Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:49]1[CH:50]=[N:51][CH:52]=[C:53]([N+:56]([O-:58])=[O:57])[C:54]=1[NH2:55]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.O.CN(C=O)C>[F:16][C:14]1[CH:15]=[C:2]([C:49]2[CH:50]=[N:51][CH:52]=[C:53]([N+:56]([O-:58])=[O:57])[C:54]=2[NH2:55])[CH:3]=[C:4]([CH2:5][N:6]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[CH:13]=1
Reactant: CN1CCN(Cc2cc(F)cc(Br)c2)CC1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(Cc2cc(F)cc(-c3cncc([N+](=O)[O-])c3N)c2)CC1
Temperature: 90 °C
Yield: 42 %

Procedure:
A solution of 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) (528 mg, 1.84 mmol), bis(pinacolato)diboron (560 mg, 2.21 mmol), KOAc (541 mg, 5.51 mmol) and dry DMF (26 mL) was purged with argon. PdCl2(dppf)2 (90 mg, 0.11 mmol) was added to the reaction and purged again with argon. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (CII), the solution was cooled to room temperature. To this solution was added K3PO4 (588 mg, 2.76 mmol), 3-bromo-5-nitropyridin-4-amine (LXIX) (400 mg, 1.84 mmol), Pd(PPh3)4 (106 mg, 0.09 mmol) and water (5 mL). The solution was purged with argon and heated at 90° C. for 4 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between CHCl3 and water. The aqueous phase was separated and washed 2×CHCl3. The combined organic phases were washed with brine, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3) to give 3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-5-nitropyridin-4-amine (CIV) as a yellow amorphous solid (419 mg, 1.21 mmol, 42% yield for 2 steps). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.27-2.41 (m, 8H), 3.52 (s, 2H), 7.16-7.22 (m, 3H), 7.42 (brs, 2H), 8.11 (s, 1H), 9.04 (s, 1H); ESIMS found for C17H20FN5O2 m/z 346.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: Nc1ccc(-c2n[nH]c(-c3ccncc3)n2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(-c2n[nH]c(-c3ccncc3)n2)cc1
Reaction time: 0.5 h

Procedure:
To 3-(p-aminophenyl)-5-(4-pyridyl)-1,2,4-triazole (1 g.) is added acetic anhydride (20 ml.) and the resulting suspension is heated 18 hours on a steam bath. The excess acetic anhydride is removed under reduced pressure and water (25 ml.) is added to the residue. After stirring 0.5 hour, the solid is filtered and recrystallized to yield 3-(p-acetylaminophenyl)-5-(4-pyridyl)-1,2,4-triazole.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)[O:8][CH2:7]2)(=[O:3])[CH3:2].[F:23][C:24]([F:37])([F:36])[C:25]([C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[C:29]([Cl:35])[CH:28]=1)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.FC(C1C=CC=CC=1)(F)F.COC(C)(C)C>[F:37][C:24]([F:23])([F:36])[C:25]([C:27]1[CH:28]=[C:29]([Cl:35])[C:30]([Cl:34])=[C:31]([Cl:33])[CH:32]=1)=[CH:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]1)[O:8][CH2:7]2)=[O:3]
Reactant: CC(=O)c1ccc2c(c1)COC21CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: FC(F)(F)c1ccccc1
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
In 100 mL two neck RBF fitted with dean-stark apparatus, a stirred solution of tert-butyl 5′-acetyl-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 1, 7 g, 23.1mmol) in toluene (21 mL) and trifluoro methyl benzene (21 mL) was added followed by addition of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone (7.37 g, 26.6 mmol) and Cs2CO3 (0.751 g, 2.31 mmol) at room temperature. Resulting reaction mixture was stirred at 110° C. for 16 hours. Reaction was monitored by TLC, after complete consumption of starting material; reaction mixture was dissolved in tert-butyl methyl ether (50 mL), and filtered through celite bed. The filtrate was concentrated under reduced pressure to get crude compound as brown sticky oil 14.1 g. Purification was done by column chromatography using silica gel 230-400 mesh. Desired compound was eluted in 20% ethyl acetate in n-hexane to give compound as light yellow solid (8.6 g, 66.15%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.11 (d, J=9.6 Hz, 2H), 4.32 (d, J=9.52 Hz, 2H), 5.12 (s, 2H), 7.28 (s, 1H), 7.40 (m, 1H), 7.54-7.56 (m, 1H), 7.66 (s, 1H), 7.83 (d, J=7.92 Hz, 1H). VETERINARY (m/z): 560.0 (M−H).
Reaction SMILES: C([Sn](=O)CCCC)CCC.C[Si]([N:15]=[N+:16]=[N-:17])(C)C.[F:18][C:19]([F:45])([F:44])[C:20]([C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1)=[CH:21][C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1>C1(C)C=CC=CC=1>[F:18][C:19]([F:44])([F:45])[C:20]([C:36]1[CH:43]=[CH:42][C:39]([C:40]2[NH:41][N:17]=[N:16][N:15]=2)=[CH:38][CH:37]=1)=[CH:21][C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C=C(c3ccc(C#N)cc3)C(F)(F)F)ccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)c2cc(C=C(c3ccc(-c4nnn[nH]4)cc3)C(F)(F)F)ccc21
Temperature: 110 °C
Yield: 58 %

