Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:35]=[N:36][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[N:38][CH:39]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:43][C:40]5([C:37]6[N:36]=[CH:35][C:34]([CH3:33])=[CH:39][N:38]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1cnc(C2(N)CC2)nc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)cn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(5-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.025 g (49%). 1H NMR (400 MHz, CD3OD): δ 8.50 (d, J=0.8 Hz, 2H), 8.01-7.96 (m, 2H), 7.92 (s, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 7.34 (dd, J=1.9, 8.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.15 (s, 1H), 4.08 (s, 3H), 2.96 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 1.80-1.69 (m, 2H), 1.52-1.43 (m, 2H). 19F NMR (376.47 MHz, CD3OD): 6-113.45 LCMS: (ES+) m/z=565.2 (M+H)+
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:23])[N:5]([P@:13]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])CC1C=CC=CC=1.[NH2:25][O:26][K].Cl>>[OH:26][NH:25][C:3](=[O:2])[C@H:4]([NH:5][P@:13]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH3:23]
Reactant: CC[P@](=O)(c1ccccc1)N(Cc1ccccc1)[C@H](C)C(=O)OC
Reactant: NO[K]
Agent: Cl
Product: CC[P@@](=O)(N[C@H](C)C(=O)NO)c1ccccc1
Reaction time: 16 h

Procedure:
N-((S)-Ethylphenylphosphinyl)-N-benzyl-D-alanine methyl ester (105 mg, 0.30 mmol) is treated with a solution of NH2OK (1.0 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The residue is purified by silica gel flash chromatography (95:5 ethyl acetate:methanol) to give N-hydroxy-2(R)-[[(S)-ethylphenylphosphinyl]amino]-propionamide as colorless solid: MS-IS m/z 347 [M+H]+, 369 [M+Na]+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[C:3]1=[O:20].[C:21]([O:24][CH2:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][C:27]=1[N:41]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:47]=2)[C:42]1=[O:54])(=[O:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.O>[C:21]([O:24][CH2:25][C:26]1[C:31]([C:6]2[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[C:3](=[O:20])[N:2]([CH3:1])[CH:7]=2)=[CH:30][CH:29]=[CH:28][C:27]=1[N:41]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:47]=2)[C:42]1=[O:54])(=[O:23])[CH3:22]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc([N+](=O)[O-])c(=O)n(C)c2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Temperature: 100 °C
Yield: 81.7 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 122b (560 mg, 2.00 mmol), 103f (830 mg, 2.00 mmol), sodium carbonate (848 mg, 8.00 mmol), dioxane (30 mL) and water (6 mL). This mixture was degassed with nitrogen for 15 min. Tetrakis(triphenyl-phosphine)palladium (231 mg, 0.200 mmol) was added. After heating at 100° C. for 5 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The resulting mixture was washed with saturated aqueous sodium bicarbonate (30 mL) and brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to afford an 81% yield (800 mg) of 122c as a crude product, which was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:13]([O-])=O.[Na+].C(Cl)Cl.CO>O.Cl>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][NH2:13]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Cl)c(NN)c1
Reaction time: 1 h

Procedure:
A solution of 11.9 g (63.9 mmole) of methyl 3-amino-4-chlorobenzoate (prepared as in Step A) was maintained at -5° to +5° C. and subjected to vigorous mechanical stirring as a solution of 4.41 g (63.9 mmole) of sodium nitrite in 19.3 mL of H2O was added slowly via a dropping funnel. Stirring was continued at this temperature for 1 hour, and the mixture was filtered while cold. The filtrate was immediately added to a rapidly stirred solution of 28.8 g (128 mmole) of stannous chloride dihydrate in 37.3 mL of concentrated HCl, which was also maintained at >0° C. Precipitation of a cream-colored solid began at once. After being stirred at 0° C. for 0.5 hour, the mixture was refrigerated overnight. The solid was collected on a filter and triturated with ether to give, after air-drying, approximately 22 g of cream-colored solid (mp 218°-220° C.), which was stored in the freezer. As needed, a portion of this hydrochloride salt was partitioned between 5% NaHCO3 (aqueous) and a mixture of CH2Cl2 and ethyl acetate to liberate the title compound as the free base, which was isolated by concentration of the organic phase to give a cream-colored solid, homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (EI) m/e 200 (M+). This material was used immediately in the next reaction.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:3].C(OCC1OC1)C1OC1.C(N)(C)C>>[CH3:3][CH:2]([NH:4][CH2:5][C@H:6]([OH:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:11][CH:10]=1)[CH3:1]
Reactant: CC(C)NCC(O)COc1ccc(CC(N)=O)cc1
Agent: C(OCC1CO1)C1CO1
Solvent: CC(C)N
Product: CC(C)NC[C@H](O)COc1ccc(CC(N)=O)cc1

Procedure:
In order to prevent the reaction of produced atenolol with the optically active glycidyl ether (4) it is preferable to add the optically active glycidyl ether (4) to isopropyl amine in a solvent. The removal of excess isopropyl amine by distillation gave desired (S)-atenolol (1). Preferably, the distillation is carried out at atmospheric pressure at the initial stages and under reduced pressure at later stages, keeping the reaction mass temperature below 60° to 70° C., through out the distillation process. The crude residue may be purified, if required, by dissolving it in 1N HCl, treating this solution with activated charcoal, filtering the charcoal followed by treatment of alkali to precipitate the product. Thus, the solid product was isolated by conventional method such as filtration to get (S)-atenolol (1) of optical purity of 98% ee and above. If, necessary, the optically active (S)-atenolol (1) may be crystallized from an appropriate solvent such as water, alcohols, such as methanol, ethanol, isopropyl alcohol, butanol etc., ethers, such as diethyl ether, methyl tbutyl ether, diisopropyl ether or ketones, such as acetone, ethyl methyl ketone, methyl isobutyl ketone etc.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15]I)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Zn]>[NH2:21][C:20]1[CH:19]=[CH:18][C:24]([O:25][CH3:26])=[C:23]([CH2:15][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:22]=1
Reactant: COC(=O)C[C@H](CI)NC(=O)OC(C)(C)C
Reactant: COc1ccc(N)cc1I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Zn]
Product: COC(=O)C[C@H](Cc1cc(N)ccc1OC)NC(=O)OC(C)(C)C
Yield: 66 %

Procedure:
Following the General Procedure of Description 15 (Part A), the zinc insertion product of (5c) was used in situ to cross couple with commercial 3-iodo-4-methoxy-aniline (249 mg, 1.0 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (23 mg, 0.025 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (30 mg, 0.10 mmol, 10 mol-%) in anhydrous degassed DMF (3 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography with ethyl acetate (EtOAc)/hexane and dichloromethane(DCM)/EtOAc mixtures (EtOAc/hexane=1:1, v/v→DCM/EtOAc=1:1, v/v) furnished ˜280 mg (66% yield; ˜80% purity by AUC) of the title compound (7a) as a yellow viscous oil. Rf˜0.23 (EtOAc/hexane=1:1, v/v). 1H NMR (300 MHz, CDCl3): δ 6.90 (br s, 1H), 6.78 (br. d, J=8.1 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 5.28 (br. d, J=8.1 Hz, 1H), 4.40-4.10 (m, 1H), 3.37 (s, 3H), 2.90-2.80 (br. m, 1H), 2.75 (dd, J=12.6, 6.3 Hz, 1H), 2.50 (d, J=5.1 Hz, 2H), 1.35 (s, 9H) ppm. LC/MS: Rt=0.908 min; ESI (pos.) m/z=339.15 (M+H+)+, 677.40 (2M+H+)+, 699.35 (2M+Na+)+.
Reaction SMILES: ClC1C=CC=C(F)C=1[C:9]1[N:10]=[C:11]([C:17]2[C:18]([CH3:26])=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)[S:12][C:13]=1[C:14]([OH:16])=[O:15].[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([O:35][CH3:36])[C:29]=1B(O)O>>[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([O:35][CH3:36])[C:29]=1[C:9]1[N:10]=[C:11]([C:17]2[C:18]([CH3:26])=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)[S:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: Cc1nn2ccccc2c1-c1nc(-c2c(F)cccc2Cl)c(C(=O)O)s1
Reactant: COc1ccc(F)c(F)c1B(O)O
Product: COc1ccc(F)c(F)c1-c1nc(-c2c(C)nn3ccccc23)sc1C(=O)O

Procedure:
According to the similar manner described in Example 97-B (i) and (ii), the title compound (237 mg, 78%) has been obtained as a brown solid by the Suzuki coupling reaction followed by standard ester hydrolysis reaction using methyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (339 mg, 0.805 mmol) obtained in Example 13-B (ii) and 2,3-difluoro-6-methoxyphenylboronic acid (303 mg, 1.61 mmol). The pure title compound has been obtained by washing with EtOAc (10 mL).
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1.C1(C(C2C=CC=CC=2)N2CCN(C([C@@H](NC(=O)OC(C)(C)C)CC(C)C)=O)CC2)C=CC=CC=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([C:15]([C@@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:17])[CH2:29][CH2:28]2)=[CH:22][CH:21]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(CN2CCNCC2)cc1
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: O
Product: COc1ccc(CN2CCN(C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC2)cc1
Yield: 95.5 %

Procedure:
Tert-butoxycarbonyl-L-leucine monohydrate (7.47 g) and 1-(4-methoxy-phenylmethyl)piperazine (6.18 g) were condensed in the same manner as employed in the preparation of tert-butyl (s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate to yield 12.0 g of tert-butyl (s)-1-[4-(4-methoxyphenylmethyl)piperazine-1-yl carbonyl]-3-methylbutylcarbamate as a colorless amorphous substance (yield: 95%).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:18]2[CH:17]=[C:16]3[C:8]([C:9]4[CH:10]=[C:11]5[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:26])([CH3:25])[C:12]5=[CH:13][C:14]=4[CH2:15]3)=[CH:7][C:6]=2[C:5]([CH3:28])([CH3:27])[CH2:4][CH2:3]1.CCCCCC.[Li]CCCC.[C:41]1([C:47]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:48]2[CH:52]=[CH:51][CH:50]=[CH:49]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[CH:48]1([C:47]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:20]2[CH2:21][C:22]([CH3:24])([CH3:23])[C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][C:12]=3[C:19]2([CH3:26])[CH3:25])[CH2:15][C:16]2[CH:17]=[C:18]3[C:2]([CH3:29])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:28])([CH3:27])[C:6]3=[CH:7][C:8]4=2)[CH:49]=[CH:50][CH:51]=[CH:52]1
Reactant: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(c1ccccc1)(c1ccccc1)C1C=CC=C1)C2(C)C
Temperature: 1 °C
Yield: 79 %

Procedure:
In a 200 ml three-necked flask purged with nitrogen, 2.64 g (6.83 mmol, 1 eq) of 1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorene was placed at room temperature. Then, 40 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (light yellow solution). To the solution, 4.6 ml (7.50 mmol, 1.10 eq) of a hexane solution of n-BuLi was dropwise added over a period of 10 minutes. Then, the ice bath was removed, and the solution was stirred at room temperature for 23 hours (dark red solution). The solution was cooled to 1° C. with an ice bath, and to the solution, a solution of 2.06 (8.94 mmol, 1.31 eq) of 6,6-diphenylfulvene in 20 ml of dehydrated THF was dropwise added over a period of 20 minutes (dark red slurry). The ice bath was removed, and the solution was stirred at room temperature for 65 hours. The resulting dark reddish brown solution was poured into 100 ml of a diluted hydrochloric acid solution to perform quenching. From the aqueous layer, the soluble component was extracted with diethyl ether, and the organic phase was washed with 100 ml of a saturated saline solution. The dispensed organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain an orangy yellow amorphous product. The amorphous product was washed with methanol, then filtered and dried in a vacuum disiccator to obtain 3.31 g of a slightly yellow powder (yield: 79%).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.CN1CCOCC1.[CH3:15][O:16][C:17](Cl)=[O:18]>C1COCC1>[CH3:15][O:16][C:17]([N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7])=[O:18]
Reactant: O=C1CCC(=O)N1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)N1C(=O)CCC1=O
Reaction time: 2 h

Procedure:
To a solution of 19.8 g (200 mmole) of succinimide and 22 ml (200 mmole) of N-methylmorpholine in 350 ml THF at -5° was added 15.5 ml (200 mmole) methylchloroformate over 20 minutes. After stirring for two hours at 25°, the solvent was removed under reduced pressure and the residue was taken up in EtOAc. The suspension was filtered, and washed with saturated NaCl, saturated NaHCO3, and saturated NaCl. After drying, the solution was concentrated under reduced pressure and Et2O was added, giving the product as a crystalline solid, 10.0 g. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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.COCCOC>[CH2:26]1[O:27][C:21]2[CH:20]=[CH:19][C:24]([C:2]3[CH:3]=[CH:4][C:5]4[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=4[CH:16]=3)=[CH:23][C:22]=2[O:25]1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCO2
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
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)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a mixture of methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (0.57 g), 3,4-methlenedioxyphenyl borate(0.47 g) and sodium carbonate (0.42 g) were added water (2 ml) and 1,2-dimethoxyethane(12 ml). Under argon atmosphere, the mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (0.16 g). The mixture was stirred at 80° C. for 14 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give methyl 7-(3,4-methlenedioxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (0.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:15][CH:14]=[CH2:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(C(=O)OC)cc(Cl)c1O
Yield: 83.3 %

Procedure:
To a 250 mL round-bottom flask equipped with a magnetic stir bar and a reflux condenser was added a solution of 10.33 g (55.4 mmol) of methyl 3-chloro-4-hydroxybenzoate dissolved in 110 mL of acetone and 5.27 mL (60.9 mmol) of allyl bromide and 15.30 g (111 mmol) of powdered potassium carbonate was added. The reaction was stirred and refluxed for 6 hours, then cooled and filtered. The filtrate was evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 10% EtOAc-hexane to afford 10.462 g (84%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:22])[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[Cl-].[CH3:24][Zn+]>C1COCC1.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>[Cl:1][C:2]1[N:3]=[C:4]([Cl:22])[C:5]2[C:10]([CH3:24])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2,4-dichloro-5-iodo-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (800 mg, 1.71 mmol) and Pd(PPh3)4 (40 mg, 0.034 mmol) were combined in dry THF (20 ml) and a 2M solution of methylzinc chloride in THF (1.28 ml, 2.56 mmol) was added under N2. The reaction mixture was let stir at 60° C. for 18 h at which time the reaction was diluted with ethyl acetate and the organic layer was washed with a saturated solution of sodium bicarbonate, water and a saturated brine solution, then dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2,4-dichloro-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (487 mg, 1.37 mmol) as a tan solid. This reaction was repeated to synthesize sufficient material as needed for subsequent reactions. ESIMS(M+H)+=357.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH2:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:16]([N:26]([CH3:34])[C@H:27]([C:31](O)=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16]([N:26]([CH:27]([CH:28]([CH3:30])[CH3:29])[C:31]([NH:15][CH:13]([CH3:14])[CH2:12][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:32])[CH3:34])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)C(C(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.31 g (1.50 mmol) of 2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethylamine, 0.40 g (1.50 mmol) of Z-N-Me-Val-OH and 0.30 g (2.25 mmol) of HOBT in DMF (5 ml), 0.35 ml (2.25 mmol) of DIC was added under cooling with ice. After being stirred at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3, water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol=125:1) to give 2-[N-(benzyloxycarbonyl)-N-methylamino]-N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-3-methylbutanamide in the amount of 0.55 g (81%).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[Br:11].[CH2:12]([Li])CCC.COS(OC)(=O)=O.Cl>C(OCC)C.CCCCCC>[CH3:12][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[Br:11]
Reactant: [Li]CCCC
Reactant: Brc1sc2ccccc2c1Br
Agent: Cl
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Solvent: CCCCCC
Product: Cc1sc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 15.88 g of 2,3-dibromobenzo[b]thiophene in 150 ml of dry diethyl ether at 0° C. was added a solution of 20 ml of diethyl ether and 34 ml of a 1.6M solution of n-butyl lithium in hexane. After stirring for one hour at 0° C., a solution of 10.2 ml of dimethylsulfate in 20 ml of diethyl ether was added and the reaction was stirred at 0° C. for 4 hours. The mixture was allowed to warm to room temperature. After the addition of 125 ml of 1N hydrochloric acid, the reaction mixture was stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined ether extracts were dried over magnesium sulfate and evaporated in vacuo giving an oil. The oil was cooled and it solidified. The resulting crystals were recovered by filtration providing 8.7 g of the desired subtitled intermediate, m.p. 39°-40° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[O-].[Na+]>[Cu].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Reactant: Nc1ccc(I)cn1
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(Sc2ccccn2)cn1

Procedure:
11.0 G. (0.05 moles) of 2-amino-5-iodo pyridine, 6.1 g. (0.055 moles) of 2-mercapto pyridine, 2.97 g. (0.055 moles) of sodium methoxide and 1.0 g. of copper powder are combined in 200 ml. of methanol and heated at 150° C. for 12 hours in a glass lined bomb. The reaction mixture is filtered and the filtrate evaporated to dryness in vacuo. The residue is dissolved in 300 ml. of methylenechloride and washed 5 times with 2.5 N sodium hydroxide and 3 times with saturated sodium chloride solution. The methylene chloride is dried over magnesium sulfate, and evaporated to dryness. The residue is dissolved in boiling methanol, treated with decolorizing carbon, filtered and evaporated to dryness affording 2-amino-5-(2-pyridylthio) pyridine, m.p. 121° C.