Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([NH:12][C@H:13]([C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[O:11])[CH2:2]1.C([N:51](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N>CN(C=O)C.CO>[NH2:51][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][O:19][C:18]1[CH:26]=[CH:27][C:15]([CH2:14][C@H:13]([NH:12][C:10](=[O:11])[O:9][C@@H:3]2[C@H:4]3[C@H:5]([O:6][CH2:7][CH2:8]3)[O:1][CH2:2]2)[C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[CH:16][CH:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
A solution of 25 mg (0.037 mmol) of 4-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)butanoic acid and 19 μL (0.11 mmol) of N,N-diisopropylethylamine in 1 mL of anhydrous DMF was treated with 28 mg (0.074 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). The resulting solution was stirred at RT for 15 minutes and was then treated with 0.5 mL of 2M NH3 in MeOH. After 20 minutes TLC indicated the reaction to be complete. The solution was concentrated to dryness at reduced pressure and the residue subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 11 mg (44%) of the desired compound as a white powder. 1H NMR (CDCl3): 7.30 (d, 1H), 7.14 (s, 1H), 7.07 (d, 2H), 6.85 (d, 2H), 6.75 (d, 2H), 6.05 (s, 2H), 5.60 (d, 1H), 5.56-5.34 (m, 2H), 4.97 (m, 2H), 3.94 (m, 3H), 3.78 (m, 3H), 3.66 (m, 2H), 3.09 (m, 1H), 3.00-2.64 (m, 7H), 2.40 (t, 2H), 2.08 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.48 (m, 1H), 0.90 (d, 3H), 0.82 (d, 3H). MS(ESI): 678(M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:41])(=[O:40])[NH2:39])=[CH:28][C:27]=2[F:42])[C:7](=[O:24])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:11]=2[Cl:23])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>CCOCC>[CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:40])(=[O:41])[NH:39][C:46](=[O:47])[C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[Cl:43])=[CH:28][C:27]=2[F:42])[C:7](=[O:24])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:11]=2[Cl:23])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(N)(=O)=O)cc3F)c2=O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3F)c2=O)c1
Yield: 42 %

Procedure:
By the procedure of Example 51, 5-n-butyl-2-[5-(N-n-butylcarbamoyl)-2-chlorophenyl]-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step G) was reacted with 2-chlorobenzoic acid (2 equivalents), CDI (2 equiv), and DBU (2 equiv). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) followed by trituration with ether afforded a 42% yield of the title compound as a white solid, mp 218°-220° C.; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 753 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1/[N+:8](/[O-:11])=[N:9]/[O-:10].[Na+].Br[CH2:14][CH2:15][CH2:16][CH3:17]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:14]([O:10]/[N:9]=[N+:8](/[N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH2:2][OH:1])\[O-:11])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCBr
Reactant: [O-]/N=[N+](\[O-])N1CCC[C@H]1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCO/N=[N+](\[O-])N1CCC[C@H]1CO
Temperature: 65 °C

Procedure:
To a suspension of sodium (2S)-2-(hydroxymethyl)-1-[(Z)-oxido-NNO-azoxy]pyrrolidine (447 mg, 2.44 mmol) and tetrabutylammonium iodide (90 mg, 0.24 mmol) in DMF (10 mL) was added 1-bromobutane (315 μL, 2.93 mmol). The resulting suspension was allowed to stir at 65° C. over night. After cooling to rt, the mixture was partitioned between Et2O (50 mL) and brine (50 mL). The organic layer was separated and washed with brine (2×50 mL), dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Biotage 40+M) using 35-50% ethyl acetate in hexanes gradient, affording the title product: 1H NMR (500 MHz, CDCl3) δ 4.21 (t, J=6.7 Hz, 2H), 4.07-4.02 (m, 1H), 3.75 (dd, J=3.6, 11.3 Hz, 1H), 3.63-3.54 (m, 3H), 3.06 (br. s, 1H), 2.12-2.04 (m, 1H), 1.98-1.91 (m, 2H), 1.81-1.71 (m, 3H), 1.47-1.39 (m, 2H), 0.95 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[C:25]([CH3:33])=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[C:25]([CH3:33])=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:20])[CH3:21])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: Cc1c(Cl)cccc1B(O)O
Product: Cc1c(Cl)cccc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-chloro-2-methylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(3′-chloro-2-fluoro-2′-methylbiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (5 mg, 4%): m/z (ES+) 413 [MH+].