Procedure:
Dibutyl tin oxide (15.1 mg, 10% mol) and trimethylsilyl azide (0.16 ml, 1.22 mmol), are added successively to a solution of the (E) compound 4-[1-trifluoromethyl-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-ethenyl]benzonitrile (0.24 g, 0.61 mmol) in anhydrous toluene (1.25 ml). The reaction medium is heated for 16 hours at reflux (110° C.) under an atmosphere of argon and with magnetic stirring. The mixture is purified by flash chromatography on silica (eluent CH2Cl2 then MeOH:CH2Cl2=5:95) to obtain, after evaporation and washing with pentane, a greenish powder, compound (E) 5-[4-[1-trifluoromethyl-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-ethenyl]phenyl]-1H-tetrazole (compound CB77402) (yield=58%), which is dried at 50° C. (24 hours) in a desiccator. This solid can be recrystallised with chloroform.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:48]=[CH:49][C:50]=1[CH2:51][O:52][Si](C(C)(C)C)(C)C)[CH2:31][O:32][C:33]1[CH:34]=[C:35]([C:39]([CH3:47])=[CH:40][CH:41]=[CH:42][C:43]([CH3:46])([OH:45])[CH3:44])[CH:36]=[CH:37][CH:38]=1)(C(C)(C)C)(C)C>C1COCC1>[OH:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:48]=[CH:49][C:50]=1[CH2:51][OH:52])[CH2:31][O:32][C:33]1[CH:34]=[C:35]([C:39]([CH3:47])=[CH:40][CH:41]=[CH:42][C:43]([CH3:44])([OH:45])[CH3:46])[CH:36]=[CH:37][CH:38]=1
Reactant: CC(=CC=CC(C)(C)O)c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=CC=CC(C)(C)O)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 3(i), by reacting 1.6 ml of tetrabutylammonium fluoride 1M/THF with 424 mg (0.71 mmol) of 6-{3-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)benzyloxy]phenyl}-2-methylhepta-3,5-dien-2-ol in 15 ml of THF, after purification on a silica column (ethyl acetate 90-heptane 10), a yellow oil (m=206 mg; Y=79%) is obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.C[Si]([C:26]#[C:27][Sn](CCCC)(CCCC)CCCC)(C)C>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[C:26]#[CH:27]
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Product: C#Cc1cc(-c2ccc(O)c(F)c2)nc2c(Cl)cc(O)cc12
Yield: 73 %

