Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:25](=[CH:26][CH:27]=1)[O:24][C:13]1([CH2:18][CH2:17][N:16]([C:19](=[O:23])[NH:20][CH2:21][CH3:22])[CH2:15][CH2:14]1)[CH2:12][C:11]2=[O:28]>O1CCOCC1.O>[CH2:21]([NH:20][C:19]([N:16]1[CH2:17][CH2:18][C:13]2([CH2:12][C:11](=[O:28])[C:10]3[C:25](=[CH:26][CH:27]=[C:8](/[CH:7]=[CH:6]/[C:5]([OH:29])=[O:4])[CH:9]=3)[O:24]2)[CH2:14][CH2:15]1)=[O:23])[CH3:22]
Reactant: CCNC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)OC)ccc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 M NaOH (0.148 ml, 0.591 mmol) was added to a solution of (E)-3-{1′-ethylcarbamoyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (220 mg, 0.591 mmol) in dioxane (3 ml) and water (3 ml) and the mixture was stirred at RT for 1 h. Further 4 M NaOH (0.073 ml) was added and the mixture was stirred for additional 2 h. Dioxane was removed under vacuum and the residue was acidified with 2 M HCl. The resulting precipitate was filtered to give (E)-3-{1′-ethylcarbamoyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid. The crude compound (163 mg) was dissolved in a mixture of DCM (3 ml) and TEA (0.126 ml, 0.91 mmol). EDC (174 mg, 0.91 mmol) and HOBT (61 mg, 0.45 mmol) were added at 0° C. and the resulting solution was stirred at RT for 1 h. NH2OTHP (66 mg, 0.56 mmol) was added and the mixture was stirred at RT for 4 h and then washed with 5% aqueous solution of NaHCO3. The organic phase was washed with water, dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.3) and the resulting (E)-3-{1′-ethylcarbamoyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide was dissolved in DCM and treated with 4 M HCl in dioxane for 2 h. The precipitate was filtered and washed with DCM to give the title compound as a pale yellow powder (118 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([N:7]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:8][CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].[Cl:20][C:21]1[CH:39]=[CH:38][C:24]2[O:25][C:26]3[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=3[CH2:28][N:29]([C:30]([NH:32][NH2:33])=[O:31])[C:23]=2[CH:22]=1>O>[CH3:19][C:2]([CH3:1])([O:4][C:5]([N:7]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:8][CH2:9][C:10]([NH:33][NH:32][C:30]([N:29]1[CH2:28][C:27]2[CH:34]=[CH:35][CH:36]=[CH:37][C:26]=2[O:25][C:24]2[CH:38]=[CH:39][C:21]([Cl:20])=[CH:22][C:23]1=2)=[O:31])=[O:12])=[O:6])[CH3:3]
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)Cc1cccs1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Cc1cccs1

Procedure:
1.1 mmol of 3-[[(1,1-dimethylethoxy)carbonyl](2-thienylmethyl)amino]-propanoic acid (16), prepared as described above in Example 16, was reacted with 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, in the same manner described in Example 9. The yield of product was 0.31 g (51%). Analysis calculated for C27H29N4O5SCl 0.25 H2O (M.W. 561.57): C, 57.29.; H, 5.34; N, 9.90. Found: C, 57.42; H, 5.40; N, 9.96.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]3[CH:8]=[CH:9][CH:10]=[CH:11][C:2]2=3)[CH2:15][CH2:14]1
Reactant: CN1CCC(=O)CC1
Reactant: c1ccc2c(c1)CCCCN2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(N2CCCCc3ccccc32)CC1
Reaction time: 15 h
Yield: 49.4 %

