Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C1([OH:15])C=CC=CC=1>O>[C:1]1([OH:2])[CH:8]=[CH:7][CH:6]=[CH:4][CH:3]=1.[CH:8]1[C:1]([OH:2])=[CH:3][C:4]([OH:5])=[CH:6][C:7]=1[OH:15]
Reactant: Oc1cccc(O)c1
Solvent: Oc1ccccc1
Solvent: O
Product: Oc1cc(O)cc(O)c1

Procedure:
60 cc of distilled water was added to 0.70 g of natural montmorillonite (as the clay; Kunipia P, made by Kunimine Industries), and this was put into a sealed plastic vessel along with a Teflon® agitator and shaken vigorously, which gave a uniform dispersion. To this dispersion was added 0.30 g of resorcinol powder (as a polyhydric phenol; made by Wako Pure Chemical Industries), and this dispersion was poured into a flat-bottomed brass tray that had a circular bottom measuring about 15 cm in diameter, and the dispersion was allowed to stand horizontally so that the clay particles would gradually settle. With the tray held horizontal, the dispersion was dried for 5 hours at a temperature of 50° C. in a forced air oven, which gave a uniform polyhydric phenol composite clay thin film (phloroglucin Kunipia P thin film) with a thickness of approximately 30 μm. The clay thin film thus produced was dried in an oven held at 110° C. This gave a clay thin film that could be easily peeled from the tray.
Reaction SMILES: CS(O[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)(=O)=O.[I:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.CCOC(C)=O>CN(C=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][CH:6]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[N:34]2[C:33]2[CH:35]=[CH:36][C:30]([I:29])=[CH:31][CH:32]=2)=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Nc1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(C2CCC(c3ccc(Br)cc3)N2c2ccc(I)cc2)cc1
Temperature: 45 °C

Procedure:
The product from Example 42B (1.39 g, 2.499 mmol) in DMF (6.25 mL) was treated with 4-iodoaniline (Aldrich, 4.38 g, 19.99 mmol), heated at 40-50° C. for two hours, cooled and diluted into EtOAc. The EtOAc layer was washed 3×50 mL with 1 M HCl, with water, brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on an ISCO 40 g silica cartridge eluting with 0-20% EtOAc in hexane afforded the title compound as a tan foam as a mixture of stereoisomers (0.96 g, 66%). MS (ESI) m/z 584 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]1[N:9]([CH3:10])[C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:7][N:6]=1.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[O:21][N:20]=1>CN(C=O)C>[Cl:30][C:26]1[CH:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([CH2:18][N:4]([CH3:3])[C:5]3[N:9]([CH3:10])[C:8]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[N:7][N:6]=3)[N:23]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Reactant: CNc1nnc(-c2ccncc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1noc(-c2cccc(Cl)c2)n1)c1nnc(-c2ccncc2)n1C
Yield: 53.7 %