Procedure:
This compound was prepared from 45a following a combination of method J using (trimethylsilylethynyl)tributyltin and method L. Yellow solid; Yield: 73%; mp 210° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 5.06 (s, 1H), 7.09 (dd, J=8.9, 8.8 Hz, 1H), 7.45 (d, J=2.6 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 8.00 (dd, J=8.5, 1.7 Hz, 1H), 8.12 (dd, J=12.9, 2.2 Hz, 1H), 8.26 (s, 1H), 10.34 (s, 1H), 10.60 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.30 (dd, J=13.2, 9.3 Hz); MS (ESI) m/z 312/314 ([M−H]−), 314/316 ([M+H]+); Anal. Calcd for C17H9ClFNO2: C, 65.09; H, 2.89; N, 4.46. Found: C, 64.86; H, 3.14; N, 4.05.
Reaction SMILES: [NH2:1][OH:2].[OH-].[Na+].[C:5](#[N:14])[C:6]1[CH:13]=[CH:12][CH:11]=[C:8]([C:9]#[N:10])[CH:7]=1>C(O)C>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[C:5](=[N:1][OH:2])[NH2:14])#[N:10]
Reactant: N#Cc1cccc(C#N)c1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cccc(C(N)=NO)c1
Temperature: 25 °C

Procedure:
Hydroxylamine (Aldrich, 7.65 g, 100 mmol) in ethanol (100 mL) was treated with 10 N NaOH (10 mL, 100 mmol). To this solution, isophthalonitrile (Aldrich, 12.8 g, 100 mmol) in 100 mL of ethanol was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed under vacuum and the residue was purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 5.98 (bs, 2 H), 7.59 (t, J=7.4 Hz, 1 H), 8.06-8.0 (m, 2 H), 9.89 (s, 1 H) ppm; MS (DCI/NH3) m/z 162 (M+H)+.
Reaction SMILES: ClC1C(Cl)=C(OC(C)C)C=CC=1C(N[C@@H](C[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3C(C)=CC=C[N:21]3[CH:27]=2)=CC=1)CCO)=O.C(N(CC)CC)C.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>>[N:21]1[C:27]2[CH:12]=[CH:17][CH:16]=[CH:15][C:18]=2[NH:19][CH:20]=1
Reactant: Cc1cccn2cc(-c3ccc(C[C@@H](CCO)NC(=O)c4ccc(OC(C)C)c(Cl)c4Cl)cc3)nc12
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 193.1 %

Procedure:
To a 0° C. crude solution of compound 2 (4.1 g, 15.34 mmol) and triethylamine (6.4 mL, 46.02 mmol) in dicholoromethane (200 mL) was added pentafluorophenyl trifluoroacetate (6.35 mL, 36.82 mmol) via syringe over 3 min. After another 5 min, the ice bath was removed and the reaction mixture stirred while warming to room temperature for another 2 hours. The reaction mixture was concentrated in vacuo, and the resulting residue purified by flash chromatography (silica gel, hexanes/ethyl acetate=1:0, 50:1) to give compound 3 (3.5 g, 50% yield).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][S:4][C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:19])([F:18])[F:17])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH3:20].ClC1C=CC=C(C(OO)=[O:31])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:22][C:2]([F:1])([F:21])[CH2:3][S:4]([C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:17])([F:18])[F:19])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH3:20])=[O:31]
Reactant: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S(=O)CC(F)(F)F
Yield: 37.2 %

Procedure:
To 1.68 g (4.9 mmol) of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfide (Compound No. V-292 of the present invention) in 5 ml of chloroform, 1.02 g (5.1 mmol) of m-chloroperbenzoic acid was added at 0° C. with stirring, and the reaction mixture was stirred at 0° C. for 1 hour. The reaction solution was mixed with 10 ml of 10% aqueous sodium sulfite and stirred at room temperature for 10 minutes, and then 20 ml of chloroform was added. The chloroform layer was washed with 20 ml of saturated aqueous sodium hydrogen carbonate three times and dried over anhydrous magnesium sulfate, and the chloroform was distilled off under reduced pressure to obtain 0.65 g of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfoxide (yield 37.1%) as a pale yellow solid (m.p. 109-110° C.).
Reaction SMILES: N#N.[CH2:3]([CH:5]1[O:7][CH2:6]1)Cl.[C:8]1([O:18][CH3:19])[C:9](=[CH:11][CH:12]=[C:13]([CH:17]=1)[CH2:14][CH:15]=[CH2:16])[OH:10].[OH-].[Na+]>>[CH2:3]([O:10][C:9]1[CH:11]=[CH:12][C:13]([CH2:14][CH:15]=[CH2:16])=[CH:17][C:8]=1[O:18][CH3:19])[CH:5]1[O:7][CH2:6]1
Reactant: ClCC1CO1
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1ccc(OCC2CO2)c(OC)c1