Procedure:
A solution of compound 2 (1.0 g, 6.79 mmol), N-methyl-4-piperidone (1.00 mL, 8.15 mmol) and acetic acid (0.96 mL, 16.98 mmol) in dry methanol (10 mL) was treated with NaCNBH3 (0.51 g, 8.15 mmol) at 0° C. The reaction mixture was brought to room temperature and stirred overnight (15 hours). The reaction was quenched with 2N NaOH (100 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic fractions were washed with brine (30 mL), dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (2.0 N NH3 in MeOH:CH2Cl2, 3:97) to give compound 3 (0.82 g, 49.4%) as a yellow oil. 1H-NMR (DMSO-d6) δ 1.55 (m, 4H), 1.74 (m, 4H), 1.96 (td, 2H, J=11.3, 2.6 Hz), 2.15 (s, 3H), 2.66 (m, 2H), 2.78 (m, 2H), 2.93 (m, 2H), 3.17 (m, 1H), 6.74 (t, 1H, J=7.3 Hz), 6.90 (d, 1H, J=8.2 Hz), 7.01 (m, 2H); EI-MS (m/z, %): 244 (M+, 24), 97 (100), 71 (37).
Reaction SMILES: C([C:5]1[C:10]([NH2:11])=[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13]2)[CH:8]=[CH:7][N:6]=1)(C)(C)C.[NH2:26][C:27]1[C:28]([C:34](O)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1>>[NH2:26][C:27]1[C:28]([C:34]([NH:11][C:10]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20])[CH2:13]2)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1
Reactant: CC(C)(C)c1nccc(N2CCC[C@@H](O[Si](C)(C)C(C)(C)C)C2)c1N
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, tert-butyl (R)-4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-amine was coupled to 3-amino-6-bromopicolinic acid yielding (R)-3-amino-6-bromo-N-(4-(3-(tert-butyldimethyl-silyloxy)piperidin-1-yl)pyridin-3-yl)picolinamide. LCMS (m/z): 506.2 (MH+); LC Rt=4.03 min.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[OH-].[K+]>O1CCOCC1.O>[F:1][C:2]([F:16])([F:17])[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)(c1ccc(C(=O)O)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (6.0 g, 24.2 mmol) and KOH (2.72 g, 48.4 mmol) in 1,4-dioxane (100 mL) and H2O (50 mL) was refluxed for 2 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to remove the 1,4-dioxane. The aqueous residue was acidified with 2N HCl and extracted with CH2Cl2. The extracts were washed with brine and dried. Flash chromatography of the residue, using 3:7 EtOAc-Hexane, gave 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid: 1H NMR (CDCl3) δ 11.0 (br, 1H), 7.95 (d, J=6.8 Hz, 2H), 7.71 (d, J=6.8 Hz, 2H), 6.73 (s, 1H), 1.71 (s, 3H); m/z 235.0 (M+H+).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH2:5]([NH:12][C:13]1[C:14]2[S:22][CH:21]=[C:20]([CH3:23])[C:15]=2[N:16]=[C:17](Cl)[N:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[CH2:1]([NH:4][C:17]1[N:18]=[C:13]([NH:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:14]2[S:22][CH:21]=[C:20]([CH3:23])[C:15]=2[N:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Solvent: O
Product: C=CCNc1nc(NCc2ccccc2)c2scc(C)c2n1
Temperature: 140 °C
Yield: 77.7 %

Procedure:
In 2.28 g (40.0 mmol) of allylamine was dissolved 250 mg (0.9 mmol) of 4-benzylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine, and the resulting solution was heated in a sealed tube at 140° C. for 24 hours. After the reaction mixture was cooled, 100 ml of water was added thereto, followed by extraction with ethyl acetate (20 ml×3). The organic layer was washed with 20 ml of water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane=1/4) to give 217 mg (yield: 81.3%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H][H]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc2cc(CC3(C)OCCO3)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(CC3(C)OCCO3)ccc2n1Cc1ccc(N)cc1
Yield: 102.9 %

