Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[CH3:30][C:31]1([CH3:48])[CH2:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]([CH3:47])([CH3:46])[NH:32]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH:11]1([N:8]2[C:6]3[N:7]=[C:2]([C:35]4[CH2:34][C:33]([CH3:47])([CH3:46])[NH:32][C:31]([CH3:48])([CH3:30])[CH:36]=4)[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:5]=3[CH:10]=[N:9]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCCCC2)c(=O)[nH]1
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
A solution of 6-bromo-1-cyclohexyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) solution was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (7% yield). LCMS: 517.35 (M+1)+; HPLC: 99.68% (@ 254 nm), (Rt; 5.761); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (bs, 1H), 8.86 (t, 1H), 8.25 (s, 1H), 7.78 (s, 1H), 6.78 (s, 1H), 5.89 (s, 1H), 4.82-4.76 (m, 1H), 4.38 (d, 2H, J=4.8 Hz), 2.22 (s, 3H), 2.12 (s, 3H), 2.01-1.85 (m, 8H), 1.53-1.44 (m, 2H), 1.27 (bs, 6H), 1.23 (bs, 2H), 1.17 (bs, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:10].[CH3:11][NH2:12]>>[Cl:10][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:2]=1[NH:12][CH3:11])[C:8]#[N:9]
Reactant: CN
Reactant: N#Cc1cncc(Cl)c1Cl
Product: CNc1c(Cl)cncc1C#N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
4,5-Dichloronicotinonitrile (500 mg, 2.89 mmol) was suspended in 41% aqueous methylamine solution (5 mL). The resultant mixture was heated, with stirring, up to 60° C. over ca. 30 min. The mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with water, followed by brine then dried (MgSO4) and evaporated to provide the title compound (340 mg, 70%) as a white solid. 1H NMR (CDCl3) 8.39 (1H, s), 8.29 (1H, s), 5.50 (1H, s, br), 3.43 (3H, d, J=5.5 Hz).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([NH:27][C:28]1[CH:29]=[C:30]([C:33]#N)[S:31][CH:32]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C[OH:36].ClCCl.CCCCCC>C1(C)C=CC=CC=1>[CH2:11]([NH:27][C:28]1[CH:29]=[C:30]([CH:33]=[O:36])[S:31][CH:32]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCNc1csc(C#N)c1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1csc(C=O)c1
Temperature: 0 °C

Procedure:
Di-isobutylaluminum hydride (14 ml., 25% solution in toluene) is added with stirring to a solution of 2.9 g. of 4-hexadecylamino-2-cyanothiophene in toluene under a nitrogen atmosphere. The temperature rises during the addition and the reaction is then stirred for 1 hour. A solution of methanol in toluene (14 ml., 1:1) is added over 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (125 ml., 5%). After 10 minutes diatomaceous earth (7.5 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (25 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give crude product. The product is obtained by recrystallization from dichloromethane-hexane.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[CH3:5])[CH3:2].[H-].[Na+].[CH3:9][C:10]1[N:11]=[C:12](S(CC2C=CC=CC=2)=O)[O:13][CH:14]=1.O>CN(C)C=O>[CH2:1]([N:3]([C:12]1[O:13][CH:14]=[C:10]([CH3:9])[N:11]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: Cc1coc(S(=O)Cc2ccccc2)n1
Reactant: CCNC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1nc(C)co1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
N-Ethyl-acetamide (1.18 g, 0.0135 m) in dry dimethylformamide (10 ml) was stirred at room temperature under nitrogen during the portionwise addition of 50% sodium hydride/oil dispersion (0.65 g, 0.0135 m). After the addition, the mixture was warmed to 50° C. and then 4-methyl-2-phenylmethylsulphinyloxazole (3.0 g, 0.0135 m) was added. The mixture was stirred at 50° C. for 5 hours and then hydrolysed with water. The solvent was evaporated in vacuo and the residue extracted with diethyl ether. Column chromatography on silica using ether gave a pale yellow oil which gave the title product as a colourless oil on distillation, b.p. 50°-51° C./0.05 mm.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C(OC)=C(C(CBr)=CC=1)C(OC)=O.[F:38]C1C=CC(S)=CC=1>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([F:38])=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: Fc1ccc(S)cc1
Agent: COC(=O)c1c(CBr)ccc(Br)c1OC
Product: COC(=O)c1c(CSc2ccc(F)cc2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 73, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 4-fluorothiophenol and used without further characterisation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[O:13])=[S:10])=[C:4]([CH:38]([CH3:40])[CH3:39])[CH:3]=1.[C:41]([O-])(=[O:43])[CH3:42].[Na+].BrCC(OC)=O.C(#N)C>[Cl-].[Na+].O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:41](=[O:43])[CH2:42][S:10]/[C:9]/2=[N:11]\[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[O:13])=[C:4]([CH:38]([CH3:40])[CH3:39])[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)c1cc(F)ccc1NC(=S)NC(=O)NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: COC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cc(F)ccc1N1C(=O)CS/C1=N\C(=O)NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 65 °C
Yield: 59.2 %