Procedure:
A 2,000 mL, 3-necked, round-bottom flask was equipped with a mechanical stirrer, a 250 mL pressure equalizing addition funnel and a reflux condenser. The addition funnel served as the N2 inlet and the reflux condenser served as the N2 outlet. The flask was purged with a vigorous stream of N2 for 10 min. prior to its use. The flask was charged with epichlorohydrin (740 g, 8.0 mol) and eugenol (328 g, 2.0 mol). These were heated to ca. 80° using a heating mantle while stirring at a moderate rate (ca. 500 rpm). The 50% NaOH (168 g, 2.0 mol) was placed in the addition funnel and was added dropwise to the reaction flask over a 3 hour period. The mixture was allowed to cool and was filtered through a Buchner funnel. The epichlorohydrin was removed by rotary evaporation. The residue was taken up in CH2Cl2 (800 mL) and was washed with 10% NaOH (100 mL) brine and dried (Na2SO4). The crude product was vacuum distilled through a 10 cm Vigreux column to yield 4-allyl-2-methoxyphenyl glycidyl ether, i.e., ##STR22##
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16]C(=O)CC)[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(Cl)N=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H](N3[N:80]=[C:79]([CH2:81][OH:82])[CH:78]=[N:77]3)[C@@H](O)[C@H]2O)=C(Cl)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:80]=[C:79]([CH2:81][OH:82])[CH:78]=[N:77]3)[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Agent: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
(1R,2S,3R,5S)-3-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide by replacing N-[(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide, with (1R,2S,3R,5S)-3-(2,6-dichloro-purin-9-yl)-5-(4-hydroxymethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol (Intermediate FC).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:29]([NH:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(NCc2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.33 h

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (10 mg, 0.026 mmol), benzaldehyde (2.8 mg, 0.026 mmol) and acetic acid (0.5 ml) in 1,2-dichloroethane (1.0 ml) were stirred at RT. After 20 minutes, NaBH(OAc)3 was added and the reaction mixture was stirred for additional 15 minutes, quenched with saturated NH4OH (4.0 ml), extracted with dichloromethane (3×3 ml), dried over Na2SO4, concentrated and purified by silica gel flash chromatography to isolate 376 as a yellow film (1.3 mg, 11%). [M+H]+=446.2.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: NC1CCOCC1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 43 %

