Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].N1C=CN=C1.[C:12]([Si:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)Cl)([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[Si:16]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:12]([CH3:15])([CH3:14])[CH3:13])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45 %

Procedure:
Commercially available 1,4-butanediol (400 g) was dissolved in DMF (120 ml), added with imidazole (3.02 g) and t-butyldiphenylchlorosilane (12.2 g), and stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and then added with a saturated aqueous ammonium chloride solution, followed by separation/extraction with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (6.56 g) as a transparent and colorless oily substance.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12]1COCC1>>[CH2:12]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: O=C1CCCc2ccccc21
Reactant: C1CCOC1
Product: C=C1CCc2ccccc2C1=O

Procedure:
To a solution of 1-tetralone (164.5 g) in about 400 ml THF was added, in four separate portions, TAMA (243 g) and trioxymethylene (99 g) over 31/2 hours, and the mixture refluxed for 20 hours. The mixture was cooled and portioned between Et2O and water, the layers separated and the aqueous layer extracted twice with Et2O. The combined Et2O layers are exhaustively washed with water, NaHCO3 and then with brine, dried (MgSO4) and concentrated in vacuo to yield an oil which is flash chromatographed on silica gel using CH2Cl2 in several runs of 10-20 g per run. Fractions containing the fast moving material are combined, concentrated in vacuo to obtain the desired 2-methylene-1-tetralone.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CCC.IC1C=NNC=1>>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]=1[CH3:7]
Reactant: Cc1n[nH]c(C)c1Br
Reactant: CCCCCCCCBr
Agent: Ic1cn[nH]c1
Product: CCCCCn1nc(C)c(Br)c1C

Procedure:
The desired product was prepared by substituting 5-iodopentane and 4-bromo-3,5-dimethylpyrazole for 1-bromooctane and 4-iodopyrazole, respectively, in Example 198A. MS (ESI(+)) m/e 245, 247 (M+H)+.
Reaction SMILES: C1([SiH3])C=CC=CC=1.[NH2:8][C:9]1[C:23]([C:24]([O:26]CC=C)=[O:25])=[C:12]2[N:13]=[C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][N:11]2[N:10]=1.CCOCC>C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[NH2:8][C:9]1[C:23]([C:24]([OH:26])=[O:25])=[C:12]2[N:13]=[C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][N:11]2[N:10]=1
Reactant: C=CCOC(=O)c1c(N)nn2ccc(OCCN(C)C)nc12
Agent: [Pd]
Agent: [SiH3]c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C)CCOc1ccn2nc(N)c(C(=O)O)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
Palladium triphenylphosphane (170.3 mg, 0.1474 mmol) was added to a solution of phenylsilane (478.5 mg, 550 μL, 4.422 mmol) and allyl 2-amino-5-[2-(dimethylamino)ethoxy]pyrazolo[1,5-a]pyrimidine-3-carboxylate 4b (900 mg, 2.948 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 3 h. Ether was slowly added and the white solid was then filtered off, washed with small amount of diethyl ether and dried to afford pure product as off-white solid (yield 67%); LC-MS (M+H)+=266.1; 1H NMR (500 MHz, DMSO-d6) δ 12.35 (brs, 1H), 9.65 (brs, 1H), 8.72 (d, 1H), 6.55 (d, 1H), 6.25-6.15 (m, 2H), 4.73-4.70 (m, 2H), 3.58-3.55 (m, 2H), 2.90 (s, 6H);
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([O:11][C:12]2[CH:13]=[CH:14][C:15]([N+:19]([O-])=O)=[C:16]([CH:18]=2)[NH2:17])=[N:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([C:7]([F:9])([F:10])[F:8])=[CH:5][C:4]([O:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:19])=[C:16]([NH2:17])[CH:18]=2)=[N:3]1
Reactant: Cn1nc(Oc2ccc([N+](=O)[O-])c(N)c2)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1nc(Oc2ccc(N)c(N)c2)cc1C(F)(F)F
Reaction time: 1.5 h

