Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([O:8][C:9](=[O:29])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]1[CH3:28])[CH3:7]>>[CH2:6]([O:8][C:9](=[O:29])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:26][CH:27]=2)=[C:12]1[CH3:28])[CH3:7]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2)c2cc(F)ccc21
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)Cl)cc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To chlorosulfonic acid (1.5 mL) at 0° C. under nitrogen was added portionwise over 10 minutes 2-(3-benzyl-5-fluoro-2-methyl-1H-indol-1-yl)acetic acid ethyl ester (900 mg, 2.76 mmol). After stirring at this temperature for 2 hours the solution was warmed to room temperature and stirred for a further 2 hours. The reaction mixture was then poured onto ice, and extracted with ethyl acetate. The separated organics were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 2-(3-(4-(chlorosulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetic acid ethyl ester (˜1.1 g, 2.59 mmol, 94%) as a brown oil, which was used directly without further purification.
Reaction SMILES: C(O)CCCCCCC/C=C\CC.[CH2:14]([OH:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH2:27]CCCCCC.C=CCC>C1COCC1>[CH2:14]([OH:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27]
Reactant: CCCCCCCCC=CCCCCCCCCCCO
Agent: C=CCC
Agent: CC/C=C\CCCCCCCCO
Solvent: C1CCOC1
Product: CC/C=C\CCCCCCCCCCO
Yield: 47 %

Procedure:
According to the procedure for compound 7, 11-eicosenol (1.1 g, 3.7 mmol) and THF (3 mL) were reacted with 1 (0.047 g, 2 mol %) and 1-butene to provide 9 (0.37 g, 47% yield, 76% Z as determined by 13C-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.29-5.45 (2H, m), 3.63 (2H, t, J=6.6 Hz), 1.94-2.06 (4H, m), 1.56 (2H, dt, J=13.5, 6.7 Hz), 1.27, (15H, m), 0.96 (3H, m); 13C NMR (CDCl3): δ 131.7, 129.5, 63.2, 33.0, 29.9, 29.7, 29.7, 29.7, 29.6, 29.4, 27.2, 25.9, 20.7, 14.6; HRMS (FAB): 212.2135, [C14H28O]+ requires 212.2140.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4](OCC)=[O:5].CN(C1C=CC(C(O)(C(F)(F)F)C(F)(F)F)=CC=1)CC(OCC)=O>>[CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][OH:5]
Reactant: CCOC(=O)CN(C)c1ccccc1
Agent: CCOC(=O)CN(C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Product: CN(CCO)c1ccccc1
Yield: 89 %

Procedure:
Prepared in the manner of Example 23 except ethyl N-methyl-N-phenylglycinate was substituted for ethyl N-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}glycinate. Purification by flash chromatography (1:1 hexanes/EtOAc) afforded the title compound as a yellow oil (89%). MS (ES+) m/z 152 (MH+).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[S:21]1[C:29]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]=2[CH:23]=[CH:22]1>CN(C)C=O.C(O)C>[S:21]1[C:29]2[CH2:28][CH2:27][N:26]([CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[CH:18][CH:19]=5)[O:14][N:13]=4)[CH:7]=3)[CH2:25][C:24]=2[CH:23]=[CH:22]1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Reactant: c1cc2c(s1)CCNC2
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCc2sccc2C1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=408.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([OH:31])=O.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([NH:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)=[O:31]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 49 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine in place of benzylamine, the title compound was obtained as a white powder in 49% yield: mp 107-108° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.44 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.23-7.19 (m, 1H), 5.59 (s, 1H), 4.55 (d, J=5.7 Hz, 2H), 4.47 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.43 (t, J=8.1 Hz, 2H), 2.55 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 157.2, 155.4, 153.5, 149.1, 148.6, 139.6, 135.8, 134.1, 130.5, 128.4, 125.8, 123.6, 122.1, 117.1, 47.5, 42.0, 41.8, 41.3, 17.2; MS (ES+) m/z 476.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[O:11]1[CH:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:17]=2)[CH2:12]1>CCCCCO>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[CH2:12][CH:13]([OH:11])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:17]=1
Reactant: c1ccc(Cc2cccc(OCC3CO3)c2)nc1
Reactant: CC1(C)CCCC(C)(C)N1
Solvent: CCCCCO
Product: CC1(C)CCCC(C)(C)N1CC(O)COc1cccc(Cc2ccccn2)c1
Yield: 18.9 %