Procedure:
A solution of crude 5-(2-methyl-[1,3]dioxolan-2-ylmethyl)-1-(4-nitrobenzyl)-1H-indole-2-carboxylic acid ethyl ester (2.4 g, ≈5 mmol) in dry tetrahydrofuran (20 ml) was shaken in a Parr apparatus with 10% palladium on carbon (200 mg) under 40 psi hydrogen for about four hours. The mixture was filtered and evaporated under reduced pressure to give the title compound (2.03 g), which was reacted without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1.Cl.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=3)[CH2:18][CH2:17]2)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COC(=O)c1ccc2c(c1)NCC2
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1c(C)cc(OC)cc1C)CC2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
4-Methoxy-2,6-dimethylbenzene-1-sulfonyl chloride (1.3 g, 0.0056 mol) was added at 25° C., under argon, to a solution of methyl indoline-6-carboxylate hydrochloride (1.2 g, 0.0056 mol) in dry pyridine (12 ml), and the resulting reaction mixture was stirred overnight at 70° C. The solvent was removed in vacuo, and the residue was taken up in dichloromethane and washed with water (2×), saturated copper sulfate solution (2×) and saturated sodium chloride solution, then dried (Na2SO4) and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 10-30% ethyl acetate in hexane). Yield: 1.9 g (90%)
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[C:20]([Br:21])=[CH:19][N:18]2[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=[C:17]2[CH:16]=1)(C)(C)C>C(Cl)Cl>[Br:21][C:20]1[C:15]([NH2:14])=[CH:16][C:17]2[N:18]([CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc2nc(-c3ccccc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (15 ml) was added to a solution of (6-bromo-2-phenyl-imidazo[1,2-a]pyridin-7-yl)-carbamic acid tert-butyl ester (2.75 g, 7.1 mmol) in CH2Cl2 (15 ml), and the mixture was stirred at r.t. overnight. The mixture was then washed (water, 2×50 ml), dried (Na2SO4), and the solvent was evaporated to give a first crop of the desired product. The water layer was made alkaline by addition of NaOH (conc. 14 ml), and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and evaporated to give a second crop of the desired product. The combined crops (2.02 g, 99%) were used in the next step without further purification. MS (m/e)=288.0 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@@H:7]([NH2:29])[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[C:31](=N)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:1]([O:5][C:6](=[O:30])[C@@H:7]([N:29]=[C:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N=C(c1ccccc1)c1ccccc1

Procedure:
The 2(R)-amino-3-tritylsulfanyl-propionic acid tert-butyl ester is reacted with benzhydrylideneamine in dichloromethane at room temperature to form 2(R)-(benzhydrylidene-amino)-3-tritylsulfanyl-propionic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:31]([CH2:34][C:35]([O:37]CC)=[O:36])=[C:32]=[S:33]>C(Cl)(Cl)Cl>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:32]([NH:31][CH2:34][C:35]([OH:37])=[O:36])=[S:33])[C:10](=[O:14])[N:9]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:8]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CC(=O)N(C2CCCCC2)C(=O)N1C1CCCCC1
Reactant: CCOC(=O)CN=C=S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(O)CNC(=S)c1c(O)n(C2CCCCC2)c(=O)n(C2CCCCC2)c1=O
Reaction time: 8 h
Yield: 14.7 %

Procedure:
A mixture of 1,3-dicyclohexyl-2,4,6(1H,3H,5H)-pyrimidinetrione (660 mg, 2.25 mmoles), diisopropylethylamine (780 uL, 4.5 mmoles) and ethyl isothiocyanatoacetate (340 uL, 2.75 mmoles) in chloroform (20 mL) was stirred overnight. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The solid residue was purified by flash chromatography (dichloromethane) and the fractions evaporated, dissolved in ethanol (5 mL, some heating) and treated with 1 molar sodium hydroxide (3 mL). The mixture was stirred for 30 minutes and acidified to give a solid which recrystallized from ethanol-water to give the title compound (135 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (s, 1 H), 12.54 (t, J=4.80 Hz, 1 H), 4.69 (t, J=12.00 Hz, 2 H), 4.35 (d, J=5.05 Hz, 2 H), 2.25 (q, 4 H), 1.79 (d, J=12.38 Hz, 4 H), 1.63 (d, J=12.38 Hz, 6 H), 1.29 (q, 4 H), 1.13 (q, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:12]=[C:11]([CH2:19][O:20][Si](C(C)C)(C(C)C)C(C)C)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([CH2:19][OH:20])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCOc1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)nc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCOc1ccc(CO)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-benzyloxy-3-propoxy-6-triisopropylsilanyloxymethyl-pyridine (860 mg, 2.0 mmole) is added 1M tetrabutylammonium fluoride solution in tetrahydrofuran (4.0 mL, 4.0 mmole) and the mixture stirred at room temperature for four hours. The reaction mixture is diluted with water and extracted with ether. The combined ether layers were combined and washed with water, dried over sodium sulfate, filtered, chromatographed on silica gel eluting with 1:1 hexanes/ether to give a white solid, 355 mg, (65%); m.p. 50-1° C., MS (ES+): m/z 274.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Br[CH2:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[CH:57]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:56][CH3:55])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3R,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester was reacted with 1-(bromo-propyl)-benzene and NaHCO3 in DMF according to General Procedure P to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester. This product, upon hydrolysis according to General Procedure B, gave the title compound (6 mg). LCMS (m/z): 852.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([OH:37])[C:5]=2[N:4]=1.Br[CH2:40][CH2:41][CH2:42][OH:43].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:40][CH2:41][CH2:42][OH:43])[C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(O)cccc43)n2)CC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OCCCO)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
A mixture of 0.60 g (1.1 mmol) of tert-butyl 4-[4-[2-(difluoromethyl)-4-hydroxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate (Example 5), 0.47 g (3.3 mmol) of 3-bromo-1-propanol, and 0.80 g (5.5 mmol) of powdered K2CO3 in 20 mL dry DMF was stirred at room temperature for 8 hrs. Dilution with water, filtration, and dry gave 0.66 g (99% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: 1H NMR (CDCl3) δ 7.94 (dd, J=8.4. 0.7 Hz, 1H), 7.49 (t, JHF=53.4 Hz, 1H), 7.34 (t, J=8.1 Hz, 1H), 6.92 (dd, J=8.0, 0.6 Hz, 1H), 4.47 (t, J=5.9 Hz, 2H), 3.98 (t, J=5.4 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.54 (m, 4H), 3.30 (m, exchangeable with D2O, 1H), 2.14 (pentet, J=5.8 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.C([Li])CCC.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[S:5][CH:6]=1
Reactant: Cc1cscn1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1csc(-c2ccccc2[N+](=O)[O-])n1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 16.9 %

