Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]2)[CH:9]=1.[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].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.O>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n2)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To 10-20 mL microwave flask was added ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (Int-5m, 500 mg, 741 μmol), phenylboronic acid (181 mg, 1.48 mmol), K3PO4 (314 mg, 1.48 mmol), Pd(PPh3)4 (86 mg, 74 mol) and 3:1 1,4-dioxane:H2O (8 mL). The flask was flushed with argon and sealed. The reaction was stirred in a microwave at 150° C. for 30 minutes. After 30 minutes, the reaction was diluted with DCM and washed with H2O. The aqueous was extracted with DCM (x2) and the combined organic layers were dried over Na2SO4. The solvent was reduced in vacuo and the title compound was purified via silica gel chromatography.
Reaction SMILES: [CH3:1][SiH:2]([Cl:4])[Cl:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.CC(O)C>[CH3:1][Si:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([Cl:4])[Cl:3]
Reactant: C[SiH](Cl)Cl
Reactant: C=CCCCCCCCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCCCCCCCCC[Si](C)(Cl)Cl
Yield: 94 %

Procedure:
2.25 Parts of methyl dichlorosilane, 4.04 parts of 1-decene and a solution containing about 0.0005 part of chloroplatinic acid catalyst in 0.006 part of 2-propanol were charged to a reaction vessel and heated to about 100°-120° C. for six hours. The product was vacuum distilled in 110°-114° C. at 1-3 Torr. 4.7 Parts (94% yield) of methyl decyl dichlorosilane was obtained.
Reaction SMILES: Cl.[CH:2]([C:5]1[S:6][CH:7]=[C:8]([C:10]([N:12]2[CH2:17][C:16]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:15][CH2:14][CH2:13]2)=[O:11])[N:9]=1)([CH3:4])[CH3:3].Br[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][OH:34])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:34][CH2:33][CH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:24][N:20]1[CH2:19][CH2:18][C:16]2([O:15][CH2:14][CH2:13][N:12]([C:10]([C:8]3[N:9]=[C:5]([CH:2]([CH3:4])[CH3:3])[S:6][CH:7]=3)=[O:11])[CH2:17]2)[CH2:22][CH2:21]1
Reactant: OCCc1cccc(CCBr)c1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 60 °C

Procedure:
A mixture of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride [Example 27, step a] (13.6 g) and 2-(3-(2-bromoethyl)phenyl)ethanol [Organometallics 2002, 21(20), 4217] (13.51 g) and potassium carbonate (21.7 g) in acetonitrile (700 mL) and water (13 mL) was heated at 60° C. for 36 hours. The solvent was decanted off and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and brine, the aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were dried, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography, using 5% methanol in ethyl acetate containing 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 13.2 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH3:44])=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:28][CH2:29]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH3:44])=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:33])[F:34])[N:3]=1
Reactant: CCCc1ccc([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)c(-c2cccc(S(C)(=O)=O)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1ccc([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OCC)C4)nc(N)n2)C(F)(F)F)c(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate in CH2Cl2 (4 mL) was added TFA (2.0 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/MeOH) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:29]=[C:30]([CH3:32])[CH:31]=2)[O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(=O)OCC)=S)=[N:18][CH:19]=2)=[O:8])=[CH:5][C:4]([CH3:33])=[N:3]1.[Cl-].O[NH3+].C([N:40](CC)C(C)C)(C)C.C(O)C>CO>[NH2:40][C:21]1[N:20]=[C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=4)=[O:8])[CH:31]=[C:30]([CH3:32])[CH:29]=3)=[CH:19][N:18]2[N:23]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cc(C)cc(NC(=O)c3cc(C)nn3C)c2)cn1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)nn3c2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 71.8 %

