Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:41])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:33][C:32]3[CH:31]=[N:30][N:29]([CH3:34])[C:28]=3[N:27]([CH3:35])[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]2=3)=[O:23])=[CH:18][C:17]=1[CH3:40])(C)(C)C>ClCCl>[CH3:34][N:29]1[C:28]2[N:27]([CH3:35])[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:41])=[O:12])=[C:17]([CH3:40])[CH:18]=3)=[O:23])[CH2:33][C:32]=2[CH:31]=[N:30]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (2 ml) was added to 3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-propionic acid tert-butyl ester from Example E80.1 (46 mg, 0.10 mmol) in dichloromethane (5 ml). The mixture was stirred for 2 h at room temperature then concentrated in vacuo to yield the title compound (40 mg, 100%).
Reaction SMILES: OO.[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:5])[CH3:4].C=O.[C:20]([OH:23])(=[O:22])[CH3:21]>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]([O:23][C:20](=[O:22])[CH3:21])[CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)OCCCCCc1ccccn1
Reactant: CC(=O)O
Agent: C=O
Agent: OO
Product: CC(=O)OCCCCC(OC(C)=O)c1ccccn1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
Aqueous hydrogen peroxide (13 mls of 30% solution) was added over 2 hours to a solution of 5-(2-pyridyl)-pentan-1-yl acetate (13.0 gms) in acetic acid (50 mls) at 75° C. After 16 hours and mixture was heated to 95° C and paraformaldehyde (1.8 gms) was added. After a further 2 hours the solvent was evaporated in vacuo and the residual oil was added to acetic anhydride (50 mls) and heated at 95° C for 6 hours. The solvent was evaporated and the product was poured onto ice, neutralised with potassium carbonate and extracted into diethyl ether. Evaporation of the ether and distillation of the residual oil yielded 1-(2-pyridyl)-1,5-diacetoxy pentane, b.p. 140°-141° C/1 mm (8 gms; 40%). Characterised by the following spectral data:
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]3[N:21]([CH3:35])[N:22]([C:25]4[CH:34]=[N:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[C:23](=[O:24])[C:17]=3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[OH:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]3[N:21]([CH3:35])[N:22]([C:25]4[CH:34]=[N:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[C:23](=[O:24])[C:17]=3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8]
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of (R)-1-[4-(1-methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 75, Step D, 248 mg, 0.52 mmol) in a 5:2 mixture of methanol/tetrahydrofuran (7 mL) was added potassium carbonate (218 mg, 1.57 mmol). This mixture was stirred at room temperature overnight and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5→3% methanol/chloroform) to give 150 mg (71%) of the title compound as a white solid. mp: 217-219° C. (dec); 1H NMR (CDCl3, 250 MHz) δ 9.66 (s, 1H), 8.25 (d, 1H), 8.12 (dd, 1H), 7.99 (m, 1H), 7.68-7.78 (c, 2H), 6.47 (d, 1H), 4.72 (q, 12H), 4.32 (s, 2H), 4.194.14 (c, 3H), 3.41 (s, 3H), 2.80 (t, 2H), 1.51 (d, 3H); MS (APCI) 404 (MH); [α]D+13.4 (c, 1.5, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)CCCOc1ccccc1Cl
Temperature: 25 °C
Reaction time: 21 h
Yield: 96.3 %

Procedure:
A 500 mL 3-neck round bottom flask equipped with a magnetic stirrer bar and a reflux condenser was charged with 12.88 g (100 mmol) of 2-chlorophenol, 22.54 g (110 mmol) of ethyl 4-bromobutyrate, 16.59 g, 120 mmol potassium carbonate and 350 mL of 2-butanone. The slurry was heated to reflux. After stirring for 21 hr at reflux, the reaction mixture was cooled to 25° C., filtered and concentrated. The residue was taken up in 400 mL of water and treated with 100 mL of 2N aqueous sodium hydroxide (200 mmol). The reaction mixture was heated to reflux for 120 min and cooled to 25° C. The resulting solution was acidified with aqueous 105 ml of 2N hydrochloric acid. The resulting white solid was isolated by filtration by washing with hexanes to yield 20.68 g of 4-(2-Chlorophenoxy)butanoic acid. Mp 85-87° C. Combustion analysis: Found: C, 55.97; H, 5.13%; Cl, 16.55%; C10H11ClO3 requires C, 55.96; H, 5.17%; Cl, 16.52%; 1H NMR (d6-DMSO): δ 12.1, bs, 1H (COOH); δ 7.42, dd, 1H, (H ortho to Cl); δ 7.29, t, 1H (H para to Cl); δ 7.13, d, 1H, (H ortho to OR); δ 6.95, t, 1H (H para to OR); δ 4.07, t, 2H, (CH2 α to O); δ 2.44, t, 2H (CH2 α to COOH); δ 1.98, p, 2H (CH2 β to ArO and COOH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:11]([Mg]Cl)=[CH2:12].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]([OH:6])[CH:11]=[CH2:12])[C:3]=1[OH:10]
Reactant: O=Cc1cccc(Cl)c1O
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(Cl)c1O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
After a solution of 3-chloro-2-hydroxybenzaldehyde (15.4 g, 98 mmol) in THF (100 ml) was cooled to 0° C., a solution of vinyl magnesium chloride in THF (1.9M, 126 ml, 240 mmol) was added thereto over 40 minutes. The mixture was gradually warmed to room temperature and stirred at room temperature for 14 hours. The mixture was cooled to 0° C. and a 20% aqueous ammonium chloride solution (200 ml) was added thereto at 0° C. The mixture was extracted with ethyl acetate. The organic layer was combined and successively washed with water and a saturated aqueous NaCl solution, followed by drying with anhydrous sodium sulfate. The solid was removed by filtration and the filtrate was concentrated to obtain a brown oil. This oil was purified by silica gel column chromatography (elution with hexane:ethyl acetate=5:1) to obtain 15.1 g of 2-chloro-6-(1-hydroxy-2-propenyl)phenol as a pale brown oil. 1H-NMR (500 MHz, CDCl3)•ppm: 7.28 (1H, dd, J=7.7 and 1.1 Hz), 7.16 (1H, s), 7.08 (1H, dd, J=7.7 and 1.1 Hz), 6.84 (1H, t, J=7.7 Hz), 6.12 (1H, ddd, J=17.0, 10.4, and 6.0 Hz), 5.44 (1H, d, J=4.4 Hz), 5.36 (1H, dt, J=17.0 and 1.1 Hz), 5.26 (1H, dt, J=10.4 and 1.1 Hz), 2.63 (1H, d, J=3.3 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH:55]1[CH2:58][CH:57]([OH:59])[CH2:56]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:55]2[CH2:58][CH:57]([OH:59])[CH2:56]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: OC1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (2.1 g, 5.3 mmol), prepared using procedures similar to those in U.S. Pat. No. 7,019,033, was taken into DMF (10 mL) followed by addition of PyBOP (2.6 g, 5.3 mmol) and the mixture was allowed to stir at room temperature over 15 minutes. Azetidin-3-ol hydrochloride (870 mg, 8.0 mmol) and DIPEA (1.85 mL, 11.2 mmol) was then added and the mixture was allowed to stir an additional hour at room temperature. The mixture was then partitioned with ethyl acetate and 0.5 M aqueous sodium hydroxide solution. The organic layer was then washed with water (3×) then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography using ethyl acetate:hexanes (5:1) eluent afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (2.09 g, 87% yield) as a colorless amorphous solid. 1H NMR (400 MHz, CDCl3): 8.47 (s, 1H), 7.39 (dd, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.78 (m, 1H), 6.63-6.57 (m, 1H), 4.74-4.67 (m, 1H), 4.43-4.39 (m, 2H), 4.20-3.96 (br d, 2H), 2.50 (d, 1H).
Reaction SMILES: O=[C:2]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[N:8]1([CH2:2][CH2:3][CH2:4][CH2:5][OH:6])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(O)CCC(=O)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
4-Oxo-4-(1-pyrrolidinyl)butyric acid (0.30 g; 1.75 mmol) in 10 mL of THF in an argon-filled flask was treated with lithium aluminum hydride (0.17 g; 4.38 mmol) at 70° C. for 4 h. After cooling the mixture to room temperature, hydrolysis was effected by addition of 0.17 mL each of water and 5 N NaOH, followed by 0.51 mL of water. Stirring was continued for 0.5 h. The mixture was filtered and concentrated under reduced pressure to give the title compound as a colorless oil (0.21 g; 84% yield).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1ccncc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccncc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 0.72 g of 3-trifluoromethyl isonicotinic acid and 4 ml of thionyl chloride was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure to give 3-trifluoromethyl isonicotinic acid chloride. A mixture of the resultant 3-trifluoromethyl isonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.66 g of 2-amino-4-trifluoromethylphenol, 0.76 g of triethylamine, 4 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour and stirred while heating at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.62 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-(trifluoromethyl)isonicotinamide.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11](O)=[O:12])C1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:18][CH:19]([OH:21])[CH3:20]>C(Cl)Cl>[OH:12][CH2:11][CH2:10][C:9]([O:21][CH:19]([CH3:20])[CH3:18])=[O:8]
Reactant: CC(C)O
Reactant: O=C(O)CCOCc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 3-benzyloxypropanoic acid (27.7 mmol) in propan-2-ol (40 mL) under nitrogen at 0° C. was added dropwise thionyl chloride (30.5 mmol). The reaction mixture was allowed to reach room temperature over 30 minutes and stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3 and brine. The organic layer was dried on Na2SO4, filtered and concentrated under reduced pressure. The crude was diluted with isopropanol (80 mL) and Pd(OH)2 (20%, 1 g) in isopropanol was added. The system (reaction in a stainless steel reactor) was purged with nitrogen, vacuum and H2 and the reaction mixture was stirred under H2 atmosphere (3 bars) overnight at room temperature. The reaction mixture was filtered through autocup and the precipitate was washed with isopropanol. The filtrates were concentrated under reduced pressure and dried under vacuum pump to give the expected compound in 78% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.26 (d, J=6.31 Hz, 6H), 2.19 (brs, 1H), 2.54 (t, J=5.56 Hz, 2H), 3.86 (t, J=5.56 Hz, 2H), 5.06 (heptuplet, J=6.25 Hz, 1H).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[N:1]1([CH2:7][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1)N1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1cc(-c2ccc(OCCCN3CCCCC3)cc2)ccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.9 %

Procedure:
To a solution of 1-(3-{[4′-(piperidinocarbonyl)biphenyl-4-yl]oxy}propyl)-piperidine (500 mg) in tetrahydrofuran (20 mL) is added lithium aluminium hydride (105 mg). The suspension is stirred at room temperature for three hours, then hydrolysed through the successive addition of water (110 μL), 15% aqueous solution of sodium hydroxide (110 μL) and water (330 μL). The mixture is stirred for an half hour and filtrated. The filtrate is dried over magnesium sulfate and concentrated under reduced pressure. The product thus obtained is recrystallized in diisopropyl oxide and purified by chromatography over silica gel with a gradient dichloromethane/methanol from 98/2 to 85/15. Fraction containing the expected product are pooled, concentrated under reduced pressure to give 125 mg of 1-(3-{[4′-(piperidinomethyl)biphenyl-4-yl]oxy}propyl)piperidine as white crystals melting at 90° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)=O)[N:10]=2)[CH2:4][C:3]1([CH3:21])[CH3:20].O[C@@H]1CC[C@H](NC2C(C#N)=CN=C(S(C)(=O)=O)N=2)CC1(C)C.Cl.[CH3:45][C:46]1[N:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[CH2:57][NH2:58])[N:49]=[N:48][N:47]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:58][CH2:57][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=3[N:50]3[C:46]([CH3:45])=[N:47][N:48]=[N:49]3)[N:10]=2)[CH2:4][C:3]1([CH3:21])[CH3:20]
Reactant: Cc1nnnn1-c1ccccc1CN
Reactant: CS(=O)c1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Agent: CC1(C)C[C@@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nnnn1-c1ccccc1CNc1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a mixture of 4-(((1S,4R)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile and 4-(((1S,4R)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (1.0 equiv) in dioxane (0.4M) was added (2-(5-methyl-1H-tetrazol-1-yl)phenyl)methanamine hydrochloride (1.0 equiv.) and DIEA (2.0 equiv.). The mixture was stirred at 120° C. in microwave for 2 h. After completion of the reaction and standard work-up, the desired product was obtained (37% yield). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.12 (s, 1H), 7.82-7.78 (m, 1H), 7.63-7.61 (m, 1H), 7.58-7.51 (m, 3H), 7.02-6.92 (m, 1H), 4.32-4.17 (m, 3H), 4.01-3.99 (m, 1H), 3.21-3.14 (m, 1H), 2.41-2.36 (m, 3H), 1.65-1.47 (m, 1H), 1.36 (br, 1H), 1.23-1.17 (m, 2H), 0.81 (s, 3H), 0.73 (s, 3H); MS (ESI) m/z 434.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[C@H:11]([OH:16])[CH2:10]2)[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>CS(C)=O>[C:20]([NH:24][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[C@H:11]([OH:16])[CH2:10]2)[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: C[C@@H]1CC[C@@H](Nc2nc(Cl)ncc2C(N)=O)C[C@H]1O
Solvent: CS(C)=O
Product: C[C@@H]1CC[C@@H](Nc2nc(NC(C)(C)C)ncc2C(N)=O)C[C@H]1O
Temperature: 68 °C
Reaction time: 80 h

Procedure:
To a reactor was charged 2-chloro-4-{[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino}pyrimidine-5-carboxamide (41 kg), t-butylamine (105.3 kg) and DMSO (205 L). The batch was heated to 68° C. under 10 psig of nitrogen pressure, held for 80 h, and cooled to 25° C. The batch was filtered through a 0.45 μm in-line filter to a second reactor. The batch was heated to 60° C., and water (205 L) was charged through a 0.45 μm in-line filter. The batch was seeded with micronized Compound 1 (820 g) agitated at 60° C. for over an hour, and water (615 L) was charged to the batch through a 0.45 μm in-line filter in 3 h at 60° C. The batch was agitated for 1 h at 60° C., cooled to 25° C. over 6 h, filtered, and washed with water (410 mL), which was filtered through a 0.45 μm in-line filter. The solids were dried in a vacuum oven at 40° C. with nitrogen bleed for over 72 h to give 2-(tert-butylamino)-4-{[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino}pyrimidine-5-carboxamide as Form A and a white solid (43.5 kg, 94% yield). 1H NMR (DMSO-d6) δ 0.95 (d, J=6.2 Hz, 3H), 0.97-1.28 (m, 4H), 1.37 (s, 9H), 1.60-1.75 (m, 1H), 1.83-2.00 (m, IH), 2.06-2.26 (m, 1H), 2.86-3.07 (m, 1H), 3.74-4.01 (m, 1H), 4.59 (d, J=5.7 Hz, 1H), 6.65 (br. s., 1H), 7.03 (br. s., 1H), 7.57 (br. s., 1H), 8.36 (s, 1H), 8.93 (br. s., 1H).
Reaction SMILES: O[CH2:2][C:3]([CH3:21])([CH3:20])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:23]>C1(C)C(C)=CC=CC=1>[Cl:23][CH2:2][C:3]([CH3:21])([CH3:20])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1
Reactant: CC(C)(CO)COCc1cccc(Oc2ccccc2)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: CC(C)(CCl)COCc1cccc(Oc2ccccc2)n1
Temperature: 0 °C

Procedure:
0.5 Gram of 6-phenoxy-2-pyridylmethyl 3-hydroxy-2,2-dimethylpropyl ether was dissolved in 20 ml of dry xylene, and 0.73 g of phosphorus pentachloride was added, followed by heating under reflux for 3 hours. Thereafter, the reaction solution was poured into ice water and extracted with xylene. The xylene layer was washed with water, dried and concentrated. The residue was subjected to column chromatography on silica gel (developing solvent, hexane:ethyl acetate=50:1) to obtain 90 mg of desired 6-phenoxy-2-pyridylmethyl 3-chloro-2,2-dimethylpropyl ether [present compound (1)].
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][C@@H:8]([C:27]1[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[N:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[NH:18][C:19]2[NH:20][CH2:21][CH2:22][CH2:23][N:24]=2)[C:10]1=[O:26])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:34][O:33][C:30]1[N:29]=[CH:28][C:27]([C@@H:8]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[NH:18][C:19]3[NH:20][CH2:21][CH2:22][CH2:23][N:24]=3)[C:10]2=[O:26])[CH2:7][C:6]([OH:35])=[O:5])=[CH:32][CH:31]=1
Reactant: COc1ccc([C@H](CC(=O)OC(C)(C)C)N2CCN(CCCC(=O)NC3=NCCCN3)C2=O)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@H](CC(=O)O)N2CCN(CCCC(=O)NC3=NCCCN3)C2=O)cn1

Procedure:
A solution of the ester 1-9(110 mg) in dichloromethane (10 mL) and trifluoroacetic acid (10 mL) were stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, dissolved in water, frozen and lyophilized to give 1-10as a powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[CH2:20][OH:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][C@H:9]1[CH:20]=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a stirred mixture of (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylmethanol (2.75 g, 9.37 mmol), Et3N (7.84 ml, 56.2 mmol), DMSO (6.66 ml, 9.37 mmol) in CH2Cl2 (30 ml) at 0° C. was added SO3-pyridine (4.47 g, 28.1 mmol), then the resulting mixture was allowed to raise to room temperature. After 2.5 h stirring, the mixture was concentrated in vacuo. To the resulting mixture was added water and extracted with Et2O. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel [100 g, CHCl3/acetone (5/1)] to give (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidine carbaldehyde (2.54 g, 93%) as a yellow oil. 1H-NMR (CDCl3) δ1.45 (s, 9H, one of isomers), 1.49 (s, 9H, one of isomers), 2.17 (br, 2H), 3.65-4.31 (m, 3H), 4.91 (br, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.77 (m, 1H), 7.28 (m, 2H), 9.66 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:25][CH2:26][CH2:27][NH:28][CH2:29][CH:30]([OH:32])[CH3:31])[CH:10]=[CH:11][C:12]=3[NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH:22]([OH:24])[CH3:23])[C:7](=[O:33])[C:6]=2[C:5]([OH:34])=[CH:4][CH:3]=1.[C:35](OC)(=[O:40])[C:36](OC)=[O:37]>CS(C)=O>[CH3:31][CH:30]1[O:32][C:36](=[O:37])[C:35](=[O:40])[N:28]([CH2:27][CH2:26][NH:25][C:9]2[C:8]3[C:7](=[O:33])[C:6]4[C:15](=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=4[OH:34])[C:14](=[O:16])[C:13]=3[C:12]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH:22]([OH:24])[CH3:23])=[CH:11][CH:10]=2)[CH2:29]1
Reactant: CC(O)CNCCNc1ccc(NCCNCC(C)O)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Reactant: COC(=O)C(=O)OC
Solvent: CS(C)=O
Product: CC(O)CNCCNc1ccc(NCCN2CC(C)OC(=O)C2=O)c2c1C(=O)c1c(O)ccc(O)c1C2=O

Procedure:
A solution of 2.60 g of 1,4-dihydroxy-5,8-bis-[2-(2-hydroxypropylamino)ethylamino]anthraquinone (prepared in Example 3) and 0.650 g of dimethyl oxalate in 25.0 ml of dried dimethyl sulfoxide is processed as described in Example 2 to give the desired product as a blue-black solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][NH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[K+].[I:13]I>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([I:13])=[N:9][NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2[nH]ncc2n1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc2[nH]nc(I)c2n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (100 mg, 0.65 mmol) in DMF (5 mL), was added KOH (91 mg, 1.63 mmol), I2 (247 mg, 0.98 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 5 min and then stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and water. The organic phase was washed by sat. NaHSO3, dried over MgSO4, filtered, concentrated, and purified by silica gel column, eluting by 0-70% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C6H3ClIN3: 279.9 (M+H+); Found: 279.3 (M+H+).