Procedure:
To a 20 mL vial was added 1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea (PC3) (0.092 g, 0.16 mmol), sodium acetate (0.040 g, 0.48 mmol), methyl 2-bromoacetate (0.084 mL, 0.80 mmol) and acetonitrile (2.0 mL). The vial was sealed and the reaction was heated overnight at 65° C. The reaction mixture was diluted with brine solution and dichloromethane and passed through a phase separator. The organic layer was concentrated and the resulting residue was purified by flash column chromatography using 10-80% ethyl acetate/hexanes as eluent providing the title compound as a white solid (0.058 g, 58%).
Reaction SMILES: [F:1][CH2:2][C:3](OC)=[O:4].O([Si](C)(C)C)[K].Cl.[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C@H:31]4[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]4)[CH2:25][CH2:24]3)[C:17]=2[O:16][CH2:15]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>O1CCOCC1>[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C@H:31]4[CH2:32][CH2:33][C@H:34]([NH:37][C:3](=[O:4])[CH2:2][F:1])[CH2:35][CH2:36]4)[CH2:25][CH2:24]3)[C:17]=2[O:16][CH2:15]1
Reactant: COC(=O)CF
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[Si](C)(C)O[K]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CF)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Temperature: 25 °C

Procedure:
A mixture of methyl 2-fluoroacetate (11.3 mg, 123 μmol, Eq: 1.5) and KOSiMe3 (21 mg, 164 μmol, Eq: 2) in Dioxane (1 ml) was stirred at room temperature over night. Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.8 μmol), N,N-diisopropylethylamine (42.3 mg, 57.0 μl, 327 μmol, Eq: 4) and TBTU (39.4 mg, 123 μmol, Eq: 1.5) were added. Reaction mixture was stirred 4 h at room temperature. The reaction mixture was solved with sat NaHCO3 (1×10 mL) and extracted with dichloromethane (2×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 20% MeOH in dichloromethane) to yield the title compound as an off-white solid (21.3 mg, 66.7%), MS (ISP) m/z=391.2 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccsc2C(=O)O)CC1