Procedure:
A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-5-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (2.65 g, 4.76 mmol), hydroxylammonium chloride (2.96 g, 42.5 mmol), N,N-diisopropylethylamine (5.00 mL, 28.7 mmol), ethanol (100 mL) and methanol (100 mL) was stirred at 80° C. for 14 hr. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure and washed with ethanol-ethyl acetate to give the title compound (1.29 g, 72%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.B(F)(F)F.[CH3:26]COCC.[Zn](C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:26])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOCC
Reactant: OC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Agent: C[Zn]C
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,6-dichloro-3-fluorophenyl)methanol (5.05 g, 12.9 mmol) was dissolved in anhydrous THF (100 mL). To this solution was added BF3.OEt2 (10.66 mL, 6.5 eq.) at −78° C. The resulting solution was stirred for 10 min at the same temp before a solution of ZnMe2 (35.60 mL, 5.5 eq., 2 N in toluene) was added. The resulting mixture was allowed to warm up to rt in 1 h. The solution was then stirred at 65° C. for 3.5 h. Reaction was monitored by LC-MS. After achieving >95% conversion, the reaction was allowed to cool down to rt. Then it was further cooled down to −78° C. and quenched by adding sat. aq. NH4Cl solution (10 mL). The mixture was slowly warmed up to rt. Solvents were removed under reduced pressure. To the residue was added aq. NaHCO3 solution and the mixture was then extracted with CHCl3 (100 mL×4). The organic extracts were combined, dried (Na2SO4), and concentrated in vacuo to give a crude residue which was purified by flash chromatography (eluent: 10% ethyl acetate in hexane). 1H NMR (400 MHz DMSO-d6): δ=11.85 (br. s., 1H), 8.21 (d, J=2.0 Hz, 1H), 7.49-7.59 (m, 2H), 7.41 (dd, J=8.8, 8.6 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 5.11 (q, J=7.3 Hz, 1H), 1.80 (d, J=7.3 Hz, 3H); 13C NMR (100.6 MHz, DMSO-d6): δ=156.74 (JCF=247.4 Hz), 146.91, 142.24, 141.02, 129.37, 127.56, 125.98, 121.73 (JCF=19.8 Hz), 120.18, 115.98 (JCF=23.4 Hz), 113.62, 109.99, 33.53, 15.94. MS (ES+): m/z=386.93, 388.91, 390.89 [MH+]. HPLC: tR=4.17 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[OH:21].F.B(F)(F)F.[C:27](=[O:30])(O)[O-].[Na+]>O>[CH3:5][C:4]1[CH:3]=[C:2]([CH:10]=[C:9]([CH3:8])[C:27]=1[OH:30])[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([C:1](=[O:12])[C:18]2[CH:17]=[C:16]([CH3:20])[C:15]([OH:21])=[C:14]([CH3:13])[CH:19]=2)[CH:3]=1)=[O:7]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: Cc1cccc(C)c1O
Agent: F
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(=O)c2cccc(C(=O)c3cc(C)c(O)c(C)c3)c2)cc(C)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Isophthalic acid (66 g, 0.40 mole) and 2,6-dimethylphenol (96 g, 0.80 mole) were charged to a one-liter Hastalloy C® shaker tube. The tube was cooled and hydrogen fluoride (400 g) was condensed in. The tube was then warmed to room temperature and pressured to 50 psig with boron trifluoride. The tube was then warmed to 50° C. and shaken 4 hr at 50° C. After being cooled and vented, the tube was discharged of its contents which was a dark red solution. This solution was allowed to evaporate in the hood. The dark red solid which resulted was stirred in 2 l. of water, heated to boiling, and the solid was isolated by filtration of the hot slurry. The precipitate was stirred in 2 l. of water, heated to boiling, and neutralized with sodium bicarbonate. Filtration of the hot slurry and air drying of the precipitate afforded the title product as a salmon-colored powder with an i.r. spectrum identical with that of the analytical sample. The yield was 136.5 g (91%).