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[NH:9][C:10](=[O:19])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8]2[NH:9][C:10](=[O:19])[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cnc(Nc2ccc(-c3ccccc3)cc2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cnc(Nc2ccc(-c3ccccc3)cc2)[nH]c1=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
A mixture of ethyl 2-((1,1′-biphenyl)-4-ylamino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (100 mg, 0.298 mmol), sodium hydroxide (1M, aq), and methanol was stirred at 70° C. for 2 hours and for 40° C. overnight. The ester did not dissolve in 3 mL methanol. The ester was then put in 3 mL dioxane and heated to 103° C. for 4 hours with an additional 1 mL of NaOH added. The reaction mixture was then heated at 40° C. overnight. After the overnight heating, the reaction mixture was cooled and the solvent removed. The reaction mixture was diluted with water, and the pH was adjusted to about 3.0. The reaction mixture was filtered to obtain the end product. 1H-NMR confirmed the product (55 mg, 60.0% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:20])[S:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[N:6][CH:7]=1.[BH4-].[K+].Cl>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:20])[S:10][CH2:11][CH:12]([OH:13])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:6][CH:7]=1
Reactant: O=C(CSC(=S)Nc1ccc(Cl)cn1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OC(CSC(=S)Nc1ccc(Cl)cn1)c1ccccc1
Reaction time: 0.75 h
Yield: 58.5 %

Procedure:
The procedure of Example 8 is followed, but a suspension of phenacyl 5-chloropyrid-2-yldithiocarbamate (23.1 g) in acetonitrile (240 cc) and a solution of potassium borohydride (3.9 g) in distilled water (60 cc) are used as the starting materials at between 20° and 28° C. The reaction is allowed to proceed for 45 minutes at 25° C. After adding a 3 N aqueous solution of hydrochloric acid (23.8 cc), filtering off the crystals, washing them with ice-cooled acetonitrile (15 cc) and then three times with distilled water (180 cc in total) and drying them under reduced pressure (0.2 mm Hg) at 40° C., 2-hydroxy-2-phenylethyl 5-chloropyrid-2-yldithiocarbamate (13.6 g), which melts at 116° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=3[CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][NH:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[CH:30]=[N:29][N:28]2[C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Nc1cccc2c1cnn2-c1ccc(F)cc1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane and 1-(4-fluorophenyl)-1H-indazol-4-amine (Intermediate 2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:20])[CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl-].[Li+]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:20])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)c1ccccc1Br
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC(C)c1ccccc1Br
Temperature: 150 °C
Yield: 61.5 %

Procedure:
To a solution of 52.96 g the crude ethyl 3-(2-bromophenyl)-2-ethoxycarbonyl-3-methylpropionate (168.13 mmole) in dimethylsulfoxide (250 ml) and water (3 ml) was added 14 g of lithium chloride, and the mixture was heated at 150° C. for 2.5 hours. After cooling the mixture, dimethylsulfoxide was removed under reduced pressure, and the residue was diluted with an aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase was washed with an aqueous ammonium chloride solution and dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residual concentrate was further purified by distillation to give 28.04 g of ethyl 3-(2-bromophenyl)-3-methylpropionate (65%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:34][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[NH:30][CH:31]=[CH:32][N:33]=5)[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.C(N(CC)CC)C.