Procedure:
The product from Step 1 is saponified with aqueous NaOH to give 3-(1-tert-butyloxycarbonylpiperidin-4-ylamino)thiophene-2-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[I-].[Na+].C(N(CC)CC)C.[CH2:36]1[CH2:46]C[N:44]2[C:39](=NC[CH2:42][CH2:43]2)[CH2:38][CH2:37]1.C(C1C=CN=CC=1)#C>[Zn].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.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:46]#[C:36][C:37]2[CH:38]=[CH:39][N:44]=[CH:43][CH:42]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C1CCC2=NCCCN2CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#Cc1ccncc1
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2cc(C#Cc3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 31 from 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.15 g, 0.401 mmol), sodium iodide (0.012 g, 0.080 mmol), zinc (5.25 mg, 0.080 mmol), DMSO (4.0 mL), triethylamine (0.168 mL, 1.204 mmol), DBU (0.121 mL, 0.802), 4-ethynylpyridine (0.112 g, 0.802 mmol), and Pd(Ph3P)4 (0.046 g, 0.040 mmol). The crude product was purified by silica gel chromatography (eluent: Gradient of 5-100% of DCM and chloroform containing 10% 2M Ammonia (in methanol)). The isolated product was dried in vacuum oven for 18 hr. to afford the final product as 0.032 g (18%). LCMS E-S (M+H)=441.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.57 Hz, 6 H), 2.13 (s, 3 H), 2.21 (s, 3 H), 4.37 (d, J=4.80 Hz, 2 H), 5.20-5.32 (m, 1 H), 5.90 (s, 1 H), 7.62-7.69 (m, 2 H), 7.93 (s, 1 H), 8.45 (s, 1 H), 8.67-8.75 (m, 2 H), 8.93 (t, J=4.80 Hz, 1 H), 11.55 (s, 1 H).
Reaction SMILES: C(Cl)CCl.ClC(Cl)C(O)=O.[NH2:11][C:12](=[O:39])[CH:13]([OH:38])[CH:14]([NH:22][C:23]([C@H:25]1[CH2:29][CH2:28][C:27](=[O:30])[N:26]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)(=O)C>CS(C)=O.O>[NH2:11][C:12](=[O:39])[C:13](=[O:38])[CH:14]([NH:22][C:23]([C@H:25]1[CH2:29][CH2:28][C:27](=[O:30])[N:26]1[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:24])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCCl
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
EDC (1543 mg, 8.05 mmol) and 2,2-dichloroacetic acid (0.446 ml; 696 mg, 5.4 mmol) were added to a solution of (2R)—N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-1-benzyl-5-oxopyrrolidine-2-carboxamide (400 mg, 1.012 mmol) in 8 ml of dry dimethylsulfoxide (DMSO), resulting in a slight exotheric reaction (40° C.). After stirring overnight at room temperature ethyl acetate and water were added, the formed precipitate filtered off and the remaining organic layer concentrated to dryness under reduced pressure. Precipitate and obtained residue were combined, and after addition of water and stirring at about 5° C. for 30 minutes the formed precipitate was filtered off and dried under reduced pressure. The title compound was obtained as an off-white powder (243 mg, yield: 61%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=O)[NH:9]2)=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[N:9]2)=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2ncc(Br)cc2[nH]1
Product: Clc1ccc2ncc(Br)cc2n1
Yield: 62.9 %

Procedure:
7-bromo-1,5-naphthyridin-2(1H)-one (C-4) (3.1 g, 13.78 mmol, 1.0 eq) was dissolved in POCl3 (20 mL) and the resulting mixture was stirred at reflux for 1 h. The reaction was complete based on TLC analysis. The mixture was concentrated in vacuo to remove POCl3. The residue was poured into ice water (30 mL) and neutralized with saturated aqueous Na2CO3 solution to adjust the pH value to 7-8 while keeping the temperature below 10° C. The resulting mixture was extracted with ethyl acetate (3×30 mL), the combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the desired product 7-bromo-2-chloro-1,5-naphthyridine (F-31) (2.11 g, 62.9% yield). ESI-MS m/z: 242.9 [M+H]+.
Reaction SMILES: [O:1]1[C:19]2=[C:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C:18]2=[O:21])[C@@H:14]2[C@H:4]([C@H:5]4[C@:11]([CH3:23])([CH2:12][CH2:13]2)[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6]4)[C@@H:3]2[O:24][C@:2]123.C(O)C.[BH4-].[Na+].Cl>O>[O:1]1[C:19]2=[C:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C@@H:18]2[OH:21])[C@@H:14]2[C@H:4]([C@H:5]4[C@:11]([CH3:23])([CH2:12][CH2:13]2)[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6]4)[C@@H:3]2[O:24][C@:2]123
Reactant: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4O)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 0.105 g (0.237 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3one and 6 ml of ethanol was added 9 mg (0.237 mmole) of sodium borohydride at a temperature of 0° C. and the mixture was stirred at 0° C. for 30 minutes. To the reaction mixture were added water and 1N-hydrochloric acid in the order mentioned and the mixture was extracted with methylene chloride. The aqueous layer was further extracted with methylene chloride and the extract was pooled with the previous methylene chloride extract. The mixture was washed successively with cold saturated sodium hydrogen carbonate solution and aqueous sodium chloride solution and the organic layer was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:10, v/v) to recover 0.084 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3β-ol (yield: 80%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: N#Cc1cccc(COc2ccc(Br)cc2C(=O)O)c1
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1cccc(COc2ccc(Br)cc2C(=O)Nc2cccnc2)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (113 mg, 1.20 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(3-cyanophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 26; 200 mg, 0.60 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (139 mg, 0.72 mmol) and 1-Hydroxybenzotriazole (98 mg, 0.72 mmol) in DMF (20 ml) sunder nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 170 mg.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([C:19](OCC)=[O:20])[NH:11][C:10]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO>C(O)(C)(C)C>[C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([CH2:19][OH:20])[NH:11][C:10]1=[O:24])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1CCCCCCC(CC(=O)OC(C)(C)C)C(=O)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CO
Product: CC(C)(C)OC(=O)CC1CCCCCCC(CO)NC1=O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
The major isomer of ethyl 3-t-butoxycarbonylmethyl-2-oxo-1-azacyclodecane-10-carboxylate (0.68 g, 2.0 mmol) is dissolved in t-butanol (10 mL). Sodium borohydride (0.23 g, 6.0 mmol) is added and the reaction is warmed to 55° C. Methanol (2.0 mL) is added over a twenty minute period, and the reaction is kept at 55° C. for an additional 1 hour. The reaction is then partitioned between ethyl acetate and water, and the aqueous phase is extracted several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (50% ethyl acetate/hexane) to give 3-t-butoxycarbonylmethyl-10-hydroxymethyl-2-oxo-1-azacyclodecane, MS: M+1=300.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=3[OH:17])[N:9]=[C:5]2[CH:4]=1.C(N(CC)CC)C.[CH2:29]([CH:31]([CH2:35][CH2:36][CH2:37][CH3:38])[C:32](Cl)=[O:33])[CH3:30].O>C1(C)C=CC=CC=1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:32](=[O:33])[CH:31]([CH2:29][CH3:30])[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:12][C:11]=3[OH:17])[N:9]=[C:5]2[CH:4]=1
Reactant: CCCCC(CC)C(=O)Cl
Reactant: Nc1ccc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC(CC)C(=O)Nc1ccc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c1

