Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]C1C=CC(C2C=CC=CC=2)=CC=1C#N.N1C=CC=CC=1.[C:22](Cl)(Cl)=[O:23].[C:26]1([C:32]2[CH:33]=[CH:34][C:35]3[O:39][C:38]([CH2:40][OH:41])=[CH:37][C:36]=3[CH:42]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:26]1([C:32]2[CH:33]=[CH:34][C:35]3[O:39][C:38]([CH2:40][O:41][C:22](=[O:23])[NH2:1])=[CH:37][C:36]=3[CH:42]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N#Cc1cc(-c2ccccc2)ccc1N
Reactant: O=C(Cl)Cl
Reactant: OCc1cc2cc(-c3ccccc3)ccc2o1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 90 °C

Procedure:
To a solution of 4-amino-biphenyl-3-carbonitrile (1.2 g, 6.33 mmol) and pyridine (2 mL, 25.3 mmol) was added 20% phosgene in toluene (5.7 mL(10.8 mmol) and the mixture was heated to 90° C. for 2 hrs. The mixture was filtered and the filtrate was concentrated to dryness. The crude material was dissolved in THF, and (5-phenyl-benzofuran-2-yl)-methanol (0.52 g, 2.3 mmol) and triethylamine (0.70 g, 6.9 mmol) were added. The mixture was heated at 50° C. for 15 h. The solvent was evaporated to dryness. Purification by chromatography gave 0.78 g of 3-cyano-biphenyl-4-yl)-carbamic acid-5-phenyl-benzofuran-2-yl-methyl ester as a light yellow solid.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12](O)=[C:11](O)[CH:10]=1)=[O:8])([CH3:4])[CH3:3].C(Cl)(=O)CCCCCCCCC=CCC=CCCCC>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: CCCCC=CCC=CCCCCCCCCC(=O)Cl
Agent: Cl
Product: CC(C)NCC(=O)c1ccccc1

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 10,13-octadecadienoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(10,13-octadec a dienoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is reduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained 3-hydroxy-4-(10,13-octadecadienoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate. By catalytic hydrogenation of 3-hydroxy-4-(10,13-octadienoyloxy)phenyl isopropylaminomethyl ketone methanesulfonate, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(octadecanoyloxy)-alpha-(isopropylaminomethyl)benzyl methanesulfonate.
Reaction SMILES: [C:1]([C:3]1[N:4]([CH3:9])[CH:5]=[C:6]([NH2:8])[CH:7]=1)#[N:2].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl.Cl>[CH3:17][S:18]([NH:8][C:6]1[CH:7]=[C:3]([C:1]#[N:2])[N:4]([CH3:9])[CH:5]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(N)cc1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(NS(C)(=O)=O)cc1C#N
Temperature: 0 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
Compound 22-6 (310 mg) was dissolved in dichloromethane (30 ml) and cooled to 0° C. To the solution were added triethylamine (430 μl) and methanesulfonyl chloride (210 μl) successively through an injector, followed by stirring at room temperature for 24 hours. The resulting mixture was diluted with 1 N aqueous hydrochloric acid, and an organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by column-chromatography (ethyl aceate/hexane=1/1) to yield the compound 22-7 (400 mg, 78.5%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]3)[C:14]3[CH:13]=[C:12]([Cl:23])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[Cl:23][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C:15]4([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:30]1[C:25]([F:24])=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:7][CH:6]=3
Reactant: NC1=NC2(COCC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1cccnc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC1=NC2(COCC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 90 °C