[C:43]([N:47]=C=O)([CH3:46])([CH3:45])[CH3:44]>CO>[C:43]([NH:47][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:34][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[NH:33][CH:32]=[CH:31][N:30]=5)[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ncc[nH]5)c4)ncnc3[nH]2)CC1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ncc[nH]5)c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into the solution of 4-{4-[3-(1H-imidazol-2-yl)-phenylamino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (59.4 mg, 0.118 mmol) in methanol (1.0 mL) was added HCl in methanol (9 M, 11.0 mL). The above mixture was stirred at rt for 4 h. After that time, the mixture was concentrated in vacuo and was then suspended in DMF (2 mL). Into the above suspension were added triethylamine (159 μL, 1.18 mmol) and tert-butyl isocyanate (14.8 μL, 0.130 mmol). The above mixture was stirred at rt under an atmosphere of N2 for 1 h. After that time, the mixture was concentrated in vacuo to obtain brown oil that was purified by HPLC to yield the title compound. 1H NMR (CD3OD, 400 MHz): δ=1.35 (s, 9H), 2.55 (brs, 2H), 3.59 (t, 2H, J=4.2 Hz), 4.05 (brs, 2H), 6.28 (brs, 1H), 6.65 (s, 1H), 7.13 (d, 2H, J=1.2 Hz), 7.42 (t, 1H, J=8.4 Hz), 7.55 (dd, 1H, J=0.8 & 7.6 Hz), 7.74 (dd, 1H, J=0.8 & 8.0 Hz), 7.75-8.19 (m, 1H), 8.23 (d, 1H, J=1.2 Hz). MS (ES+): m/z 457.12 (100) [MH+]. HPLC: tR=2.00 min (ZQ2000, polar—5 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N:10](C)C)[C:5]([N+]([O-])=O)=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])=O.[NH4+]>[Pd].CO.C(Cl)Cl>[N:16]1([C:4]2[CH:5]=[C:6]3[CH:8]=[CH:9][NH:10][C:7]3=[CH:2][N:3]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: CN(C)C=Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: c1cc2cc(N3CCOCC3)ncc2[nH]1
Temperature: 65 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A solution of 450 mg (2 mmol) of [2-(2-chloro-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine in a 20 mL of mixed solvent of MeOH-CH2Cl2 (1:1) was treated with 3 mL of morpholine. The reaction mixture was stirred at 65° C. for 8 h. Volatiles were then removed. CH2Cl2 (100 mL) and H2O (30 mL) were added. The organic layer was separated and washed with H2O (30 mL), brine (30 mL), dried over Na2SO4, and concentrated. The red powder was treated with 4.0 g (63 mmol, 32 eq) of ammonium formate and 10% Pd—C (120 mg). The reaction mixture was stirred at 65° C. for 30 min. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. Column chromatography (silica, 5% MeOH/CH2Cl2) provided 210 mg (52% for 2 steps) of 5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridine as a yellow solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.40. MS (electrospray): exact mass calculated for C11H13N3O, 203.11; m/z found, 204.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:27][CH2:26]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:27][CH2:26]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[OH:9]
Reactant: COCCOCOc1c(OC)cc(C=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1O
Yield: 65.6 %

Procedure:
To a solution of 276 mg (0.456 mmol) of the amide compound in methanol (6 ml) was added 79 mg (0.415 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 20 minutes. Water was added to the reaction mixture, which was adjusted to a pH value of 11 by the addition of an aqueous solution of sodium carbonate and then extracted with ethyl acetate. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (20:1), to give 162 mg (0.299 mmol) of 1-[2-[3-(3,5-dimethoxy-4-hydroxyphenyl)-2-propenoyl]aminoethyl]-4-benzhydroxypiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]2[CH2:14][C:13](=[O:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:11]2[CH3:23])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]2[C@@H:14]([CH3:25])[C:13](=[O:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:11]2[CH3:23])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc([C@@H]2CC(=O)N(C(=O)OC(C)(C)C)[C@H]2C)cc1Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2[C@@H](C)C(=O)N(C(=O)OC(C)(C)C)[C@H]2C)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a solution of (2S,3S)-tert-butyl 3-(3-chloro-4-methoxyphenyl)-2-methyl-5-oxopyrrolidine-1-carboxylate (intermediate J1, 0.85 g, 2.5 mmol) in THF (20 mL) was added LiHMDS (2.5 mL, 2.5 mmol) at −78° C. After 30 mins, MeI (0.187 mL, 3.00 mmol) was added. The reaction mixture was stirred at −78° C. for 1.5 hr. It was warmed up to 0° C. for 30 min and then warmed up to RT for 30 min. The reaction mixture was quenched with 2 mL of AcOH and 100 mL of NH4Cl. The product was extracted with EtOAc (3×100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluted with 30% EtOAc/Hexane to give (2S,3S,4R)-tert-butyl 3-(3-chloro-4-methoxyphenyl)-2,4-dimethyl-5-oxopyrrolidine-1-carboxylate (intermediate J2, 0.55 g, yield of 62%) as off-white solid. 