 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl) ethanone from Step 1 (3.03 g, 10.38 mmol) in acetic acid (40 mL) was added HBr in acetic acid (2 mL, 48% by wt. ) and bromine (0.64 mL, 1.99 g, 12.45 mmol). Within minutes the slurry became homogeneous. After 1 hour, the reaction was concentrated in vacuo, diluted with methylene chloride and reconcentrated in vacuo yielding 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl) ethanone as a tan solid (3.53 g, 95%) which could be used without further purification. mp 140°-141° C., 1H NMR (CDCl3) 300 mHz δ8.05 (dd, J=5.16, 8.84 Hz, 2H), 7.96 (d, J=8.48 Hz, 2H), 7.75 (d, J=8.48 Hz, 2H), 7.17 (t, J=8.48 Hz, 2H), 6.29 (s, 1H), 3.06 (s, 3H). MS: m/e 371/373 (MH+). HRMS Δ=5.5 mmu.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:21]=[CH:20][C:13]3[NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].Br[C:24]1[CH:29]=[CH:28][NH+:27]=[CH:26][CH:25]=1>ClCCl>[C:1]1([S:7]([C:10]2[CH:21]=[CH:20][C:13]3[N:14]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH2:15][C:16]([CH3:18])([CH3:19])[O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)CNc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Reactant: Brc1cc[nH+]cc1
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CN(c2ccncc2)c2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 185 °C
Yield: 50 %

Procedure:
A mixture of 7-benzenesulfonyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.257 g., 0.847 mmol) and 4-bromopyridinium chloride (0.658 g., 3.388 mmol) was heated without solvent at 185° C. for 45 minutes. The reaction mixture was cooled to room temperature, suspended in 5 mL dichloromethane and concentrated in vacuo. The resulting crude oil was dissolved in a mixture of 50 mL ethyl acetate and 50 mL water. The aqueous layer was made strongly basic with 50 mL of 2N aqueous potassium carbonate, and the phases were separated. The organic phase was washed with twice with 50 mL water and once with 50 mL brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude oil was purified by flash chromatography (3% methanol in dichloromethane) to give 161 mg (54%) of 7-benzenesulfonyl-2,2-dimethyl-4-pyridin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine as a foam. MS: 381 (M+H)+, mp: 112.7-120.4° C. (as hydrochloride salt).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:40])[CH3:39])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: CC(=O)O
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 66.1 %

Procedure:
Using 7-(2,5-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.07 g, 0.12 mmol) obtained in Example 22 step 5 and acetic acid (0.036 mL, 0.62 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.048 g, 64%) was obtained.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.CCOC(C)=O>[Si:20]([O:1][CH2:2][C@H:3]1[O:4][C@@H:9]([OH:10])[C@@H:7]([OH:8])[CH:5]1[OH:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](O)[C@@H](O)C1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
To a stirred solution of D-arabinose (50 g, 0.33 mol) in DMF (500 mL) was added imidazole (45 g, 0.66 mol) and tert-butylchlorodiphenylsilane (109 g, 0.4 mol). After being stirred at room temperature for 2 hours, the resulting solution was diluted with EtOAc (2000 mL), washed with water, brine and dried over Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:11 EtOAc in petroleum ether) to afford 33 g of (2R,3S,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]tetrahydrofuran-2,3,4-triol (compound 25a).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=O)[NH:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:12])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[Cl:12][C:5]1[N:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(=O)[nH]c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(Cl)nc1C
Temperature: 100 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
5,6-dimethyl-2(1H)pyridinone (Example 476, 0.39 g, 3.2 mmol) was suspended in phosphorous oxychloride (5.00 mL, 53.6 mmol) and heated to 100° C. Then, phosphorous pentachloride (4.00 g, 19.2 mmol) was added, and the mixture was heated to 140° C. After 16 h, the mixture was cooled to rt, diluted with CH2Cl2 (5 mL), and slowly poured into a 0° C. solution of potassium hydroxide (5 g) and potassium carbonate (5 g) in water (100 mL). Upon complete addition, the mixture was allowed to warm to rt and stirred for 1 h. The aqueous solution was extracted with CH2Cl2, and the combined organics layers were dried (MgSO4), filtered, and concentrated in vacuo to provide the title compound (0.35 g, 77%) as a brown oil. The material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.36 (d, 1H), 7.07 (d, 1H), 2.49 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[NH2:2]/[C:1](=[N:17]\[OH:18])/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/O
Yield: 93 %