Procedure:
To a mixture of 4 g of 5-trifluoromethyl-2-(2-hydroxy-4-aminophenyl)-2H-benzotriazole and 1.4 g of triethylamine in 75 mL of toluene is added dropwise a mixture of 2-ethylhexanoyl chloride in 125 mL of toluene. The resulting mixture is treated with 100 mL of water and the crude product formed is purified by column chromatography to give 1.9 g of the title compound melting at 179-181° C. The structure is confirmed by nmr.
Reaction SMILES: NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3C=CC=CC=3)=CC=CC=4)C)N=C(C3C=NC(N)=NC=3)C=12.[NH2:37][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([CH:48]([C:50]3[O:51][C:52](=[O:67])[C:53]4[C:58]([C:59]=3[CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH3:49])[N:45]=[C:46](I)[C:39]=12.[F:68][C:69]1[CH:70]=[C:71](B(O)O)[CH:72]=[C:73]([OH:75])[CH:74]=1>>[NH2:37][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([CH:48]([C:50]3[O:51][C:52](=[O:67])[C:53]4[C:58]([C:59]=3[CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH3:49])[N:45]=[C:46]([C:71]3[CH:72]=[C:73]([OH:75])[CH:74]=[C:69]([F:68])[CH:70]=3)[C:39]=12
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: CC(c1oc(=O)c2ccccc2c1Cc1ccccc1)n1nc(I)c2c(N)ncnc21
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnc(N)nc2)c2c(N)ncnc21
Product: CC(c1oc(=O)c2ccccc2c1Cc1ccccc1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Yield: 29.8 %

Procedure:
The title compound was made in a similar way as that of the compound of example 51 from 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-benzyl-1H-isochromen-1-one (Intermediate D15, 45 mg, 0.086 mmol), (3-fluoro-5-hydroxyphenyl)boronic acid (26.8 mg, 0.172 mmol), to give the title compound (13 mg, 19.8%) as brown pale solid.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.Br[CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39]>>[F:37][C:35]1[CH:34]=[CH:33][C:32]([C:38]([F:39])([F:40])[F:41])=[C:31]([CH:36]=1)[CH2:30][O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(O)c4c3)cn2)CC1
Product: Fc1ccc(C(F)(F)F)c(COn2ccc3ncc(-c4cnn(C5CCNCC5)c4)cc32)c1

Procedure:
The entitled compound is prepared from tert-butyl 4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate and 2-(bromomethyl)-4-fluoro-1-(trifluoromethyl)benzene as described in the last 2 steps of Example 18.