Procedure:
10 mg (0.4 mmol) NaH was added to a solution of 38 mg (0.2 mmol) methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine in 3 ml DMF under an atmosphere of nitrogen. After 10 min a solution of 50 mg (0.22 mmol) 3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole in 2 ml DMF was added. After stirring for 45 min NH4Cl(sat) was added and the mixture was extracted twice with CHCl3. The organic phase was dried and concentrated. Flashchromatography (CH2Cl2/MeOH 20:1) afforded 41 mg (54%) of the desired product. 1H NMR (CDCl3), d (ppm): 3.07 (s, 3 H) 3.71 (s, 3 H) 4.56 (s, 2 H) 7.45 (m, 1 H) 7.55 (m, 1 H) 7.62 (d, 2 H) 7.98 (d, 1 H) 8.09 (m, 1 H) 8.73 (d, 2 H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[O:69][N:68]=[C:67]([C:70](O)=[O:71])[CH:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:67]5[CH:66]=[C:65]([CH3:64])[O:69][N:68]=5)=[O:71])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: Cc1cc(C(=O)O)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2cc(C)on2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.6 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 5-methyl-3-isoxazolecarboxylic acid (0.127 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.115 g). 1H NMR Spectrum: (DMSO d6 373K) 1.87 (m, 2H), 2.08 (m, 2H), 2.48 (s, 3H), 3.61 (m, 2H), 3.89 (m, 2H), 3.96 (s, 3H), 4.80 (m, 1H), 6.40 (s, 1H), 7.22 (m, 1H), 7.22 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.90 (s, 1H), 8.39 (s, 1H), 9.26 (br s, 1H); Mass Spectrum: (M+H)+ 512.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([Sn](C)(C)C)[S:17][C:10]=12>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[S:17][C:10]=12
Reactant: Brc1cncnc1
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Solvent: Cc1ccccc1
Product: Clc1ccnc2cc(-c3cncnc3)sc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Tereakis(triphenylphosphine)palladium (17 mg) was added to a solution of 5-bromopyrimidine (0.057 g, 0.36 mmole) and 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.119 g, 0.36 mmole) in toluene (10 ml). The reaction mixture was stirred at 90° C. overnight. After cooling to room temperature, the mixture was filtered, washed with CH2Cl2 and was partitioned between H2O (20 ml) and CH2Cl2 (2×20 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 0–1% MeOH in CH2Cl2 to give white solid (0.045 g, 51%); 1H NMR (300 MHz, C6D6) δ 9.25 (1H, s), 9.10 (2H, s), 8.64 (1H, d, J=5.1 Hz), 7.89 (1H, s), 7.34 (1H, d, J=5.1 Hz); ESIMS (MH+): 248.00.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:4]2[CH:5]=[CH:6][O:2][CH:3]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: NCC(=O)c1ccoc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccc(Cl)cc1)c1ccoc1
Yield: 100.5 %

Procedure:
5 g of (3-furylcarbonyl)methylamine hydrochloride, 6.0 g of sodium bicarbonate and 6.0 g of 4-chlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(1). 8.2 g of N-(4-chlorobenzoyl)-(3-furylcarbonyl)methylamine are thereby obtained. Yield: 100%
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:32])[N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[O:31]=[C:25]1[CH:24]([N:17]2[C:16](=[O:32])[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][NH:12][C:8]([NH:7][C:3]3[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=3)=[O:9])[C:18]2=[O:23])[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
m-Tolyl isocyanate (0.4 g, 3.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.8 g, 2.3 mmol) and triethylamine (0.3 g, 3.2 mmol) in THF (40 mL) at 5° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with ether (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-m-tolyl-urea (0.7 g, 76%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.23 (s, 3H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 4.71 (d, J=6.0 Hz, 2H), 5.13-5.20 (dd, J=5.4 and 12.6 Hz, 1H), 6.70-6.77 (m, 2H), 7.05-7.17 (m, 2H), 7.25 (s, 1H), 7.75-7.88 (m, 3H), 8.70 (s, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 21.19, 21.99, 30.93, 38.71, 48.86, 114.90, 118.25, 121.85, 121.95, 127.18, 128.46, 131.60, 133.66, 134.71, 137.73, 140.18, 140.30, 155.22, 167.01, 167.59, 169.82, 172.76; Anal. calcd. for C22H20N4O5+0.5H2O: C, 61.53; H, 4.93; N, 13.05. Found: C, 61.87; H, 4.72; N, 12.92.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:4]12[CH2:5][C:6]([OH:8])=[O:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C@@H:17]([OH:25])[CH2:18][CH2:19]1)[N:14]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13]3.O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1>C(Cl)Cl>[CH:2]([C@H:3]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:4]12[CH2:5][C:6]([OH:8])=[O:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[N:14]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13]3)=[O:1]
Reactant: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](CO)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CC[C@H](O)C=C12
Agent: O=[Cr](=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](C=O)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12

Procedure:
A solution of 17β-hydroxymethyl-3β-hydroxy-6-t-butylcarboxy-6-azaandrost-4-ene (182 mg, 0.448 mmol), prepared in part A above, in methylene chloride (7 mL) is added to freshly prepared Collins' reagent. (CrO3 ·2 pyridine) in methylene chloride (12 mL) at 0° C. After 15 minutes the solvent is decanted from the tar, the tar is triturated with methylene chloride (2×30 mL), the combined methylene chloride washed with 2N NaOH, saturated aqueous NaHSO4, saturated aqueous NaCl, dried over MgSO4, concentrated and chromatographed on silica gel (50% ehtyl acetate/hexanes) to give crude 17β-formyl-6-t-butylcarboxy-6-azaandrost-4-en-3-one of sufficient purity to carry on to the following steps; yield: 125 mg (69%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.[CH2:26]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH3:27]>O1CCOCC1>[CH2:26]([C:28]1[N:29]([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=3[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=2)[CH:30]=[CH:31][N:32]=1)[CH3:27]
Reactant: CCc1ncc[nH]1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Solvent: C1COCCO1
Product: CCc1nccn1Cc1cccc(-c2cc(CC(C)C)sc2S(=O)(=O)NC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (70 mg, 0.158 mmol; see Example 1(e)) in dioxane (2.0 mL) was added 2-ethylimidazole (45.4 mg, 0.473 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the sub-title compound in 85% yield as a colourless syrup (61.2 mg, 0.134 mmol).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1)[CH3:2].[CH2:16]([O:18][C@H:19]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=O)=[CH:23][CH:22]=1)[CH3:17].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:16]([O:18][C@@H:19]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][CH:6]=2)=[O:29])=[CH:30][CH:31]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:17]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCNCc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(OC(F)(F)F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of N-ethyl-N-[4-(trifluoromethoxy)benzyl]amine (0.438 g, 2.00 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (40 mL) and the organic phase was washed with 5% HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methylene chloride/ethyl acetate 10:1 as the eluent yielded 0.57 g (58%) of a colourless oil.
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]=C(SC)C=C2OC1C=CC(NC(C2(C(NC3C=CC(F)=CC=3)=O)CC2)=O)=CC=1F.CS[C:43]([S:54][CH3:55])=[C:44]1[C:49](=[O:50])[O:48][C:47]([CH3:52])([CH3:51])[O:46][C:45]1=[O:53]>CCO>[CH3:14][O:13][C:12]1[CH:11]=[C:10]([NH:9][C:43]([S:54][CH3:55])=[C:44]2[C:49](=[O:50])[O:48][C:47]([CH3:52])([CH3:51])[O:46][C:45]2=[O:53])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CSC(SC)=C1C(=O)OC(C)(C)OC1=O
Reactant: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Solvent: CCO
Product: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Yield: 83 %

Procedure:
Synthesis of N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Commercially available 5-(bis-methylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (3.5 g, 14 mmol) and 3,4-dimethoxyoaniline (2.2 g, 14 mmol) were reflux in EtOH (20 mL) for 2 hours. The EtOH was removed under reduced pressure and EtOAc was added to the residue. The product was filtered and washed with cold EtOAc (3×). 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione was obtained as a white solid (1.7 g, 47% yield) and used without further purification. LCMS: m/z 352 (M−H)−.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[CH3:26]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCNC4=O)cc1F

Procedure:
The title compound, light yellow solid (53 mg, 64%), MS (ISP) m/z=334.6 [(M+H)+], mp 255° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)CC)C>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](NC(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (45.31 g) is suspended in dichloromethane (1000 ml), thereto is added 4-chlorobutyryl chloride (31.5 ml) under ice-cooling and to the mixture is added dropwise a solution of triethylamine (81.5 ml) in dichloromethane (80 ml). The reaction solution is warmed to room temperature, stirred for 3 hours and the reaction solution is concentrated under reduced pressure. To the resulting residue are poured ethyl acetate and 5% hydrochloric acid, and the organic layer is separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over sodium sulfate and treated with activated carbon, and the filtrate is concentrated under reduced pressure. The resulting residue is suspended in diisopropyl ether, filtered to collect the precipitates, dried to give methyl trans-4-(4-chlorobutyrylamino)cyclohexanecarboxylate (38.81 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:25]([C:20]2[NH:21][C:22]3[C:18]([CH:19]=2)=[CH:17][C:16]([Cl:15])=[CH:24][CH:23]=3)=[O:26])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc3cc(Cl)ccc3[nH]2)C1

Procedure:
69.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-chloro-1H-indole-2-carboxylic acid to give (R)-3-{[(5-chloro-1H-indole-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Pale yellow solid. MS 376.4 ([M−H]−)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B(O)O)[C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][N:4]=1.Br[C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]>>[Cl:25][C:23]1[CH:24]=[CH:17][C:18]([C:19]#[N:20])=[C:21]([C:7]2[C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:22]=1
Reactant: N#Cc1ccc(Cl)cc1Br
Reactant: COc1cc(B(O)O)c(C(F)(F)F)cn1
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(C(F)(F)F)cn1

Procedure:
1.0 g (4.4 mmol) of 2-methoxy-5-trifluoromethylpyridin-4-ylboronic acid and 0.95 g (4.4 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 351 mg (purity 71%, 18% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([NH:35][C@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])(=[O:34])=[O:33])=[CH:27][C:26]=3[F:42])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:43][CH3:44].C([O-])([O-])=O.[K+].[K+].[Br:51][CH2:52][CH2:53][CH2:54]Br>CC#N>[Br:51][CH2:52][CH2:53][CH2:54][N:35]([C@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])[S:32]([C:28]1[CH:27]=[C:26]([F:42])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:43][CH3:44])[CH:4]=3)([CH3:9])[CH3:10])=[CH:12][N:13]=2)=[C:30]([F:31])[CH:29]=1)(=[O:33])=[O:34]
Reactant: BrCCCBr
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@@H](C)N(CCCBr)S(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Temperature: 60 °C
Yield: 0 %

Procedure:
To a solution of (R)-methyl 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)propanoate (200 mg, 0.30 mol) in MeCN (4 mL) were added K2CO3 (124 mg, 0.90 mol) and 1,3-dibromopropane (121 mg, 0.60 mol). The reaction flask was heated at 60° C. for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting product was purified by column chromatography (silica, Hex/EtOAc, 1:1) to afford (R)-methyl 2-(N-(3-bromopropyl)-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)propanoate (113 mg, 47%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 2H), 7.19 (s, 1H), 7.16-7.18 (d, 1H), 6.80-6.84 (t, 2H), 6.50-6.53 (m, 2H), 6.43-6.46 (m, 2H), 4.63-4.65 (q, 1H), 4.13 (s, 2H), 3.72 (s, 3H), 3.55 (s, 3H), 3.27-3.45 (m, 4H), 2.10-2.31 (m, 2H), 1.47 (s, 6H), 1.45 (s, 3H).
Reaction SMILES: Cl[C:2]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[N:3][OH:4].[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].C(N(CC)CC)C>C(OCC)C>[CH2:12]([O:14][C:15]([C:16]1[C:2]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:10]=2[Cl:11])=[N:3][O:4][C:17]=1[CH3:18])=[O:19])[CH3:13]
Reactant: ON=C(Cl)c1cnccc1Cl
Reactant: CC#CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2cnccc2Cl)noc1C
Yield: 27.4 %

Procedure:
Combine chloro(4-chloro(3-pyridyl))(hydroxyimino)methane (2.40 g, 0.013 mol) with ethyl-2-butynoate (3.66 mL, 0.031 mol) in diethyl ether (150 mL) under a nitrogen atmosphere. Add triethylamine (2.27 mL, 0.016 mol) in a dropwise manner and stir over a weekend at ambient temperature. Quench the mixture with water and extract with ethyl acetate. Concentrate the combined extracts and elute over silica gel with methanol/dichloromethane to give the desired isoxazole (0.95 g, 27%) as an oil. ES(EI): M+ 266.0, 267.0, 268.0 m/z.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(Br)oc1C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2cccc(OC)c2)oc1C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 3-methoxyphenylboronic acid (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.3 g, 92%) as a white solid.