Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH3:23])[C:9]3[N:13]=[C:12]([C:14]4[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=4I)[NH:11][C:10]=3[CH:22]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:24][OH:25].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[F-].[Cs+]>CN(C=O)C>[N:1]1([C:6]2[CH:7]=[C:8]([CH3:23])[C:9]3[N:13]=[C:12]([C:14]4[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=4[O:25][CH2:24][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)[NH:11][C:10]=3[CH:22]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1ccncc1
Reactant: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(I)cc[nH]c3=O)nc12
Reactant: CO
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(OCc4ccccn4)cc[nH]c3=O)nc12
Temperature: 130 °C
Yield: 34.3 %

Procedure:
To a solution of 3-(6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl)-4-iodo-1H-pyridin-2-one (25 mg, 0.06 mmol) in DMF (2 mL) were added pyridine carbinol (26 mg, 0.24 mmol) and cesium fluoride (36 mg, 0.24 mmol). The reaction mixture was heated to 130° C. for 14 h and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the title compound (8.2 mg, 34%). 1H NMR (300 MHz, CD3OD) δ 9.58 (1H, narrow d, J=1.2 Hz), 8.92 (1H, d, J=4.9 Hz), 8.19 (1H, narrow t, J=1.2 Hz), 8.12 (1H, s), 7.97–8.02 (2H, m), 7.85 (1H, narrow t, J=1.8 Hz), 7.81 (1H, narrow t, J=1.0 Hz), 7.63 (1H, d, J=7.9 Hz), 7.54 (1H, t, J=6.2 Hz), 6.81 (1H, J=7.5 Hz), 5.86 (2H, s), 2.86 (3H, s). LCMS (M+H)+ m/z 399 (t=1.07 min.).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([C:13]1[CH:25]=[CH:24][C:16]([C:17]([C:19]([O:21]CC)=O)=[O:18])=[CH:15][CH:14]=1)[CH:10]([CH3:12])[CH3:11].[OH:26][C:27]1[C:28](=O)[O:29][C:30](C)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)C=1O>C1COCC1>[OH:21][C:19]1[C:17]([C:16]2[CH:15]=[CH:14][C:13]([CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:25][CH:24]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:18][C:27](=[O:26])[C:28]=1[O:29][CH2:30][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)C(=O)c1ccc(CC(C)C)cc1
Reactant: Br[Mg]c1ccccc1
Reactant: CC1(c2ccccc2)OC(=O)C(O)=C1O
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C2(c3ccccc3)OC(=O)C(OCc3ccccc3)=C2O)cc1
Yield: 29 %

Procedure:
A total of 3.5 mL (10.5 mmol) of 3.0M phenylmagnesium bromide was added to a solution of 2.3 g (10 mmol) of ethyl 4-isobutylbenzoylformate in THF in an analogous manner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide an oil, which was purified over 400 g of SiO2 by eluting with 5000 mL of CHCl3, 500 mL of EtOH/CHCl3 (3/97) and 500 mL of EtOH/CHCl3 (8/92) to provide 1.2 g (29% yield) of 4-hydroxy-5-(4-isobutylphenyl)-5-phenyl-3-phenylmethoxy-2(5H)-furanone as a tan powder recrystallized from CHCl3 and hexanes.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.[I:12](O)(=O)=O>C(O)(=O)C.O.ClCCl.S(=O)(=O)(O)O>[CH:7]([C:1]1[CH:6]=[CH:5][C:4]([I:12])=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1ccccc1
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CC(C)c1ccc(I)cc1
Temperature: 85 °C
Yield: 94 %

