Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[Br:32][C:33]1[C:34]([C:39](Cl)=[O:40])=[N:35][N:36]([CH3:38])[CH:37]=1>>[Br:32][C:33]1[C:34]([C:39]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][CH:11]=3)=[C:2]([F:1])[CH:3]=2)=[O:40])=[N:35][N:36]([CH3:38])[CH:37]=1
Reactant: Cn1cc(Br)c(C(=O)Cl)n1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Oc3ccc(NC(=O)c4nn(C)cc4Br)cc3F)ccnc2cc1OCCCN1CCOCC1

Procedure:
Q2 was prepared from 3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]aniline and 4-bromo-1-methyl-1H-pyrazole-3-carbonyl chloride following the general procedure reported in Preparative Example 1 Step 3. 1H NMR (400 MHz, d4-MeOD, 300K) δ 2.20 (m, 2H), 2.73 (m, 4H), 2.81 (t, J=7.4 Hz, 2H), 3.80 (t, J=4.7 Hz, 4H), 4.02 (s, 3H), 4.05 (s, 3H), 4.29 (t, J=6.1 Hz, 2H), 6.54 (dd, J=5.4 Hz, J=1.0 Hz, 1H), 7.37 (t, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 7.86 (s, 1H), 7.95 (dd, J=12.9 Hz, J=2.4 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H). MS (ES) C28H29BrFN5O5 requires: 614. Found: 614/616 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[C:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH2:11][CH2:12][C:13]#[CH:14].C(N)(C)(C)C>[Cu]I.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.CN(C=O)C>[OH:9][CH2:8][C:4]1[N:3]=[C:2]([C:14]#[C:13][CH2:12][CH2:11][C:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCC(=O)OC(C)(C)C
Reactant: OCc1cccc(Br)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)(C)N
Product: CC(C)(C)OC(=O)CCC#Cc1cccc(CO)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 56.9 %

Procedure:
To a 200 mL round-bottom flask, 3.49 g of 2-bromopyridine-6-methanol, 3.0 g of t-butyl 4-pentynoate, 190 mg of BHT, 1.17 g of copper(I) iodide, 877 mg of tetrakis(triphenylphosphine)palladium(0), 2.72 g of t-butylamine and 56 mL of DMF were added, and the mixture was stirred under argon atmosphere at 80° C. for 6 hours. After the DMF was removed under reduced pressure from the reaction mixture, saturated aqueous sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by chromatography on silica gel (n-hexane-ethyl acetate=2:1) to give 2.76 g of t-butyl 5-(6-hydroxymethylpyridin-2-yl)pent-4-ynoate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7]2.[N+:16]([C:19]1[CH:20]=[C:21]([C:28](Cl)=[O:29])[CH:22]=[C:23]([C:25](Cl)=[O:26])[CH:24]=1)([O-:18])=[O:17]>N1C=CC=CC=1.O1CCOCC1.C(Cl)(Cl)Cl>[N+:16]([C:19]1[CH:20]=[C:21]([C:28]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:7]3)=[O:29])[CH:22]=[C:23]([C:25](=[O:26])[NH:1][C:2]2[C:3]3[C:8](=[CH:7][C:6]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:5][CH:4]=3)[CH:9]=[CH:10][CH:11]=2)[CH:24]=1)([O-:18])=[O:17]
Reactant: Nc1cccc2cc(S(=O)(=O)O)ccc12
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(Nc1cccc2cc(S(=O)(=O)O)ccc12)c1cc(C(=O)Nc2cccc3cc(S(=O)(=O)O)ccc23)cc([N+](=O)[O-])c1
Reaction time: 1.5 h

Procedure:
22.33 g (0.10 mol) of 5-amino-2-naphthalenesulfonic acid was suspended in 150 mL of pyridine and added to the above di-acid chloride in 50 mL (50:50) of dioxane and CHCl3 under vigorous stirring for 1-2 hrs. The crude product was precipitated with dioxane. The oily product was collected on a Büchner funnel. The brown colored oily product was dissolved in 500 mL water, then allowed to precipitate out over 30 min. The solid material was collected using filtration. It yielded 16.2 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15]>>[CH2:11]([O:12][CH2:13][CH2:14][CH2:15][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:10][CH3:9]
Reactant: O=C1CCNCC1
Reactant: CCCOCCCCl
Product: CCCOCCCN1CCC(=O)CC1

