Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH2:13][N:14]=C=O)([CH3:12])[CH2:5]1)=C=O>C1(C)C=CC=CC=1>[NH2:1][CH:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[CH2:7][C:6]([CH2:13][NH2:14])([CH3:12])[CH2:5]1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Solvent: Cc1ccccc1
Product: CC1(C)CC(N)CC(C)(CN)C1

Procedure:
In the same apparatus as described in Example 1, a preadduct is produced from 67.03 parts, by weight, of a polyester of adipic acid and 1,4-butane diol (hydroxyl number 52.2; acid number 0.6), 3.06 parts, by weight, of a polydimethyl siloxane containing terminal methylol groups and having a hydroxyl number of 198.0 and 24.06 parts, by weight, of 1-isocyanato-3-isocyanatomethyl-3,5,5-trimethylcyclohexane by heating the mixture for 2.5 hours at 100° C. After dilution with 141.5 parts, by weight, of toluene, the solution is maintained at a temperature of 80° C. The mixture is then reacted to form the polyurethane in the same way as in Example 1, 1.49 kg/h of 1-amino-3-aminomethyl-3,5,5-trimethyl cyclohexane being additionally introduced as further reaction component into the reaction mixture in a pinned-disc mixer following the preheater and the reactor being heated using steam under a pressure of 25 bars. A 25% solution in toluene-isopropanol (1:1) prepared immediately after production of the reaction product has a viscosity of 6390 cP/20° C. After storage for 1 week at room temperature, the final viscosity amounts to 7250 cP/20° C.
Reaction SMILES: [C:1](=[O:21])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1>CN(C=O)C>[F:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH3:10])[CH2:8][CH2:9]3)=[O:21])[CH2:40][CH2:39]2)=[CH:36][CH:37]=1
Reactant: CN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(COC(=O)N2CCN(c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.8 %

Procedure:
(1-Methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 1; 4.99 g, 16.9 mmol) was dissolved in DMF (40 mL). DIPEA (5.90 mL, 33.9 mmol) and 4-(4-fluoro-phenyl)piperazine (3.21 g, 17.8 mmol) were added. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was dissolved in EtOAc (400 mL) and then washed sequentially with 1 M aq NaOH solution (6×150 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and methyl isocyanate resin (1.0 g) was added. The reaction mixture was shaken for 14 h, filtered and then concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.67 g, 11.8%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:6][OH:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].[O:8]=[C:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].S(=O)(=O)(O)O>>[C:1]([O:6][O:7][C:9]1([O:8][O:6][C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)OO
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCCC1(OOC(C)(C)CC)OOC(C)(C)CC
Temperature: -10 °C

Procedure:
Ethyl 2,2-di(tertiary-amylperoxy)-1-cyclopentanecarboxylate was prepared by the addition of 92.64% TAHP (tertiary amyl hydroperoxide) (42.16 g, 0.3750 mol) to 95% ethyl 2-oxo-1-cyclopentanecarboxylate (16.44 g, 0.1000 mol) at room temperature in a three necked 250-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was then cooled via a dry ice-acetone bath to −10° C. and 78% sulfuric acid (15.09 g, 0.1200 mol) added dropwise to the solution with temperature at −10° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for three hours with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then dissolved in petroleum ether and washed with saturated NaCl solution followed by 2% NaOH solution to bring aqueous washings to a pH of 4.5 to 7.0. The organic layer was then dried over MgSO4, filtered, stripped to remove the organic solvent and then analyzed for purity by gas chromatography (66% by area). Purification by chromatography (silica gel, petroleum ether) afforded a liquid product: 13C NMR (75 MHz, CDCl3) δ 171.9 (C═O), 116.8 (O—C—O, cyclic), 81.8 (C(CH3)2), 81.4 (C(CH3)2, 59.9 (O—CH2CH3), 49.5 (CH, cyclic), 33.0 (CH2, cyclic), 31.6 (CCH2CH3, (2X)), 27.9 (CH2, cyclic), 23.8 (C(CH3)2, (2x)), 22.2 (CH2, cyclic), 13.8 (O—CH2CH3), 8.0 (CCH2CH3, (2x)); IR (neat) ν 1736, 1366, 1202, 875 cm−1; Analysis calculated for C18H34O6: C, 62.40; H, 9.89; O, 27.71; found: C, 62.40: H, 10.14; O, 26.93.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[C:5]2[OH:15].S(Cl)(Cl)=O.[C:20](OCC)(=O)C>CO>[CH3:20][O:13][C:12]([C:7]1[CH:6]=[C:5]([OH:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: O=C(O)c1cc(O)c2cc(F)ccc2c1
Reactant: CCOC(C)=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)c2cc(F)ccc2c1
Yield: 28 %

