Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][O:13][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCCOC2CCCCO2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[(4-Nitrophenyl)oxy]ethanol (1 g, 5.4 mmol), in toluene (50 mL) was added 3,4-dihydro-2H-pyran (1.5 mL) and APTS (catalytic amount). The reaction was stirred at 60° C. for 3 hours. The dark solution was then concentrated and purified by flash chromatography using DCM/cyclohexane 30/70 as eluent. The title compound was obtained as an oil (1.33 g, 92%). LC: Rt: 3.12 min.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][C@:6]1([OH:34])[CH:11]=[CH:10][C@H:9]2[C@H:12]3[C:21]([C@@H:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=4)[CH2:23][C@:7]12[CH3:8])=[C:20]1[C:15](=[CH:16][C:17](=[O:33])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:5]([C@:6]1([OH:34])[CH:11]=[CH:10][C@H:9]2[C@H:12]3[C:21]([C@@H:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=4)[CH2:23][C@:7]12[CH3:8])=[C:20]1[C:15](=[CH:16][C:17](=[O:33])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)[C:4]#[CH:3]
Reactant: CC(=O)c1ccc([C@H]2C[C@@]3(C)[C@@H](C=C[C@@]3(O)CC#C[Si](C)(C)C)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CC[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(C(C)=O)cc3)C[C@@]21C
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
350 mg of 17-(3-trimethylsilyl-prop-2-inyl)-17β-hydroxy-11β-(4-acetylphenyl)-4,9,15-estratrien-3-one is dissolved in methanol and stirred at 23° C. for 1.5 hours after addition of 387 mg of potassium carbonate. This is poured into water and extracted with acetic ester. The combined organic phases are dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed with a mixture of hexane/acetic ester over silica gel. 205 mg of the title compound is isolated as white foam. Crystallisation from ether yields 176 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCOCC1>[C:38]([O:37][C:35]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([C:15]5[N:16]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:17]=[CH:18][N:19]=5)[S:8][C:7]=4[C:6]=3[N:28]=2)[CH2:31][CH2:30]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 112 °C
Yield: 54 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (208 mg×4, 2.0 mmol) tert-butyl piperazine-1-carboxylate (445 mg, 2.4 mmol) Pd(OAc) (45 mg, 0.20 mmol) Xphos (95 mg, 2.0 mmol) t-BuONa (460 mg, 4.0 mmol) and dioxane (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 112° C. for 7 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC (DCM/EtOAc=10:1) to give 4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-piperazine-1-carboxylic acid tert-butyl ester (612 mg, yield: 54%). 1HNMR (DMSO-d6, 400 MHz): δ8.30 (s, 1H), 7.99-7.90 (m, 1H), 7.79-7.70 (m, 2H), 7.32 (s, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 6.78 (d, J=8.8 Hz, 1H), 4.19 (s, 4H), 4.04-4.02 (m, 4H), 3.44 (m, 1H), 3.12 (s, 1H), 1.57 (s, 9H) ESI-MS: m/z=567 [M+H+]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=12)[NH2:5].Cl[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[C:23]([NH2:31])[N:22]=1.Cl.[OH-].[Na+]>O.C(O)C>[Cl:19][C:18]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:7]=[CH:6][C:4]([NH:5][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[N:24]=[C:23]([NH2:31])[N:22]=3)=[CH:3][C:2]=2[F:1])[NH:16][CH:17]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]cc(Cl)c34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
67 mg (0.24 mmol) of 3-fluoro-4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 47 mg (0.24 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 4 ml of water/ethanol 1:1. 25 μl (0.29 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 7, and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue is purified by preparative HPLC.
Reaction SMILES: CS([N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:16][NH:17][CH3:18])=[CH:11][CH:12]=2)[C:7]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6]1)(=O)=O.[OH-].[K+]>CO>[CH3:28][S:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([CH:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:16][NH:17][CH3:18])[CH:9]=2)[NH:5][CH:6]=1)(=[O:27])=[O:26]
