Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15](Cl)(Cl)=[O:16].[C:19]1(C)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH2:11]([O:10][C:15](=[O:16])[CH2:4][N:5]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:8](=[O:9])[NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH3:12]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63 %

Procedure:
4-Amino-1-N-Boc-piperidine (760 mg, 3.79 mmol) was dissolved in a mixture of dichloromethane (40 mL) and aqueous sodium bicarbonate (30 mL). A solution of 20% phosgene in toluene (10 mL, 18.9 mmol) was added to the mixture with vigorous stirring. Reaction stirred vigorously at room temperature for 40 minutes. Reaction layers were partitioned. Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Residue was dissolved in toluene (30 mL). N-Phenylglycine ethyl ester was added to the mixture. Reaction was heated at reflux for 15 hours. Mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). Mixture was washed successively with 1N hydrochloric acid (3×50 mL) and brine (30 mL). Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as pale yellow solid in 63% yield. 1H NMR (300 MHz, CDCl3): δ=7.47-7.26 (m, 5H), 4.30 (s, 1H), 4.16 (q, J=7.32, 2H), 3.88 (d, J=12.81, 2H), 3.81-3.69 (m, 1H), 2.89-2.70 (m, 2H), 1.83 (dd, J1=12.62, J2=3.11, 2H), 1.38 (s, 9H), 1.23 (t, J=7.14, 3H), 1.19-1.03 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:12][N:13]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15]([CH2:16][C@H:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:14]2)[CH2:11][CH2:10][CH2:9]1.[CH2:28]([O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1)[C:29]#[C:30][CH3:31]>O.O1CCOCC1>[CH2:28]([O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:18][CH:17]([CH2:16][C:15]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:13]([CH2:12][CH:8]3[CH2:11][CH2:10][CH2:9]3)[CH:14]=2)[C:19]([OH:21])=[O:20])(=[O:41])=[O:40])=[CH:35][CH:34]=1)[C:29]#[C:30][CH3:31]
Reactant: N[C@H](Cc1cn(CC2CCC2)c2ccccc12)C(=O)O
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2cn(CC3CCC3)c3ccccc23)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Triethylamine (0.275 mL, 1.97 mmol) was added to a solution of crude 1-cyclobutylmethyl-D-tryptophan of Step 2 (0.657 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride (0.177 g, 0.723 mmol) in H2O-dioxane (2 mL:3 mL) at room temperature. The reaction mixture was stirred for 20 hours at room temperature. The mixture was then concentrated and acidified with HCl. The mixture was extracted with ethyl acetate (3×10 mL). The organic solution was washed with H2O and brine, dried over Na2SO4, and concentrated. The residue was purified by RP-HPLC to give 0.152 g (48% in 3 steps) of the title compound as a yellow solid. 1H NMR (DMSO-d6): 400 MHz δ 12.57 (bs, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 7.02 (s, 1H), 6.96-6.88 (m, 3H), 4.77 (q, J=2.4 Hz, 2H), 4.04 (d, J=6.8 Hz, 2H), 3.84 (q, J=6.8 Hz, 1H), 3.02 (dd J=14.4, 6.4 Hz, 1H), 2.82 (dd J=14.4, 8.4 Hz, 1H), 2.67 (p, J=7.6 Hz, 1H), 1.91 (m, 2H), 1.83 (m, 5H), 1.75 (m, 2H); HRMS: calcd for C26H29N2O5S (ESI+, [M+H]1+), 481.1792; found 481.1786; LCMS m/z (ESI) [M+H] 481, retention time=3.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].CCCCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]([C:19](=[O:20])[CH2:18][Cl:17])[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1
Temperature: -15 °C

Procedure:
A mixture of 25 g (0.11 mol) N-(2′-chloro-6′-fluorophenyl)-4-methylaniline and 40 ml (0.5 mol) of chloroacetylchloride is heated under a nitrogen atmosphere for 15 minutes at 60°. The solvent is evaporated under reduced pressure to give an oil which is dissolved in 25 ml of ethyl acetate. Pentane (250 ml) is added dropwise over 15 minutes to precipitate the product. The mixture is cooled to −15° C. and the solid is filtered and washed with pentane to give N-(2′-chloro-6′-fluorophenyl)-N-chloroacetyl-4-methylaniline, m.p. 80-83°.
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12]>C(Cl)Cl>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:12][CH:3]=[CH:4][C:5](=[O:7])[CH3:6]
Reactant: COC=CC(C)=O
Reactant: NCc1ccccc1Cl
Solvent: ClCCl
Product: CC(=O)C=CNCc1ccccc1Cl
Yield: 99.7 %