Procedure:
To a solution of 6-fluoro-4-hydroxy-naphthalene-2-carboxylic acid (0.500 g, 2.42 mmol) in MeOH (10 mL) was added thionyl chloride (0.265 ml, 3.63 mmol) drop-wise at 0° C. and the resulting mixture was refluxed for 5 hours. Methanol was distilled off under reduced pressure, and the residue was diluted with water (5 mL) and extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with water (5 mL) followed by brine (5 mL), dried and concentrated under reduced pressure to obtain the crude product. Silica gel column chromatography (5% ethyl acetate in hexanes) afforded 6-fluoro-4-hydroxy-naphthalene-2-carboxylic acid methyl ester (0.150 g, 28%) as a light yellow solid. MS cald. for C12H10FO3 [(M+H)+]: 221, obsd. 221.2.
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:20]1[CH:21]=[C:22]([CH:25]=[O:26])[NH:23][CH:24]=1>>[CH3:1][C:2]1[C:3]([C:20]2[CH:21]=[C:22]([CH:25]=[O:26])[NH:23][CH:24]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: O=Cc1cc(Br)c[nH]1
Product: Cc1cc2c(cc1-c1c[nH]c(C=O)c1)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(b), by reaction of 2.47 g (10 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid with 1.5 g (8.4 mmol) of 4-bromo-2-pyrrolecarboxaldehyde, 950 mg (38.5%) of the expected aldehyde are obtained, with a melting point of 128-9° C.
Reaction SMILES: [I:1]I.[CH2:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:4].C([O-])(=O)C.[Tl+]>C(Cl)Cl>[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([I:1])=[C:7]([OH:11])[CH:6]=1)[CH3:4]
Reactant: II
Reactant: CCc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: [Tl+]
Solvent: ClCCl
Product: CCc1ccc(I)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
Iodine (6.35 g, 25 mmol) in methylene chloride (360 mL) was added dropwise over 3 h to a stirred suspension of 3-ethyl-phenol (3.05 g, 25 mmol) and thallium (I) acetate (7.90 g, 30 mmol) in methylene chloride (300 mL). The resulting mixture was stirred at room temperature for 24 h and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-5% ethyl acetate in hexanes to afford 5-ethyl-2-iodophenol (3.49g, 56%).
Reaction SMILES: [CH3:1][C@H:2]([C@H:17]([CH3:20])[CH2:18][CH3:19])[C:3](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:4].O[Li].O.OO.[OH:26]S([O-])=O.[Na+]>CCCCCC.O.O1CCCC1>[CH3:1][C@H:2]([C@H:17]([CH3:20])[CH2:18][CH3:19])[C:3]([OH:4])=[O:26]
Reactant: O=S([O-])O
Reactant: CC[C@@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](C)[C@@H](C)C(=O)O
Temperature: 15 °C

Procedure:
A 20 L jacketed flask was fit with a gas inlet. A nitrogen purge was begun over the reactor and maintained throughout the process. To the flask was charged 450 g (1.634 mol) of (2R,3R,4S)-3-(2,3-dimethyl-pentanoyl)-4-phenyl-oxazolidin-2-one and 3.375 L tetrahydrofuran. The contents of the reactor were stirred at 15° C. In a separate 3 L round bottom flask, placed in an ice bath, was charged 500 mL of water, 137 g (3.269 mol) of LiOH—H2O and 942 mL (9.81 mol) of 30% wt/wt H2O2. The contents of the 3 L round bottom flask were stirred for 3 minutes and then poured into the 20 L jacketed reactor at a rate such that the temperature did not exceed 25° C. The reaction was stirred at 15° C. for 2 hours and then raised to 25° C. and stirred for an additional 2 hours. The jacket temperature of the reactor was set to −20° C. To the reaction was added 1.66 L of saturated NaHSO3 at a rate such that the temperature of the reaction did not exceed 25° C. The layers were separated. The aqueous layer was extracted 2× with 1 L aliquots of MTBE. The organic phases were combined and concentrated to give a solid/oil mixture. The solid/oil mixture was slurried in 1.7 L of hexane. The slurry was filtered and the collected solids were washed with 1.7 L of hexane. The hexane filtrates were extracted 2× with 1.35 L aliquots of 1N NaOH. The aqueous extracts were combined and extracted with 800 mL of dichloromethane. The aqueous layer was then acidified with 240 mL of concentrated hydrochloric acid. The aqueous solution was extracted 2× with 1 L aliquots of dichloromethane. The organic extracts were combined, dried over MgSO4 and concentrated to give 201 g of the titled compound: 1H-NMR (DMSO) 11.925 (bs, 1H), 2.204–2.135 (m, 1H), 1.556–1.490 (m, 1H), 1.382–1.300 (m, 1H), 1.111–1.000 (m, 1H), 0.952–0.934 (d, 3H, J=7.018), 0.809–0.767 (m, 6H); Gas Chromatogram 9.308 minutes, 98.91% area; Anal Calc'd for C7H14O2: C, 64.58; H, 10.84; N, O. Found: C, 64.39; H, 10.77; N, 0.18. MS (ion Mode: APCl) m/z=131 [M+1]+.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Reactant: CS(=O)(=O)Cl
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(S(C)(=O)=O)C2)ncc1Cl