Procedure:
A vial was charged with (E)-7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine (280.9 mg, 0.712 mmol), 2-fluoropyridin-3-ylboronic acid (150 mg, 1.068 mmol), Pd(AmPhos)2Cl2 (25.2 mg, 0.036 mmol), and potassium phosphate (453 mg, 2.135 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (2669 μL) and water (890 μL) were added in sequence. The vial was sealed and heated in a microwave reactor for 20 min at 90° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The crude product was purified by chromatography on silica gel (0-10% MeOH/DCM) to give (E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH:4]=[N:3]1.S(Cl)([Cl:31])=O>C(Cl)Cl>[ClH:31].[ClH:31].[Cl:31][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:15]([N:12]3[CH2:13][CH2:14][N:9]([CH2:8][C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:6]=4[CH3:7])[CH2:10][CH2:11]3)=[N:16][CH:17]=[CH:18][N:19]=2)=[CH:22][CH:23]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CO)cc3)CC2)cnn1C
Solvent: ClCCl
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CCl)cc3)CC2)cnn1C
Product: Cl
Yield: 100 %

Procedure:
Dissolve {4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenyl}-methanol (1.00 g, 2.64 mmol) in DCM (60 mL). Add thionyl chloride (6 mL) and stir at room temperature for 2 hr. Concentrate in vacuo to give 3′-(4-chloromethyl-phenyl)-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride as a yellow solid (1.20 g, 100%). MS (ES): m/z=397 [M+H]+
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14](=[O:32])[C:15]#[C:16][C:17]2[CH:22]=[C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[C:20]([O:28][CH3:29])=[CH:19][C:18]=2[O:30][CH3:31])=[CH:8][C:7]=1[O:33][CH3:34].[OH-].[Na+]>C1COCC1.CO.Cl.C(OC(C)C)(=O)C>[CH3:31][O:30][C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:22][C:17]=1[C:16]#[C:15][C:14]([C:9]1[CH:10]=[C:11]([O:12][CH3:13])[C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]([O:33][CH3:34])[CH:8]=1)=[O:32]
Reactant: COC(=O)COc1c(OC)cc(C(=O)C#Cc2cc(-c3cccs3)c(OC)cc2OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)OC(C)C
Product: COc1cc(OC)c(-c2cccs2)cc1C#CC(=O)c1cc(OC)c(OCC(=O)O)c(OC)c1
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
Ex-4: {4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-2,6-dimethoxy-phenoxy}-acetic acid methyl ester (500 mg, 1.01 mmol) from Ex-3 was dissolved in THF (5 mL) and methanol (5 mL). Sodium hydroxide solution (1 N, 5 mL) was added and the resulting solution was stirred at room termperature under nitrogen for 30 min. The reaction-was then diluted with 1 N HCl and isopropyl acetate and the layers cut. The organic phase was concentrated to dryness under reduced pressure, diluted with a small amount of ethanol and filtered to afford 350 mg (73%) of the desired {4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-2,6-dimethoxy-phenoxy}-acetic acid as a yellow solid, m.p. 192–194° C. 1H-NMR (300 MHz, d6-DMSO) δ 7.95 (s, 1H), 7.56 (dd, 1H, J=3.5 and 1.4 Hz), 7.49 (m, 1H), 7.47 (s, 2H), 7.07 (dd, 1H, J=5.1 and 3.5 Hz), 6.86 (s, 1H), 4.61 (s, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.84 (s, 6H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[F:17])([CH3:4])([CH3:3])[CH3:2].C[Li].[CH3:22][Si](C)(C)Cl>C1COCC1.C(OCC)C>[C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:16]=[CH:15][C:11]([C:12](=[O:14])[CH3:22])=[CH:10][C:9]=1[F:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)O)cc1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(C(C)(C)O[SiH2]C(C)(C)C)c(F)c1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A solution of 540 mg (1.90 mmol) 4-(tert-butyl-dimethyl-silanyloxymethyl)-3-fluoro-benzoic acid (preparation 16d) in 20 mL THF is degassed and cooled to −30° C. 3.56 mL (5.67 mmol) 1.6 M methyl-lithium solution in diethylether is added, the mixture is stirred 2 h at −30° C. and 3.12 mL (24.7 mmol) trimethyl-chloro-silane are added. The mixture is stirred 2 min and is transferred to a pH 7 buffer solution (0° C.). The aqueous phase is extracted with EtOAc and diethylether. The combined organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified by silica gel column chromatography with PE/EtOAc (9:1) as eluent.