Procedure:
The nitroaniline obtained in step A (2 g, 6.6 mmol) was dissolved in 50% aqueous ethanol (100 cm3) and sodium dithionite (4.61 g 26.5 mmol) added portionwise over 20 minutes to the stirred solution, each portion being allowed to dissolve before adding the next. The reaction mixture was heated under reflux with stirring for 1.5 hours and after cooling was poured into water (50 cm3) and neutralised with aqueous sodium bicarbonate before being extracted with ethyl acetate (2×100 cm3). The combined extracts were dried (MgSO4) and the solvent removed in vacuo leaving a light brown solid which was triturated with hexane, filtered and dried, to give 4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)-o-phenylenediamine m.p. 109°-111° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](O)=[O:15])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:24]1([CH2:30][CH2:31][O:32][C:33]2[CH:51]=[CH:50][C:36]3[N:37]4[CH:42]=[C:41]([C:43]5[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=5)[N:40]=[C:38]4[S:39][C:35]=3[CH:34]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:14]([NH:47][C:46]2[CH:45]=[CH:44][C:43]([C:41]3[N:40]=[C:38]4[N:37]([CH:42]=3)[C:36]3[CH:50]=[CH:51][C:33]([O:32][CH2:31][CH2:30][N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[CH:34][C:35]=3[S:39]4)=[CH:49][CH:48]=2)=[O:15])=[O:11])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)c1
Reactant: Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)c1
Temperature: 155 °C
Reaction time: 24 h

Procedure:
Working as in the example 4, but using (S)-2-(2-(3,5-dimethylphenyl)acetamido)-3-phenyl-propionic acid and [4-(7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b]benzothiazol-2-yl]aniline and reagents as HATU and DIPHEA in dry DMF. The reaction mixture was stirred at room temperature for 6 h, at 70° C. for 48 h and at 155° C. for 24 h. Then the solvent was removed under reduced pressure and the crude mixture was purified by flash chromatography to give the desired product (S)-2-(3,5-dimethylphenylacetamido)-3-phenyl-N-[4-(7-(2-morpholin-4-yl-ethoxy)-imidazo[2,1-b]benzothiazol-2-yl)phenyl]propanamide
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=O)[CH2:10][CH2:11][CH3:12].[OH-].[K+]>>[CH2:1]([NH:8]/[CH:9]=[CH:10]/[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCCC=O
Agent: [K+]
Agent: [OH-]
Product: CC/C=C/NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To benzylamine (5.46 mL, 50 mmol), at 0° C., was added butyraldehyde (4.51 mL, 50 mmol). The mixture was warmed to room temperature and KOH (1.5 g) was added. The mix was stirred at room temperature for 15 minutes, the water was removed and 0.5 g of KOH was added. The mixture was stirred at room temperature overnight and filtered to remove the KOH to yield 6 g (74%) of 62a.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C([O-])(=[O:16])C.[Na+].CN(C)C=O>O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][OH:16]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc2ccccc2n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 2-chloromethylquinoline hydrochloride (21.4 g), sodium acetate (32.8 g) and N,N-dimethylformamide (200 ml) was stirred at 60° C. overnight. After cooling, the reaction solution was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. A mixture of the residue, 4N aqueous sodium hydroxide solution (50 ml), tetrahydrofuran (100 ml) and methanol (100 ml) was stirred at room temperature for 1 hour, and poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-quinolylmethanol (14.0 g, yield 88%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 68–69° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:30]=1[CH2:31]Br>C1COCC1>[C:13]([NH:21][CH:22]([CH2:31][C:30]1[C:29]([Cl:28])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:37])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CCOC(=O)CNC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1c(Cl)cccc1Cl)NC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution comprised of N,N-diisopropylamine (3.97 mL, 22.8 mmol) in dry THF (57 mL) was cooled to −78° C. under nitrogen and then solutions of n-butyl lithium in hexanes (14.25 mL, 22.8 mmol) and ethyl benzoylaminoacetate (2.37 g, 11.4 mmol) in dry THF (23 mL) were added dropwise sequentially. The mixture was stirred for 1 hour and then a solution comprised of 2,6-dichlorobenzyl bromide (1.87 g, 11.4 mmol) in dry TMF (2 mL) was added dropwise. The mixture was stirred for 1 hour at −78° C. and then for 30 minutes while allowing to warm. The mixture then was quenched with water (8 mL) and extracted with ethyl acetate (2×54 mL). The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane) to provide crude ethyl 2-benzoylamino-3-(2,6-dichlorophenyl)propionate. The propionate ester was treated with lithium hydroxide (118.8 mg, 4.96 mmol) in ethanol (12 mL) and water (50 mL) for 15 hours. The mixture was then diluted with 1M hydrochloric acid (12 mL) and ethyl acetate (24 mL). The aqueous layer was separated and extracted with ethyl acetate (2×4 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL), dried (Na2SO4), filtered and concentrated on a rotary evaporator to provide 2-benzoylamino-3-(2,6-dichlorophenyl)propionic acid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2(SCC)[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:31])[C@:7]1([CH3:30])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:29])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]>C(C1C=CC=CC=1CC)C>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH:18]=[C:19]2[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:31])[C@:7]1([CH3:30])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:29])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Agent: CCc1ccccc1CC
Product: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Temperature: 180 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A suspension of 5.2 g of 11β-(acetyloxy)-17,17-bis(ethylthio)-9-fluoroandrosta-1,4-dien-3-one in 85 ml of dry diethylbenzene was stirred at 180° C. (oil bath temperature) for 1.0 hour; the suspension gradually became a homogeneous solution during the heating. The resulting solution was cooled to 0° C. and the solid that precipitated was filtered and dried in vacuo to give 3.6 g of the title compound, melting point 211°-214° C.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:33]([CH2:38][OH:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.Br.[N+:41]([C:44]1[C:45]([S:50][S:51][CH2:52][CH2:53][C:54]([OH:56])=O)=[N:46][CH:47]=[CH:48][CH:49]=1)([O-:43])=[O:42].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)C.C(O)(=O)C>[N+:41]([C:44]1[C:45]([S:50][S:51][CH2:52][CH2:53][C:54]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:33]([CH2:38][OH:39])[CH2:34][CH:35]([CH3:36])[CH3:37])=[O:31])[CH2:24][C:25]2[N:29]=[CH:28][NH:27][CH:26]=2)=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:56])=[N:46][CH:47]=[CH:48][CH:49]=1)([O-:43])=[O:42]
Reactant: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: O=C(O)CCSSc1ncccc1[N+](=O)[O-]
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CCSSc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.16 g. (0.3 mmole) of N-benzyloxycarbonyl-L-phenylalanyl-L-histidyl-L-leucinol were added 3 ml. of a 25% w/v glacial acetic acid solution of hydrogen bromide. The mixture was stirred at room temperature for 30 minutes, and then anhydrous diethyl ether was added thereto. The precipitate thus formed was separated by filtration and dissolved in 5 ml. of dimethylformamide. The solution was cooled with ice, and then there were added 30 mg. of N-methylmorpholine for neutralization. To the neutralized solution were added an active ester prepared from 86 mg. (0.33 mmole) of 3-(3-nitro-2-pyridyldithio)propionic acid, 39 mg. (0.33 mmole) of 1-hydroxybenztriazole and 74 mg. (0.36 mmole) of DCC. The mixture was stirred for 1 hour whilst cooling with ice and then overnight at room temperature, after which it was treated in a conventional manner to give a yellow powder, which was purified by silica gel column chromatography (eluent: chloroform/methanol=8:1 by volume), to afford 47 mg. of the desired compound as a yellow powdery solid, melting at 109°-112° C.; [α]22 -33.8° (C=0.5, methanol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:37]=[CH:36][C:27]([CH2:28][CH2:29][CH2:30][PH:31](=[O:35])[O:32]CC)=[CH:26][C:25]=3[O:38][CH3:39])[N:14]=2)=[CH:4][CH:3]=1.Br[Si](C)(C)C.CO>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:37]=[CH:36][C:27]([CH2:28][CH2:29][CH2:30][PH:31](=[O:32])[OH:35])=[CH:26][C:25]=3[O:38][CH3:39])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCO[PH](=O)CCCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Agent: C[Si](C)(C)Br
Solvent: c1ccncc1
Solvent: CO
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of ethyl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)ethylphosphinate (Compound 67C, 1.11 g, 1.76 mmol) in pyridine (15.0 mL) was cooled to 0° C. and then charged with bromotrimethylsilane (1.39 mL, 10.6 mmol). The reaction mixture was slowly warmed to rt with stirring for 72 hours. The reaction mixture was quenched with MeOH (2.3 mL, 57 mmol) and then concentrated under reduced pressure to a yellow oil. The material was dissolved in DCM (10 mL) and washed with 3N HCl (10 mL), was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to a light yellow solid. The acid layer was saturated with solid NaCl and extracted with DCM (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to a light yellow solid. Both batches of solid were combined (932.5 mg, 88%). 1H NMR (CDCl3, 400 MHz): δ=8.91 (d, J=8.3 Hz, 1H), 8.34 (s, 1H), 8.10 (q, J=4.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 6.89 (s, 1H), 6.82 (d, J=8.1 Hz, 1H), 3.87 (s, 3H), 3.00-3.10 (m, 5H), 1.54-1.68 (m, 2H), 1.13 (td, J=7.5, 18.3 Hz, 3H). MS (ESI): m/z 603.42/605.40 [M+H]+. UPLC: tR=1.24 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=CC=3S[C:3]=12.[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH2:20].Cl.N1C=CC=CC=1>CO>[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:16][CH:15]=[CH:14][C:3]=12
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: N#Cc1cnc2ccccc2c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 250 mg (1.02 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, 530 mg (3.27 mmol) of 2,4-dichloroaniline and 112 mg of pyridine hydrochloride is heated until no 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile remained as measured by thin layer chromatography. The reaction mire is cooled to room temperature and the solid is treated with methanol and then partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the solid is collected by filtration to give 225 mg (66%) of a yellow solid. An analytical sample is obtained by column chromatography, eluting with 6:1 hexane/ethyl acetate, to provide a fight yellow solid, mp 260–262° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:15]2[C:16](=[O:19])[CH2:17][O:18][C:14]=2[C:13]([CH3:20])=[C:12]([CH3:21])[CH:11]=1>C(Cl)Cl>[Br:1][C:11]1[C:12]([CH3:21])=[C:13]([CH3:20])[C:14]2[O:18][CH2:17][C:16](=[O:19])[C:15]=2[C:10]=1[CH3:9]
Reactant: Cc1cc(C)c2c(c1C)OCC2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1Br)C(=O)CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.4 %

Procedure:
N-bromosuccinimide (27.1 g, 152 mmol) was added to a solution of methylene chloride (200 mL) containing 4,6,7-trimethyl-1-benzofuran-3(2H)-one (20.7 g, 117 mmol) synthesized in Reference Example 44, and the mixture was stirred at room temperature for 24 hours. After that, the solvent was removed under reduced pressure, and water was added to the residue. The generated crystals were collected by filtration, and recrystallized from ethyl acetate to give 24.0 g of the title compound (yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1.C(=O)([O-])[O-:19].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH2:17])=[O:19])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(-c2ccc(CO)cc2Cl)c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cccc(-c2ccc(CO)cc2Cl)c1
Reaction time: 18 h

Procedure:
2′-Chloro-4′-hydroxymethyl-biphenyl-3-carbonitrile (I-6c) was dissolved in 50 mL of dimethylsulfoxide and treated with potassium carbonate (2.8 g) followed by an aqueous hydrogen peroxide solution (10 mL of a 30% solution). After 18 hours, the reaction mixture was combined with 200 mL of water and extracted with ethyl acetate. The organic layer was washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (I-6d).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][C:28]#[CH:29])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[CH:31]1([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41](I)[CH:40]=2)(=[O:38])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>CC#N.C(N(CC)CC)C>[CH:31]1([S:36]([C:39]2[CH:40]=[C:41]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]3[CH2:13][C@@H:12]([C:10]4[CH:9]=[CH:8][C:6]5[O:7][C:2]([CH3:30])([CH3:1])[O:3][CH2:4][C:5]=5[CH:11]=4)[O:16][C:15]3=[O:17])[CH:42]=[CH:43][CH:44]=2)(=[O:37])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C#CCCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Reactant: O=S(=O)(c1cccc(I)c1)C1CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCC#Cc4cccc(S(=O)(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Reaction time: 4 h
Yield: 78.2 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(4-pentyn-1-yloxy)hexyl]-1,3-oxazolidin-2-one (207 mg) and 1-(cyclopentylsulfonyl)-3-iodobenzene (Example 8iii.) (202 mg) in MeCN (8 ml) and triethylamine (4 ml) was deoxygenated by bubbling a nitrogen stream through for 10 min. Copper (I) iodide (10 mg) and dichlorobis(triphenylphosphine)palladium (II) (18 mg) were added and the mixture stirred at 20° for 4 h. The solvent was evaporated in vacuo and the residues purified by using a SPE silica bond elut cartridge (10 g, silica). Elution with DCM (1vol), EtOAc-cyclohexane (1:4) (3vols), (1:3) (1vol) then (1:1) (3vols) gave the title compound (243 mg). LCMS RT=3.79 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([S:13](Cl)(=[O:15])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[NH2:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]([NH:38]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:29]([N:31]3[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]3)=[O:30])[S:26][C:22]=2[CH:21]=[CH:20][N:19]=1>>[NH2:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]([NH:38][S:13]([N:9]3[CH2:8][CH2:7][C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:10]3)(=[O:15])=[O:14])[C:29]([N:31]3[CH2:32][CH2:33][CH:34]([CH3:37])[CH2:35][CH2:36]3)=[O:30])[S:26][C:22]=2[CH:21]=[CH:20][N:19]=1
Reactant: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Product: COc1ccc2c(c1)CN(S(=O)(=O)NC(Cc1cc3c(N)nccc3s1)C(=O)N1CCC(C)CC1)CC2

Procedure:
This compound was prepared from 200 mg of 7-methoxy-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 110 mg; m.p. 175-176° C., (+)-FAB-MS: 544 (MH+).