Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:12])[CH3:11])\[C:6]([O:8][CH3:9])=[O:7].[O:23]1CCOCC1.O.Cl([O-])=O.[Na+]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:23])=[O:21])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:11])[CH3:12])\[C:6]([O:8][CH3:9])=[O:7]
Reactant: C1COCCO1
Reactant: COC(=O)/C(Cc1ccc(C=O)cc1)=C(\C(=O)OC)C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)/C(Cc1ccc(C(=O)O)cc1)=C(\C(=O)OC)C(C)C
Yield: 96 %

Procedure:
To a suspension of 2-(4-formylbenzyl)-3-isopropylmaleic acid dimethyl ester (79 mg, 0.259 mmol) in a mixed solvent of dioxane (3.0 mL) and water (3.0 mL) were added amide sulfate (38 mg, 0.39 mmol) and sodium chlorite (35 mg, 0.39 mmol) with stirring under ice cooling, and the mixture was stirred for 30 min. The reaction mixture was directly concentrated, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 1:2) to give 80 mg of the title compound as oil (yield: 96%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:16])(=[O:15])NCCO)=[CH:6][CH:5]=1.C(C1C=CC(S(Cl)(=O)=O)=CC=1)#N.Cl.[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[CH3:32]>>[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH:36][S:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3](=[NH:17])[NH:2][OH:1])=[CH:9][CH:8]=1)(=[O:16])=[O:15])[CH3:32]
Reactant: N=C(NO)c1ccc(S(=O)(=O)NCCO)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(=O)CNS(=O)(=O)c1ccc(C(=N)NO)cc1

Procedure:
The title compound is prepared in analogy to N-hydroxy-4-(2-hydroxy-ethylsulfamoyl)-benzamidine starting from 4-cyano-benzenesulfonyl chloride and glycine ethyl ester hydrochloride; LC-MS: tR=0.27 min; [M+1]+=302.03;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>[Ni].CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N:8]1[C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[NH2:16]
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCOCCC1=O
Agent: [Ni]
Solvent: CO
Product: Cc1cc(N)ccc1N1CCOCCC1=O

Procedure:
Prepared analogously to Example 1c from 3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-1-nitro-benzene with Raney nickel under a hydrogen atmosphere in methanol.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][CH2:12][CH2:13][CH:14](O)[C:3]=12.C1(C)C=CC(S([Cl:25])(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>N1C=CC=CC=1>[ClH:25].[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][CH2:12][CH2:13][CH:14]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:3]=12
Reactant: Cc1c2n(c3ccccc13)CCCC2O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: c1ccncc1
Solvent: O
Product: Cc1c2n(c3ccccc13)CCCC2N1CCOCC1
Product: Cl
Reaction time: 1 h

Procedure:
To a solution of 6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-ol (2.01 g, 10 mmol, described in Example 2, Step (1) in dry pyridine (150 mL) was added a solution of p-toluenesulfonyl chloride (7.6 g, 40 mmol) in the same solvent (50 mL) at 0° C. Maintaining this temperature, stirring was continued for 60 minutes, and an excess of morpholine was added. The reaction mixture was stirred at ambient temperature for 3 hours, poured into water, and extracted with methylene chloride. The combined extracts were evaporated, and the residue was chromatographed. Elution with methylene chloride/methanol 20:1 afforded the title base. The hydrochloride salt was crystallized from EtOH, m.p. 172°-174° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:15][C:14]1[C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH:18]=[CH:17][C:6]=3[N:7]=2)=[C:11]([NH2:16])[NH:12][N:13]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Reactant: CN1CCNCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CN3CCN(C)CC3)cc2s1

Procedure:
The title compound (9 mg) was prepared starting from 20 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess 1-methylpiperazine. MS (m/z, ES+): 343.1 (M+1, 20%), 244.1 (M-CH3N(CH2)4N+1, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 10.4 g (55.2 mmol) of 4-bromothiophenol and 6.49 g (55.4 mmol of ethyl acrylate in 5 mL of dichloromethane was added 4.13 g (41 mmol) of triethylamine at 0 ° C. under argon. The resulting solution was warmed to room temperature and stirred for 12 hours. The solution was then treated with 50 mL 10% aqueous NaOH and the product extracted into 3×100 mL ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH:5]=[N:6][OH:7].OC1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[C:34]#[CH:35]>C(#N)C.C(OCC)(=O)C>[CH2:38]([O:37][C:33]([C:34]1[O:7][N:6]=[C:5]([C:4]2[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=2)[CH:35]=1)=[O:36])[CH3:39]
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1F
Reactant: C#CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])c(F)c2)no1
Yield: 70.1 %

Procedure:
To a solution of 3-fluoro-4-nitro-benzaldehyde oxime (6 g; 32.6 mmol) in acetonitrile (120 mL) was added hydroxy tosyloxy iodobenzene (16.58 g; 42.3 mmol) and ethyl propiolate (6.38 g; 65.2 mmol) under stirring. The resulting reaction mixture was stirred at 80° C. for 2-3 h. After the completion of the reaction, it was evaporated to dryness. The solid thus obtained was dissolved in ethyl acetate and washed with brine and dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by flash chromatography over silica gel with 20% ethyl acetate in light petroleum to give 6.4 g (74%) of the title compound. IR (KBr): 3134, 3060, 2975, 1717, 1610, 1593, 1522, 1458, 1446 cm−1; MS (m/z): 279 (M−−1); 1H NMR (DMSO-d6) δ: 1.31-136 (t, 3H, CH2CH3), 4.36-4.43 (q, 2H, CH2CH3), 8.04 (d, 1H, J=9.0, 6′-H), 8.09 (s, 1H, 4-H), 8.16 (d, 1H), 8.30 (t, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:30][CH3:31])=[CH:19][C:20]([CH:27]4[CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22](OC)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH2:32][NH2:33]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]([CH2:30][CH3:31])=[CH:19][C:20]([CH:27]4[CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:32][NH2:33])=[O:23])=[O:16])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: NN
Solvent: CCO
Product: CCc1cc(C2CC2)c(C(=O)NN)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a round-bottom flask was added a solution of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate (compound 228.1, 830 mg, 1.99 mmol, 1.00 equiv) in ethanol (15 mL). Hydrazine (5 mL, 100 equiv) was added to the reaction. The resulting solution was stirred for 15 h at 100° C., then concentrated in vacuo. The residue was extracted with 100 mL of dichloromethane and the combined organic layers were washed with 1×30 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 0.800 g (96%) of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:26]([NH:25][C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)=[S:27])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Fc1ccc(NC(=S)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (0.20 g, 0.8 mmol) and 4-fluorophenyl isothiocyanate (0.14 g, 0.9 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a solid after column chromatography with hexane-EtOAc.
Reaction SMILES: C([CH:3]1[CH2:8][CH:7]([C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][C:4]1=O)C.[NH:14]1[CH2:17][CH:16]([NH:18][C:19](=[O:36])[CH2:20][NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:10][C:9]([F:12])([F:11])[CH:7]1[CH2:8][CH2:3][CH:4]([N:14]2[CH2:15][CH:16]([NH:18][C:19](=[O:36])[CH2:20][NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:34])([F:33])[F:35])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH2:17]2)[CH2:5][CH2:6]1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCC1CC(C(F)(F)F)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(C(F)(F)F)CC2)C1