Procedure:
A solution of 4-methoxy-3-buten-2-one (100.1 mg, 1 mmol) and 2-chlorobenzylamine (141.6 mg, 1 mmol) in dry CH2Cl2 (5 mL) is stirred under reflux for 2 h. The solvent is evaporated under reduced pressure to afford the title compound 45 as a yellow oil (Yield 209 mg, 100%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([N+]([O-])=O)[CH:10]=[CH:9][N:8]=1.CCOCC>C(OC(=O)C)(=O)C>[C:1]([O:4][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:6])[C:12]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: Cc1nccc([N+](=O)[O-])c1C
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccnc(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
Anhydrous potassium acetate (49 g, 0.5 mol) was added to a solution of 2,3-dimethyl-4-nitropyridine (45.6 g, 0.3 mol) prepared in Step 2 in 300 ml of acetic anhydride and then refluxed under stirring for 16 hours. The reaction mixture was cooled to room temperature and then 400 ml of anhydrous ether was added thereto. The reaction mixture was stirred for 1 hour, filtered with Celite, and then concentrated under reduced pressure to give 4-acetoxy-2,3-dimethylpyridine (45 g, 91%). The resulting residue was added to 250 ml of water, refluxed under stirring for 4 hours, and then left overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give 32.6 g of 2,3-dimethyl-4-hydroxypyridine as a liquid form. The liquid product was dissolved in 120 ml of concentrated sulfuric acid and heated to 60° C. A mixture of 90% nitric acid (40 ml) and sulfuric acid (30 ml) was slowly added to the reaction mixture for 45 minutes, while maintaining the temperature at 60-65° C. The reaction mixture was heated for 2 hours at 65° C. and then for 30 minutes at 75° C. The reaction mixture was cooled to room temperature and then added to ice water. The resulting solution was brought to pH 5˜6 with ammonium hydroxide to give a pale yellow solid. The resulting solid was filtered, washed with cold water, and then dried at 80˜90° C. to give 34.5 g of the titled compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=3)[CH2:8][CH2:9][O:10][C:11]=2[N:12]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C.CN(C)C(=O)C>>[CH:21]([N:20]1[C:16]([C:14]2[N:15]=[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)=[N:12][C:11]=4[O:10][CH2:9][CH2:8][N:7]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CN1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Cl)nc1OCC2
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCN(C)CC3)nc1OCC2

Procedure:
A solution of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine (66.0 mg, 0.200 mmol), 1-methyl-piperazine, (88.5 uL, 0.798 mmol) and Triethylamine (167 uL, 1.20 mmol) in N,N-Dimethylacetamide (3.00 mL, 32.3 mmol) was heated in microwave at 16° C. for 20 min. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed water, brine. The organic layer was dried Na2SO4, concentrated. The crude product was purified by rHPLC to give 323. MS: (ESI+)=395.2. 1H NMR (400 MHz, DMSO) δ 8.50 (d, J=8.7 Hz, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 6.72 (d, J=8.8 Hz, 1H), 5.88 (dt, J=13.2, 6.7 Hz, 1H), 4.49 (m, 4H), 3.61-3.48 (m, 4H), 2.42-2.34 (m, 4H), 2.21 (s, 3H), 1.47 (d, J=6.6 Hz, 6H)
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([Sn](C=C)(CCCC)CCCC)[CH2:27]CC>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>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH:26]=[CH2:27])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1