Procedure:
2-[5-Chloro-2-(10-methanesulfonyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide was prepared from 2-[2-(10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide and methanesulfonyl chloride in an analogous manner to Example 278. Product isolated as a white solid (29 mg, 83%). m.p.=135-139° C.; LCMS (m/e) 563 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.12 (s, 1H), 8.48 (d, 1H, J=8.3 Hz), 8.15 (s, 1H), 7.97 (dd, 1H, J=1.5 and 7.8 Hz), 7.61-7.55 (m, 1H), 2.65 (d, 1H, J=2.3 Hz), 7.35-7.22 (m, 2H), 7.05 (d, 1H, J=8.1 Hz), 6.94 (bs, 1H), 3.87 (m, 2H), 3.20-3.12 (m, 1H), 3.10-3.00 (m, 3H), 2.65 (d, 3H, J=5.3 Hz), 2.52 (s, 3H), 2.25-1.90 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([O:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:14]([CH:19]=1)[O:13][C:10]1([CH3:12])[CH2:11][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C)(Oc2cc(Br)ccc2OCCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(Oc2cc(Br)ccc2OCCc2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A mixture of 3-(5-bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (20 mg) and TFA (1 mL) in CH2Cl2 (2 mL) was stirred at rt for 2 h. The reaction was concentrated in vacuo and purified by PTLC followed by additional purification using RP HPLC (Agilent) to give the title compound as an oil (12 mg, 77%). MS (ESI): mass calcd. for C18H20BrNO2, 362.3; m/z found, 362.0 [M+H]+. 1H NMR (CDCl3): 7.38-7.18 (m, 5H), 7.04 (dd, J=8.6, 2.3 Hz, 1H), 6.74 (dd, J=5.5, 3.1, 2H), 4.15 (t, J=7.2 Hz, 2H), 3.97 (d, J=8.9 Hz, 2H), 3.45 (d, J=9.2 Hz, 2H), 3.11 (t, J=7.1 Hz, 2H), 1.98 (s, 1H), 1.65 (s, 3H).
Reaction SMILES: C(O)(=O)C(O)=O.[Br:7][C:8]1[CH:28]=[CH:27][C:11]([CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][NH:14]2)=[CH:10][CH:9]=1.[OH-].[Na+].C(Cl)[Cl:32]>>[ClH:32].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][NH:14]2)=[CH:27][CH:28]=1
Reactant: ClCCl
Agent: COc1cc2c(cc1OC)C(Cc1ccc(Br)cc1)NCC2
Agent: O=C(O)C(=O)O
Agent: [Na+]
Product: Cl
Temperature: 25 °C

Procedure:
1-(4-bromo-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline hydrochloride (33) was prepared as follows: 1-(4-bromo-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline oxalate (1.24 g, 2.74 mmol) was added to a mixture of 50 mL CH2Cl2 and 50 ml of 1N NaOH. The reaction mixture was stirred at room temperature. After dissolving of precipitate, the organic phase was separated, dried over Na2SO4, filtered, and evaporated. A residue was dissolved in MeOH and 10 mL of 1M solution of HCl in Et2O was added. Hydrochloride was crystallized from MeOH-Et2O mixture. Yield is 0.958 g (87.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:24])[N:15]3[CH2:18][C:17]4([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:16]3)[C:9]2=[O:25])=[CH:4][CH:3]=1.Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:24])[N:15]3[CH2:18][C:17]4([CH2:19][CH2:20][N:21]([CH2:34][C:35]5[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:40]=5)[CH2:22][CH2:23]4)[CH2:16]3)[C:9]2=[O:25])=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCNCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccc(C(F)(F)F)cc3)CC2)C1
Temperature: 40 °C