Procedure:
(C9H11I), FW=246.09 g/mol. Cumene (45.0 g, 377 mmol), iodine (38.25 g, 151 mmol) and iodic acid (15.38 g, 87.4 mmol) were dissolved in a solution of acetic acid (188 mL), water (30 mL), dichloromethane (19 mL), and sulfuric acid (7.5 mL). The solution was heated to 85° C. for three hours. Once the reaction was complete, the reaction was worked up with water and dichloromethane. The dichloromethane was washed with sodium hydrosulfite, dried over magnesium sulfate and concentrated, yielding a red liquid in 94% yield. Rf 0.63 (hexanes) 1H NMR (300 MHz, CDCl3, ppm) d 7.58 (d, 2H, J=8.3 Hz), 6.96 (s, 2H, J=8.3 Hz), 2.83 (septet, 1H, J=6.9 Hz), 1.20 (d, 6H, J=6.9 Hz); 13C NMR (75.5 MHz, CDCl3, ppm) d 148.2, 137.2, 128.5, 90.7, 33.6, 23.8; LR MS (EI) m/z 246.
Reaction SMILES: CCN(CC)CC.[NH2:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[S:26][C:27]([Cl:29])=[CH:28][C:23]=2[CH:22]=1)=[O:20].[Cl:30][CH2:31][C:32](Cl)=[O:33].C([O-])(O)=O.[Na+]>ClCCl>[Cl:29][C:27]1[S:26][C:24]2[NH:25][C:21]([C:19]([NH:18][C@@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@H:9]3[NH:8][C:32](=[O:33])[CH2:31][Cl:30])=[O:20])=[CH:22][C:23]=2[CH:28]=1
Reactant: O=C(Cl)CCl
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Et3N (3 mL, 21.6 mmol) was added to a suspension of N-[(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 21, 3.11 g, 6.98 mmol) in anhydrous dichloromethane (55 mL) and stirred at ambient temperature for 5 miuntes. The suspension was cooled to −78° C. and chloroacetylchloride (611 μL, 7.68 mmol) was added and the reaction was warmed to 0° C. and stirred at this temperature for 3 hours. NaHCO3 (50 mL) was added, the phases were separated and the aqueous phase was extracted with THF (2×50 mL). The combined organic fractions were washed with water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was triturated (THF:isohexane, 1:5), collected by filtration, washed with hexane (20 mL) and dried to give the title compound (1.92 mg, 68%) as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>CCOCC>[ClH:17].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:9]1)=[O:22]
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3cccc(Cl)c3)c3ccccc23)CC1
Product: Cl
Temperature: 100 °C
Yield: 67.7 %

Procedure:
A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of 3-chlorobenzoyl chloride was heated at 100° C. for 2 hours. The reaction was allowed to cool, and ether was added. The resultant solid was collected and recrystallized twice from isopropyl alcohol to yield 3.7 g (67.7%) of product, mp 209°-211° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].I[CH2:12][CH3:13]>CN(C=O)C.C1COCC1.O>[CH2:12]([O:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:13]
Reactant: COC(=O)C(C)(C)O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)(C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A 0° C. suspension of NaH (60% wt. in mineral oil, 1.4 g, 35.0 mmol) in DMF (11 mL) under Ar was treated drop-wise with a solution of methyl 2-hydroxyisobutyrate (2.0 g, 16.93 mmol) in THF (5 mL), stirred at 0° C. for 0.5 h, allowed to warm to RT, and stirred for 0.5 h. The mixture was re-cooled to 0° C., treated drop-wise with iodoethane (6.0 g, 35.3 mmol) and stirred overnight as the cooling bath expired. The mixture was diluted with water, extracted with Et2O (5×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford methyl 2-ethoxy-2-methylpropanoate (1.6 g, 65%) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 3.63 (s, 3H), 3.31 (q, J=7.0 Hz, 2H), 1.30 (s, 6H), 1.06 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7].N1C=CC=CC=1.ClCl>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]=[N:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7]
Reactant: COCCOC(=O)NNC(=O)OCCOC
Agent: ClCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COCCOC(=O)N=NC(=O)OCCOC
Yield: 59.6 %

