Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9](=[O:32])[CH:10]([N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](=[O:31])C(Cl)(Cl)Cl)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])C1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:37][NH2:38].C(N(CC)CC)C.Cl>CN(C)C=O>[CH2:14]([O:13][C:11]([CH:10]1[N:21]2[CH:25]=[CH:24][CH:23]=[C:22]2[C:26](=[O:31])[N:38]([CH2:37][C:36]2[CH:39]=[CH:40][C:41]([Cl:42])=[C:34]([Cl:33])[CH:35]=2)[C:9]1=[O:32])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)n1cccc1C(=O)C(Cl)(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)C1C(=O)N(Cc2ccc(Cl)c(Cl)c2)C(=O)c2cccn21
Temperature: 70 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid dibenzyl ester (30.0 g), 3,4 dichlorobenzylamine (11.7 g) and triethylamine (18.4 g, 25.0 ml) in anhydrous dimethylformamide (70 ml) was stirred under the stream of nitrogen at 70° C. for 2 hours. After cooling, the reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (3:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (16.0 g, 59.5%) as colorless crystals, mp 104°-106° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH3:13])[CH2:8][CH2:7]1.Cl[C:19]1[N:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([N:12]([CH3:13])[C:19]2[N:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:10][CH2:11]1
Reactant: CNC1CCN(Cc2ccc(F)c(F)c2)CC1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1ccc(C(F)(F)F)nn1)C1CCN(Cc2ccc(F)c(F)c2)CC1

Procedure:
A solution of D5 (480 mg, 2 mmol), 3-chloro-6-trifluoromethylpyridazine (182 mg, 1 mmol) and diisopropylethylamine (260 mg, 2 mmol) in n-butanol (4 ml) was heated at 190° C. in a microwave reactor (Emrys Optimizer; 0-9 Barr) for 2 h. After this period, the reaction mixture was evaporated in vacuo and the residue extracted with dichloromethane. The organic layer was washed with a saturated solution of sodium hydrogen carbonate, dried (MgSO4) and the solvents evaporated in vacuo. Purification by reverse phase HPLC (conditions as previously described) gave E12 (210 mg, 54%). C18H19F5N4 requires 386; Found 387 (MH+). 1H NMR (CDCl3) δ 1.74 (br.d, J=12.0 Hz, 2H), 1.88 (qd, J=12.0, 3.9 Hz, 2H), 2.17 (td, J=11.8, 2.5 Hz, 2H), 2.96 (br.d, J=11.6 Hz, 2H), 3.00 (s, 3H), 3.47 (s, 2H), 4.85 (t, J=12.1 Hz, 1H), 6.78 (d, J=9.6 Hz, 1H), 6.99-7.05 (m, 1H), 7.10 (dt, J=10.2, 8.1 Hz, 1H), 7.20 (ddd, J=11.4, 7.8, 2.1 Hz, 1H), 7.46 (d, J=9.6 Hz, 1H)
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])=[N:7][C:6](=[O:16])[C:5](=[O:17])[N:4]=2.C(N(CC)CC)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:25]1([CH2:31][C:32]([O:1][C:2]2[C:3]3[C:8]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=2[O:12][CH3:13])=[N:7][C:6](=[O:16])[C:5](=[O:17])[N:4]=3)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc2c(c(O)c1OC)=NC(=O)C(=O)N=2
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(c(OC(=O)Cc3ccccc3)c1OC)=NC(=O)C(=O)N=2
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
To a suspension of 5-hydroxy-6,7-dimethoxy-2,3-quinoxalinedione (48) (50 mg, 0.22 mmol) in 3 mL of methylene dichloride was added 0.14 mL of triethylamine and phenylacetyl chloride (77.5 mg, 0.5 mmol, Aldrich) at 0° C. The resulting mixture was stirred at room temperature for 12 hr. The reaction mixture was then poured into ice-water (5 g). A white solid precipitated and was collected by suction filtration, washed with water (3×5 mL) and ethyl acetate (3×2 mL), and dried in vacuo, giving 60 mg (77%) of the product as a white solid; mp 298-300° C.; 1H NMR (DMSO-d6, 300 MHz) δ 3.405 (s, 3 H), 3.728 (s, 3 H), 4.024 (s, 2H), 6.653 (s, 1 H), 7.359 (m, 5 H), 11.773 (s, 1 H), 11.846 (s, 1 H). EIMS m/e 356 (25, M+), 238 (100). (HPLC 100%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: [H][H]
Reactant: COc1ccc(CC2CCCN2Cc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CC2CCCN2)cc1OC

