Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:26])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=2)[O:6][C:5]1=[O:25])[CH:2]=[CH2:3].[NH2:27][C@@H:28]([CH:31]1[CH2:33][CH2:32]1)[CH2:29][OH:30]>C(OCC)(=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH:7]([OH:6])[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH2:9][C@:4]([CH3:26])([CH2:1][CH:2]=[CH2:3])[C:5]([NH:27][C@@H:28]([CH:31]2[CH2:33][CH2:32]2)[CH2:29][OH:30])=[O:25])=[CH:18][C:19]=1[F:24]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)c(F)c2)OC1=O
Reactant: N[C@H](CO)C1CC1
Solvent: CCOC(C)=O
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)C(O)c1ccc(Cl)c(F)c1)C(=O)N[C@H](CO)C1CC1
Temperature: 100 °C

Procedure:
(3S,5R,6R)-3-Allyl-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (32 g, 81 mmol, Example 4, Step E) was combined with (S)-2-amino-2-cyclopropylethanol (26.7 g, 265 mmol) and the suspension was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with 1 N hydrochloric acid (2×), water, and brine. The organic layer was dried over magnesium sulfate and concentrated under vacuum to provide the title compound as a white solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([C:30]3[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)[CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[N:34][CH:35]=3)[C:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:17]=4)[C:11]=3[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[CH3:55][S:56]([N:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:18]2[CH:17]=[C:16]([N:13]3[C:11]4[N:12]=[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[N:8]=[C:9]([C:30]5[CH:31]=[N:32][C:33]([N:36]([CH2:37][C:38]6[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=6)[CH2:46][C:47]6[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=6)=[N:34][CH:35]=5)[C:10]=4[CH2:15][CH2:14]3)[CH:21]=[CH:20][CH:19]=2)[CH2:25][CH2:26]1)(=[O:58])=[O:57]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CCN4CCNCC4)c3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CCN4CCN(S(C)(=O)=O)CC4)c3)cn2)cc1

Procedure:
In the same manner as Example 1-D-134, using a crude product (80 mg) of 5-{2-morpholin-4-yl-7-[3-(2-piperazin-1-yl-ethyl)-phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine obtained in Example 1-D-134 and methanesulfonyl chloride (0.017 ml) instead of acetyl chloride, a crude product of 5-(7-{3-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained as a pale yellow solid (82 mg, 93%). Using this crude product (82 mg) of 5-(7-{3-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2,5-(7-{3-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-ylamine was obtained as a colorless powder (28 mg, 49%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:33])[CH2:15][C:16]2[C:21](Cl)=[CH:20][N:19]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:33][C:21]3[CH:20]=[N:19][C:18]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)=[N:17][C:16]=3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)Cc2nc(-c3ccc(S(C)(=O)=O)cc3)ncc2Cl)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3nc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-{2-[5-chloro-2-(4-methanesulfonyl-phenyl)-pyrimidin-4-yl]-1-hydroxy-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg), palladium acetate (3 mg), racemic 2-(di-tert-butylphosphino)-1,1′-binapthyl (6 mg), and cesium carbonate (50 mg) in toluene (1 mL) is heated in an oil bath at 70° C. under an argon atmosphere for 6 h. After cooling to room temperature ethyl acetate is added and the organic phase is separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel [dichloromethane/(dichloromethane/methanol/NH4OH 24:24:1) 96:4→90:10]. The crude product is triturated with diethyl ether, filtered off, and dried to give the title compound. LC (method 7): tR=1.44 min; Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7]([CH3:10])=[N:8][CH:9]=1.[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([O:11][C:6]1[C:7]([CH3:10])=[N:8][CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ncc(CO)cc1O
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(CO)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.7 g. of 5-hydroxymethyl-2-methyl-3-pyridinol hydrochloride in 10 ml. of dimethylformamide was added a solution of 0.9 g. of 50% sodium hydride in 6 ml. of dimethylformamide. The mixture was stirred at room temperature for 3 hours and to the solution was added 1.25 g. of benzyl chloride and additional stirring was continued overnight at room temperature.
Reaction SMILES: [CH2:1]([P:17](=[O:20])([OH:19])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+:22]>CCCCCC>[Na+:22].[CH2:1]([P:17](=[O:18])([OH:20])[O-:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCP(=O)([O-])O
Yield: 98 %

Procedure:
Example 17 is repeated with 306 g (1 mol) of hexadecylphosphonic acid (produced as in example 13) and 100 ml of a 10 molar solution of sodium hydroxide being reacted in 1.5 l of hexane to obtain 320 g (98% of theory) of hexadecylphosphonic acid monosodium salt as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](C)([C:14](OCC)=O)[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[Li+:20].[OH-]>CO.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:14])[C:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[Li+:20]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(Cl)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)[O-])c1ccc(Cl)nn1

Procedure:
A solution of diethyl 2-(6-chloropyridazin-3-yl)-2-methylmalonate (19.8 g, 69.1 mmol) and LiOH (3.31 g, 138 mmol) in MeOH:Water (3:1, 200 mL) was stirred at 25° C. for 3 hrs. MeOH was removed from the reaction via rotary evaporation, and the resulting residue was reconstituted in H2O (300 mL). The aqueous mixture was washed with Et2O (3×100 mL) and then lyophilized to dryness to provide lithium 2-(6-chloropyridazin-3-yl)propanoate 48B in quantitative yield. The material was used without further work-up. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (3 H, d, J=7.33 Hz) 3.63 (1 H, q, J=7.24 Hz) 7.71 (2 H, s). ESI-MS:m/z 187.0 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[CH2:7][CH2:8][C@H:9]([NH:20]C(OCC1C=CC=CC=1)=O)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])C.[C:33]1([CH:40]=[CH:39][CH:38]=[C:36]([OH:37])[CH:35]=1)[OH:34].CCOCC.C(O)(C(F)(F)F)=O>CS(O)(=O)=O.O.CC#N>[CH:40]1[C:33]([OH:34])=[CH:35][C:36]2[O:37][C:4]([CH:5]=[C:6]([CH2:7][CH2:8][C@@H:9]([NH2:20])[C:10]([OH:12])=[O:11])[C:38]=2[CH:39]=1)=[O:3]
Reactant: CCOC(=O)CC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: Oc1cccc(O)c1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: N[C@H](CCc1cc(=O)oc2cc(O)ccc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
(2S)-2 Benzyloxycarbonylamino-5-oxo-heptanedioic acid 1-benzyl ester 7-ethyl ester from the previous step (2.35 g, 5 mmol) was added slowly to resorcinol (3 g, 25 mmol) in methanesulfonic acid (20 ml) and stirred for two hours at room temperature. Five volumes of ether were then added to the mixture and was cooled to −30° C. The precipitate was washed with cold ether, dissolved in water, filtered, and lyophilized. L-(7-hydroxycoumarin-4-yl)ethylglycine was purified by reverse phase HPLC to afford a brown solid in 50% yield (YMC AA12S052503WT column, 12 ml/min flow rate, from 10% to 90% CH3CN, 0.1% TFA (w/v) in water, over the course of 12 min). 1H-NMR (DMSO): δ 2.06 (s, 2H), 2.70-2.90 (m, 2H), 3.82-4.0 (m, 1H), 6.06 (s, 1H), 6.75 (dd, J=8.8, 2.4, 1H), 6.82 (d, J=2.4, 1H), 7.62 (d, J=8.8, 1H), 8.17 (s, 3H). LC-MS (ESI) calc. for C13H14NO5 (M+H+) 264.08 Da, obsd. 264.0 Da.
Reaction SMILES: C(OC1C=CC=CC=1N1CCCN(C[CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[CH:27][C:28](=[O:32])[NH:29]3)=[CH:24][CH:23]=2)CC1)C.[Br:33]CCCBr.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:33][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28](=[O:32])[NH:29]2)=[CH:24][CH:23]=1
Reactant: BrCCCBr
Reactant: CCOc1ccccc1N1CCCN(CCCCOc2ccc3ccc(=O)[nH]c3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=c1ccc2ccc(OCCCBr)cc2[nH]1
Yield: 54.6 %

Procedure:
A mixture of intermediate 14 (193 mg, 1.2 mmol), 1,3-dibromopropane (0.37 mL, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=2:1) to give 7-(3-bromopropoxy)quinolin-2(1H)-one (intermediate 32) (185 mg, 55%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:13][CH3:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CSc1ccccc1N=C=O
Product: CSc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 60.9 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-methylthio phenyl isocyanate(3.24 mmol) by general Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.63 g, 61%). EI-MS m/z 320(M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:20]C)=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[B].O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1C(=O)O
Agent: [B]
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cc2c(-c3cccc(F)c3)n[nH]c2cc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
A total of 96.2 mg of 3-(3-fluoro-phenyl)-6-methoxy-1H-indazole-5-carboxylic acid obtained in Production Example II-1-e was dissolved in 3.36 ml of dichloromethane, 4.0 ml of a 1.0 M solution of boron tribormide in dichloromethane was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The resulting organic layer was washed brine, dried over magnesium sulfate and the solvent was evaporated, to give 84.1 mg of the crude product of the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]3[C:15]([C:16]([C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:25][CH:24]=4)=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)O1.FC(F)(F)S(O[C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][C:50]([O:56][CH3:57])=[CH:51][CH:52]=2)[CH:47]=1)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C(=CC(=CC=1)C)C)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.CC(O)C>[CH3:57][O:56][C:50]1[CH:49]=[C:48]2[C:53]([CH:54]=[CH:55][C:46]([C:9]3[C:22]4[C:17]([C:16]([C:23]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)=[CH:25][CH:24]=5)=[C:15]5[C:10]=3[CH:11]=[CH:12][CH:13]=[CH:14]5)=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:47]2)=[CH:52][CH:51]=1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Reactant: CC1(C)OB(c2c3ccccc3c(-c3ccc(-c4ccccc4)c4ccccc34)c3ccccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(C)c(C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2ccc(-c3c4ccccc4c(-c4ccc(-c5ccccc5)c5ccccc45)c4ccccc34)cc2c1
Yield: 66.9 %

Procedure:
Under the nitrogen atmosphere, 4,4,5,5-tetramethyl-2-(10-(4-phenylnaphthalen-1-yl)anthracen-9-yl)-1,3,2-dioxaborolane (23.0 g) as the nineteenth intermediate compound, 7-methoxynaphthalen-2-yl trifluoromethane sulfonate (18.0 g), Pd(PPh3)4 (1.6 g), potassium phosphate (19.3 g), and a mixture solvent (125 ml) of pseudo cumene, IPA, and water (pseudo cumene/IPA/water=20/4/1 (volume ratio)) were added to a flask and refluxed for 5 hours. Once the heating is completed, liquid separation was performed by adding water and toluene. The solvent was distilled off under reduced pressure and the resulting solid was purified by silica gel column chromatography (solvent: heptane/toluene=1/1). The obtained crude product was washed further with methanol to give 9-(7-methoxynaphthalen-2-yl)-10-(4-phenylnaphthalen-1-yl)anthracene (16.3 g) as a twentieth intermediate compound. The scheme is shown in the following “Reaction 32”.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][S:10][C:11]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=2[NH2:13])=[C:6]([CH:8]=1)[NH2:7].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]([S:10][S:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:8][C:6]=2[NH:7][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:29])=[O:30])=[C:12]([NH:13][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:30])=[O:29])[CH:14]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1SSc1ccc(Cl)cc1N
Product: O=S(=O)(Nc1cc(Cl)ccc1SSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1)c1cc2ccccc2o1

Procedure:
Following General Procedure F, the title compound was prepared from 2,2′-dithiobis(5-chloroaniline) and 1-benzofuran-2-sulfonyl chloride.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:23]O>>[C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH3:23])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)c1cccc2cc(-c3ccccc3)oc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2cc(-c3ccccc3)oc12

Procedure:
7.0 g of 2-phenylbenzofuran-7-carboxylic acid are dissolved in 70 ml of methanol, and 6.4 ml of thionyl chloride are added dropwise thereto at 0° C. The mixture is refluxed for 1 hour and evaporated to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from n-hexane to give 7.04 g of methyl 2-phenylbenzofuran-7-carboxylate as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH:21]3[O:17][CH:18]([CH:19]=[CH:20]3)[CH:13]2[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)C=CC(=O)O)cc1
Reactant: c1ccoc1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)C2C3C=CC(O3)C2C(=O)O)cc1
Temperature: 55 °C

Procedure:
3-(4-Methoxyphenylsulfonyl)propenoic acid (200 mgs), excess furan (5.0 ml), and dry toluene (5.0 ml) were combined and warmed to 55° C. (at which time starting material went into solution) for overnight. The cooled reaction was concentrated in vacuo to a tan solid which was a mixture of starting material and product. The material was taken up in toluene (5 ml) and furan (10 ml) and heated to 69° C. overnight. The cooled reaction mixture was concentrated in vacuo to give 251 mgs of crude 3-(4-Methoxyphenylsulfonyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as a dark tan solid.
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[C:13]2[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=2[CH2:7][S:6]1)[CH3:4].[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C@@H:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])[C:29]([N:17]2[CH2:16][CH2:15][N:14]([C:12]3[C:13]4[CH:5]([CH2:3][CH3:4])[S:6][CH2:7][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:19][CH2:18]2)=[O:30])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CCC1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1SCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
To a solution of 5-ethyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (50 mg, 0.15 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (46 mg, 0.15 mmol) in DCM (10 mL) and triethylamine (1 mL) was added HBTU (59 mg, 0.15 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with DCM/ethyl acetate (1:1) to give tert-butyl (R)-3-(4-chlorophenyl)-1-(4-(5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (50 mg, 60%). 1H NMR (CDCl3, 400 MHz) δ 8.53 (s, 1H), 7.26-7.14 (m, 4H), 5.36 (m, 1H), 4.82 (m, 1H), 4.62 (m, 1H), 4.14 (m, 1H), 3.80-2.90 (m, 8H), 1.94 (m, 1H). 1.68 (m, 1H), 1.54 (m, 1H), 1.42 (s, 9H), 0.94 (m, 3H). MS (APCI+) [M+H]+ 533.
Reaction SMILES: ClC(Cl)(Cl)[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CO>[CH3:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCN(C(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N1
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.2 %

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (3.01 g, 5.66 mmol) in tetrahydrofuran/methanol (1:1, 60 mL) was stirred at 0° C. Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran, 11.3 mL, 11.3 mmol) was added and the reaction mixture was stirred at room temperature for 22 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 afford the title compound (2.14 g, 91%) as a white foam. 1H NMR (300 MHz, CDCl3) δ □0.91 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 1.32 (d, J=6.9 Hz, 3H), 1.46 (s, 9H), 1.61-2.17 (m, 6H), 2.80-2.88 (m, 1H), 3.47-3.58 (m, 1H), 3.73-3.78 (s, 3H), 3.94-4.02 (m, 1H), 4.33-4.38 (m, 1H), 5.13 (d, J=8.3 Hz, 1H), 5.27-5.37 (m, 1H), 6.75 (d, J=7.6 Hz, 1H). LCMS (m/z) 415.1 [M+H], Tr=3.17 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:22])(=[O:21])[NH:19][CH3:20])=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][C:6]=2[CH:27]=1.B([O-])([O-])O[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(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.C1(C)C=CC=CC=1>[CH2:40]([O:39][CH2:38][CH2:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([C:12]4[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:22])[NH:19][CH3:20])=[CH:14][CH:13]=4)[CH2:10][CH2:9][C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][C:6]=3[CH:27]=2)=[CH:35][CH:34]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CNS(=O)(=O)c1ccc(N2CCC(C(=O)OC)=Cc3cc(Br)ccc32)cc1
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: CCO
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(S(=O)(=O)NC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A mixture of methyl 7-bromo-1-(N-methyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1 g), 4-(2-butoxyethoxy)phenyl borate (0.69 g), 1M potassium carbonate solution (8 ml), ethanol (8 ml) and toluene (100 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.13 g), and the mixture was refluxed under argon atmosphere for 2.5 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(N-methyl4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.1 g) as colorless crystals.