Reactant: CNCCC(c1ccccc1)c1ccc2c(c1)c(S(C)(=O)=O)cn2S(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CNCCC(c1ccccc1)c1ccc2[nH]cc(S(C)(=O)=O)c2c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of [3-(1,3-bis-methanesulfonyl-1H-indol-5-yl)-3-phenyl-propyl]-methyl-amine LXXIX (36 mg, 0.0865 mmol) in MeOH (3 ml) was added a solution of KOH (7.29 mg, 0.13 mmol) in MeOH. After stirring for 50 minutes at room temperature, the mixture was concentrated, and the residue was partitioned between EtOAc and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH) to provide [3-(3-methanesulfonyl-1H-indol-5-yl)-3-phenyl-propyl]-methyl-amine LXXX as a white powder (13 mg, 36% yield). MS (M+H)=343.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH3:6])[CH2:3][OH:4].CCN(CC)CC.O.CCOCC>CS(C)=O>[CH3:1][C@@H:2]([C@@H:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH3:6])[CH:3]=[O:4]
Reactant: C[C@H](CO)[C@H](C)OC1CCCCO1
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](C=O)[C@H](C)OC1CCCCO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
The Py.SO3 complex (7.06 g, 44.36 mmol) was added in portions at 0° C. to a solution of (2R,3S)-2-methyl-3-tetrahydropyranyloxybutanol (5) (1.39 g, 7.39 mmol) and anhydrous Et3N (4.94 g, 6.78 ml, 48.77 mmol) in DMSO (25 ml). The reaction mixture was stirred at 0° C. for 3 hours, and then at room temperature for 1 hour, and then it was divided between water and ether. The aqueous layer was extracted with ether. The combined ether extracts were washed with 1M HCl, water, saturated NaHCO3, brine, and they were dried over Na2SO4 and evaporated in order to obtain crude (2S,3S)-2-methyl-3-tetrahydropyranyloxybutyraldehyde (6) (1.39 g, 100%) which was used directly for the next reaction without purification: 1H NMR (250 MHz, CDCl3) δ 9.78 (d, J=2.7 Hz, 0.5H); 9.74 (d, J=2.0 Hz, 0.5H); 4.76 to 4.62 (m, 1H); 4.15 to 3.73 (m, 2H); 3.53 to 3.43 (m, 1H); 2.62 to 2.46 (m, 1H); 1.82 to 1.51 (m, 6H); 1.29 (d, J=6.2 Hz, 1.5H); 1.18 (d, J=6.2 Hz, 1.5H); 1.11 (d, J=7.2 Hz, 1.5H); 1.07 (d, J=7.1 Hz, 1.5H); 13C NMR (62.5 MHz, CDCl3) δ 203.5; 203.1; 99.0; 95.1; 74.4; 71.0; 62.0; 51.6; 51.1; 30.5; 25.0; 19.2; 19.1; 18.6; 16.0; 9.7; 9.1; MS (CI) m/z 187. [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:19](=[O:22])([O-])[O-].[Na+].[Na+]>COCCOC.O.C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:3]2[CH:4]=[CH:5][C:19]([OH:22])=[CH:7][CH:2]=2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18]
Reactant: Nc1ncc(Br)cc1OCc1c(Cl)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ncc(-c2ccc(O)cc2)cc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (example [(a), 100 mg, 0.29 mmol), 4-(4,4,5,5-tetramethyl-1,3-(2-dioxabordan-2-yl) phenol (86 mg, 0.35 mmol), bis(triphenylphosphine) palladium(II) chloride (8 mg, 0.009 mmol) and sodium carbonate (91 mg, 0.87 mmol) in ethylene glycol dimethyl ether (10 mL) and water (0.5 mL) was heated to reflux under nitrogen for 18 hours. The reaction was cooled to ambient temperature and diluted with ethyl acetate. The mixture was washed with water, brine, dried over Na2SO4, and purified on silica column to afford 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenol as light pine crystals (89 mg, 85% yield).
Reaction SMILES: [OH:1][C:2]([CH3:30])([CH3:29])[CH2:3][O:4][C@H:5]1[C@H:10]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=3[N:13]=[C:12]2[CH3:21])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.[ClH:31]>O1CCOCC1>[ClH:31].[ClH:31].[OH:1][C:2]([CH3:30])([CH3:29])[CH2:3][O:4][C@H:5]1[C@H:10]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=3[N:13]=[C:12]2[CH3:21])[CH2:9][CH2:8][NH:7][CH2:6]1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1OCC(C)(C)O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)nc(C)n2[C@@H]1CCNC[C@H]1OCC(C)(C)O

