Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:27])=[N:9][C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(Cl)Cl.O1CCCC1>[C:19]([C:15]1[CH:14]=[C:13]([C:12]2[CH:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=[C:8]([CH3:27])[C:7]=2[NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:18]=[CH:17][CH:16]=1)#[N:20]
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1NC(=O)CCCl
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1NC(=O)CCN1CCOCC1
Yield: 88.1 %

Procedure:
A mixture of 3-(3-chloropropionylamino)-4-(3-cyanophenyl)-2-methyl-6-phenylpyridine (0.45 g) and morpholine (0.23 g) in a mixture of methylene chloride (5 ml) and tetrahydrofuran (10 ml) was refluxed for 8 hours. The mixture was concentrated, diluted with water (20 ml) and chloroform (20 ml). The separated organic layer was washed with water, dried and concentrated in vacuo. The residue was triturated with diethyl ether to give 4-(3-cyanophenyl)-2-methyl-3-(3-morpholinopropionylamino)-6-phenylpyridine (0.45 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[C:29]([Si:31]([CH3:34])([CH3:33])[CH3:32])#[CH:30].O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:32][Si:31]([C:29]#[C:30][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1)([CH3:34])[CH3:33]
Reactant: C#C[Si](C)(C)C
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)cnc43)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a stirred suspension of (1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (152 mg, 0.30 mmol) from Step 2 of this Example in DMF (3 mL) were added CuI (6 mg, 0.032 mmol) and PdCl2(PPh3)2 (11 mg, 0.015 mmol). The mixture was purged with argon while ethynyltrimethylsilane (85 μL, 0.60 mmol) and TEA (127 μL, 0.90 mmol) were added sequentially. The resulting mixture was stirred at rt for 1 h. LCMS analysis showed that the reaction was complete. Water (30 mL) was added and the resulting dark brown solid was collected by filtration and dried to give crude (1R,2R)-2-((6-((6-((trimethylsilyl)ethynyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 70%). LCMS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].Br[C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[C:20]([N+:38]([O-:40])=[O:39])=[CH:19][N:18]=1>CN(C=O)C.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27][CH2:26]3)[C:20]([N+:38]([O-:40])=[O:39])=[CH:19][N:18]=2)=[N:3][CH:4]=1)#[N:9]
Reactant: N#Cc1cnc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(Br)ncc2[N+](=O)[O-])CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(COc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.2 %

Procedure:
Palladium (II) acetate (14.7 mg, 0.07 mmol) was added to (±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (123 mg, 0.2 mmol) in DMF-toluene (1:1, 5 mL) and the mixture was degassed for 10 minutes under a stream of nitrogen gas. 2-Amino-5-cyanopyrazine (95 mg, 0.79 mmol), sodium-t-butoxide (76 mg, 0.79 mmol) and tert-butyl 4-((2-bromo-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate (273 mg, 0.67 mmol) were added and the mixture was degassed for a further 5 minutes before stirring at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water and brine, then dried (Na2SO4) and concentrated to give crude tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate (379 mg) which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3>CO.[Pd]>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:12]2[CH:13]=[C:14]3[C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]4[CH:3]=[CH:2][N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)[CH:22]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1cnc(Cl)cc12
Agent: [Pd]
Solvent: CO
Product: NC1=N[C@]2(CO1)c1ccncc1Oc1ccc(-c3cccnc3)cc12
Reaction time: 24 h

Procedure:
To the solution of (S)-3-chloro-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (23 mg, 0.063 mmol) in MeOH (2 mL) was added 10% Pd on Carbon (10 mg, 0.073 mmol). The mixture was hydrogenated under 1 atm of H2 for 24 h. After filtration and concentration, the crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with isocratic % to 20% MeOH in CH2CL2, to provide (S)-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][C:38](=[O:41])[NH:37][CH2:36]1>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:35]4[CH2:40][CH2:39][C:38](=[O:41])[NH:37][CH2:36]4)=[CH:29][CH:28]=3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: O=C1CCNCN1
Product: Nc1ncnn2c(-c3ccc(CN4CCC(=O)NC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 4.5 %

Procedure:
Using a procedure similar to that of Example 282, step 2, with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and tetrahydro-pyrimidin-4-one as starting materials, 14 mg (4.5%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.60 (s, 2 H), 3.20 (t, 2 H), 2.95 (s, 2 H), 2.60 (t, 2 H); ES-MS m/z 529.29 [M+H]+, HPLC RT (min) 2.24.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7](O)[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]=[CH:6][C:5]1=[O:57])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Yield: 92.1 %