Procedure:
The title compound was prepared from 44 mg of 2-[(S)-1-phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine, 87 μL tributylstannyl ethylene and 1.15 mg Pd(PPh3)4 using the procedure described in EXAMPLE 273 to give 8.5 mg of the title compound. RF: 0.45 (5% MeOH in CH2Cl2). 1H NMR (500 MHz, 1:1 CD3OD/CDCl3): δ 1.59 (d, J=6.8 Hz, 3H), 5.13 (m, 1H), 5.24 (d, J=11.2 Hz, 1H), 5.76 (d, J=17.4 Hz, 1H), 6.79 (dd, J=17.6, 11 Hz, 1H), 6.87 (d, J=5.7 Hz, 1H), 7.21 (br s, J=7.3 Hz, 1H), 7.27-7.34 (m, 3H), 7.41 (br s, J=7.3 Hz, 2H), 7.6-7.8 (m, 1H), 7.67 (br s, 1H), 8.31 (br s, J=5.7 Hz, 1H), 8.55-8.7 (m, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 342.3 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([OH:25])=O)[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)[CH2:35][CH2:34]1)([CH3:32])[C:28]([O:30][CH3:31])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[CH:49][C:50]([C:53]([F:56])([F:54])[F:55])=[CH:51][CH:52]=3)=[CH:43][CH:42]=2)[CH:36]2[CH2:37][CH2:38][N:33]([C:27]([CH3:26])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:34][CH2:35]2)=[O:25])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2ccccc21
Reactant: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1 (4H)-quinazolinyl]acetic acid (Int. C1) (100 mg, 1 equiv), methyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B1) (130 mg, 1.03 equiv), DIPEA (0.1 ml, 3.6 equiv), acetonitrile (2 ml) and HATU (130 mg, 1.4 equiv) was stirred at room temperature for 1 h, then evaporated and redissolved in acetonitrile. Purification by reverse phase HPLC (Preparative Method A) gave methyl 2-[4-({[2-[2-(2,3-difluoro-phenyl)ethyl]-4-oxo-1 (4H)-quinazolinyl]acetyl} {[4′-(trifluoromethyl)-4-biphenylyl]-methyl}amino)-1-piperidinyl]-2-methylpropanoate (128 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[N:25]2)[CH:21]=[CH:20][C:3]=1[O:4][CH:5]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].O.[OH-].[Li+].CO.C1COCC1>O>[CH3:1][C:2]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[N:25]2)[CH:21]=[CH:20][C:3]=1[O:4][CH:5]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A mixture of ethyl 4-(1-(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoate (90 mg, 0.2 mmol), lithium hydroxide monohydrate (24 mg, 1.0 mmol), methanol (2 ml), THF (3 ml), and water (1 ml) was stirred at +450 for 18 hours. The mixture was concentrated, diluted with 8 ml of water and 2 ml of 1 M potassium hydrogen sulfate. The mixture was extracted with ethyl acetate-heptane (1:1), extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the target product as a white solid (84 mg, 99%). MS (M+1): 419.2.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C@H:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:19]2)=[CH:14][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:64][C:65]([F:73])(S(F)(=O)=O)C(O)=O.O>C(#N)C>[CH2:41]([O:40][C@H:21]1[C@H:22]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:18]([C:15]2[CH:16]=[CH:17][C:2]([Cl:1])=[C:3]([CH2:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][O:13][CH:65]([F:73])[F:64])=[CH:9][CH:10]=3)[CH:14]=2)[O:19][C@@H:20]1[CH2:48][O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: OCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: FC(F)OCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reaction time: 1 h
Yield: 33 %

Procedure:
To a mixture of 2-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)ethanol (intermediate BL) (20 mg, 0.020 mmol) and sodium sulfate (0.40 mg, 0.003 mmol) in anhydrous acetonitrile (0.5 mL) kept at 45° C. was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (4.63 mg, 2.7 μL, 0.026 mmol). The mixture was stirred at this temp for 1 h and poured into 3 mL water. Product was extracted into ether (3×1 mL), dried (Na2SO4) and evaporated. The residue was purified by TLC using 6:1 hexane:EtOAc to obtain intermediate BM (7 mg, yield 33%).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][N:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[CH2:42][CH2:41]4)[C:38]([CH3:52])=[C:37]([OH:53])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][N:43]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[CH2:42][CH2:41]4)[C:38]([CH3:52])=[C:37]([O:53][CH3:3])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1C1CCN(c2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOCC
Solvent: CO
Product: COC1=C(C)C(C2CCN(c3ccccc3)CC2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/5 v/v, 18 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(1-phenylpiperidin-4-yl)-1H-pyrrol-2(5H)-one (0.280 g, 0.72 mmol, 1 eq) and MeOH (15 ml), the product was further purified by prep TLC; yield: 0.021 g (5.2%); MS m/z: 403.1 [M+H]+; 1H-NMR: (400 MHz, CDCl3) δ: 7.95 (s, 1H), 7.65-7.60 (m, 1H), 7.17 (m, 3H), 6.80 (d, 1H), 4.52 (s, 1H), 4.03 (s, 3H), 3.69-3.66 (m, 3H), 2.54-2.41 (m, 3H), 2.05 (s, 4H), 1.88 (m, 5H), 1.41-1.25 (m, 2H); HPLC (METHOD [A]): rt 6.05 min (88.89%)
Reaction SMILES: ClC(Cl)C.[O-:5][S:6]([O-:8])=[O:7].[CH3:9][N:10]([CH3:13])[CH:11]=[O:12]>>[CH3:9][N:10]([CH3:13])[CH:11]=[O:12].[S:6](=[O:8])(=[O:7])=[O:5]
Reactant: O=S([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)=O

Procedure:
8.8 g of dimethyl formamide was admixed with 100 ml of dichloroethane and 8.0 g of sulfuric anhydride was added dropwise to the mixture at 15° C to give white needle-like crystals of dimethyl formamidesulfur trioxide complex in stoichometrical amount.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)[CH2:16][CH2:15]1)[CH3:13]>>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:12][CH3:13])[CH2:15][CH2:16]2)[CH:22]=1)=[O:5]
Reactant: CCN1CCC(Oc2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Product: CCN1CCC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Product: Cl