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1.Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=2)[N:32]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46]C)[N:41]=2)[C:30]=1[CH3:48]>CN1C(=O)CCC1>[F:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:30]([CH3:48])[C:31]([C:40]3[N:41]=[C:42]([OH:46])[CH:43]=[CH:44][CH:45]=3)=[N:32]2)=[CH:37][CH:36]=1
Reactant: COc1cccc(-c2nc3cc(F)ccc3c(Cl)c2C)n1
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2cccc(O)n2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-morpholino-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (87 mg, 0.32 mmol) (described herein), 4.0M hydrochloric acid in 1,4-dioxane (66 μL, 0.25 mmol), 4-chloro-7-fluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline (80 mg, 0.25 mmol) (described herein), and NMP (440 μL), and heating in a microwave at 150° C. for 180 min. Purification afforded 6-(7-fluoro-3-methyl-4-(6-(4-morpholinyl)-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)-2-quinolinyl)-2-pyridinol as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.65-7.85 (2H, m), 7.48-7.61 (1H, m), 7.27-7.32 (1H, m), 7.15 (1H, d, J=8.2 Hz), 6.78 (1H, d, J=6.7 Hz), 6.73 (1H, d, J=9.4 Hz), 6.37 (1H, dd, J=8.2, 2.3 Hz), 5.56 (1H, d, J=2.3 Hz), 3.98-4.09 (2H, m), 3.88-3.98 (2H, m), 3.62-3.78 (4H, m), 3.47-3.61 (2H, m), 2.84-3.03 (4H, m), 2.51 (3H, s), 2.09-2.24 (2H, m), 1.83-1.93 (1H, m), 1.71-1.83 (1H, m). Mass Spectrum (ESI) m/e=527 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)[CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]1=[O:19].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:43][C:44]([F:52])([F:51])[CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:48]3[CH2:49][CH2:50][CH:45]([C:44]([F:52])([F:51])[F:43])[CH2:46][CH2:47]3)=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][C:11]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:10]1=[O:19]
Reactant: FC(F)(F)C1CCNCC1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(CN3CCC4(CCCCC4)C3=O)c(Cl)c2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(CN3CCC4(CCCCC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Treat a solution of Example 4 (0.079 g, 0.18 mmol) in CH2Cl2 (8 mL) with 1,1′-carbonyldiimidazole (0.047 g, 0.29 mmol) and stir for 1 hour at room temperature under N2. Then, treat the reaction with 4-(trifluoromethyl)piperidine HCl (0.087 g, 0.46 mmol) and diisopropylethylamine (0.12 g, 0.92 mmol) and stir for 16 hours at room temperature under N2. Dilute the reaction with ethyl acetate and wash with 1N HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify on silica with a 0 to 10% methanol in CH2Cl2 gradient on silica gel and then isocratically with 50/50 ethyl acetate/hexanes gradient on silica gel to afford 0.067 g (64%) of the titled product. Rf=0.68 (9/1 CH2Cl2/methanol). MS (m/z): 567 (M+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:14][CH2:15][CH2:16][OH:17])[CH2:13][CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1>>[Si:1]([O:8][CH2:9][C:10]1([CH2:14][CH2:15][CH2:16][O:17][C:21]2[CH:22]=[CH:23][N:24]=[C:19]([Cl:18])[N:20]=2)[CH2:11][CH2:12][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)OCC1(CCCO)CCC1
Product: CC(C)(C)[Si](C)(C)OCC1(CCCOc2ccnc(Cl)n2)CCC1

