Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][OH:16])[CH:8]=2)[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:1][C:2]1([CH3:22])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][O:16][C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=3)[CH:8]=2)[O:3]1
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Yield: 76.4 %

Procedure:
0.5 g of (RS)-2-(2,2,4,4-tetramethyl-chroman-6-yl)-heptanol dissolved in 35 ml THF were treated with 480 mg of triphenylphosphine, 275 mg of methyl 4-hydroxybenzoate and 0.28 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 100 ml of ether and washed with two portions of 30 ml of water and one portion of 30 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes), giving 550 mg of (RS)-methyl 4-[2-(2,2,4,4-tetramethyl-chroman-6-yl)-heptyloxy]-benzoate as a pale yellow oil. 1H NMR (CDCl3): 7.95 (d, J=8.8 Hz, 2H), 7.10 (d, J=2.2 Hz, 1H), 6.94 (dd, J=8.3, 2.2 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.3 Hz, 1H), 4.20-4.00 (m, 2H), 3.87 (s, 3H), 3.05-2.90 (m, 1H), 1.95-1.85 (m, 1H), 1.82 (s, 2H), 1.70-1.60 (m, 1H), 1.34 (s, 6H), 1.33 (s, 3H), 1.32 (s, 3H), 1.30-1.20 (m, 6H), 0.90-0.80 (m, 3H).
Reaction SMILES: C([Li])CCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=1.[C:30](=[O:32])=[O:31]>O1CCCC1>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([CH3:29])=[CH:27][C:28]=1[C:30]([OH:32])=[O:31]
Reactant: O=C=O
Reactant: Cc1ccc(Cl)nc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cnc(Cl)c(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2.5M solution of butyllithium in hexane (9.4 mL, 23.5 mmol) was added to tetrahydrofuran (50 mL) and the mixture cooled to −78° C. The mixture was treated with 2,2,6,6-tetramethylpiperidine (4.4 mL, 26.0 mmol) and stirred at −78° C. for 30 minutes. The reaction mixture was then treated with 2-chloro-5-methylpyridine (3.00 g, 23.5 mmol) and stirred at −78° C. for a further 2.5 hours. The reaction mixture was poured into a beaker of dry ice and warmed to room temperature on a water bath, then extracted into water. The mixture was acidified with 2M hydrochloric acid, extracted into ether and washed with water (×2) and brine. The solution was dried over magnesium sulphate to yield the title product as a yellow solid, 1.65 g.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[C:9]([CH3:21])=[C:10]([CH3:20])[C:11]([CH:18]=O)=[C:12]([CH:17]=2)[C:13](OC)=[O:14])=[CH:5][C:4]=1[F:24])#[N:2].[NH2:25][C@@H:26]1[C@@H:31]([OH:32])[CH2:30][CH2:29][O:28][CH2:27]1>C1COCC1>[C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[CH:17]=[C:12]3[C:11]([CH2:18][N:25]([C@@H:26]4[C@@H:31]([OH:32])[CH2:30][CH2:29][O:28][CH2:27]4)[C:13]3=[O:14])=[C:10]([CH3:20])[C:9]=2[CH3:21])=[CH:5][C:4]=1[F:24])#[N:2]
Reactant: COC(=O)c1cc(Cc2ccc(C#N)c(F)c2)c(C)c(C)c1C=O
Reactant: N[C@H]1COCC[C@@H]1O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(C#N)c(F)c2)cc2c(c1C)CN([C@H]1COCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of methyl 5-(4-cyano-3-fluorobenzyl)-2-formyl-3,4-dimethylbenzoate (0.25 g) in THF (5.00 mL) was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.09 g), and the mixture was stirred overnight at room temperature under argon atmosphere. The reaction mixture was concentrated, and the residue was diluted with acetic acid (5.00 mL). Then, sodium triacetoxyborohydride (0.24 g) was added thereto and the mixture was stirred at room temperature for 2 hr under argon atmosphere. To the reaction mixture was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, methanol/ethyl acetate) to give the title compound (0.16 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39].O>CN(C=O)C>[CH2:1]([N:8]([CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[O:11][Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=[N+]([O-])c1cccc([C@@H](O)CN(CCOCc2ccccc2)Cc2ccccc2)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H](CN(CCOCc1ccccc1)Cc1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-(Benzyl(2-(benzyloxy)ethyl)amino)-1-(3-nitrophenyl)ethanol (30.371 g) which can be prepared according to the method described in Reference example 57, etc. and imidazole (6.1318 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) were dissolved in dehydrated DMF (150 mL), added with chlorotriethylsilane (15.1 mL; manufactured by Shin-Etsu Chemical Co., Ltd.), followed by stirring overnight at room temperature. The reaction solution was poured to water and extracted twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over magnesium sulfate. After concentrating under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=100:0→87:13) to obtain the title compound (36.655 g).