Procedure:
Racemic trans-3-[2-hydroxy-2-methylpropoxy]-4-[2,5-dimethylbenzimidazol-1yl]-N-Boc-piperidine (320 mg; 0.77 mmol) was treated with 4M HCl in dioxane for 1 h after which all volatiles were removed under reduced pressure to yield the product trans-3-[2-hydroxy-2-methylpropoxy]-4-[2,5-dimethylbenzimidazol-1yl]-piperidine dihydrochloride (300 mg; quant.). LRMS (M+1)—Calculated: 317.2. Found: 317.2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])(=[O:3])[CH3:2].Cl.N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>O.CCOCC.CCCCCC>[C:1]([C:4]1[CH:5]=[C:6]([N:7]=[N+:16]=[N-:17])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(N)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)c1cccc(N=[N+]=[N-])c1
Reaction time: 0.33 h

Procedure:
A mixture of 10.8g. (0.08 mole) of 3-acetylaniline in 50 ml. of water was treated with 20 ml. of concentrated HCl and cooled to 0° C. There was then added a solution of 6.07g. (0.088 mole) of NaNO2 in 20 ml. of water. The reaction mixture was aged for 20 minutes, and there was then added 25 ml. of hexane and 25 ml. of ether, followed by a solution fo 5.72g. (0.088 mole) of NaN3 in 20 ml. of water. The reaction mixture was aged for 1/2 hour at room temperature, after which the aqueous and organic components were separated, and the aqueous component extracted with 50 ml. of ether. The organic component and extract were dried over MgSO4 and concentrated under reduced pressure to 12.72g. (99%) of product whose structure as 3-acetylphenylazide was confirmed by IR.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C@H:11]3[O:26][C:25](=[O:27])[CH:24]=[CH:23][C:22]([CH3:29])([CH3:28])[C:21](=[O:30])[C@H:20]([CH3:31])[C@@H:19]([OH:32])[C@@H:18]([CH3:33])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]3)=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:34].[OH:35]CC([C@H]([C@@H]([C@@H](CO)O)O)O)=O.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>CC#N.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C@H:11]3[O:26][C:25](=[O:27])[CH:24]=[CH:23][C:22]([CH3:28])([CH3:29])[C:21](=[O:30])[C@H:20]([CH3:31])[C@@H:19]([OH:32])[C@@H:18]([CH3:33])[CH2:17][CH2:16][CH2:15][C@H:14]4[C@@H:13]([O:35]4)[CH2:12]3)=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:34]
Reactant: Cc1nc2cc([C@@H]3CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)C=CC(=O)O3)ccc2n1C
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cc1nc2cc([C@@H]3C/C=C/CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)/C=C/C(=O)O3)ccc2n1C
Agent: Cc1nc2cc([C@@H]3C[C@@H]4O[C@H]4CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)/C=C/C(=O)O3)ccc2n1C
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Solvent: O
Solvent: CC#N
Product: Cc1nc2cc([C@@H]3C[C@@H]4O[C@H]4CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)C=CC(=O)O3)ccc2n1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 55 (40 mg, 0.0857 mmol) in 1.3 mL CH3CN/DMM—1/1 at rt were added successively 0.8 mL of a buffer solution (Na2B4O7.10 H2O [0.05M] in Na2EDTA [4.10−4M]), BU4N(HSO4) (1.2 mg, 0.003 mmol) and fructose-derived ketone (17.7 mg, 0.0685 mmol). The reaction mixture is cooled to 0° C. and were added separately, in a same time over 1 h30, Oxone® (73.8 mg, 0.120 mmol) in 1 mL Na2EDTA and K2CO3 (68.7 mg, 0.497 mmol) in 1 mL H2O. The solution is stirred 3 h at 0° C. and then is quenched with H2O, extracted 3 times with 10 mL AcOEt. The combined organic layers are dried (MgSO4) and concentrated in vacuum. Purification of crude product by prep-HPLC afforded 56, 50% conversion in a 8/1 ratio.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:25][CH:24]=1.Cl>CN1C(=O)CCC1>[F:33][C:32]([F:34])([F:35])[CH2:31][C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:2]2[C:11]3[CH2:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:8](=[O:21])[NH:7][C:6]=3[N:5]=[CH:4][CH:3]=2)=[CH:24][CH:25]=1)=[O:36]
Reactant: Nc1ccc(NC(=O)CC(F)(F)F)cc1
Reactant: COc1ccc(CN2Cc3c(Cl)ccnc3NC2=O)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(CN2Cc3c(Nc4ccc(NC(=O)CC(F)(F)F)cc4)ccnc3NC2=O)cc1
Temperature: 150 °C
Reaction time: 1.67 h
Yield: 39 %

Procedure:
1 (52 mg, 0.17 mmol), N-(4-aminophenyl)-3,3,3-trifluoropropanamide (44 mg, 0.17 mmol), and HCl (43 μL, 4.0M in dioxane, 0.17 mmol) were suspended in NMP (1 mL), and stirred in a microwave at 150° C. for 100 min. The crude product was purified directly via HPLC to provide 100 (39% yield). LC-MS (M+H=486, obsd.=486).
Reaction SMILES: [CH:1]([C@@:9]1([OH:25])[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>>[C:31]1(=[O:32])[N:27]([CH:14]([OH:15])[C@H:13]2[O:12][C@@H:11]([N:16]3[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]3=[O:18])[CH2:10][C@:9]2([CH:1]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:25])[C:28](=[O:37])[C:29]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:30]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cn([C@H]2C[C@@](O)(C=Cc3ccccc3)[C@@H](CO)O2)c(=O)[nH]c1=O
Product: Cc1cn([C@H]2C[C@@](O)(C=Cc3ccccc3)[C@@H](C(O)N3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Yield: 97 %

Procedure:
Mitsunobu reaction of 3'-C-styrylthymidine with N-hydroxyphthalimide gave 97% yield of 5'-C-phtalimido-3'-C-styrylthymidine as a white solid. Anal.: C26H23N3O6Calcd.: C% 65.95; H% 4.89; N% 8.87; Found: C% 65.69; H% 5.11; N% 8.59.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@H:72]([NH2:76])([CH2:74][CH3:75])[CH3:73]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([NH:76][CH:72]([CH2:74][CH3:75])[CH3:73])[N:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(OCc2ccccc2)c1
Reactant: CC[C@@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCC(C)Nc1cc(C(=O)OC)cc(OCc2ccccc2)n1
Temperature: 105 °C
Reaction time: 20 h

Procedure:
Degas a sealed tube for 5 min and add a suspension 2-benzyloxy-6-chloro-isonicotinic acid methyl ester (1 g, 3.604 mmol), palladium acetate (100 mg, 0.445 mmol), racemic 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (307 mg, 0.493 mmol), cesium carbonate (1.2 g, 3.683 mmol) and (R)-sec-butylamine (0.5 mL, 1.387 mmol) in toluene (14 mL). Heat to 105° C. and stir for 20 h. Cool to room temperature, concentrate and purify (silica gel chromatography, eluting with 3:97 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[S:10]([C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[N:19][C:15]=2[CH:14]=1)(=[O:12])=[O:11])=[O:5])[CH3:2].[ClH:39].C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)C>[ClH:39].[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[S:10]([C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:44])[NH2:29])=[CH:24][CH:23]=3)=[N:19][C:15]=2[CH:14]=1)(=[O:12])=[O:11])=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CCCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C
Yield: 57 %