Procedure:
The title compound was prepared from 3-[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]-1-propanol and 2,4-dichloropyrimidine using the same experimental procedure as in example 25a. 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=6 Hz, 1H), 6.59 (d, J=6 Hz, 1H), 4.33 (t, J=6 Hz, 2H), 3.44 (s, 2H), 1.81-1.51 (m, 8H), 1.21 (m, 2H), 0.84 (s, 9H), −0.002 (s, 6H). GC-MS m/z 371 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[CH:8]([C:11]([O:13]CC)=O)[C:9]#[N:10].[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1>C1(C)C(C)=CC=CC=1>[O:16]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[CH:8]([C:11](=[O:13])[NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:9]#[N:10]
Reactant: CCOC(=O)C(C#N)C(=O)c1cccn1C
Reactant: Nc1cccnc1
Solvent: Cc1ccccc1C
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1cccnc1
Temperature: 25 °C

Procedure:
The mixture of 1.1 g of 1-methyl-β-oxo-α-ethoxycarbonyl-2-pyrrolepropionitrile (U.S. Pat. No. 4,256,759), 1.2 g of 3-aminopyridine and 60 ml of xylene, is refluxed for 41/2 hours. After standing and cooling to room temperature overnight, the solution is filtered, evaporated and the residue is purified to yield β-oxo-α-(3-pyridylcarbamoyl)-β-(1-methyl-2-pyrrolyl)propionitrile.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[C:18](O)=[O:19])[O:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH3:23][C@H:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([CH3:30])[N:25]1[CH2:31][CH2:32][NH2:33]>>[NH3:9].[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[C:18]([NH:33][CH2:32][CH2:31][N:25]3[C@H:26]([CH3:30])[CH2:27][CH2:28][CH2:29][C@@H:24]3[CH3:23])=[O:19])[O:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: CC(=O)Oc1ccc2nc(N3CCCC[C@H]3C(=O)O)oc2c1
Product: CC(=O)Oc1ccc2nc(N3CCCC[C@H]3C(=O)NCCN3[C@H](C)CCC[C@@H]3C)oc2c1
Product: N

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-[6-(acetyloxy)-1,3-benzoxazol-2-yl]-2-piperidinecarboxylic acid [see Preparation 37] and 2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamine [J. Med. Chem, 27(5), (1984), 684-691]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0:0, changing to 99.4:1.4:0.2, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution, to afford 2-[(2S)-2-[(2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamino)carbonyl]-1-piperidinyl]-1,3-benzoxazol-6-yl acetate as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:23][CH2:24][CH2:25][NH2:26].[OH-].[Na+]>>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:23][CH2:24][CH2:25][N:26]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc(C2=NCCN2)c1
Temperature: 210 °C
Yield: 22.3 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (5.48 g, 36.0 mmol) and 1,2-diaminoethane monotosylate (9.85 g, 42.4 mmol) is heated at 210° C. for 7 hours. After cooling, the mixture is stirred with aqueous 2N sodium hydroxide and extracted with ethyl acetate. The precipitate which formed and is present in the aqueous layer is collected by filtration and dried in vacuo to give 1.3 g (22%) of 2-(3-hydroxyphenyl)imidazoline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([O:20][CH2:21][CH2:22]CO)[CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9][N:8]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30](F)[CH:29]=2)[CH:7]=1)=[O:5])[CH3:2].C(OC([C:42]1[C:48]2[NH:49][C:50]3[CH:51]=C(O)C=CC=3C=2C(C)(C)CN(C(=O)C2C=CC(F)=CC=2)C=1)=O)C.C(N(C(C)C)CC)(C)C.BrCCC[OH:81]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([O:20][CH2:21][CH2:22][N:49]4[CH2:48][CH2:42][O:81][CH2:51][CH2:50]4)[CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9][N:8]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: OCCCBr
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1cc(OCCCO)ccc21
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(O)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(OCCN3CCOCC3)ccc21
Temperature: 75 °C
Reaction time: 10 h