Procedure:
A solution of 4-methylthiazole (4.0 g, 40.33 mmol) in THF (80 mL) was cooled to −78° C. under nitrogen. n-Butyl lithium (20.4 mL of 2M in hexanes, 40.8 mmol) was added to the reaction mixture slowly over 3 minutes. The reaction mixture was stirred for about 1.5 hours at −78° C., and then 2-fluoronitrobenzene (6.24 g, 44.23 mmol) was added. After stirring at −78° C. for another 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for about 2 hours at room temperature and then the reaction was quenched with water (70 mL). The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered and concentrated. The product was isolated by silica gel chromatography (5-10% ethyl acetate in hexanes) to give the title compound as an orange/brown oil (1.5 g). MS m/z: [M+H+] calcd for C10H8N2O2S 221.03; found 221. Retention time (HPLC 2-90)=4.54
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CC(C)=O>[CH2:27]([O:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Dissolve 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1 g, 3.9 mmol) in acetone (5 mL) and add powdered potassium carbonate (2.8 g, 20 mmol). Add dropwise a solution of allyl bromide (1.04 mL, 12 mmol) in acetone (3 mL) over 10 min and stir at ambient temperature overnight. Filter solids, wash with acetone and concentrate in vacuo to give the desired intermediate as an off-white solid (1.15 g, 98%). GC-MS m/z: 299 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:25])=[C:11]2[CH3:26])[CH3:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:47]([CH3:52])[C:48]([O:50][CH3:51])=[O:49].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:51][O:50][C:48](=[O:49])[C@@H:47]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:25])=[C:11]2[CH3:26])[CH3:9])=[CH:6][CH:7]=1)[CH3:52]
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)c1ccc(O)cc1
Reactant: COC(=O)[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)c1ccc(O[C@@H](C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To allyl 1-(1-(4-hydroxyphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylate (0.286 g, 0.82 mmol) in THF (0.8 mL) in an ice bath was added triphenylphosphine (0.28 g, 1.07 mmol) and then (R)-methyl 2-hydroxypropanoate (0.093 mL, 0.98 mmol). DIAD (0.24 mL, 1.23 mmol) was added dropwise to the cold solution. The mixture was stirred at room temperature for 16 hr. The solvent was removed and the residue was purified by silica gel chromatography to obtain the title compound. ESI-MS (m/z): 436 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH3:34])=[C:25]([CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:26]=2)=[CH:18][CH:17]=1>>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]([CH3:34])=[C:25]([CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[N:26]=3)=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: CCS(=O)(=O)c1ccc(-c2ccc(-c3nc(CCN4CCCC4)c(C)o3)cc2)cc1

Procedure:
The title compound is prepared in a mamler substantially analogous to Example 35 starting from 4-Ethylsulfonylbenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 425.1 (M+1)