Procedure:
To a solution obtained by adding 1,2-hydrazinedicarboxylic acid bis(2-methoxyethyl) ester (1 g, 4.23 mmol), pyridine (0.34 g, 4.23 mmol), and toluene (10 ml) to a 30 ml flask, followed by cooling with an ice bath, chlorine gas was blown for 30 minutes. After the reaction, the solution was washed with water (1 mL,×2), and dehumidified with anhydrous magnesium sulfate, followed by concentration to dryness. The solid was recrystallized with toluene (1.5 mL) and hexane (7.5 mL), to give azodicarboxylic acid bis(2-methoxyethyl) ester as a pale yellow crystal (0.59 g, yield: 60%).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[CH:4]=[C:5]([C:9](=[CH2:14])[C:10]([O:12]C)=[O:11])[CH:6]=[CH:7][CH:8]=1>[OH-].[Li+].O.C(#N)C.CCCCCCC>[OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[CH:4]=[C:5]([C:9](=[CH2:14])[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(C(=O)OC)c1cccc(C(O)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCCCCCC
Product: C=C(C(=O)O)c1cccc(C(O)c2ccccc2)c1

Procedure:
A mixture of 2.40 g (8.96 mmol) of methyl 2-(3-(hydroxy-phenyl-methyl)-phenyl)-propenoate (product from Example 15a) in 1.76 g of lithium hydroxide, 16 ml of water, 18 ml of acetonitrile and 18 ml of heptane is treated overnight with intensive stirring using a mechanic stirrer. The acetonitrile/water phase is then separated and concentrated. The resulting residue is taken up in ethyl acetate and extracted with sodium hydroxide solution. The basic extract is acidified using hydrochloric acid and extracted with ethyl acetate, dried and concentrated. Yield: 1.87 g (7.36 mmol) (82.1% of theory)
Reaction SMILES: P(OC1C(C(C)(C)C)=CC=CC=1C(C)(C)C)(OC1C(C(C)(C)C)=CC=CC=1C(C)(C)C)[O:2][C:3]1C(C(C)(C)C)=CC=CC=1C(C)(C)C.C1C=CC=CC=1.[CH3:53][C:54]([CH2:56][CH2:57][CH2:58][CH:59]([CH3:62])[CH:60]=[CH2:61])=[CH2:55].[C:63](O)(=[O:65])C.O>>[CH3:55][CH:54]([CH2:56][CH2:57][CH2:58][CH:59]([CH3:62])[CH2:60][CH2:61][CH:63]=[O:65])[CH2:53][CH:3]=[O:2]
Reactant: C=CC(C)CCCC(=C)C
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1OP(Oc1c(C(C)(C)C)cccc1C(C)(C)C)Oc1c(C(C)(C)C)cccc1C(C)(C)C
Reactant: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(CC=O)CCCC(C)CCC=O
Reaction time: 5 h
Yield: 41 %

Procedure:
A 5-L pressure reaction vessel was charged with a solution comprising 83.3 mg of Rh(CO)2 (CH3COCHCOCHS3), 20.87 g of tris(2,6-di-t-butylphenyl) phosphite and 500 mL of benzene, and the vessel was pressurized to 90 atm with a mixed gas of carbon monoxide/hydrogen (1/1). After the temperature had been elevated to 100° C., 2.05 kg of 2,6-dimethyl-1,7-octadiene was added over a period of 5 hours, during which the pressure was maintained at 90 atm. After completion of the feed, the reaction was continued for a further 5 hours at the same temperature and pressure. The reaction vessel was cooled and then the gas therein was purged. The reaction mixture was taken out and then benzene was distilled off under vacuum. The residue was subjected to simple distillation to remove the catalytic components. The resulting distillate was rectified to give 3,7-dimethyldecanedial as an almost colorless liquid having a boiling point of 99° to 100° C. at 0.85 mmHg. The yield was 41% (1.20 kg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[C:5]2[S:9][C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:11][C:4]=12)=[O:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.C(OCC)C>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:1]([OH:2])[C:3]2[CH:8]=[N:7][CH:6]=[C:5]3[S:9][C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:11][C:4]=23)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1cc2c(C=O)cncc2s1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2c(C(O)c3ccc(Cl)cc3)cncc2s1