Procedure:
Hydrogenate 11.7 g of 1-benzyl-2-(3,4-dimethoxybenzyl)pyrrolidine in ethanol with 6.5 g of palladium/activated charcoal (10% strength)/hydrogen. Free the product from solvent and catalyst, and then distil it under a high vacuum. Purify via the picrate to obtain a yield of 3.2 g (38.5% of theory).
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.CC(C)(C)C(=O)CN1C2C=CC=CC=2C(C2C=CC=CC=2)=NN([CH2:61][C:62](O)=[O:63])C1=O.C(OC(=O)CSC1C=CC=C(N)C=1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:62]([O:63][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:61]
Reactant: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccc2)c2ccccc21
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)CSc1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that [1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-5-phenyl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 4, step a) and (3-amino-phenylsulfanyl)-acetic acid ethyl ester were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.60 (1H, br s), 8.40 (1H, s), 7.63-7.40 (7H, m), 7.25-7.14 (6H, m), 4.76 (2H, m), 4.43 (2H, s), 3.58 (2H, s), 1.25 (9H, s). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 50.02; H, 6.04; N, 7.59%; C30H30N5O5S.C7H17NO5.1.8C4H8O2.2.2CH2Cl2 requires: C, 50.06; H, 5.96; N, 7.55%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][Cl:11])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[Cl-:11].[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][P+:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1ccc(/C=C/CCl)cc1Oc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Fc1ccc(/C=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Oc1ccccc1
Product: [Cl-]

Procedure:
A mixture of E-3-(4-fluoro-3-phenoxyphenyl)-1-chloroprop-2-ene (42 g), triphenylphosphine (42 g) and xylene (300 cm3) was heated at the reflux temperature for 16 hours. After cooling, crystals of E-3-(4-fluoro-3-phenoxyphenyl)prop-2-en-1-yl triphenyl phosphonium chloride (68 g) were filtered from the reaction mixture, washed with dry diethyl ether, dried by suction and stored in a desiccator under vacuum.
Reaction SMILES: FC1C=C(OC)C=C(F)C=1C[NH2:5].C(N(CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[F:41][C:42]1[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[C:68]([F:74])[C:43]=1[CH2:44][N:45]1[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][C:49]=2[S:48](=[O:56])(=[O:55])[N:47]([C:57]2[CH:62]=C[C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=2)[C:46]1=[O:67]>CN(C=O)C>[F:41][C:42]1[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[C:68]([F:74])[C:43]=1[CH2:44][N:45]1[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][C:49]=2[S:48](=[O:56])(=[O:55])[N:47]([C:57]2[CH:62]=[N:5][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=2)[C:46]1=[O:67]
Reactant: COc1cc(F)c(CN)c(F)c1
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3cnc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1

Procedure:
The title compound (134 mg, 0.27 mmol) was prepared in two steps from (IntC4) (165 mg, 0.5 mmol), 2,6-difluoro-4-methoxybenzylamine (90 uL, 0.6 mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by 1,1′-carbonyldiimidazole (331 mg, 2.04 mmol), triethylamine (0.14 mL, 1.00 mmol) in DMF (1.5 mL) using the methods of (95).
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:18][C:19]1[CH:20]=[C:21]([O:26][CH3:27])[C:22]([NH2:25])=[N:23][CH:24]=1>>[Br:18][C:19]1[CH:20]=[C:21]([O:26][CH3:27])[C:22]([NH:25][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([S:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:7])=[O:8])[CH:10]=2)=[N:23][CH:24]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCC2)c1
Reactant: COc1cc(Br)cnc1N
Product: COc1cc(Br)cnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1

Procedure:
The intended substance was produced according to the method of Example 92 but using 3-(pyrrolidin-1-ylsulfonyl)benzoic acid and 5-bromo-3-methoxypyridine-2-amine as the starting materials.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CN(C)C=O>[I:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:6]=1
Reactant: C1CNCCN1
Reactant: Clc1ncc(I)cn1
Solvent: CN(C)C=O
Product: Ic1cnc(N2CCNCC2)nc1

Procedure:
0.02 mol of 2-chloro-5-iodopyrimidine, 0.06 mol of piperazine and 100 ml of absolute dimethylformamide are heated to 100° for 45 minutes and then evaporated. The crystalline residue is shaken with potassium bicarbonate solution and methylene chloride. The substance contained in the methylene chloride phase is purified by column chromatography over silica gel 60. The amine obtained by elution with methylene chloride/methanol (7:3) is stirred with isopropyl ether and filtered off with suction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[N:13][N:14]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=5)[CH:15]=4)=[CH:9][N:8]([S:24]([C:27]4[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=4)(=[O:25])=[O:26])[C:5]3=[N:6][CH:7]=2)=[CH:37][C:36]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52]
Reactant: CC1(C)OB(c2ccc(F)c(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 94.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (166 mg, 0.317 mmol) was coupled with N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 65) (100 mg, 0.317 mmol) using sodium carbonate (101 mg, 0.952 mmol) and Pd(PPh3)2Cl2 (12 mg, 0.015 mmol) in DME/water (15/2 mL). This afforded 190 mg (94.5% yield) of the titled compound. MS: m/z=634.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O>>[CH3:14][O:15][C:16]1[CH:17]=[C:18](/[CH:19]=[C:9]2/[C:10](=[O:11])/[C:12](=[CH:1]/[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:13][CH3:12])[CH:3]=3)/[O:13][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:8]/2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(/C=C2\Oc3ccc(C)cc3O/C(=C\c3ccc(OC)c(OC)c3)C2=O)cc1OC