Procedure:
A solution of 17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (800 mg) and a catalytic amount of p-toluenesulfonic acid in 40 ml of dry benzene was refluxed for 1.5 h under nitrogen atmosphere. The solvent was removed under reduced pressure and the dark brown residue was purified by column chromatography on silica gel (eluted with ether) to give 720 mg of 17-allyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone as a white solid. This material (500 mg) was dissolved in dry toluene (30 ml) and to this solution was added tetrakistriphenylphosphine palladium° (50 mg) and acetic acid (50 μl) at room temperature. To this yellow solution was added tri-n-butyltin hydride (200 mg) and the mixture was stirred for 1 h. The Brown colored solution was directly applied to column chromatography on silica gel (first eluted with hexane, then with ether) to give 380 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].Br[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[OH:6])[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: COc1ccccc1C=O
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2ccccc2OC)c1
Yield: 84.6 %

Procedure:
2-Methoxybenzaldehyde (0.81 g, 5.95 mmol), 1-bromo-3,5-dimethoxybenzene (1.42 g, 6.54 mmol), and n-butyl lithium (2.62 ml, 6.54 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (3,5-dimethoxy-phenyl)-(2-methoxy-phenyl)-methanol as a greenish oil (1.38 g, 85%): 1HNMR (CDCl3) 7.30-7.18 (m, 2H, Ar), 6.96-6.88 (m, 2H, Ar), 6.57 (d, J=1 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H, Ar), 5.99 (d, J=5 Hz, 1H, CHOH), 3.84 (s, 3H, OCH3), 3.77 (s, 6H, 2OCH3), 3.04 (d, J=5 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ccc(O)cc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(O)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(4-hydroxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:24]1([N:30]2[CH:34]=[N:33][C:32]([C:35](Cl)=[O:36])=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:35]([C:32]2[N:33]=[CH:34][N:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:31]=2)=[O:36])[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ncn(-c2ccccc2)n1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 2.19 g (10.5 mmol) 3-methyl-piperazine-1-carboxylic acid tert-butyl ester and 2.50 mL (14.6 mmol) DIPEA in 15 mL DCM was added a solution of 2.18 g (10.5 mmol) 1-phenyl-1H-[1,2,4]-triazole-3-carbonyl chloride in 15 mL DCM. The reaction mixture was stirred at RT for 3 days, then washed with water. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[N:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1[N:7]([CH:8]([C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[N:5][CH:4]=1)=[O:1]
Reactant: COC(=O)CC(c1ccc(C#N)cc1)n1cncc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)CC(c1ccc(C#N)cc1)n1cncc1C=O
Reaction time: 3 h

Procedure:
To a solution of the title B compound, methyl 3-[5-(hydroxymethyl)-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate (0.60 g, 2.11 mmol) in DCM (7.0 mL) is added Dess-Martin periodinane (15% wt solution, 7.0 mL, 3.2 mmol) and the reaction is stirred for 3 h. The reaction mixture is partitioned between EtOAc and sodium bicarbonate-sodium thiosulfate. The combined organic phases are washed with brine and dried (anhydrous sodium sulfate) and concentrated. The residue is subjected to flash chromatography (silica) eluting with EtOAc:MeOH (9:1) to give methyl 3-[5-formyl-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate as an oil: 1H-NMR (CDCl3) δ 9.68 (1H, s), 8.00 (1H, s), 7.87 (1H, s), 7.65 (2H, d, J=8.5), 7.37 (2H, d, J=8.5), 6.63 (1H, m), 3.66 (3H, s), 3.43 (1H, dd, J=16.5, 8.5), 3.30 (1H, dd, J=16.5, 6.6); 13C-NMR (CDCl3) δ 178.9, 169.2, 144.9, 143.0, 141.8, 132.7, 130.8, 127.4, 118.0, 112.5, 56.5, 52.4, 39.0; e/z (ES) 284 (M+1, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33]C(OC(C)(C)C)=O)[CH2:28]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[ClH:48]>C(Cl)Cl.CCOCC>[ClH:48].[NH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][N:27]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[O:19][CH2:18][CH2:17][NH:16][CH2:15]4)=[O:13])[C:4]=23)[CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CN(C(=O)OC(C)(C)C)CCO4)c23)C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CNCCO4)c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 2-(5-bromo-4-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate diastereomer #2 (80 mg, 0.13 mmol) in DCM (3 mL) at room temperature was treated with TFA (1 mL). The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase HPLC (0-50% ACN in water). The product isolated was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)morpholine-2-carboxamide hydrochloride diastereomer #2 (44 mg, 64% yield). 1H NMR (400 MHz, D2O) δ 8.18 (s, 1H), 7.57 (s, 1H), 4.55-4.51 (m, 1H), 4.20-4.16 (m, 1H), 3.97-3.90 (m, 1H), 3.67-3.64 (m, 1H), 3.49-3.29 (m, 5H), 3.20-3.08 (m, 2H), 2.95-2.92 (m, 1H), 2.09-2.06 (m, 1H), 1.81-1.69 (m, 2H), 1.53-1.49 (m, 1H); LCMS (APCI+) m/z 423, 425 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=3)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[K+].[C:27]([C:29]1[N:30]=[C:31]([C:42]([O-])=[O:43])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=1)#[N:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:19]1([C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:25])[CH3:1])=[CH:11][CH:10]=3)[CH:17]=[CH:16][C:15]=2[NH:18][C:42]([C:31]2[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[C:29]([C:27]#[N:28])[N:30]=2)=[O:43])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CN(C)S(=O)(=O)c1ccc(-c2ccc(N)c(C3=CCCCC3)c2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)cc1