Procedure:
To a solution of Example 237E (0.25 g, 0.95 mmol) in anhydrous THF (5 mL) at −5° C. was slowly added a 1 M solution of p-chlorophenylmagnesium bromide in diethyl ether (2.85 mL, 2.85 mmol). The reaction was quench after 10 minutes with dropwise addition of water (1 mL) and partitioned between dichloromethane (25 mL) and 50% sat. aq NaHCO3 (50 mL). The aqueous phase was extracted with dichloromethane (25 mL) and the organic extracts combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc/hexane as eluent to provide the title compound as a foam, which was crushed and dried in a desiccator to yield a powder (0.36 g, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH2:14])[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].Br[CH2:16][C:17]([C:19]1[N:20]=[CH:21][S:22][CH:23]=1)=[O:18]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:16][CH:17]([OH:18])[C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Reactant: O=C(CBr)c1cscn1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cscn2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-(4-carbomethoxyphenyl)-1-methylethylamine with 4-bromoacetyl-thiazole, followed by reduction and purification of the base on a silica gel plate using ethyl acetate/methanol=8:2 as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:42][C:39]3([C:36]4[CH:37]=[CH:38][C:33]([C:32]([F:31])([F:43])[F:44])=[CH:34][CH:35]=4)[CH2:41][CH2:40]3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)NC3(c4ccc(C(F)(F)F)cc4)CC3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 10.1 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 1-[4-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-37, 0.078 g, 0.388 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.38 (d, J=9.0 Hz, 4H), 1.52 (s, 6H), 3.07 (s, 2H), 7.32-7.35 (m, 6H), 7.61-7.64 (m, 2H), 8.39 (s, 1H), 9.20 (s, 1H), 11.0 (s, 1H); MS [M+H]+: 559.25.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][NH:27][CH2:28][CH3:29])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH3:5].C(N(CC)CC)C.[CH2:38]([N:45]=[C:46]=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[C@@H:4]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=2[CH2:26][N:27]([CH2:28][CH3:29])[C:46]([NH:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:47])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1)[CH3:5]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)OC)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)OC)cc(C(F)(F)F)c1)C(=O)NCc1ccccc1

Procedure:
(R)-2-(2′-Ethylaminomethyl-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-propionic acid methyl ester (0.10 mmol) in CH2Cl2 was treated with triethylamine (0.03 mL, 0.20 mmol) and benzyl isocyanate (0.02 mL, 0.20 mmol) at room temperature for 2 hours. The mixture was worked up with CH2Cl2 and H2O to give the title compound.
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[C:19]([CH2:26][O:27][CH2:28][CH3:29])=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1.[H-].[Na+].O>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][C:22]([O:24][CH2:2][CH2:1][S:3]([CH3:6])(=[O:5])=[O:4])([CH3:23])[CH3:25])[C:19]([CH2:26][O:27][CH2:28][CH3:29])=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A solution of methyl vinyl sulfone (3.0 g, 29 mmol) and 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (5.4 g, 14 mmol) in anhydrous THF (57 mL) was purged with nitrogen; solid sodium hydride (available as a 60% dispersion in mineral oil, 57 mg, 1.4 mmol) was added. The reaction was stirred for 70 minutes at ambient temperature, at which time an analysis by HPLC indicated a ratio of product to starting material of 3:1. The reaction mixture was combined with material from another run, and water (100 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (100 mL, 50 mL). The combined organic fractions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 7-bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.[N:30]1[CH:35]=[C:34]([CH:36]=O)[CH:33]=[N:32][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:36][C:34]4[CH:35]=[N:30][CH:31]=[N:32][CH:33]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: O=Cc1cncnc1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(Cc5cncnc5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (45 mg, 0.1 mmol) and pyrimidine-5-carbaldehyde (32 mg, 0.3 mmol) in DCM (1.5 mL) was added NaBH(OAc)3 (64 mg, 0.3 mmol), followed by addition of AcOH (12 uL). After stirring at room temperature in a sealed vial for 16 h, the reaction was quenched with EtOAc (50 mL). The reaction mixture was sequentially washed with water (10 mL), brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica chromatography (0-10% MeOH in EtOAc gradient with 1% NH3 in MeOH additive) to give 5-Chloro-N2-(2-fluoro-5-methyl-4-(1-(pyrimidin-5-ylmethyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as an off white solid; 1H NMR (400 MHz, CD3OD) δ 9.09 (s, 1H), 8.81 (s, 2H), 8.00 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 6.99 (d, J=13.2 Hz, 1H), 6.23 (br s, 1H), 3.65 (s, 2H), 3.03 (m, 2H), 2.76 (m, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 2.25 (m, 2H), 1.80-1.68 (m, 4H); ESMS m/z 508.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1)[CH3:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=4[F:11])=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CCOc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 160 °C
Yield: 38.5 %