Procedure:
A solution of tert-butyl (2S)-2-cyano-1-piperidinecarboxylate (13.10 g) [see Preparation 3] in methanol (500 ml) was added to a solution of hydroxylamine hydrochloride (21.6 g) and sodium carbonate (33.0 g) in water (600 ml). The reaction mixture was warmed to the reflux temperature and stirred for 8 hours after which time the methanol was removed under reduced pressure and the product extracted from the aqueous layer with ethyl acetate (3×500 ml). The combined organic layers were washed with water (500 ml), dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate (14.1 g) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12]C)[C:8](=[O:14])[O:7][CH2:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[C:8](=[O:14])[O:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)OC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1OCc2cc(O)c(O)cc21
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A solution of compound 24 (7.00 g, 36.1 mmol) in CH2Cl2 (150 mL) was cooled to −78° C. and BBr3 (8.52 mL, 90.2 mmol) was added at the same temperature. Stirring was continued at −78° C. for 30 min, and the reaction mixture was brought to room temperature and stirred for 16 h. The reaction mixture was quenched with MeOH at 0° C. and the solvent was removed. The residue was portioned between water (100 mL) and EtOAc (200 mL); the EtOAc layer was separated. The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layer was concentrated and the residue was purified by column chromatography (silica gel, 40-60% EtOAc in hexanes) to afford compound 25 (5.00 g, 83%) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 10.18 (br s, 1H), 9.65 (br s, 1H), 7.06 (s, 1H), 6.92 (s, 1H), 5.16 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:26]1([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38]OS(C3C=CC(C)=CC=3)(=O)=O)[N:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:35]4[N:36]=[C:32]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[O:33][C:34]=4[CH3:50])=[CH:9][CH:8]=3)[C:4]([OH:3])=[O:25])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc3c(c2)OCO3)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 78. 1H NMR (400 MHz, CDCl3) δ 7.13 (d, 2H, J=8.30 Hz), 6.75 (d, 2H, J=8.79 Hz), 6.61 (d, 2H, J=8.30 Hz), 6.42 (d, 2H, J=2.44 Hz), 6.33 (dd, 1H, J=8.30, J=2.44 Hz), 5.88 (d, 2H, J=0.98 Hz), 4.11 (t, 2H, J=5.86 Hz), 3.15 (d, 1H, J=13.68 Hz), 3.03 (d, 1H, J=13.68 Hz), 2.93 (t, 2H, J=5.86 Hz), 2.86 (tt, 1H, J=11.72 Hz, J=3.42 Hz), 2.27 (s, 3H), 1.99-1.96 (m, 2H), 1.80-1.75 (m, 2H), 1.71-1.65 (m, 1H), 1.57-1.46 (m, 2H), 1.37-1.33 (m, 1H), 1.32 (s, 3H), 1.29-1.19 (m, 2H); HRMS (ES+) m/z exact mass calcd for C29H34NO7 508.2335, found 508.2351.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Li].[CH2:20](OCC)C.N1(C([O-])=O)CCC(=O)CC1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([OH:17])([CH3:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C1CCN(C(=O)[O-])CC1
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Product: CC1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Yield: 90 %

Procedure:
Benzyl(4-oxopiperidin-1-yl)carboxylate (4.7 g, 20 mmol) was dissolved in tetrahydrofuran (200 ml); methyllithium-diethylether solution (9.0 ml (1.02 M)+11.6 ml (1.14 M), total 22 mmol) was added dropwise thereto (internal temperature: −60° C. or below) while stirred at −78° C. under nitrogen atmosphere; and then the reaction mixture was stirred for 1.5 hours as it stands. On the other hand, a similar reaction was performed by using piperidin-4-one-1-carboxylate (1.1 g, 5.0 mmol) in another container. After the saturated aqueous solution of ammonium chloride was added to each reaction mixture, the two reaction mixtures were mixed. Extraction was performed with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate system) to yield the title compound (4.5 g, 18 mmol, 73%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][CH2:12][CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9][C:8]=2[CH:24]=1.[BrH:27].CC(O)=O>C(OCC)C>[BrH:27].[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[CH:24]=1.[BrH:27]
Reactant: O=C(OCc1ccccc1)N1CCSc2ccc(OC(F)(F)F)cc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc2c(c1)CNCCS2

Procedure:
The starting material 30 (200 mg) was treated with 3 mL of HBr/AcOH solution for 1 h. To the reaction mixture was added diethyl ether (20 mL). The white solid was filtered to give the title compound as HBr salt. Yield: 182 mg.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH3:7][CH:8]([C:13]1[CH:19]=[C:18]([C:20](F)(F)[C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=1[NH2:15])[CH2:9][CH:10]([CH3:12])[CH3:11].O.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[CH3:7][CH:8]([C:13]1[CH:19]=[C:18]([CH2:20][C:21]([F:22])([F:24])[F:23])[CH:17]=[CH:16][C:14]=1[NH2:15])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)CC(C)c1cc(C(F)(F)C(F)(F)F)ccc1N
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(C)c1cc(CC(F)(F)F)ccc1N
Reaction time: 0.17 h
Yield: 30.4 %