Procedure:
1-(3-Propoxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-propoxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:51]=[CH:50][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:47]=[CH:48][CH:49]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([C:42]([O:44]CC)=[O:43])[CH2:37]2)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>C(OCC)(=O)C.O1CCCC1>[CH2:1]([N:8]([CH2:21][C:22]1[CH:51]=[CH:50][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:47]=[CH:48][CH:49]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([C:42]([OH:44])=[O:43])[CH2:37]2)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCN(C(=O)CCCOc2cccc(Oc3ccc(CN(Cc4ccccc4)c4cccc(NS(C)(=O)=O)c4C)cc3)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)N3CCCC(C(=O)O)C3)c2)cc1

Procedure:
The product from Example 279A was treated with 2N NaOH aqueous solution (1 mL), ethyl alcohol (0.5 mL) and tetrahydrofuran (0.5 mL) at room temperature overnight. 1N hydrochloric acid was dropped to the reaction mixture until pH=2˜3. Ethyl acetate (3 mL) was used to extract the product. The organic layer was separated, dried (Na2SO4), concentrated in vaccuo, and purified by HPLC to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.03-12.70 (br.s, 1 H), 8.95 (s, 1 H), 7.24 (m, 8 H), 7.04 (m, 1 H), 6.94 (m, 4 H), 6.69 (m, 1 H), 6.49 (m, 2 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.94 (t, J=6.4 Hz, 2 H), 3.82 (m, 1 H), 3.72 (m, 1 H), 3.31 (dd, J=13.6, 9.2 Hz, 1 H), 2.98 (t, J=11.1 Hz, 1 H), 2.91 (s, 3 H), 2.38 (m, 5 H), 2.24 (m, 1 H), 1.90 (m, 3 H), 1.65 (m, 1 H), 1.52 (m, 1 H), 1.34 (m, 1 H); MS (APCI+) m/z 686.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].[CH3:11][C:12]1[C:13](B(O)O)=[CH:14][C:15]2[C:16](C)([CH3:24])[CH2:17][CH2:18][C:19]([CH3:23])([CH3:22])[C:20]=2[CH:21]=1.[CH2:29](O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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.O>[Cl:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:13]1[C:12]([CH3:11])=[CH:21][C:20]2[C:19]([CH3:22])([CH3:23])[CH2:18][CH:17]([CH3:29])[CH:16]([CH3:24])[C:15]=2[CH:14]=1
Reactant: O=Cc1ccc(Cl)c(Br)c1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1-c1cc(C=O)ccc1Cl)C(C)C(C)CC2(C)C
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 3-bromo-4-chlorobenzaldehyde (2.5 g, 11.39 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl) boronic acid (3.1 g, 12.53 mmol) in a mixture of toluene (25 mL), ethanol (5 mL) and water (4 mL) was added potassium carbonate (3.15 g, 22.78 mmol). The solution was degased with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.23 mmol) was added and the mixture heated at reflux under argon overnight. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (biotage: eluant: ethyl acetate/hexane, 5:95) to give 3.0 g of 4-chloro-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl) benzaldehyde (77%). 1H NMR (300 MHz; DMSO) 1.18 (s, 3H); 1.20 (s, 3H); 1.24 (s, 3H); 1.26 (s, 3H); 1.36 (s, 4H); 1.98 (s, 3H); 7.04 (s, 1H); 7.23 (s, 1H); 7.75 (d, J=7.8 Hz, 1H); 7.80 (d, J=1.8 Hz, 1H); 7.88 (dd, J1=7.8 Hz, J2=1.8 Hz, 1H); 9.99 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2[O:31][C:32]3[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37][C:33]=3[C:34]=2[S:35][CH3:36])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2[O:31][C:32]3[CH:40]=[CH:39][C:38]([CH2:41][C:42]([N:17]4[CH2:18][CH2:19][N:14]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH2:15][CH2:16]4)=[O:43])=[CH:37][C:33]=3[C:34]=2[S:35][CH3:36])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2oc3ccc(CC(=O)O)cc3c2SC)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2oc3ccc(CC(=O)N4CCN(c5ccccc5)CC4)cc3c2SC)cc1OC
Reaction time: 16 h
Yield: 554 %