Procedure:
8.9 g of 2,2,6,6-tetramethylpiperidine is added to a solution of 15.0 g of 1,2-epoxy- 3-[3-(2-pyridylmethyl)phenoxy]propane in 45 ml of n-amyl alcohol, and the resulting mixture is heated on a water bath for 2 hours. The solvent is then removed, 200 ml of benzene is added to the residue, and the insoluble matter is filtered off with activated charcoal. The filtrate is washed with water, and extracted with two 100 ml portions of 5% hydrochloric acid. The aqueous layer is made alkaline with sodium hydroxide, and the separated oil is extracted with benzene. The benzene layer is washed with water, dried over anhydrous potassium carbonate, and the solvent is removed. The residual oil is purified by distillation to give 4.5 g of 1-(2,2,6,6-tetramethylpiperidino)-3-[3-(2-pyridylmethyl)phenoxy]-2 -propanol, boiling at 230°-235°C/0.15 mmHg.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[C:40](=[O:41])[N:39]([CH2:42][CH2:43][CH2:44][C:45]([F:48])([F:47])[F:46])[N:38]=[CH:37]2)[S:31][C:32]=1[C:33]([OH:35])=O.[N:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][NH2:56])[CH:50]=1>>[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[C:40](=[O:41])[N:39]([CH2:42][CH2:43][CH2:44][C:45]([F:48])([F:47])[F:46])[N:38]=[CH:37]2)[S:31][C:32]=1[C:33]([NH:56][CH2:55][C:51]1[CH:50]=[N:49][CH:54]=[CH:53][CH:52]=1)=[O:35]
Reactant: Cc1nc(-n2cnn(CCCC(F)(F)F)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(CCCC(F)(F)F)c2=O)sc1C(=O)NCc1cccnc1
Yield: 35 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 4-methyl-2-(5-oxo-1-(4,4,4-trifluorobutyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 35% yield: mp 184-185° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.57 (br s, 1H), 8.49 (br s, 1H), 8.27 (s, 1H), 7.75-7.63 (m, 1H), 7.32-7.20 (m, 1H), 6.62 (t, J=5.6 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 3.91 (t, J=6.5 Hz, 2H), 2.63 (s, 3H), 2.28-1.96 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 161.7, 153.4, 150.9, 150.0, 149.2, 149.1, 135.8, 131.0, 128.5, 124.8, 121.2, 44.5, 41.2, 31.3, 30.9, 21.3, 17.2; MS (ES+) m/z 427.3 (M+1).
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:20]3[C:19]4[C:14]5=[C:15]([C:21](=[O:30])[N:22]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:23](=[O:24])[N:13]5[C:12]=3[CH:11]=[CH:10][C:9]=2[CH:31]=1)[CH:16]=[CH:17][CH:18]=4)(=[O:4])[CH3:3].Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[ClH:1].[CH3:29][N:27]([CH3:28])[CH2:26][CH2:25][N:22]1[C:21](=[O:30])[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:20]4[C:8]5[CH:7]=[CH:6][C:5]([CH:2]([OH:4])[CH3:3])=[CH:31][C:9]=5[CH:10]=[CH:11][C:12]=4[N:13]([C:14]=23)[C:23]1=[O:24]
Reactant: CC(=O)c1ccc2c(ccc3c2c2cccc4c(=O)n(CCN(C)C)c(=O)n3c42)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(O)c1ccc2c(ccc3c2c2cccc4c(=O)n(CCN(C)C)c(=O)n3c42)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
21 μl (0.168 mmol) of a borane/pyridine complex (about 8 M) was added to a suspension of 84 mg (0.211 mmol) of a compound prepared by converting the compound of Example 2 into its free base in acetic acid (1.5 ml) and the obtained mixture was stirred at 70° C. for 3 hours. Then it was acidified by adding 1 N hydrochloric acid thereto at room temperature, stirred for 1 minute and neutralized with a saturated aqueous solution of sodium bicarbonate. Next, it was extracted by adding thereto a mixture of dichloromethane with ethanol. The organic layer was taken up, washed with water, dried over sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography and converted into its hydrochloride by using 1 N hydrochloric acid to thereby give 44 mg of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=O.C(N(C(C)C)CC)(C)C.[N:25]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[NH4+].[Cl-]>C1COCC1.C(Cl)Cl.CCOC(C)=O>[I:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([NH:34][CH2:33][CH2:32][CH2:31][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:11]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: NCCCN1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)NCCCN2CCOCC2)cc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.3 %