Procedure:
Prepared analogously to Example 32 from 1-methyl-2-[(4-cyanophenyl)oxymethyl]benzimidazol-5-yl-sulfonic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenylamide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 57% of theory, C28H31N5O5S (549.7); EKA mass spectrum: (M+H)+=550.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:11])[CH3:10])=[N:7][CH:8]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:9]([C:6]1[N:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1ccc(CO)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc(C=O)cn1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 5.1 g of 5-hydroxymethyl-2-isopropylpyridine in 70 ml of chloroform, 20 g of active manganese dioxide is added, and the mixture is refluxed with stirring for 1 hour. The insoluble manganese dioxide is filtered off, and the filtrate is concentrated to give 3.7 g of crude 6-isopropyl-3-pyridinecarbaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[NH:24][CH2:23][CH2:22][C:21]2[C:16]1=[CH:17][CH:18]=[C:19]1[O:27][CH2:26][O:25][C:20]1=2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]5[O:27][CH2:26][O:25][C:20]5=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c1ccc1c2OCO1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc3c(c2CCN1C(=O)c1cc2ncc(Br)cn2n1)OCO3

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methyl-6,7,8,9-tetrahydro-1,3-dioxa-7-aza-cyclopenta[a]naphthalene to provide the title compound in moderate yield.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:26])[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:26])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccccc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccccc32)CC1

Procedure:
tert-Butyl{1-[2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 98) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([CH3:12])=[CH:4][C:3]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[CH3:27][OH:28]>O1CCCC1>[CH3:12][C:5]1[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:7][C:2]2[NH:1][C:27](=[O:28])[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[C:3]=2[CH:4]=1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1OC(C)C
Reactant: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cc1OC(C)C)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 85 %

Procedure:
A solution of 1,1-dimethylethyl 4-({2-amino-5-methyl-4-[(1-methylethyl)oxy]phenyl}amino)-1-piperidinecarboxylate (D75) (0.16 mmol, 60 mg) in tetrahydrofuran (0.5 mL) was treated with N,N′-carbonyldiimidazole (0.24 mmol, 38.5 mg, 1.5 eq) under argon at room temperature, then the mixture was heated at 50° C. for 1 h, concentrated under reduced pressure, and the residue was treated with 10% aqueous sodium carbonate solution and extracted twice with ethyl acetate. The organics were combined, dried and concentrated under reduced pressure. The residue was finally purified by chromatography on silica (ethyl acetate/petrol ether then methanol) to give the title compound (0.14 mmol, 53 mg, 85% yield). M+H 390.3, 334.3, 316.3 (full molecule and fragments for loss of tert-butyl group and loss of Boc group).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2[NH:27][CH2:28][CH:29]=[CH2:30])=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:31])=[CH:13][CH:12]=[CH:11][C@H:10]([O:32][CH3:33])[C@@H:9]([O:34][C:35]([NH2:37])=[O:36])[C:8]([CH3:38])=[CH:7][C@H:6]([CH3:39])[C@@H:5]([OH:40])[C@@H:4]([O:41][CH3:42])[CH2:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[ClH:51].O1CCOCC1>ClCCl>[CH3:1][C@H:2]1[CH2:3][C@H:4]([O:41][CH3:42])[C@H:5]([OH:40])[C@@H:6]([CH3:39])[CH:7]=[C:8]([CH3:38])[C@H:9]([O:34][C:35]([NH2:37])=[O:36])[C@@H:10]([O:32][CH3:33])[CH:11]=[CH:12][CH:13]=[C:14]([CH3:31])[C:15](=[O:16])[NH:17][C:18]2=[C:25]([OH:26])[C:23](=[C:22]([NH:27][CH2:28][CH:29]=[CH2:30])[C:20]([OH:21])=[CH:19]2)[CH2:24]1.[ClH:51]
Reactant: C=CCNC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Agent: C=CCNC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: C=CCNc1c(O)cc2c(O)c1C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CCNc1c(O)cc2c(O)c1C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)N2
Reaction time: 0.5 h

Procedure:
Compound of Formula (1) (0.450 g, 0.768 mmol, 1.0 equiv) is dissolved in dichloromethane (50 mL) and stirred with a 10% aqueous solution of sodium hydrosulfite (50 mL). The solution is stirred for 30 minutes. The organic layer was collected, dried over Na2SO4, filtered and transferred to a round bottom flask. To this solution was added a solution of HCl in dioxane (4 N, 0.211 mL, 1.1 equiv.). The resulting mixture was allowed to stir under nitrogen for 30 minutes. A yellow solid slowly crashed out of solution. The yellow solid was purified by recrystallization form MeOH/EtOAc to yield 0.386 g of the IPI-504 (15).