Procedure:
As described for example 5d, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (358 mg, 1.2 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (160 mg, 43%) which was obtained as a white solid after purification by chromatography (silica, 0 to 70% ethyl acetate in heptane). MS: m/e=374.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)=[O:12])[N:7]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH2:33][N:32](C(OC(C)(C)C)=O)[CH:31]([C:44](OCC)=[O:45])[CH2:30]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:49][CH2:50][CH:51]([OH:54])[CH2:52][OH:53]>Cl.CO>[OH:54][CH:51]([CH2:52][OH:53])[CH2:50][NH:49][C:44]([CH:31]1[C:30]2[C:29](=[CH:28][C:27]([N:7]3[C:8]([NH:10][C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[CH:15]=4)=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]3)=[CH:36][CH:35]=2)[CH2:34][CH2:33][NH:32]1)=[O:45]
Reactant: CCOC(=O)C1Cc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Oc4cccnc4)c3)ccc2CN1C(=O)OC(C)(C)C
Reactant: NCC(O)CO
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3cccnc3)c2)n(-c2ccc3c(c2)CCNC3C(=O)NCC(O)CO)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
Using the same procedureas for Example 179, 2-t-butyl 3-ethyl 6-(3-t-butyl-5-(3-(3-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (0.029 g, 0.044 mmol), available from experimental 184) in 3N hydrochloric acid in MeOH (10.0 mL) was stirred at RT for 1 h. The solvent was evaporated and the residue was dissolved in 3-amino-1,2-dihydroxypropane (0.200 g, 2.2 mmol) in MeOH (0.5 mL) and the solution was stirred at RT for 2 d. The solvent was evaporated and the residue was purified by reverse phase chromatography and coevaporated with THF/4N HCl to yield 1-(1-(1-((2,3-dihydroxypropyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (24 mg, 81% yield) as a pale yellow solid. 1H-NMR (MeOH-d4): δ 8.68 (d, 1H, J=3.2 Hz), 8.60 (d, 1H, J=7.6 Hz), 8.23 (ddd, 1H, J=8.8, 2.6, 1.0 Hz), 8.06 (dd, 1H, J=8.4, 1.4 Hz), 7.70 (dd, 1H, J=−9.0, 1.8 Hz), 7.58-7.54 (m, 3H), 7.42 (t, 1H, J=8.0 Hz), 7.22 (dt, 1H, J=8.4, 1.0 Hz), 6.90 (dd, 1H, J=6.8, 1.6 Hz), 6.58 (d, 1H, J=1.2 Hz), 5.29 (s, 1H), 3.84-3.63 (m, 2H), 3.63-3.51 (m, 5H), 3.30-2.87 (m, 2H), 1.37 (s, 9H), urea, amine, hydroxy and amide protons not visible. MS expected 600.3 found 600.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:19]([CH2:20][C:21]#[N:22])=[C:18]([CH3:23])[N:17]=[C:5]2[N:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:7]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:19]([CH2:20][C:21]#[N:22])=[C:18]([CH3:23])[N:17]=[C:5]2[N:6]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])[CH:7]=1
Reactant: Cc1nc2n(CC(=O)c3ccccc3)cc(Cl)cc-2c1CC#N
Agent: [BH4-]
Agent: [Na+]
Product: Cc1nc2n(CC(O)c3ccccc3)cc(Cl)cc-2c1CC#N

Procedure:
The title compound was prepared from 5-chloro-3-cyanomethyl-2-methyl-7-phenacylpyrrolo[2,3-b]pyridine (example 33) and NaBH4 on a 0.33 mmol scale according to the procedure described in example 11. Chromatography of the crude material (silica, CH2Cl2 /MeOH; 96/4) afforded 45 mg (42%) pure product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)c2ccccc21

Procedure:
A solution of 1.0 g of ethyl 1-(tert-butoxycarbonyl)indole-3-carboxylate in 20 ml of anhydrous ethanol is hydrogenated in the presence of 0.50 g of palladium-on-charcoal (5% of Pd) at 80° C. until the reaction has ended. After the reaction mixture has been filtered over Celite '545 and the filtrate has been concentrated, the oily residue is purified by means of FC over 15 g of silica gel with a 15:1 mixture of hexane and ethyl acetate as the mobile phase. This gives the title compound: Rf (G)=0.39; anal. calc. for C16H21NO4 : C65.96%, H7.27%, N4.81%; found C65.67%, H7.18%, N4.77%.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:34])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:23]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.Cl.[OH-].[K+]>C(O)(=O)C.O>[F:21][C:19]1[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23]2)=[CH:17][C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:34])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5ccccc5)C4)c(F)cc3cc2c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccccc5)C4)cc3nc21
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A solution of (RS)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4 -dihydrobenzo[b][1,8]naphthyridine (1.07 g) in acetic acid (10 cc) and 17.5% strength aqueous hydrochloric acid solution (10 cc) is heated to a temperature in the region of 100° C. for 40 minutes. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at approximately 60° C. The dry extract is taken up with ethanol (10 cc), drained and washed with ethanol (2×10 cc) and ethyl ether (2×10 cc). The solid obtained is suspended in water (30 cc) and heated to a temperature in the region of 95° C. After the addition of 2 N aqueous potassium hydroxide (1.35 cc) and stirring for 30 minutes, the solid is drained at approximately 95° C. and washed with water (3×20 cc) at approximately 80° C., ethanol (3×15 cc) at approximately 60° C. and ethyl ether (3×20 cc). After 1 recrystallization in a mixture of dimethylformamide (12 cc) and ethanol (6 cc), (RS)-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.7 g) is obtained in the form of a yellow solid, m.p. 265° C.