Procedure:
Triethylamine and 12.992 mg of 1-phenyl-piperazine (0.080 mM) were added to the solution containing 35 mg of 3[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-acetic acid (35a; 0.068 mM) dissolved in 2 ml of dichloromethane. The reaction mixture was stirred for 16 hours and the remaining solvent was removed. The remaining residue was purified with Silica gel column chromatography with a mobile phase (dichloromethane:methanol=20:1) to obtain white solid type of 2-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl)-1-(4-phenyl-piperazin-1-yl)-ethanone (37a; 223 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][NH:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:29]1[C:30](=[O:39])[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:40](Cl)(Cl)(=[O:42])=[O:41].[CH:45](N(C(C)C)CC)(C)[CH3:46]>CN(C)C=O>[C:25]([O:24][C:22]([NH:21][CH2:20][CH2:19][N:18]([CH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]([C:29]1[C:30](=[O:39])[NH:31][C:32]3[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:10]2)[S:40]([CH:45]=[CH2:46])(=[O:42])=[O:41])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc2c(c1)cc(-c1cc3ccccc3[nH]c1=O)n2C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CS(=O)(=O)N(CCNC(=O)OC(C)(C)C)Cc1ccc2c(c1)cc(-c1cc3ccccc3[nH]c1=O)n2C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
The amine made above 11-2 (120 mg, 0.23 mmol) was dissolved in 5.0 mL of dry N,N-dimethylformamide and allowed to stir at ambient temperature. Then sulfonyl chloride (35 μL, 0.34 mmol) and diisopropylethylamine (125 μL, 0.72 mmol) were added via pipette, respectively. The reaction was stirred for 10 hours until completion via LCMS analysis. The crude reaction solution was partitioned between ethyl acetate (15 mL) and half-saturated NaHCO3 solution (100 mL). The layers were separated and the aqueous layer was extracted several times with ethyl acetate (3×10 mL). The combined organic layers were washed with water (4×15 mL), brine, separated, dried (Na2SO4) and concentrated in vacuo to afford a yellow oil. Chromatography (SiO2, 30% to 50% ethyl acetate in hexanes) followed by concentration afforded 11-3 as a pale yellow solid; 1H NMR (300 MM, CDCl3) δ 12.73 (s, 1 H), 8.25 (d, 1H, J=8.4 Hz), 7.93 (s, 1 H), 7.62 (d, 1 H, J=7.2 Hz), 7.61 (s, 1 H), 7.50 (m, 1 H), 7.40 (d, 1 H, J=8.1 Hz), 7.39 (d, 1 H, J=8.4 Hz), 7.24 (app t, 1 H, J=7.2 Hz), 6.69 (s, 1 H), 6.43 (dd, 1 H, J=16.5, 9.6 Hz), 6.26 (d, 1 H, J=16.5 Hz), 5.94 (d, 1 H, J=9.9 Hz), 4.82 (t, 1 H, J=5.1 Hz), 4.51 (s, 2 H), 3.25 (m, 4H), 1.43 (s, 9 H), 1.39 (s, 9 H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.N1C=CC=CC=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].C(N(CC)CC)C.[NH2:36][CH:37]1[CH2:40][N:39]([CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1>ClCCl>[CH3:12][C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:1][C:20]([NH:36][CH:37]1[CH2:40][N:39]([CH:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:38]1)=[O:21])[CH:11]=[CH:10][CH:9]=2
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc2c(N)cccc2cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2c(NC(=O)NC3CN(C(c4ccccc4)c4ccccc4)C3)cccc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
D4 (73 mg, 0.46 mmol) in dry dichloromethane (5 ml) was treated with pyridine (45 ul, 0.55 mmol) followed by phenyl chloroformate (69 ul, 0.55 mmol). After 1 h triethylamine (128 ul, 0.92 mmol) was added, followed by D16 (0.46 mmol). The reaction mixture was then stirred overnight at ambient temperature. The precipitate was separated by centrifugation, washed with DCM, diethyl ether and then dried to give the title compound as a yellow solid. MH+ 423.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[N+](C1C=CC(S(O[CH2:27][C@H:28]2[CH2:30][C:29]2([F:32])[F:31])(=O)=O)=CC=1)([O-])=O>>[F:31][C:29]1([F:32])[CH2:30][C@@H:28]1[CH2:27][O:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Reactant: CCOC(=O)c1ncc(O)cc1F
Product: CCOC(=O)c1ncc(OC[C@H]2CC2(F)F)cc1F