Procedure:
Using a method similar to Example 5, using 2-chloro-4-fluoro-benzoyl chloride (0.054 mL, 0.420 mmol) and 3-(1-ethyl-piperidin-4-yloxy)-phenylamine (preparation 29) gives the title compound as the free base (131 mg, 91%). Following a method similar to Example 2 gives the title compound as the hydrochloride salt (130 mg, white solid). Mp: 91° C.; mass spectrum (free base, ion spray): m/z=377.2 (M+1); 1H NMR (free base, CDCl3): 8.14 (bs, N—H), 7.68 (dd, J=6.1 Hz, 8.7 Hz, 1H), 7.40 (bs, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.14 (dd, J=2.5 Hz, 8.3 Hz, 1H), 7.06-7.01 (m, 2H), 6.70 (dd, J=2.4 Hz, 8.3 Hz, 1H), 4.38-4.31 (m, 1H), 2.75-2.67 (bm, 2H), 2.41 (q, J=7.1 Hz, 2H), 2.33-2.24 (bm, 2H), 2.04-1.97 (bm, 2H), 1.87-1.78 (bm, 2H), 1.08 (t, J=7.4 Hz, 3H); Analysis calculated for C20H23Cl2FN2O2.0.25H2O: C, 57.49; H, 5.67; N, 6.70. Found C, 57.45; H, 5.31; N, 6.59.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH2:12][CH3:13])[CH3:2].[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:17]=1[CH2:25][CH3:26])[CH3:15]>C(OCC)(=O)C.[Pd]>[CH2:12]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[NH2:9])[CH3:13].[CH2:25]([C:17]1[C:16]([CH2:14][CH3:15])=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:22])[CH3:26]
Reactant: CCc1cccc([N+](=O)[O-])c1CC
Reactant: CCc1ccc([N+](=O)[O-])cc1CC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(N)cc1CC
Product: CCc1cccc(N)c1CC
Yield: 19 %
Yield: 71 %

Procedure:
A mixture of 1,2-diethyl-4-nitrobenzene (16) and 1,2-diethyl-3-nitrobenzene (17) (1.4 g, 7.82 mmol) was dissolved in ethyl acetate (20 mL). To this solution was added 10% Pd-C (350 mg, 20%; Aldrich). The mixture was agitated at room temperature under a pressure of 35 psi (H) for 10 h. The catalyst was removed through a column of Celite (5 g) and washed with ethyl acetate (3×15 mL). The filtrates were combined and evaporated in vacuo to give a residue, which was separated by preparative TLC (Hexanes: EtoAc=8:2), giving 3,4-diethylaniline (19) (0.822 g, 71%) as a pale yellow oil (Rf=0.7) and 2,3-diethylaniline (20) (0.219 g, 19%) as a brown oil (Rf=0.6). 1H NMR (CDCl3,300 MHz): δ (19): 1.184 (t, 6H, J=7 Hz), 2.573 (q, 4H, J=7 Hz), 3.456 (br, s, 2H) 6.513 (m, 2H), 6.970 (d, 1H, J=7.8 Hz). (20): 1.215 (t, 6H, J=7 Hz), 2.617 (q, 4H, J=7 Hz), 6.570 (d, 1H, J=7.5 Hi), 6.650 (d, 1H, J=7.5 Hz), 6.973 (m, 1H).
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])=[CH:3][Cl:4].[CH3:16][N:17]=[C:18]=[S:19].N12CCCN=C1CCCCC2.CS(O)(=O)=O>C(#N)C.O>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:18]([NH:17][CH3:16])=[S:19])(=[O:13])=[O:14])=[CH:3][Cl:4]
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reactant: CN=C=S
Agent: CS(=O)(=O)O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CNC(=S)NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reaction time: 24 h

Procedure:
13.4 g of 2-(1,2-dichlorovinyloxy)phenylsulfonamide and 3.65 g of methyl isothiocyanate are dissolved in 50 ml of acetonitrile, and 7.8 g of 1,8-diazabicyclo[5.4.0]undec-7-ene are added with cooling (0° to 5° C.) and stirring. The resulting red reaction solution is left to stand for 24 hours, 4.8 g of methanesulfonic acid are then added and the mixture is diluted with water to a volume of 1 liter. The crystals which separate out are filtered off, washed with methanol and dried. Yield: 15 g. Melting point: 185°-187° (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[NH2:42][C@@H:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44]1>C(Cl)(Cl)Cl>[C@@H:43]1([NH:42][C:34]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:40])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H]4CCc5ccccc54)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 84.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (S)-1-aminoindane (31 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (43 mg, yield 40%).