Procedure:
The title compound was prepared from 4′-amino-3′-cyclohex-1-enyl-biphenyl-4-sulfonic acid dimethylamide (as prepared in the previous step, 64 mg, 0.17 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 60 mg, 0.19 mmol), PyBroP (117 mg, 0.350 mmol) and DIEA (69 μL, 0.39 mmol) according to the procedure in Example 11, step (f) (84 mg, 70%). Mass spectrum (ESI, m/z): Calcd. for C31H39N5O4SSi, 606.2 (M+H), found 605.9.
Reaction SMILES: [OH:1][C:2]([CH3:41])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1.C([Sn](=O)CCCC)CCC.[N:52]([Si](C)(C)C)=[N+:53]=[N-:54].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1.C1(C)C=CC=CC=1>[OH:1][C:2]([CH3:40])([CH3:41])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:54][N:53]=[N:52][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCCC[Sn](=O)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.32 g), dibutyltin oxide (0.072 g), azidotrimethylsilane (2 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium fluoride solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was dissolved in tetrahydrofuran (5 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.67 mL) was added and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was extracted with ethyl acetate and 1 N hydrochloric acid, and the ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.16 g, 45%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[CH3:16])[CH:7]=[C:6]([CH3:17])[CH:5]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.C(OCC)(=O)C>[CH3:25][S:26]([O:1][CH2:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[CH3:16])[CH:7]=[C:6]([CH3:17])[CH:5]=1)(=[O:28])=[O:27]
Reactant: Cc1cc(CCO)nc(-n2c(C)ccc2C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(CCOS(C)(=O)=O)nc(-n2c(C)ccc2C)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 100.1 %

Procedure:
A solution of 2.00 g (8.68 mmol) of 6-(2-hydroxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (from Example 58, Step A) and 1.82 mL (1.32 g, 13.1 mmol) of triethylamine in 20 mL of dichloromethane was cooled to 0° C. and 0.68 mL (1.0 g, 8.8 mmol) of methanesulfonyl chloride was added over 5 min. The mixture was stirred another 25 min at 0° C., diluted with 70 mL of ethyl acetate, and washed with 30 mL each of water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried (sodium sulfate), decanted, and evaporated to give 2.68 g (100% yield) of 6-(2-methanesulfonyloxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine as a viscous pink oil.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.C([Mg]Cl)(C)C.[B:16](OC)([O:19]C)[O:17]C>>[F:1][CH:2]([F:10])[C:3]1[CH:8]=[CH:7][C:6]([B:16]([OH:19])[OH:17])=[CH:5][CH:4]=1
Reactant: FC(F)c1ccc(I)cc1
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Product: OB(O)c1ccc(C(F)F)cc1

Procedure:
In a departure from the procedure described above the compound is prepared from 4-difluoromethyl-1-iodo-benzene (prepared from 4-iodobenzaldehyde using diethylaminosulfurtrifluoride (DAST) in dichloromethane) using iPrMgCl to generate the arylmetal compound and trapping this intermediate with trimethyl borate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10]COC.FC1C=CC2[B:22](O)[O:21]CC=2C=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[CH2:9][O:10][B:22]([OH:21])[C:2]=2[CH:7]=1
Reactant: COCOCc1ccc(F)cc1Br
Reactant: OB1OCc2cc(F)ccc21
Product: OB1OCc2ccc(F)cc21

Procedure:
This compound was made from 18m in the same manner as compound 19b: 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.29 (td, J=9.0, 2.7 Hz, 1H), 7.41-7.46 (m, 2H), 9.29 (s, 1H); ESI-MS m/z 151 (M−H)−; HPLC purity 100%; Anal (C7H6BFO2) C, H.