Procedure:
Using ethyl 3-fluoro-5-hydroxypyridine-2-carboxylate and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:13]2[CH3:16])=[CH:8][CH:7]=1.O>CC(C)=O>[CH:2]([C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:13]2[CH3:16])=[CH:8][CH:7]=1)=[O:1]
Reactant: CCOC(=O)c1cn(C)c2cc(C3OCCO3)ccc2c1=O
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2cc(C=O)ccc2c1=O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 81 %

Procedure:
Compound 9 was dissolved in acetone (EMCO), at 60° C. in a 1 L, 1-neck round bottom flask. Pre-washed Amberlite IR-120 resin (Aldrich) was added with the water and the mixture was stirred at 60° C. for 40 minutes; aliquots were removed at 20 min (MCLS0995-078-1) and 40 min. HPLC analysis of the aliquots revealed that the de-protection of the aldehyde was complete in 20 minutes. The mixture was removed from the heating bath, filtered, and concentrated to ca. 40% of the initial volume under rotary evaporation (removal of acetone). The resulting aqueous suspension was partitioned between CH2Cl2 and sat. aq. sodium bicarbonate. The aqueous layer was extracted 2×CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford product 10 (4.20 g, 81% yield).
Reaction SMILES: C([Mg]Br)C.[CH2:5]([OH:9])[CH2:6][C:7]#[CH:8].Cl[Si:11]([CH3:14])([CH3:13])[CH3:12].S(=O)(=O)(O)O>O1CCCC1>[CH3:12][Si:11]([CH3:14])([CH3:13])[C:8]#[C:7][CH2:6][CH2:5][OH:9]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCCO
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A solution of 2 mol of ethyl magnesium bromide (2.0 molar solution in tetrahydrofuran) is cooled in an ice bath and a solution of 50.5 g of 3-butyn-1-ol (0.72 mol) in 50 ml of tetrahydrofuran is slowly added. After addition of complete, the mixture was allowed to warm to room temperature and was stirred overnight. The mixture was then cooled in an ice bath and 254 ml (2 mol) of chlorotrimethylsilane was slowly added. This mixture was heated under reflux for two hours and then cooled to 20° C. and 800 ml of 1.4M aqueous sulfuric acid were added. The mixture was extracted with diethyl ether and the ether solution was dried and concentrated under vacuum. The residue was distilled to yield 72.8 g of 4-trimethylsilyl-3-butyne-1-ol, bp 43°-48° C. at 1 mm Hg.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C@@H:7]1[N:12]([C:13](=O)[CH2:14][C@@H:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][C:26]=2[S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])[CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][CH3:5])[CH3:2].C1COCC1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CO>[CH2:1]([N:3]([CH2:6][C@@H:7]1[N:12]([CH2:13][CH2:14][C@@H:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:27][C:26]=2[S:35]([C:38]([F:40])([F:39])[F:41])(=[O:37])=[O:36])[CH2:16][S:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)C[C@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)C[C@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 4-((R)-4-((S)-3-((diethylamino)methyl)morpholino)-4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 87, 360 mg, 0.55 mmol) and 1 M borane-tetrahydrofuran complex in THF (1191 μl, 1.19 mmol) was stirred at room temperature for 16 hours. The reaction mixture was treated carefully with MeOH (5 ml) and concentrated HCl (1 ml). The mixture was heated at 80° C. for 3 hours, cooled to r.t, and the pH was adjusted to pH 10 with 4 N aqueous sodium carbonate. The mixture was diluted with ethyl acetate (300 ml), washed successively with water (150 ml) and brine (150 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with 0→20% MeOH/DCM over 15 minutes) to give the title product (130 mg, yield: 37%).
Reaction SMILES: O=[C:2]([CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)[CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.[NH2:28][NH2:29]>C(O)C>[N+:24]([C:20]1[CH:19]=[C:18]([CH:8]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:29][N:28]=[C:2]2[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:23]=[CH:22][CH:21]=1)([O-:26])=[O:25]
Reactant: CCOC(=O)C(=O)C(CC(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=NNC(c2ccccc2)=CC1c1cccc([N+](=O)[O-])c1
Yield: 35.1 %