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[C:11]([NH2:29])=[N:12][CH:13]=[C:14]([C:16]3[N:20]([CH2:21][CH3:22])[N:19]=[C:18]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[N:17]=3)[N:15]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:35][C@@H:34]([C:36]([O-])=[O:37])[CH2:33][O:32]1.[K+]>>[NH2:29][C:11]1[N:12]=[CH:13][C:14]([C:16]2[N:20]([CH2:21][CH3:22])[N:19]=[C:18]([CH:23]3[CH2:28][CH2:27][N:26]([C:33](=[O:32])[C@H:34]([OH:35])[CH2:36][OH:37])[CH2:25][CH2:24]3)[N:17]=2)=[N:15][C:10]=1[C:8]1[O:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[N:6][N:7]=1
Reactant: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Reactant: CC1(C)OC[C@H](C(=O)[O-])O1
Agent: [K+]
Product: CCn1nc(C2CCN(C(=O)[C@H](O)CO)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Yield: 40 %

Procedure:
3-(5-(Tert-butyl)-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine was reacted with potassium (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate, using a similar procedure than described in Example 10 to provide the title compound (0.145 g, 40%) as a solid. 1H NMR Spectrum (400 Hz, DMSO-d6, 30° C.): 1.45 (12H, m), 1.60 (2H, m), 1.98 (2H, m), 2.85 (1H, m), 3.00 (1H, m), 3.17 (1H, m), 3.45 (1H, s), 3.55 (1H, s), 4.05 (1H, m), 4.35 (2H, m), 4.60 (2H, m), 4.70 (1H, m), 4.85 (1H, m), 7.90 (2H, m), 8.85 (1H, s); Mass Spectrum [M+H]+=486.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:26]=[CH:27][C:21]=2[N:20]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[O:31]1[CH2:30][CH2:29][N:28]([C:25]2[CH:26]=[CH:27][C:21]3[NH:20][C:19]([C:7]4[C:6]5[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=5)[N:9]([CH:13]5[CH2:18][CH2:17][CH2:16][CH2:15][O:14]5)[N:8]=4)=[N:23][C:22]=3[CH:24]=2)[CH2:33][CH2:32]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3ccc(N4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1
Yield: 53.8 %

Procedure:
4-(2-(5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-benzo[d]imidazol-6-yl)morpholine (50 mg, 0.111 mmol) was added to the 10% Pd/C (10 mg) in ethanol (20 mL) and then hydrogen gas (60 psi) was applied for overnight at room temperature. Upon The reaction mixture was filtered through Celite, and the solvent was removed in vacuum. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (25 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 7.66 (d, 1H, J=2.4 Hz), 7.56-7.51 (m, 2H), 7.15 (m, 1H), 7.06-7.01 (m, 2H), 5.81 (dd, 1H, J=2.4 and 9.6 Hz), 4.01 (m, 1H), 3.87 (m, 4H), 3.81 (m, 1H), 3.65 (t, 1H, J=6.8 Hz), 3.16 (m, 4H), 2.67-2.58 (m, 1H), 2.16 (m, 1H), 2.08 (m, 1H), 1.84 (m, 1H), 1.69 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[C:11]1([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]2[N:18]=[CH:19][N:20]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][CH:9]=[CH:10][C:3]=34)[CH:21]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: Clc1ccnc2[nH]ccc12
Product: c1ccc(-c2cn(-c3ccnc4[nH]ccc34)cn2)cc1
Yield: 291 %

Procedure:
A melt of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) in 4-phenyl-1H-imidazole (0.24 g, 0.0016 mol) was heated at 200° C. overnight. The reaction was partitioned between ethyl acetate and saturated NaHCO3, separated and the organic phase was washed with brine. The organic layer was then dried and evaporated to give 250 mg of an orange oil. The oil was chromatographed with 7% MeOH/DCM, 0.7% NH4OH, sample in solvent system. Collected 74 mg of the product as an orange glass. The glass was triturated with hot DCE (1.5 mL) to give 51 mg of a brown solid which was dried at 60° C. for 4 h to afford the desired product (50 mg, 59 yield).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([B:18]3[O:22]C(C)(C)C(C)(C)O3)=[C:14]([CH:27]=[O:28])[CH:13]=2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:29][N:2]([CH3:1])[C:3]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[B:18]([OH:22])[O:28][CH2:27][C:14]=3[CH:13]=2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: CN(C)c1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN(C)c1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 198.3 %

Procedure:
A solution of 2-dimethylamino-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (7) (370 mg, 0.94 mmol) in CH2Cl2 (5 mL) was added to a mixture of NaBH4 (26 mg, 0.66 mmol) in anhydrous methanol (10 mL) at room temperature. Additional solid NaBH4 (82 mg, 2.2 mmol) was then added portionwise over a period of 10 minutes. The reaction mixture was then stirred for a further 1 h at room temperature. The reaction was quenched by the addition of a solution of glacial acetic acid (0.2 mL) and distilled water (0.2 mL) followed by stirring for 10 minutes. The reaction was concentrated to give an oil (˜550 mg). The oil was dissolved in a mixture of acetic acid/methanol/CH2Cl2 (1/2/100 v/v/v, 100 mL) followed by the addition of silica gel (5 g, 230-400 mesh) and concentrated to dryness to give a free flowing impregnated silica. This was loaded onto a silica column (10 g, 230-400 mesh) and eluted with acetic acid/methanol/CH2Cl2 (1/2/100 v/v/v). The fractions containing D95 were collected and concentrated to give a light yellow coloured oil. The oil was freeze dried by first diluting with MeOH/CH2Cl2 (1/1 v/v, 15 mL) followed by the addition of deionised water (200 mL), the resultant white suspension was frozen in a dry-ice acetone bath and placed overnight on freeze-dryer. A white solid of D95 was obtained (70 mg, 25% isolated yield). 1H NMR 400 MHz (d6-DMSO) δ 9.23 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.23 (d, J=0.5 Hz, 1H), 7.16 (dd, J=7.8, 0.5 Hz, 1H), 6.31 (d, J=8.6 Hz, 1H), 4.98 (s, 2H), 3.14 (s, 6H). Mass Spectrum [M+H+]=296. HPLC purity 95.04% (Maxplot), 94.63% (220 nm), 92.41% (254 nm).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][N:2]1[CH:6]2[CH2:5][CH2:4][CH:3]1[CH2:9][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:7]2
Reactant: CN1C2CCC1CC(O)C2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tropine (10.0 g, 70.8 mmol), 4-dimethylaminopyridine (80 mg, 0.60 mmol), and triethylamine (11.0 mL, 78.9 mmol) in DCM (125 mL) was cooled to 0° C., charged with methanesulfonyl chloride (5.50 mL, 71.0 mmol), slowly allowed to warm to rt, and stirred for an additional 16 h at rt. The reaction mixture was partitioned between CHCl3 and sat. NaHCO3, and the layers were separated. The aqueous layer was extracted with CHCl3 (3×) and the combined organic fractions were washed with sat. NaHCO3 (2×), brine (2×), dried over Na2SO4, filtered, and concentrated in vacuo resulting in the title compound as a pale brown solid. This material was taken on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.94-2.09 (m, 6H), 2.20 (dt, J=15.4, 4.2 Hz, 2H), 2.28 (s, 3H), 2.99 (s, 3H), 3.10-3.17 (m, 2H), 4.94 (t, J=5.1 Hz, 1H).