Procedure:
A mixture of 4-ethoxy-2-fluoro-phenol (Intermediate 5; 125 mg, 0.801 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 270 mg, 0.801 mmol), and potassium carbonate (244 mg, 1.761 mmol) in 4 mL of dimethylformamide was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, the precipitate was filtered and the filtrate was extracted with ethyl acetate three times and the combined organic extracts were washed with saturated brine, and dried over sodium sulfate. The mixture was filtered, concentrated and purified by flash silica gel chromatography (4% methanol in dichloromethane) to afford 4-[4-(4-ethoxy-2-fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (141 mg, 39%) as a white solid. Mass spectrum M+H-Boc=358.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8](O)=[O:9].S(Cl)([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([Cl:14])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)cncc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c(Cl)cncc1Cl
Temperature: 50 °C

Procedure:
3,5-Dichloropyridine-4-carboxylic acid (0.5 g, 2.6 mmol; Reference Example 1) was dissolved in CH2Cl2 (1.75 mL) and DMF (50 μL). Thionyl chloride (0.21 mL, 2.86 mL) was added and the reaction mixture was heated at 50° C. for 20 h. The residue was concentrated in vacuo. The formation of the acid chloride was observed by TLC (50% EtOAc/hexane) and the crude 3,5-dichloropyridine-4-carboxylic acid chloride was used in Step E without further purification.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][CH2:8][CH:9]([CH:17]([OH:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])[CH3:3].ClC(Cl)(Cl)C(=N)O[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1>O1CCCC1.B(F)(F)F.CCOCC>[CH3:4][C:2]([Si:5]([CH3:28])([CH3:29])[O:6][CH2:7][CH2:8][CH:9]([CH:17]([O:27][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(O)CCc1ccc(I)cc1
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(COC(CCc2ccc(I)cc2)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
Boron trifluoride etherate (5.0 μL, 39 μmol) was added to a stirred solution of 1,1-dimethylethyl 2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-3-hydroxy-5-(4-iodophenyl)pentanoate (5.14 g, 9.63 mmol) and 4-methoxybenzyl 2,2,2-trichloroethanimidoate (4.05 g, 14.4 mmol) in tetrahydrofuran (40 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature at which stirring was continued for 2 h. A further portion of boron trifluoride etherate (5.0 μL, 39 μmol) was then added and stirring was continued at room temperature for a further 2 h. Two further additions of boron trifluoride etherate (5.0 μL, 39 μmol) followed by stirring at room temperature for 2 h were carried out before evaporation of the solvent. The residue was chromatographed on silica gel (0% to 10% diethyl ether: cyclohexane) to give the title compound (4.14 g, 66%) as a yellow oil which was a mixture of diastereomers. LC/MS: 4.78 min; z/e 655, calcd (M+1) 655. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.25 (2H), 6.90 (2H), 6.80 (2H), 4.55 (1H), 4.35 (1H), 3.80 (3H), 3.65(1H), 3.55 (1H), 2.95 (1H major), 2.80 (1H minor), 2.70 (1H), 2.55 (1H), 1.95-1.60 (4H), 1.45 (9H), 0.85 (9H), 0.5 (6H).