Procedure:
Reaction of ethyl 4-(trifluoromethyl)cyclohexanone with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[N:15]([CH2:16][CH:17]=[CH:18][C:19]#[N:20])[CH2:14][CH2:13][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:28]1[CH:32]=[C:31]([C:33]2[C:34]3[CH:41]=[CH:40][N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:35]=3[N:36]=[CH:37][N:38]=2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:1]([O:8][CH2:9][CH:10]1[N:15]([CH2:16][CH:17]([N:28]2[CH:32]=[C:31]([C:33]3[C:34]4[CH:41]=[CH:40][N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:35]=4[N:36]=[CH:37][N:38]=3)[CH:30]=[N:29]2)[CH2:18][C:19]#[N:20])[CH2:14][CH2:13][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCN(CC=CC#N)C(CO[Si](C)(C)C(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C(CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[3-cyanoprop-2-en-1-yl]piperazine-1-carboxylate (0.31 g, 0.78 mmol, as a mixture of E- and Z-isomers from Step 2) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.18 g, 0.56 mmol, prepared as described in WO 2007/070514 Example 65) in DMF (0.50 mL) was added potassium carbonate (0.23 g, 1.7 mmol). The mixture was stirred at ambient temperature overnight. The mixture was filtered, diluted with EtOAc, washed with water three times, and washed once with brine, dried over sodium sulfate, decanted and concentrated in vacuo. Flash chromatography, on a 40 g silica gel cartridge, eluting with a gradient from 0-70% EtOAc in hexanes afforded product as a mixture of diastereomers (330 mg, 83%). 1H NMR (400 MHz, CDCl3): δ 8.84 (s, 2H), 8.33-8.29 (m, 4H), 7.40 (d, 2H), 6.78 (d, 2H), 5.68 (s, 4H), 4.66-4.52 (m, 2H), 3.81-2.29 (m, 30H), 1.43 (s, 9H), 1.43 (s, 9H), 0.92 (dd, 4H), 0.91 (s, 9H), 0.87 (s, 9H), 0.09 (s, 6H), 0.04 (s, 6H), −0.06 (s, 18H); LCMS (M+H)+: 711.5.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1([C:14]2[O:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[O:18][C:19]=2[CH2:20][NH2:21])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.CCOC(C)=O>N1C=CC=CC=1.ClCCl>[C:8]1([C:14]2[O:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[O:18][C:19]=2[CH2:20][NH:21][C:1](=[O:3])[CH3:2])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCC1=C(c2ccccc2)Oc2ccccc2O1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NCC1=C(c2ccccc2)Oc2ccccc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.416 ml (4.4 mmol) of acetic anhydride are slowly added to a solution of 0.88 g (3.67 mmol) of the amine obtained in Step C in 10 ml of anhydrous pyridine previously cooled to 0° C. After 1 hour of stirring under argon, the medium is diluted with dichloromethane and then acidified with a hydrochloric acid solution (1N). The aqueous phase is then extracted with dichloromethane; the organic phases are then dried over magnesium sulphate. The solvent is evaporated in vacuo; the residue obtained is then passed over a silica column (eluant: AcOEt/PE: 60/40) to yield the title amide in the form of a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:27]=2[NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-2-(2-fluorophenyl)-3-methylquinoline (103 mg, 0.38 mmol), 2,5-dimorpholinoaniline (100 mg, 0.38 mmol) and a 4.0M solution of HCl in dioxane (0.095 mL, 0.38 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-2-(2-fluorophenyl)-3-methyl-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.29 (1H, d, J=8.6 Hz), 7.93 (1H, d, J=8.2 Hz), 7.68-7.76 (1H, m), 7.65 (1H, td, J=7.4, 1.6 Hz), 7.40-7.55 (3H, m), 7.34 (1H, t, J=7.4 Hz), 7.19 (1H, t, J=9.0 Hz), 7.11 (1H, d, J=8.6 Hz), 6.47 (1H, dd, J=8.8, 2.9 Hz), 6.06-6.20 (1H, m), 3.85-4.00 (4H, m), 3.67-3.80 (4H, m), 3.01-3.17 (4H, m), 2.88-3.00 (4H, m), 2.21 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=499.2 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)(=[O:3])[CH3:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)c1cccc(Br)n1