Reaction SMILES: [P:1](Cl)(Cl)([S:3][CH2:4][CH2:5][CH3:6])=[O:2].C([N:11](CC)CC)C.[F:16][C:17]1([F:27])[C:21]([F:23])([F:22])[C:20]([F:25])([F:24])[CH2:19][CH:18]1[OH:26].N>CCCCCC.C(Cl)Cl>[P:1]([NH2:11])(=[O:2])([S:3][CH2:4][CH2:5][CH3:6])[O:26][CH:18]1[CH2:19][C:20]([F:24])([F:25])[C:21]([F:22])([F:23])[C:17]1([F:27])[F:16]
Reactant: CCCSP(=O)(Cl)Cl
Reactant: OC1CC(F)(F)C(F)(F)C1(F)F
Reactant: CCN(CC)CC
Agent: N
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCSP(N)(=O)OC1CC(F)(F)C(F)(F)C1(F)F
Temperature: 20 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
20 g (0.1 mol) of S-propyl dichlorothiophosphate are dissolved in 500 ml of hexane, and the solution is first treated, between 0° and -5° C., with 20 ml (0.14 mol) of triethylamine and then with 20 g (0.1 mol) of 2,2,3,3,4,4-hexafluorocyclopentan-1-ol, dissolved in 50 ml of methylene chloride. The mixture is stirred for 2 hours at 20° C., and ammonia is then passed in at 20° C. (DC check). To complete the reaction, the mixture is stirred for 24 hours at 20° C., the solid is filtered off, and the solvent is distilled off under reduced pressure. The residue is then purified further by filtration through silica gel (cyclohexane:ethyl acetate=7:3 parts by volume). After the solvent has been distilled off, 8.6 g (27% of theory) of O-(2,2,3,3,4,4-hexafluorocyclopentyl) S-propyl thiophosphoramidate of refractive index nD20 =1.4390 are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])(=[O:11])=[O:10].[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]([CH3:34])[CH2:32][NH2:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]([CH3:34])[CH2:32][NH:33][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:13]=2[NH:12][S:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])(=[O:11])=[O:10])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Product: CC(CNC(=O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F)c1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared from 2-(2,6-difluorobenzenesulfonylamino)-4-iodo-benzoic acid and 2-(3,4-dichloro-phenyl)-propylamine as in EXAMPLE 1, Part C. HPLC: RT=11.98 min. MS (ESI−): mass calcd. for C22H17Cl2F2IN2O3S, 625.3; m/z found, 624 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.63 (s, 1H), 8.02 (d, J=1.5, 1H), 7.54-7.45 (m, 1H), 7.39 (d, J=8.2, 1H), 7.34 (d, J=1.6, 1H), 7.32 (d, J=1.8, 1H), 7.09 (dd, J=8.3, 2.1, 1H), 7.02-6.94 (m, 3H), 6.34-6.32 (br m, 1H), 3.743.65 (m, 1H), 3.40 (ddd, J=13.7, 8.5, 5.6, 1H), 3.14-3.04 (m, 1H), 1.30 (d, J=7.0, 3H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH2:39]([CH2:41][NH2:42])[OH:40].CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([NH:42][CH2:41][CH2:39][OH:40])[N:13]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: NCCO
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(NCCO)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, ethanolamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76 to give 2-[4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-ylamino]-ethanol. MS (ES+): 433.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([NH:9]/[C:10](=[CH:15]/[C:16]([O:18]C)=O)/[C:11]([O:13][CH3:14])=[O:12])=[CH:4][NH:3]1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[O:1]=[C:2]1[NH:3][C:4]2[C:16](=[O:18])[CH:15]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[NH:9][C:5]=2[C:6](=[O:8])[NH:7]1
Reactant: COC(=O)/C=C(/Nc1c[nH]c(=O)[nH]c1=O)C(=O)OC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc(=O)c2[nH]c(=O)[nH]c(=O)c2[nH]1
Temperature: 220 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
In a 2 liter-4 neck flask fitted with a reflux condenser was placed dimethyl (2E)-2-[(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)amino]-2-butenedioate (Intermediate 1.1) (38.5 g; 0.14 mol; 1 eq.) dowtherm(R) A (1 L)(phenyl ether-biphenyl eutectic). The suspension was stirred with a mechanical stirrer under argon and heated to 220° C. The reaction was monitored by HPLC/LC/MS. After 3 hours the reaction was stopped by cooling followed by the addition of 300 mL of petroleum ether. The resulting precipitate was filtered and washed with DMF (2×100 mL). Methyl 2,4,8-trioxo-1,2,3,4,5,8 hexahydropyrido[3,2-d]pyrimidine-6-carboxylate (21.02 g; 62%) (Intermediate 1.2) was isolated as a yellow powder in 100% HPLC purity.