Procedure:
Aluminum lithium hydride (1.62 g, 4.26 mmol) was dissolved in tetrahydrofuran (20 ml), followed by adding dropwise thereto 2-(1,3-dimethylbutyl)-4-pentafluoroethylaniline (974 mg, 3.3 mmol), and the resulting mixture was stirred at reflux temperature for 3 hours. Water was added to the reaction mixture in small portions under ice-cooling, followed by stirring for 10 minutes. Magnesium sulfate was added thereto and then stirred for 10 minutes. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure, after which the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 260 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:25](Cl)=[O:26])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2>>[CH3:1][O:2][C:3]([CH2:4][NH:5][C:25]([C:12]1([CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:26])=[O:6]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COC(=O)CN
Product: COC(=O)CNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from glycine-methyl ester and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: C([C:5]1[C:10]([N:11]2[C:16]3[N:17]=[C:18]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[CH:24][C:23]=4[O:34][CH3:35])[N:19]=[CH:20][C:15]=3[CH:14]=[CH:13][C:12]2=[O:36])=[CH:9][CH:8]=[CH:7][C:6]=1[N:37](C1C=CC=C(N2C3N=C(NC4C=CC(N5CCOCC5)=CC=4OC)N=CC=3C=CC2=O)C=1C(C)(C)C)C(=O)[O-])(C)(C)C.[C:77]([OH:83])([C:79]([F:82])([F:81])[F:80])=[O:78]>C(Cl)Cl>[F:80][C:79]([F:82])([F:81])[C:77]([OH:83])=[O:78].[NH2:37][C:6]1[CH:5]=[C:10]([N:11]2[C:16]3[N:17]=[C:18]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[CH:24][C:23]=4[O:34][CH3:35])[N:19]=[CH:20][C:15]=3[CH:14]=[CH:13][C:12]2=[O:36])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N(C(=O)[O-])c4cccc(-n5c(=O)ccc6cnc(Nc7ccc(N8CCOCC8)cc7OC)nc65)c4C(C)(C)C)c3C(C)(C)C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCOCC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
Crude bis(tert-butyl (3-(2-((2-methoxy-4-morpholinophenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl))carbamate (2a) was treated with DCM (5 mL) and TFA (3 mL) and stirred at RT for 15 min. The reaction mixture was concentrated and purified on a Gilson preparatory HPLC (Silicycle Silichrome XT C18 column; 30×150 mm, 5 u, 5-95% 0.1% TFA/CH3CN in 0.1% TFA/water) affording 8-(3-aminophenyl)-2-((2-methoxy-4-morpholinophenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one 2,2,2-trifluoroacetate (2b, 74 mg, 0.13 mmol, 41% yield) as a brown amorphous solid after drying in a genevac overnight. m/z (ESI, +ve ion) 446.1 (M+Na)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.86 (1H, s), 8.05 (1H, d, J=9.6 Hz), 7.51-7.58 (1H, m), 7.32 (1H, dt, J=7.6, 1.3 Hz), 7.15-7.21 (2H, m), 6.90 (1H, d, J=8.6 Hz), 6.71 (1H, d, J=9.6 Hz), 6.67 (1H, d, J=2.5 Hz), 6.53 (1H, dd, J=8.7, 2.6 Hz), 3.87-3.93 (5H, m), 3.68 (3H, s), 3.18-3.24 (4H, m).
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([N:14]1[C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])(=O)C1C=CC=CC=1.CO.N>O>[SH:9][CH2:10][CH2:11][C:12]([N:14]1[C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13]
Reactant: O=C(SCCC(=O)N1[C@@H](c2ccccc2)CC[C@H]1C(=O)O)c1ccccc1
Agent: N
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CC[C@H](c2ccccc2)N1C(=O)CCS
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This product from Example 3 was added to a solution of methanol saturated with ammonia and was stirred at 25° C. for 2 hours. The solvent was evaporated off, leaving a solid which was stirred in water and filtered. The filtrate was extracted five times with diethyl ether and was acidified. The acidified solution was then extracted with methylene chloride, washed with brine, dried over magnesium sulfate and concentrated to a solid. This residue was extracted with hot hexane from which the title compound crystallized, m.p. 61°-64° C.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)=[CH:6][C:5]=1[O:28][CH:31]([CH3:33])[CH3:32]
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(OC(C)C)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 30 mg quantity of 3-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one obtained in Example 229 was dissolved in 0.5 ml of dimethylformamide. An 18 mg quantity of 2-bromopropane and 30 mg of potassium carbonate were added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. Drying was performed with anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 23 mg of white powdery 3-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11](O)=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[Cl:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:44]([O:46][CH2:47][CH2:48][O:49][NH2:50])=[CH2:45].[NH4+].[Cl-]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:50][O:49][CH2:48][CH2:47][O:46][CH:44]=[CH2:45])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[Cl:22]
Reactant: C=COCCON
Reactant: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: C=COCCONC(=O)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylic acid (482 mg, 1.20 mmol) in CH2Cl2 (10 mL) was added HOBt (254 mg, 1.63 mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-(2-(vinyloxy)ethyl)hydroxyl-amine (172 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq.). The resultant mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 filtered, and concentrated in vacuo. The crude product (503 mg) was used directly in the next step without further purification.