Procedure:
A mixture of ethyl 2,5-dioxo-3-(3-nitrophenyl)-5-phenylpentanoate (1.5 g) and hydrazine monohydrate (0.24 g) in ethanol (30 ml) was refluxed for 5.5 hours. After evaporating the solvent in vacuo, the residue was subjected to a column chromatography on silica gel (100 ml) eluting with a mixture of benzene and ethyl acetate (50:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give ethyl 1,4-dihydro-4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxylate (0.52 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20]CC)=[O:19])=[C:12]2[C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([CH2:37][O:38][C:39]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:40]=1[CH2:41]Cl)([O:34]CC)=[O:33]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:41][C:40]1[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:39]=1[O:38][CH2:37][C:32]([OH:34])=[O:33])[C:13]([C:18]([OH:20])=[O:19])=[C:12]2[C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1-c1ccc2c(c1)OCO2
Reactant: CCOC(=O)COc1cc(OC)ccc1CCl
Product: COc1ccc(Cn2c(C(=O)O)c(-c3ccc4c(c3)OCO4)c3cc(OCc4ccccc4)ccc32)c(OCC(=O)O)c1

Procedure:
5-Benzyloxy-1-(2-carboxymethoxy-4-methoxybenzyl)-3-(3,4-methylenedioxyohenyl)indole-2-carboxylic acid. The title compound was prepared by alkylation of ethyl 5-benzyloxy-3-(3,4-methylenedioxyphenyl)indole-2-carboxylate with 2-carboethoxymethoxy-4-methoxybenzyl chloride followed by saponification using methods previously described in examples 1c and 1d; m.p. 182°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C:10]([CH2:39][CH:40]=O)([CH2:26][CH2:27][O:28][Si](C(C)C)(C(C)C)C(C)C)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C:10]([CH2:26][CH2:27][OH:28])([CH2:39][CH2:40][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC(C)[Si](OCCC1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O)(C(C)C)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1N(CC2CC2)[C@H](c2ccc(Cl)cc2)[C@@H](c2cccc(Cl)c2)CC1(CCO)CCN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 94 mg (0.15 mmol) of crude 2-((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-3-yl)acetaldehyde (Example 69, Step B, mixture of diastereomers), 66 μL (0.76 mmol) of morpholine, 97 mg (0.46 mmol) of sodium triacetoxyborohydride and 30 μL (0.53 mmol) of acetic acid was suspended in a mixture of 1,2-dichloroethane (6 mL) and DMF (2 mL). After being stirred at room temperature for 20 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase preparatory HPLC (SunFire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 50% MeCN in water to 90% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound (mixture of C-3 epimers) along with the corresponding TIPS ether (mixture of C-3 epimers) and the corresponding trifluoroacetate (mixture of C-3 epimers) as a colorless oil.