Procedure:
Thionyl chloride (5.6 mL) was added over 1 min to a 0° C. solution of 3-iodo-4-methyl benzoic acid (5 g, 19.1 mmol) in THF (30 mL). The solution was stirred for 24 h at rt and the volatile components were removed in vacuo. A portion of the crude acid chloride (1 g, 3.57 mmol) was dissolved in DCM (10 mL) and was cooled to 0° C. Diisopropylethylamine (0.78 mL, 4.46 mmol) was added followed by 3-morpholin-4-yl-propylamine (0.52 mL, 3.56 mmol) and the reaction was stirred for 1 h at rt. EtOAc (80 mL) and aq. NH4Cl (20 mL) was added and the layers were separated. The organic layer was washed with aq NH4Cl (2×10 mL), NaOH (1N, 3×20 mL), water (20 mL), brine (50 mL) and was dried over sodium sulfate. Concentration of the solution and SiO2 flash column chromatography of the residue (0–10% MeOH in DCM) yielded the product (695 mg, 50%) as a yellow glass.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:33]=[C:32]5[C:28]([C:29](=[O:36])[N:30]([CH3:35])[N:31]5[CH3:34])=[CH:27][CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:33]=[C:32]5[C:28]([C:29](=[O:36])[N:30]([CH3:35])[N:31]5[CH3:34])=[CH:27][CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(=O)n(C)n(C)c5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(=O)n(C)n(C)c5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1,2-dimethyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (9.4 mg, 0.014 mmol) in THF (0.5 mL) and methanol (0.5 mL) was added 1N NaOH solution (0.5 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H32ClN4O4S: 627.2; found: 627.2. 1H NMR (400 MHz, CD3OD) δ 8.75 (d, J=5.2 Hz, 1H), 8.49 (s, 1H), 8.06 (s, 1H), 7.96 (dd, J=5.2, 1.2 Hz, 1H), 7.90 (s, 1H), 7.85 (q, J=8.4 Hz, 2H), 7.70-7.67 (m, 1H), 7.61-7.56 (m, 3H), 5.27 (s, 1H), 3.51 (s, 3H), 3.47 (s, 3H), 2.62 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:45]=[CH:46][CH:47]=1)[O:31][C:32]1[CH:44]=[CH:43][C:35]2[N:36]=[C:37]([NH:39][C:40](=[O:42])[CH3:41])[S:38][C:34]=2[CH:33]=1>O1CCCC1.C(OCC)(=O)C.O>[C:40]([NH:39][C:37]1[S:38][C:34]2[CH:33]=[C:32]([O:31][C:30]3[CH:29]=[C:28]([NH:27][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=4[Cl:1])[CH:47]=[CH:46][CH:45]=3)[CH:44]=[CH:43][C:35]=2[N:36]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)cc2s1
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (240 mg, 1.07 mmol) in tetrahydrofuran (4 mL) were added oxalyl chloride (170 mg, 1.34 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in N,N-dimethylacetamide (4 mL). N-[6-(3-Aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x) was added and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with saturated brine (10 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100), and recrystallized from ethyl acetate/diisopropyl ether to give the title compound (201 mg, 75%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[Cl:21][C:22]1[CH:23]=[N:24][C:25]2[C:30](=O)[CH2:29][CH2:28][C:26]=2[CH:27]=1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:30]3[C:25]4=[N:24][CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]4[CH2:28][CH2:29]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: O=C1CCc2cc(Cl)cnc21
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 3-chloro-5H-cyclopentapyridin-7(6H)-one using decaborane yielded (6S)-2-amino-6-(5-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylamino)-2-fluorophenyl)-3,5,5,6-tetramethyl-5,6-dihydropyrimidin-4(3H)-one as a white foam. MS (ESI): m/z=430.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[F:23].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:32]([O:34][C:35](=[O:38])[CH2:36]Br)[CH3:33].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:25])=[C:19]([CH:20]=[CH:21][C:22]=1[F:23])[O:24][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of 3-[[2-chloro-5-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenol (128 mg, 0.35 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (172 mg, 0.53 mmol, 1.5 eq). The reaction was stirred at room temperature for 30 min then ethylbromoacetate (70.5 mg, 0.42 mmol, 1.2 eq) was added dropwise. The reaction was stirred at room temperature for further 3 h then water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, evaporated in vacuo and the residue obtained purified by chromatography (petroleum ether:EtOAc, 100:1 to 20:1) to give the title compound as a colourless oil (120 mg, 76%).
Reaction SMILES: O=[C:2]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])[C:3](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=[O:5].C(Cl)(=O)C(Cl)=O>C1C=CC=CC=1.CN(C=O)C>[CH:20]1[CH:19]=[CH:18][C:17]([CH:16]=[C:3]([C:4]2[O:5][C:9](=[O:10])[C:8]3[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[C:2]2[O:27][C:26](=[O:28])[C:25]3[C:24](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:23]=2)=[CH:22][CH:21]=1
Reactant: O=C(Nc1ccccc1C(=O)O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=c1oc(C(=Cc2ccccc2)c2nc3ccccc3c(=O)o2)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The Compound 11 (4 g, 9.28 mmol) was suspended in dry benzene (100 ml) and oxalyl chloride (3.2 ml, 37.18 mmol) was added dropwise under ice cooling. Then, with addition cf 8 drops of dry DMF, the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was removed and the residue was extracted with chloroform. The organic layer was washed with 1N.HCl, saturated brine, 4% NaHCO3 aqueous solution, and saturated brine and dried over magnesium sulfate. The solvent was evaporated. The residue was dissolved in chlcroform and applied on silica gel column for chromatography (benzene ethyl acetate=4:1). Recrystallization from isopropyl ether gave the desired compound 52 in crystal (3.26 g, yield, 89%). m.p., IR, and NMR pectra of the product fully agreed with those of the one obtained in Example 19.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:24]=[C:25]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:26]=2)[C:13](OCCN2CCOCC2)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:36]1([N:41]2[C:45]([NH2:46])=[C:44]([C:47]([NH2:49])=[O:48])[C:43]([CH2:50][CH3:51])=[N:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1.O(C)[Na].C([O-])(=O)C1C=CC=CC=1>C(O)(=O)C.O.C(O)C>[CH:36]1([N:41]2[C:45]3=[N:46][C:13]([C:12]4[CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:26]=[C:25]([O:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH:24]=4)=[N:49][C:47](=[O:48])[C:44]3=[C:43]([CH2:50][CH3:51])[NH:42]2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: O=C(OCCN1CCOCC1)c1cc(OCCN2CCOCC2)cc(OCCN2CCOCC2)c1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: CO[Na]
Agent: O=C([O-])c1ccccc1
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cc(OCCN4CCOCC4)cc(OCCN4CCOCC4)c3)nc(=O)c1-2
Reaction time: 48 h
Yield: 53.8 %