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: Cc1ccccc1
Product: CC(=O)c1cccc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a Schlenk tube charged with a solution of 200 mg (1.0 mmol) of 2-acetyl-6-bromopyridine and 23 mg (0.02 mmol) of (Ph3P)4Pd in 10 mL of degassed toluene was added a solution of 150 mg (1.2 mmol) phenylboronic acid and 270 mg (2.5 mmol) Na2CO3 in 8 mL of degassed 4:1 H2O/MeOH. The biphasic mixture was heated to 80° C. with rapid stirring for 1 h. On cooling to RT, Et2O (50 mL) was added and the layers were separated. The organic layer was dried over Na2SO4 and the volatiles were removed by rotary evaporation. The resulting oil was chromatographed on silica with 10-50% CH2Cl2/hexanes eluent to provide 176 mg (89%) of 2-acetyl-6-phenylpyridine as a white powder. 1H NMR (CDCl3); δ2.84 (s, 3H); 7.43-7.62 (m, 3H); 7.91-8.08 (m, 3H); 8.18 (d, J=6.6 Hz, 2H). Mass Spec.: m/e 197.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]1OCCOCCOCCOCCOCCOC1.[H-].[Na+].[Br:37][C:38]1[CH:39]=[C:40]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50]Br)[CH:45]=2)[CH:41]=[CH:42][CH:43]=1.[Si](C=[N+]=[N-])(C)(C)C>CN(C=O)C>[Br:37][C:38]1[CH:39]=[C:40]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][O:16][C@H:14]3[CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:10]([O:12][CH3:17])=[O:11])[CH2:13]3)[CH:45]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: BrCc1cccc(-c2cccc(Br)c2)c1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](OCc2cccc(-c3cccc(Br)c3)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
(4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (1.0 eq.) in DMF was added to a 0° C. cooled suspension of 18-crown-6 (0.1 eq.) and NaH (3.0 eq.) in DMF (0.5 M final concentration). The reaction mixture was allowed to warm up to RT and stirred for 1 h. A 0.5M solution of 3-bromo-3′-(bromomethyl)biphenyl 95 (1.0 eq.) in DMF was added dropwise and the reaction mixture was stirred at RT overnight. The reaction mixture was quenched with aqueous HCl (1N) at 0° C. and diluted with EtOAc. The organic layer was separated, washed with aqueous HCl (1N) and brine, dried (Na2SO4) and evaporated to a solid. MS (ES+) m/z 498, 500 (M+Na)+. A 0.5 M solution of the crude material in a mixture of toluene:MeOH (2:1) was cooled to 0° C. and treated dropwise with TMS-diazomethane (1.5 eq.). The reaction mixture was allowed to warm up to RT and stirred for 1 h. The solvents were evaporated under reduced pressure and the residue was purified by flash chromatography (SiO2, PE:EtOAc=8:2) to afford the title compound 96 as a yellow oil (78%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 7.90-7.86 (m, 1H), 7.71 (d, J 7.7, 1H), 7.69-7.58 (m, 3H), 7.54-7.44 (m, 2H), 7.40 (d, J 7.7, 1H), 4.66-4.55 (m, 2H), 4.31-4.21 (m, 2H), 3.74-3.65 (m, 3H), 3.60-3.45 (m, 2H), 2.51-2.37 (m, 1H), 2.10-2.00 (m, 1H), 1.44-1.31 (m, 9H). MS (ES+) m/z 512, 514 (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][CH2:15][CH2:14][C:13]=3[CH:17]=2)[CH:7]=1.[Li][CH2:20]CCC.CCCCCC.C[Si](C)(C)[O:32][C@@H:33]1[C@@H:38]([O:39][Si](C)(C)C)[C@H:37]([O:44][Si](C)(C)C)[C@@H:36]([CH2:49][O:50][Si](C)(C)C)[O:35][C:34]1=[O:55].CS(O)(=O)=O>C1(C)C=CC=CC=1.CO>[Cl:18][C:5]1[CH:4]=[CH:3][C:2]([C@@:34]2([O:55][CH3:20])[C@H:33]([OH:32])[C@@H:38]([OH:39])[C@H:37]([OH:44])[C@@H:36]([CH2:49][OH:50])[O:35]2)=[CH:7][C:6]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: Clc1ccc(Br)cc1Cc1ccc2c(c1)CCO2
Reactant: [Li]CCCC
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCCCCC
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5-[(5-bromo-2-chloro-phenyl)methyl]-2,3-dihydrobenzofuran 5d (10.0 g, 30.9 mmol) was dissolved in 90 mL of mixed solution (THF and toluene, v:v=1:2) and cooled to −78° C., followed by dropwise addition of a solution of nBuLi in n-hexane (14.83 mL, 37.1 mmol). After stirring for 1 hour at −78° C., a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-one 2f (15.87 g, 33.9 mmol) in toluene (90 mL) was dropwise added before the reaction mixture was stirred for 3 hours at −78° C. A solution of 0.6 M methanesulfonic acid in methanol (103 mL) was added before the reaction mixture was stirred for 16 hours. Thereafter, the reaction was concentrated under reduced pressure after 100 mL saturated sodium carbonate solution were added. The residue was extracted with ethyl acetate (100 mL×3) after 50 mL saturated sodium chloride solution were added and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system E to obtain the title compound (2S,3R,4S,5S,6R)-2-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 5e (6.3 g, white solid), yield: 46.7%. 1H NMR (400 MHz, CD3OD): δ 7.53 (d, 1H), 7.45 (dd, 1H), 7.35 (d, 1H), 7.03 (s, 1H), 6.91 (d, 1H), 6.60 (d, 1H), 4.48 (t, 2H), 4.13-3.91 (m, 3H), 3.84-3.73 (m, 2H), 3.61-3.56 (m, 1H), 3.44-3.39 (m, 1H), 3.11 (dd, 3H), 3.07 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11]([CH2:16][OH:17])=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:18]=[C:19]=[O:20].[CH3:21][O:22][C:23](=[O:33])[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)N.C1COCC1>C(N(CC)CC)C>[CH3:21][O:22][C:23](=[O:33])[C@H:24]([NH:18][C:19]([O:17][CH2:16][C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:15][CH:14]=2)=[O:20])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: [N-]=C=O
Reactant: OCc1cc2cc(-c3ccccc3)ccc2[nH]1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccccc3)ccc2[nH]1
Yield: 44.3 %

Procedure:
A mixture of (5-phenyl-indol-2-yl)-methanol 45 (0.259 g, 1.16 mmole), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (0.286 g, 1.39 mmole), in triethylamine (0.37 ml), and THF (10 ml) was heated to 50° C. under a nitrogen atmosphere for 22 hrs. The solvent was evaporated and the residue was purified by chromatography to give about 0.220 g of (R)-2-(5-phenyl-indol-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid methyl ester 46, mp. 142-143° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:8]=1)[CH3:2].CO[CH2:26][N:27]([CH2:35][Si](C)(C)C)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl.FC(F)(F)C(O)=O>[C:19]([O:18][C:16]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C@H:6]2[C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH2:35][N:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26]2)=[CH:8]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture of trans-tert-butyl 3-(3-ethoxy-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (2.70 g, 8.57 mmol) and N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine (2.21 mL) in dichloromethane (11 mL) was added 4 drops of trifluoroacetic acid and the mixture was stirred at 40° C. for 1 hr. Then another 0.15 mL of N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine and 2 drop of trifluoroacetic acid were added and the mixture was stirred at 40° C. for another 2 hr. After cooling down to room temperature, the mixture was concentrated under vacuum to give the title compound as a pale yellow sticky oil (quantitative yield). 1H NMR (400 MHz, CDCl3) δ 1.21 (3H, t, J=7.2 Hz), 1.65 (9H, s), 2.86 (2H, q, J=8 Hz), 3.03 (1H, t, J=8 Hz), 3.11 (1H, t, J=8 Hz), 3.19 (1H, q, J=8 Hz), 3.70 (2H, dd, J=16 28 Hz), 3.91 (1H, q, J=8 Hz), 4.13 (2H, q, J=8 Hz), 7.20–7.38 (7H, m), 7.45 (1H, s), 7.74 (1H, d, J=8 Hz), 8.10 (1H, brd s). HPLC purity (retention time): 100% (1.84 min, method C). MS: 449.38 (M+Na+).