Procedure:
To prepare 3-(3,4-difluoro-benzoyl)-1,1-dimethyl-8-(3-hydroxy-propoxy)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester, a mixture of 3-(4-fluorobenzoyl)-8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]-indole-5-carboxylic acid ethyl ester (46 mg, 0.11 mmol), diisopropylethylamine (0.5 mL), and 3-bromo-1-propanol (1.4 mL) in dry acetonitrile (1 mL) was stirred at 75° C. for 10 hours. The solvent was removed in vacuo, and the residue was purified by preparative reverse-phase HPLC, which was then acylated in the manner described in Example 2A. 1HNMR (CDCl3): δ 10.51 (1H, s), 7.86 (1H, s), 7.82 (1H, d), 7.66-7.59 (2H, m), 7.15-7.09 (2H, m), 6.87 (1H, d), 6.74 (1H, m), 4.27-4.15 (4H, m), 4.09 (2H, brs), 3.90 (2H, m), 2.11-2.05 (2H, m), 1.60 (6H, s), 1.26-1.21 (3H, m). MS (ES): 481 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:32])([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:20][C:21]([CH3:32])([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: CC(C)(CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1ccc2cc(Br)ccc2c1=O
Temperature: 70 °C
Reaction time: 10 h
Yield: 45.7 %

Procedure:
A solution of 6-bromoisoquinolin-1(2H)-one (Example 1b, 1.5 g) dissolved in NMP (15 mL) was treated with potassium carbonate (1.48 g) and (3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane (2.26 g) under nitrogen. The resulting mixture was stirred at 70° C. for 10 h (low conversion), heating was continued at 100° C. for 10 h. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (300 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution with 20% diethyl ether in isohexane) to afford the subtitle compound (1.30 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][N:10]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[C:32]2[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=2[O:41][CH3:42])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+].[N-:63]=[N+:64]=[N-:65].[Na+]>C(Cl)Cl.O>[N:63]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][N:10]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=1[O:41][CH3:42])[C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[N+:64]=[N-:65]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(O)c1ccc(Cl)cc1)C(=O)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(N=[N+]=[N-])c1ccc(Cl)cc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of benzyl [2-(4-chlorophenyl)-2-hydroxyethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. (44 mg, 0.07 mmol) in CH2Cl2 (6 mL) was cooled to 0° C. and N,N diisopropylethylamine (63 lit, 0.36 mmol) was added followed by methanesulfonyl chloride (14 μL, 0.18 mmol). The reaction was stirred at 0° C. for 30 minutes and then poured into saturated NaHCO3 (15 mL). The resultant mixture was extracted with EtOAc (50 mL) and the organic layer was washed with brine (15 mL), dried over Na2SO4, filtered through a short plug of silica gel, and concentrated. The residue was redissolved in DMPU (6 mL) and sodium azide (12 mg, 0.18 mmol) was added. The reaction was stirred at room temperature for 24 hours and then poured into H2O (15 mL). The resultant mixture was extracted with EtOAc (50 mL) and the organic layer was washed with H2O (2×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 25% EtOAc/hexanes afforded benzyl [2-azido-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.66 (25% EtOAc/hexanes). LCMS=637.3 (M+1)+. 1H NMR (C6D6, 600 MHz, peaks doubled; rotamers and/or atropisomers present) δ 8.03-6.52 (m, 15 H), 5.00-5.08 (m, 2H), 4.76-4.12 (m, 3H), 3.28-2.86 (m, 5H), 2.77 (m, 1H), 1.23-1.18 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=1
Reactant: Cc1cc(C=O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(CO)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To the solution of 2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-carbaldehyde (3.0 g, 10.8 mmol) in MeOH (20 ml) is added NaBH4 (410 mg, 10.8 mmol). The mixture is stirred at room temperature for about 2 h, diluted with ethyl acetate, washed with 1N HCl, water, brine, dried over MgSO4, and concentrated to afford 2.5 g of the titled compound as a white solid. 1H-NMR.