Reaction SMILES: C=O.[C:3](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:21]([O:28][C:29]1[CH:53]=[CH:52][C:51]([CH:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][C:30]=1[C:31]([NH:33][C:34]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([O:28][C:29]1[CH:53]=[CH:52][C:51]([CH:54]2[CH2:55][CH2:56][N:57]([CH3:3])[CH2:58][CH2:59]2)=[CH:50][C:30]=1[C:31]([NH:33][C:34]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37])=[O:32])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCNCC2)ccc1OCc1ccccc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 37% formaldehyde aqueous solution (6.3 μL), acetic acid (0.022 mL), and sodium triacetoxyborohydride (0.10 g) were sequentially added to a tetrahydrofuran (3.0 mL) solution of methyl 2-(2-(benzyloxy)-5-(piperidin-4-yl)benzamido)-4-phenylbenzoate (0.10 g), followed by stirring at room temperature for 3 hours and 30 minutes. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 98-90% chloroform/methanol] to obtain 0.086 g of methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:21]=[C:22](CCN)[CH:23]=[CH:24][CH:25]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:23]=[CH:22][CH:21]=1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Reactant: COc1cccc(CCN)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(CCNC(=S)Nc2nc3ccccc3[nH]2)c1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(3-methoxyphenyl)ethylamine (0.78 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 1.2 g (73%) of the titled product as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[NH:6])[NH2:5].C(N(CC)CC)C.[CH3:18][CH:19]([C:25](=O)[CH3:26])[C:20](OCC)=[O:21]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[N:5]=[C:20]([OH:21])[C:19]([CH3:18])=[C:25]([CH3:26])[N:6]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: N=C(N)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(-c2ccccc2Cl)nc(O)c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To 2-chlorobenzimidamide (34.07 g, 220 mmol) and triethylamine (44.50 g, 440 mmol) in ethanol (750 mL) was added ethyl 2-methyl-3-oxobutanoate (38.13 g, 264 mmol). The reaction was heated at 90° C. for 4 h. A further portion (6.36 g) of the ester was added and the reaction was stirred for 3 h. The reaction was concentrated to around 500 mL and stood overnight. Precipitation of the desired pyrimidinol (22.7 g) occurred. The mother liquors were concentrated and DCM and 1M HCl were added. The aqueous layer was extracted 7 times with DCM to give further crops of the desired product (total: 28.9 g, 56%) on concentration as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]2[CH2:27][C@H:26]3[C@H:23]([CH2:24][N:25]3C(OC(C)(C)C)=O)[CH2:22]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[ClH:35]>C(O)C.C(O)(C)C>[ClH:35].[C@H:23]12[CH2:24][NH:25][C@H:26]1[CH2:27][N:21]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=1[N:13]=[CH:12][C:11]([S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)(=[O:10])=[O:9])=[CH:20]3)[CH2:22]2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cccc4cc(S(=O)(=O)c5cccc(F)c5)cnc34)C[C@@H]21
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3C[C@H]4CN[C@H]4C3)cccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.150 g of (1S,5R)-tert-butyl 3-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate from Example 27 were dissolved in 5 ml of ethanol. 5 mL 5N HCl in isopropanol was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the residue was dissolved in small amounts of ethanol and precipitated with addition of diethyl ether. Recrystallization from ethanol/isopropanol (2:1) yielded 0.0275 g of the product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11](=[NH:13])[NH2:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23](=O)[C:24]([F:27])([F:26])[F:25]>CC#N.CCOC(C)=O>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11]2[NH:12][CH:22]=[C:23]([C:24]([F:27])([F:26])[F:25])[N:13]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(=N)N)CC1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2nc(C(F)(F)F)c[nH]2)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 5.3 %

Procedure:
To a suspension of (1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester (488 mg, 2.45 mmol) and K2CO3 (676 mg, 4.90 mmol) in MeCN (14 mL) at 85° C. was added a solution of 3-Bromo-1,1,1-trifluoro-propan-2-one (400 mg, 2.09 mmol) in MeCN (10 mL) drop wise over 30 min. The dilute reaction mixture (0.1 N) was stirred at 85° C. for 3 h before cooled to room temperature. Diluted with EtOAc and extracted three times, washed with water and Brine. Dried over MgSO4, filtered and concentrated down in vacuo. The mixture was purified by reverse phase preparation HPLC to give 32 mg of [1-(4-Trifluoromethyl-1H-imidazol-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester as a yellow solid, m/z 292.42 [M+1]+
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:15])([F:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[BH4-].[Na+].Cl>CCO.O>[F:14][C:5]([F:15])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(F)(F)CCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCC(F)(F)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
2,2-Difluoro-4-phenyl-butyric acid ethyl ester (0.23 g, 1 mmol) was dissolved in EtOH (4 ml) and treated with NaBH4 (39.4 mg, 1 mmol). After 30 minutes stirring at room temperature, the reaction mixture was cooled to 0° C., acidified to pH 1 with 1N HCl (2 ml), diluted with H2O (10 ml). The aqueous phase was extracted with ether (3 times). The combined organic phases were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed over silica gel (hexane-ethylacetate 99:1) to provide 2,2-difluoro-4-phenyl-butan-1-ol (0.11 g, 58%) as light yellow oil, MS: m/e=186.1 (M+).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:15]([O-])=[CH:14][C:13]=2[N:12]=[CH:11]1)[CH:7]([CH3:9])[CH3:8].[OH-].[NH4+]>CN(C)C=O>[Cl:3][C:14]1[C:13]2[N:12]=[CH:11][N:10]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To 40 ml of cold N,N-dimethylformamide (10°-20° C.) was added slowly 5.9 g (0.0385 mole) of phosphorus oxychloride with swirling, the temperature of the mixture being maintained at 10-20° C. 1-Isobutyl-1H-imidazo[4,5-c]quinolin-5-oxide (6.2 g; 0.0257 mole) from Step (C) above was added gradually with swirling and cooling. After addition was complete, the solution was allowed to stand at room temperature for about 30 minutes with occasional swirling. The solution was then heated on a steam bath for thirty minutes. After allowing it to cool, the solution was poured onto ice with stirring, and the resulting mixture was brought to pH 8-9 with concentrated ammonium hydroxide. The resulting off-white solid was filtered, washed with water, rinsed with ether, and dried to provide 6.0 g of crude 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline having a m.p. of 135°-138° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[OH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[C:16]3[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]3)[C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=3)=[CH:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(CO)cc3)cc2)CC(C)(C)C1
Temperature: 160 °C
Yield: 75 %

Procedure:
A sealed tube containing 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.20 g, 0.50 mmol), 4-(hydroxymethyl)phenyl boronic acid (0.16 g, 1.0 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), 2 M Na2CO3 (4 mL) and DME (4 mL) was heated at 160° C. for 25 min. Cooled to room temperature, the mixture was extracted with EtOAc. The EtOAc extracts were combined and washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as dark brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 35% EtOAc in hexanes to give 0.16 g (75%) of the title compound (246) as pale yellow solid. mp 222-223° C. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (s, 12H), 1.25 (s, 2H), 1.92 (s, 2H), 1.93 (s, 2H), 4.50 (d, J=5.7 Hz, 2H), 5.17 (t, J=5.7 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 9.26 (s, 1H). LCMS (ESI): m/z 425 (M−H)−.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: OB(O)c1ccncc1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 19) was reacted with pyridin-4-yl-boronic acid to give the title compound as colorless oil. MS: 500.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1.[ClH:21]>>[ClH:1].[ClH:21].[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][NH:11]2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Cl)c1
Agent: Cl
Product: Clc1cncc(OC[C@@H]2CCN2)c1
Yield: 80 %

Procedure:
The compound from step 39a (0.130 g, 0.44 mmol) was treated with saturated ethanolic HCl (5 mL) for 16 hr. The volatiles were removed in vacuo, and the dihydrochloride was recrystallized (EtOH/Et2O) to yield the title compound (0.094 g, 80%) as a white solid. mp 156-157° C. MS (DCI/NH3) m/e: 199 (M+H)+, 216 (M+NH4)+. 1H NMR (D2O, 300 MHz) δ: 8.41 (d, J=5.1 Hz, 1H), 8.39 (d, J=4.4 Hz, 1H), 7.94 (t, J=2.1 Hz, 1H), 5.01-4.93 (m, 1H), 4.50 (d, J=4.0 Hz, 2H), 4.20-4.03 (m, 2H), 2.69 (q, J=8.45 Hz, 2H). Anal. calc. for C9H13Cl3N2O·0.5H2O: C, 38.53; H, 5.03; N, 9.98 Found: C, 38.51; H, 5.16 N, 9.96. [α]D23 =-3.23° (c=0.16 in MeOH).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])#[N:41]>>[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:46])#[N:41]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3cccc(C#N)c3)CN2C1=O
Yield: 38.5 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 3-cyanobenzoyl chloride (87 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 47 mg (37%) of 18-(3-cyanobenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.1% pure (HPLC), MS m/z 696 (M−H)−, HRMS: calcd. 698.2860 and found 698.2849 (M+H)+, mp 151-153° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([OH:29])[CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([O:29][C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=2[C:13]([F:16])([F:15])[F:14])[CH:19]=1
Reactant: CCS(=O)(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(O)CCc1ccc(Cl)cc1O
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2CCC(=O)O)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of example 3 step viii) using the product from step i) and the product from example 35 step ii).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ncccc1Cl
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ncccc1Oc1ccc(Br)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A RBF was charged with 3-chloro-2-cyanopyridine (40 g, 289 mmol), 4-bromophenol (49.9 g, 289 mmol) and cesium carbonate (113 g, 346 mmol). The reactants were suspended in 50 mL of DMSO and allowed to stir at 85° C. overnight. The reaction was cooled to RT and 600 mL of water was added to it. The reaction was filtered and the solid washed with water, then air dried to provide 3-(4-bromophenoxy)-picolinonitrile as a tan solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N>C(O)C.[Pd].O>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:11]=2[CH2:12][NH2:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C(F)(F)F)cc1OCCN1CCOCC1
Agent: [Pd]
Agent: N
Solvent: CCO
Solvent: O
Product: NCc1ccc(C(F)(F)F)cc1OCCN1CCOCC1
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
To a solution of 2-(2-morpholin-4-ylethoxy)-4-(trifluoromethyl)benzonitrile (Description 124, 0.5 g, 1.67 mmol) in ethanol (30 ml) was added aqueous ammonia (33% aq soln, 5 ml) and a slurry of 10% Pd/C catalyst in water. The reaction was hydrogenated at 43 psi. After 45 min the reaction was complete. The catalyst was filtered off, the reaction condensed and the product azeotroped with toluene to give the desired amine (0.49 g, 96%).