Procedure:
A mixture of 4-morpholinylethyl 3,5-di-[2-(4-morpholinyl)ethoxy]benzoate (2.0 g, 4 mmol), 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.45 g, 2 mmol), NaOCH3 (0.23 g, 4 mmol) and ethanol (50 ml) was refluxed for 96 hours. The reaction was incomplete so an additional equivalent of the benzoate and NaOCH3 were added and the mixture was reluxed for 48 hours. The reaction mixture was stripped to dryness, and the residue was treated with water and acidified with acetic acid. The mixture was cooled and the product was isolated by filtration and dried at 90° C. to afford 0.61 g (54%) of 1-cyclopentyl-3-ethyl-6-[3,5-di[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 182-183° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Cl.N([O-])=O.[Na+].[I-:16].[K+].[OH-].[Na+].C(=O)(O)[O-].[Na+]>O>[I:16][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: [I-]
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: Ic1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17.3 %

Procedure:
A solution of 5-aminoindazole (5.0 g, 38 mmol) and ice (32 g) in water (16 mL) was further cooled with an ice bath. To this slurry was added concentrated hydrochloric acid (16 mL), followed immediately by sodium nitrite (2.9 g, 41 mmol in 11 mL water). After stirring for 10 min at 0° C., potassium iodide (7.5 g, 45 mmol) was added and the solution was slowly warmed to 40° C. until gas evolution slowed. The reaction mixture was stirred in a 50° C. oil bath for 30 min further, then cooled to room temperature and 3M aqueous sodium hydroxide solution (40 mL) was added, followed by 50% aqueous sodium bicarbonate solution (40 mL). The solution was vacuum filtered and a brown solid was collected, taken up in 100 mL tetrahydrofuran and stirred with 100 mL of dry silica. To this slurry was added hexanes (66 mL), and the mixture was filtered through celite/fritted glass using 40% tetrahydrofuran/hexanes to rinse the silica. Trituration from ethyl acetate gave 1.6 g (18%) of 5-iodo-1H-indazole. 1H NMR (400 MHz, CDCl3): 10.55 (broad s, 1H), 8.14 (m, 1H), 8.02 (d, 1H), 7.61 (dd, 1H), 7.31 (m, 1H); MS (EI) for C7H5N2I: 245 (MH+).
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:35])([CH3:34])[C@H:10]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[N+:31]([O-])=O)[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[Pt]>[Si:1]([O:8][C:9]([CH3:35])([CH3:34])[C@H:10]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)(O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Reaction time: 6 h
Yield: 100 %

Procedure:
N-[(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]-3-nitroquinolin-4-amine (6.51 g, 12.5 mmol) was dissolved in 75 mL toluene and the solution was placed in a pressure bottle. Platinum on carbon (5%, 2.0 g) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 6 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with toluene and 2-propanol and the combined filtrates were concentrated under reduced pressure to give N4-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]quinoline-3,4-diamine (6.12 g) as a brown foam.