Procedure:
To 3,3-bis(4-fluorophenyl)-1-(2-oxo-2-(2,7-diazaspiro[3.5]nonan-2-yl)ethyl)pyrrolidin-2-one (0.050 g, 0.114 mmol; Example 153A) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.030 g, 0.125 mmol) in dichloromethane (0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.030 mL, 0.171 mmol), and the reaction was heated to 40° C. for 1 hour. The reaction was cooled, loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences), and the title compound eluted with a gradient of 0.8% methanol/dichloromethane containing 0.2 N NH3 to 5.6% methanol/dichloromethane containing 0.2 N NH3(Flow=25 mL/minute) over 30 minutes. 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.1, 2H), 7.42 (d, J=8.0, 2H), 7.34-7.27 (m, 4H), 7.04-6.94 (m, 4H), 3.97 (s, 2H), 3.72 (d, J=19.3, 4H), 3.52 (dd, J=5.5, 12.0, 4H), 2.75 (t, J=6.5, 2H), 2.31 (s, 4H), 1.74 (d, J=4.9, 4H); MS (ESI+) m/z 598.2 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.[O:30]1[C:34]2[CH:35]=[CH:36][C:37](B(O)O)=[CH:38][C:33]=2[CH2:32][CH2:31]1>>[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:37]3[CH:36]=[CH:35][C:34]4[O:30][CH2:31][CH2:32][C:33]=4[CH:38]=3)[C:23]2=[CH:22][N:21]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: OB(O)c1ccc2c(c1)CCO2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCO5)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2,3-dihydro-1-benzofuran-5-ylboronic acid. LCMS (M+H)+=443.0/445.0.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([F:63])([F:62])[C:58]([F:59])([F:60])[F:61])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41])=[O:14]
Reactant: NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1)c1cccc2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 5-chloronaphthalene-1-carboxylic acid (176 mg, 0.849 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg, 0.849 mmol) and 1-hydroxybenzotriazole monohydrate (130 mg, 0.849 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol (318 mg, 0.809 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The mixturewas filtered using a glass filter filled with silica gel, and the filtrate was washed with ethyl actate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give 5-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethyl}-1-naphthamide (330 mg, 70%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[N:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC#N)CCN(C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Yield: 51.4 %

Procedure:
2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetonitrile (500 mg, 2 mmol) was treated with diisobutylaluminum hydride (6.2 ml, 6.2 mmol) in toluene (10 ml) at 80° C. to obtain 250 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine after purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:4]([CH:7]=[C:8]([CH:10]=C)[CH:9]=1)[C:5]#[N:6].I([O-])(=O)(=O)=[O:31].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:4]([CH:7]=[C:8]([CH:10]=[O:31])[CH:9]=1)[C:5]#[N:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(Cl)c(-n2cc3c(Nc4cc(C)ncn4)ncc(F)c3n2)c(C#N)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(C=O)cc4C#N)cc23)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Osmium (VIII) oxide (2.5% wt in tert-butanol, 0.1 mL) was added to a solution of 3-chloro-2-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]-5-vinylbenzonitrile (42 mg, 0.1 mmol) in acetone (2.0 mL) and water (0.5 mL). Sodium periodate (47 mg, 0.22 mmol) was then added and the reaction mixture was stirred at room temperature overnight. The resultant mixture was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (70-80% ethyl acetate in cyclohexane) to afford the title compound as a yellow glass (24 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1H), 10.12 (s, 1H), 9.55 (d, J=2.5 Hz, 1H), 8.72-8.62 (m, 3H), 8.37 (s, 1H), 8.03 (d, J=3.4 Hz, 1H), 2.45 (s, 3H).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9].Cl[C:18]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O.C(OCC)(=O)C>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:18]2[N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: O=C(c1cccs1)N1CCC(O)CC1
Reactant: Clc1cccc2nccn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1cccs1)N1CCC(Oc2cccc3nccn23)CC1
Yield: 4.6 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.40 g, 10 mmoles) in dimethylformamide (30 ml) was added 1-(2-thienylcarbonyl)-4-hydroxypiperidine (2.11 g, 10 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (1.53 g, 10 mmoles) with stirring under ice-cooling, followed by stirring at room temperature for 7 hours. Water was added to the reaction mixture, which was extratced with ethyl acetate and dried. After the solvent was distilled off, the residue was purified with column chromatography [eluent: ethyl acetate/hexane (1:1)→ethyl acetate/hexane (2:1)→ethyl acetate/ethanol (50:1)] to obtain 0.15 g of the desired product (4.6%, pale yellow oily product).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][NH:12][C:11]2=O.S(Cl)([Cl:23])=O>>[Cl:23][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC
Yield: 98 %

Procedure:
Dimethylformamide (0.2 ml) was added dropwise to a solution of 6,7-dimethoxy-3,4-dihydro-quinazolin-4-one (10.0 g, 48.5 mmol) in thionyl chloride (200 ml) and the reaction was heated at reflux for 6 hours. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (2×50 ml) to remove the last of the thionyl chloride. The residue was taken up in dichloromethane (550 ml), the solution was washed with saturated aqueous sodium hydrogen carbonate solution (2×250 ml) and the organic phase was dried over magnesium sulphate. Solvent evaporation in vacuo yielded 4-chloro-6,7-dimethoxyquinazoline (10.7 g, 98% yield) as a white solid: