Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2]/[CH:3]=[CH:4]/[CH3:5].[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]=[N+:23]=[N-:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].C1CCN2C(=NCCC2)CC1>CC#N>[C:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:22]=[N+:23]=[N-:24])(=[O:21])=[O:20])=[CH:17][CH:18]=1)(=[O:11])[CH3:10].[N+:22](=[C:2](/[CH:3]=[CH:4]/[CH3:5])[C:1]([O:7][CH3:8])=[O:6])=[N-:23]
Reactant: C/C=C/CC(=O)OC
Agent: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C/C=C/C(=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Methyl (E)-2-diazo-3-pentenoate (5) was prepared using the scheme set forth in FIG. 7A. To a stirred solution of trans-pent-3-enoic acid (3.0 g, 30.0 mmol) in methanol (20 mL) was added concentrated H2SO4 (1 mL). The reaction mixture was stirred for 12 h at room temperature and then slowly neutralized with saturated sodium bicarbonate (NaHCO3). The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure, and the remaining clear oil (3.30 g, 96% yield) was used for the next step, without further purification. To a stirred solution of methyl trans-pent-3-enoate (1.0 g, 8.77 mmol) and p-ABSA (3.15 g, 13.1 mmol) in CH3CN (20 mL) cooled to 0° C., was added DBU (2.66 g, 17.5 mmol) in one portion. p-ABSA (p-acetamidobenzenesulfonyl azide) was prepared using the procedure outlined in Baum et al., Synth. Commun., 17:1709ff (1987), which is hereby incorporated by reference. The reaction mixture was allowed to warm to room temperature over 7 h then quenched with saturated ammonium chloride (NH4Cl). The aqueous layer was extracted with diethyl ether, and the combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by flash chromatography (SiO2, pentane) to give methyl (E)-2-diazo-3-pentenoate (5) (0.80 g, 65% yield) as an orange oil, which was stored in pentane below −10° C. until ready for use. The spectroscopic data are consistent with previously reported data (Davies et al., J. Org. Chem., 57:3186ff (1992), which is hereby incorporated by reference).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1.FC(F)(F)C(O)=O>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.53 g, 4.77 mmol) in DMF (20 mL) was added NIS (1.18 g, 5.24 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 5 h at ambient temperature, the reaction was quenched by saturated NH4Cl (aq.). The solution was extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL) successively, dried over Na2SO4 and concentrated in vacuo to give the desired product (yellow solid, 1.90 g, 89.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.73 (s, 1H), 8.58 (d, 1H), 7.47 (m, 1H), 7.39 (m, 1H), 6.74 (m, 1H), 4.03 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:17]=2[N:18]=1.FC(F)(F)C(O)=O>C(O)C(F)(F)F>[Cl:12][C:13]1[N:14]=[C:15]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=2[C:4]([NH2:6])=[O:5])[C:16]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:23])=[O:24])[C:17]=2[N:18]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: NC(=O)c1c(N)cccc1F
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 54.7 %

Procedure:
A mixture of 2-amino-6-fluorobenzamide (10 g, 64.9 mmol, Piedmont or Ryan Scientific) and 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (17.7 g, 51.7 mmol) was taken up into trifluoroethanol (400 mL) and trifluoroacetic acid (20 mL, 260 mmol). The resulting yellow slurry was heated at 80° C. After heating for 30 minutes a clear brown solution was obtained, which was heated at 80° C. for 18 h, then at the reflux temperature for an additional 6 h. The resulting slurry was cooled to 0° C. and filtered. The filtrate was concentrated down to 200 mL volume, heated at 80C for 20 h, cooled to 0° C., then filtered. The two crops of solids were combined, taken up into isopropanol (150 mL), heated at the reflux temperature for 4 h, then filtered to give 13 g (55%) of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide as a pale yellow solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.71 (d, J=3.66 Hz, 1 H), 7.12-7.17 (m, 1 H), 7.45-7.48 (m, 2 H), 7.49-7.52 (m, 1 H), 7.61 (d, J=7.87 Hz, 1 H), 7.67 (d, J=4.03 Hz, 1 H), 7.80 (s, 1 H), 7.89 (s, 1 H), 7.95-7.98 (m, 2 H), 10.47 (s, 1 H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:49][C@H:50]([C:58]([CH:60]1[C:67]2([NH2:69])[CH2:68][CH:63]3[CH2:64][CH:65]([CH2:70][C:61]1([C:71]([O:73][CH3:74])=[O:72])[CH2:62]3)[CH2:66]2)=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CN(C)CCN>CN(C)C=O>[C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:49][C@H:50]([C:58]([CH:60]1[C:67]2([NH2:69])[CH2:68][CH:63]3[CH2:64][CH:65]([CH2:70][C:61]1([C:71]([O:73][CH3:74])=[O:72])[CH2:62]3)[CH2:66]2)=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@@H](N)Cc1ccccc1)C2
Agent: CC(C)COC(=O)Cl
Agent: CN(C)CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C2
Temperature: -50 °C
Reaction time: 1.5 h

Procedure:
5.06 Grams of Boc-L-tyrosyl-D-methionyl-glycine is dissolved in 40 ml of dimethylformamide and 1.28 ml of N-methylmorpholine is added to the solution. The reaction mixture is cooled to -50° C. and 1.51 ml of isobutylchloroformate is added causing a precipitate to form. The reaction mixture is allowed to warm to -20° over a 15 minute period and 4.45 g of methyl L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride is added followed immediately by 1.25 ml of N-methylmorpholine The gum which forms dissolves in about 45 minutes while warming to room temperature. The reaction mixture is allowed to stand for 1.5 hours at room temperature and is then stored at 5° C. for 3 days. The reaction mixture is warmed to room temperature, 1.0 ml of N,N-dimethylethylenediamine is added and the reaction mixture is stirred for 10 minutes. The dimethylformamide is removed under reduced pressure at 32° C. and the residue is dissolved in a mixture of 70 ml of water and 100 ml of ethyl acetate. The aqueous layer is separated and extracted once with ethyl acetate and the combined ethyl acetate solutions are washed three times with 70 ml of a 0.5 M solution of potassium bisulfate, once with 70 ml of water, two times with a 0.5 M solution of potassium carbonate, and three times with 70 ml of a 10% sodium sulfate solution, then dried over magnesium sulfate. The solvent is removed under reduced pressure to give the crude product which is then purified by low pressure chromatography on silica gel to give methyl Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate which is represented by the following formula ##STR25##
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:42]1[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([CH3:49])[CH:43]=1>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:25][N:26]([C:42]4[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([CH3:49])[CH:43]=4)[CH2:27][CH2:28]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCNCC1
Reactant: Cc1cc(Cl)cc(C)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCN(c2cc(C)nc(C)c2)CC1
Temperature: 150 °C
Reaction time: 25 h
Yield: 92.7 %

Procedure:
To a solution of 7-(4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (140 mg) in ethanol (3 ml) were added triethylamine (0.05 ml) and 4-chloro-2,6-dimethylpyridine (Journal of Heterocyclic Chemistry, vol. 27, p. 1841 (1990)) (45 mg) and the mixture was stirred at 150° C. for 25 hours in a sealed tube. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=4:1) and dried under reduced pressure to give the title compound (160 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([OH:15])/[C:8]/2=[CH:11]\[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.CO>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([OH:15])/[C:8]/2=[CH:11]/[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NC(=O)/C=C1/c2cc(F)ccc2CC1O
Solvent: CO
Solvent: ClCCl
Product: NC(=O)/C=C1\c2cc(F)ccc2CC1O
Yield: 24.3 %

Procedure:
A solution of (Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide (5.456 g, 0.026 mol) in dichloromethane:methanol/9:1 (1000 ml) was irradiated by an Canrad-Hanovia quartz, mecury-vapor photochemical immersion lamp, 450 wattts (Ace Glass, 7825-35) for 1h. The volitiles were removed by spin evaporation in vacuo to give a light brown solid residue. This residue was chromatographed on Silica Gel 60 using a step gradient going from ethyl acetate:hexanes/1:1 to ethyl acetate:ethanol/1:1. Fractions containing (E)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide were combined and concentrated by spin evaporation in vacuo. The resulting residue was recrystallized from ethanol-hexanes to give 1.31 g (24%) of (E)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide as an off-white crystalline solid, m.p., 159°-163° C., NMR(DMSO-d6): d 8.56 (dd, 1H, JHF =11.0 Hz, JHH =2.9 Hz), 7.67 (br s, 1H), 7.34-7.30 (m, 1H), 7.2-7.13 (m, 1H), 7.06 (br s, 1H),6.18 (s, 1H), 5.69 (d, 1H, J=6.8 Hz), 4.74 (q, 1H, J=12.1 Hz, J=6.0 Hz), 3.21-3.13 (m, 1H) 2.73-2.66(m, 1H); steady state nOe: irradiation at d6.19, observed 5.4% nOe at d4.74, 4.3% at d7.67 and 1.5% at d 5.69.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[C:21]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:30]([C:29]([CH3:33])([CH3:32])[C:21]1[CH:22]=[C:23]2[C:28](=[C:19]([C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[CH2:12][N:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:20]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)#[N:31]
Reactant: CC(C)(C#N)c1cc(-c2cccc(CNc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C#N)c1cc(-c2cccc(CN(C(=O)c3ccccc3)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1

Procedure:
Prepared according to the procedure described in EXAMPLE 36 (Step 2 and 3) but using 2-(8-{3-[(4-methanesulfonyl-phenylamino)-methyl]-phenyl}-quinolin-6-yl)-2-methyl-propionitrile and benzoyl chloride as the starting materials.
Reaction SMILES: N[C@H]([C:5](O)=[O:6])C[SeH].[Li]CCCC.[Si:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(CCN(C)C)C.CN(C=O)C.Cl>C1COCC1>[Si:13]([O:20][C:21]1[C:22]([F:27])=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[O:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: N[C@@H](C[SeH])C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1F
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1F
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
Sec-BuLi (1.3M solution in cyclohexane, 75 mL, 98 mmol) was added slowly at −78° C. to a solution of Intermediate 31, 1-(tert-Butyldimethylsilyl)oxy-2-fluorobenzene (20.1 g, 89 mmol) and TMEDA (14.8 mL, 98 mmol) in THF (200 mL) and the mixture was stirred at the same temperature for 30 min. DMF (7.5 mL, 98 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for 1.5 h. Then 10% aqueous HCl was added to attain pH˜4-5 (200 mL), and the reaction mixture was stirred at RT for 30 min. The organic layer was separated. Aqueous layer was extracted with EtOAc (200 mL). The organic layers was washed with sat. NaHCO3, brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (16.7 g, 74%, 66 mmol) as a yellow oil. 1H NMR data (dmso-d6): 10.21 (s, 1H, CHO), 7.39-7.45 (m, 1H, H—Ar), 7.32-7.38 (m, 1H, H—Ar), 7.22-7.28 (m, 1H, H—Ar), 0.97 (s, 9H, t-Bu), 0.20 (s, 6H, 2CH3).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([OH:34])[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1>>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([O:34][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: CCOC(=O)CCCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCCCC(=O)O

Procedure:
The title compound was prepared from ethyl 8-bromooctanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedures outlined in Examples 25 & 42. 1H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.81 (s, 2H), 7.93 (d, 1H), 7.19 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.91 (s, 3H), 2.18 (t, 2H), 1.66 (m, 2H), 1.54-1.40 (m, 4H), 1.36-1.24 (m, 4H); MS (ESI): 494.9.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:20])[CH:8]=2)[CH2:2]1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]([N:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:20])[CH:8]=2)[CH2:2]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cc(C2CC2)c(OCC2CNC2)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C2CC2)c(OCC2CN(C(=O)c3ccccc3)C2)cc1F
Temperature: 20 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a mixture of methyl 4-(azetidin-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (50 mg, 0.18 mmol), benzoyl chloride (28 mg, 0.20 mmol), and triethylamine (36 mg, 0.36 mmol) in DCM (10 mL) was stirred at 20° C. for 1 hour. The mixture was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get a crude product (70 mg, 99%) which was used in the next step without further purification. LCMS (ESI) m/z: 384.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)C>[CH3:17][CH:16]([NH:19][CH2:3][C@H:2]([OH:4])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=1)[CH3:18]
Reactant: COCCc1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Solvent: CCO
Product: COCCc1ccc(OC[C@@H](O)CNC(C)C)cc1

Procedure:
214 mg of (+)-4-(2-methoxyethyl)-phenyl glycidyl ether were condensed with isopropylamine as in Example 2 to obtain 146 mg of (-)-metoprolol melting at 44-46° C. with [α]D25=- 5.00° (c=1.01 in ethanol). Optical purity (method as in Example 2) was determined to be 98%. Evaporation of the mother liquor yielded 9 mg of (-)-metoprolol of 97.5% optical purity.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[CH3:11])=[O:7])=[C:4]([F:26])[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCCC1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)[CH3:11])=[O:7])=[C:4]([F:26])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: CC(CNC(=O)c1ccc(Br)cc1F)c1ccc(CN2CCCC2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(CNC(=O)c1ccc(-c2ccc(Cl)cc2)cc1F)c1ccc(CN2CCCC2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution (7 ml) of 4-bromo-2-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]propyl}benzamide (300 mg, 0.715 mmol) obtained in Example 5, 4-chlorophenylboronic acid (224 mg, 1.43 mmol) and 2N aqueous sodium carbonate solution (0.715 ml) in tetrahydrofuran was added tetrakistriphenylphosphine palladium (24.8 mg, 21.5 mmol) under a nitrogen atmosphere. This was stirred at 90° C. for 16 hrs, and allowed to cool to room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate), and powderized with isopropyl ether to give the title compound (142 mg).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>C(Cl)Cl>[C:3]1([CH:2]2[CH2:1][CH:11]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccccc1
Reaction time: 1 h

Procedure:
A solution of CH2Cl2 (12.5 mL), styrene (12 5 mL) and ethyl diazoacetate (0.25 g, 2.19 mmol) was added slowly dropwise at ambient temperature to a stirred slurry of Rh-PFIEP[SO3H] (1.0 g, 0.387 mmol, prepared as described above), styrene (2.5 mL) and CH2Cl2 (2.5 mL). Gas evolution ceased about 1 hour after the addition of the ethyl diazoacetate solution was complete. The resulting slurry was stirred for 24 hours and then allowed to settle. The solution was removed, the resulting resin was washed with 3.0 mL of CH2Cl2. The solution and the wash were combined and analyzed for cyclopropane products. Yield (based on ethyl diazoacetate): 73.9%.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29](I)[CH3:30]>CN(C=O)C.O>[CH2:29]([N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][N:9]2[C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1)[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:30]
Reactant: CSc1nccc(-n2ccc3c(NS(C)(=O)=O)cccc32)n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1cccc2c1ccn2-c1ccnc(SC)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
N-[1-(2-Methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yl]-methanesulfonamide (0.4 g) in DMF (2 mL) was treated with K2CO3 (0.83 g) followed by EtI (0.2055 g), stirred at RT overnight, diluted with water, the solid filtered, washed with water and dried at 50° C. in vacuo overnight to yield N-ethyl-N-[1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yl]-methane-sulfonamide (0.4 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[Na].O.C(O)(=O)C.[CH2:23]([O:25][C:26](=O)[O:27]CC)[CH3:24]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cc1ccc2ccccc2c1
Reactant: CCOC(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)OCC)c1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-naphtylacetate (2 g) in 23.3 ml of diethylcarbonate, kept under stirring and at room temperature, are added portionwise 0.232 g of sodium. The reaction mixture is refluxed for 2 hours 30 minutes, then it is concentrated in order to eliminate the not reacted diethylcarbonate and it is added with 20 ml of cold water. The resulting mixture is acidified with acetic acid until weak acidity is reached, then it is extracted three times with diethyl ether. The pooled organic extracts are dried over sodium sulfate and the solvent is evaporated off, to give, after recrystallization from diethyl ether (19 ml), 1.015 g of the product as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][C:9]=2[CH:16]=1)(=[O:3])[CH3:2].[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH2:14][C:13]([C:11]1[O:12][C:8]2[C:7]([CH3:17])=[C:6]([CH3:18])[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:16][C:9]=2[CH:10]=1)=[O:15]
Reactant: CC(=O)Oc1cc2cc(C(C)=O)oc2c(C)c1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc2cc(C(=O)CBr)oc2c(C)c1C
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
1-(5-Acetoxy-6,7-dimethyl-benzofuran-2-yl)-ethanone (83 mg) (prepared from 1-(5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-ethanone from Example 14 with acetanhydride and pyridine), was dissolved in chloroform (10 mL). Bromine (50 mg) was added and the solution was stirred at 70° C. for 10 min. When the color of bromine disapeared, the mixture was evaporated to dryness. The residue was purified by silica gel column eluting with 30% EtOAc in hexane to give 85 mg of 2-bromo-1-(5-acetoxy-6,7-dimethyl-benzofuran-2-yl)-ethanone as a white solid. 1H NMR (CDCl3, 300 MHz) δ: 7.58 (s, 1H), 7.26 (s, 1H), 4.43 (s, 2H), 2.51, 2.37, 2.21 (3s, 9H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 182.55, 170.13, 153.71, 150.74, 146.81, 131.21, 124.51, 122.92, 115.15, 113.28, 30.69, 21.27, 13.54, 12.80 ppm.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C(O)C.[C-:16]#[N:17].[Na+]>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([CH2:2][C:16]#[N:17])=[O:4])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 25.0 g. portion of α-bromo-p-methoxyacetophenone is suspended in 125 ml. of ethanol. A solution of 16.0 g. of sodium cyanide in 75 ml. of water is added, using an ice-water bath to keep the temperature at 25°-30° C. The mixture is stirred for 45 minutes at room temperature. A total of 1.2 liters of water is added in 200 ml. increments with filtration through celite until no more precipitate forms. The filtrate is acidified to pH 5 with acetic acid. The solid is collected, washed with water, dried and recrystallized from benzene giving p-methoxybenzoylacetonitrile.