1H NMR (500 MHz, CDCl3): δ 7.29 (s, 1H), 7.14 (d, 1H), 6.95 (d, 1H), 3.93 (s, 3H), 3.91 (m, 1H), 2.58 (m, 1H), 2.40 (m, 1H), 1.59 (s, 9H), 1.38 (d, 3H), 1.17 (d, 3H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1.[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:29]=2)[C:24](F)=[N:25][CH:26]=1.Cl>C1COCC1.CO>[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[CH2:45][C:46]3[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=3)[N:29]=2)[C:24]([NH:11][C:12]2[CH:17]=[N:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:25][CH:26]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 2 h
Yield: 47.6 %

Procedure:
LiHMDS (1 M in THF, 1250 μL, 1.250 mmol) was added to a solution of 5-amino-2-methoxypyridine (123 mg, 0.990 mmol) and 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (190 mg, 0.396 mmol) in THF (5 mL) under nitrogen at rt. A dark orange mixture formed. After 2 h, HCl (5N, 0.3 mL) was added. The mixture was partitioned between EtOAc-water (10 mL each). The aqueous layer was extracted 3× with EtOAc. The combined organic layers were washed with water 3×, NaHCO3 (satd), dried over MgSO4, and concentrated. The residue was purified on silica (10-80% EtOAc in hexane) to give a yellow oil which, upon trituration with MeOH, resulted in a yellow solid (110 mg). LCMS (ES, pos.): calcd for C31H30ClN7O3: 583.2. found: 584.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.64 (s, 1H); 8.73 (d, J=2.74 Hz, 1H); 8.25 (d, J=2.54 Hz, 1H); 8.19 (d, J=2.74 Hz, 1H); 7.83 (dd, J=9.00, 2.74 Hz, 1H); 7.19 (dd, J=16.43, 8.61 Hz, 4H); 6.78-6.92 (m, 4H); 6.70 (d, J=8.80 Hz, 1H); 4.86 (s, 2H); 4.81 (s, 2H); 3.92 (s, 3H); 3.80 (d, J=9.19 Hz, 6H); 2.57 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C@@H:21]1[CH2:23][C@H:22]1[CH:24]([NH:26][O:27][CH3:28])[CH3:25].C1N2CCN(CC2)C1>C(#N)C>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C@@H:21]1[CH2:23][C@H:22]1[CH:24]([N:26]([O:27][CH3:28])[C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:25]
Reactant: CONC(C)[C@@H]1C[C@H]1c1ccc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (80 mg; 0.41 mmol) in acetonitrile (1 ml) was added dropwise to a stirred mixture of trans-N-{1-[2-(2,4-dichlorophenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine diastereomere A (88 mg; 0.34 mmol), prepared as described in example P13 and DABCO (54 mg; 0.48 mmol) in acetonitrile (1 ml) at ambient temperature. The reaction mixture was stirred for 16 hours at ambient temperature. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (10 g) (eluent: n-hexane/ethyl acetate 1:1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:23]=[CH:24][CH:25]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 74.2 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 1,4-dibromobenzene (11.8 g, 50 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.02 g (74%) of the product 4-(3-bromo-phenyl)-1H-indole as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:30][NH2:31])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH2:30][C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:28])([F:29])[CH:25]([F:27])[F:26])=[C:16]([Cl:15])[CH:17]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: NCc1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Product: O=C1c2ccnc(Cl)c2CN1Cc1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (1.01 g, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (917 mg, 3.29 mmol, Step-1 of Intermediate-1) and (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine (800 mg, 2.93 mmol, Amine-87) in a similar manner to Intermediate-2.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[C:18]1([CH3:28])[C:19]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:28])(=[O:26])=[O:25])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)N1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and o-toluenesulfonyl chloride were used for a similar reaction and treatment as Example 169, and the title compound was obtained as a white crystalline powder.