Procedure:
Calone is reacted with 3,4-dimethoxybenzaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(3,4-dimethoxyphenyl)-meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[C:23]3[C:24]([OH:28])=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O:32][C@@H:33]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@@H:34]1OC(=N)C(Cl)(Cl)Cl)(=[O:31])[CH3:30].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[C:29]([O:32][C@@H:33]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:34]1[O:28][C:24]1[C:23]2[C:19]([CH2:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:12][CH:13]=3)=[CH:20][O:21][C:22]=2[CH:27]=[CH:26][CH:25]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(OCc1ccccc1)c1ccc(CCc2coc3cccc(O)c23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(C(=O)OCc5ccccc5)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
3-[2-(4-Benzyloxycarbonylphenyl)ethyl]-4-hydroxybenzofuran (0.26 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.41 g) were dissolved in dichloromethane (5 mL)-ethyl acetate (3 mL). To the solution was added boron trifluoride-diethyl ether complex (0.44 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous, sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2-2/3) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-benzyloxycarbonylphenyl)ethyl]-benzofuran (0.44 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added 10% palladium-carbon powder (0.2 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.37 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].C[Si]([C:14]#[N:15])(C)C.C(N(CC)C(Cl)=O)C>C(Cl)Cl>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([C:14]#[N:15])=[N:3][C:2]=1[CH3:1]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc[n+]([O-])c1C
Agent: CCN(CC)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(C#N)nc1C
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
To a slurry of N-oxide from Step 1 (8.7 g) in CH2Cl2 (125 mL) at r.t. was added trimethylsilylcyanide (9.9 mL, 74.2 mmol). After stirring for 15 minutes, N,N-diethylcarbamoyl chloride (9.4 mL, 74.2 mmol) was added and the resulting mixture was allowed to stir at r.t. for 2.5 days. The reaction was quenched by careful addition of 10% aq. K2CO3, stirred 15 minutes, and extracted (3×) with CH2Cl2. The organic layer was washed with aq. K2CO3, brine, and dried over Na2SO4 /K2CO3. Evaporation of the solvent and purification of the residue by flash chromatography (25% to 50% Et2O in hexanes) yielded 4.13 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:38])[N:15]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ON1C2N=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[CH2:62]([O:64][C:65](=[O:70])[C@H:66]([OH:69])[CH2:67][NH2:68])[CH3:63].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:62]([O:64][C:65](=[O:70])[C@H:66]([OH:69])[CH2:67][NH:68][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:15]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[C:14]([NH:13][C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:4]=2)=[O:38])=[CH:37][CH:36]=1)[CH3:63]
Reactant: CCOC(=O)[C@H](O)CN
Reactant: O=C(O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid (0.22 g, 0.39 mmol) was dissolved in DMF (3 mL) and 1-hydroxy-7-azabenzotriazole (0.06 g, 0.47 mmol) and EDAC (0.09 g, 1.2 mmol) were added. The mixture was stirred for 1.5 hour, and (R)-isoserine ethyl ester (0.10 g, 0.59 mmol) and diisopropylethylamine (0.10 mL, 0.59 mmol) in DMF (2 mL) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (25 mL). The aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phases were washed with hydrochloric acid (0.2 N, 3×10 mL) and water:saturated sodium chloride (1:1), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (35 g silica gel) using ethyl acetate and n-heptane (6:4) as eluent to afford 0.27 g of (R)-3-{4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester.
Reaction SMILES: CCN(CC)CC.[CH3:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1OS(C(F)(F)F)(=O)=O)[C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13].[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][BH:33][O:32]1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][B:33]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:9]([CH3:8])[C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:32]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(C#C[Si](C)(C)C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C#C[Si](C)(C)C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: 60 °C
Yield: 86.5 %

Procedure:
A mixture of 547 mg (2.44 mmol, 0.03 eq) of Pd(OAc)2 and 2.63 grams (4.88 mmol, 0.06 eq) of bis[2-(diphenylphosphino)phenyl]ether (DPEphos) was stirred in 163 mL of dioxane in a 500 mL round bottom flask under argon at room temperature. To this heterogenous mixture was sequentially added 22.7 mL (163 mmol, 2.0 eq) of Et3N and 28.5 grams (81.3 mmol, 1.0 eq) of triflate 7. Lastly, 17.6 mL (122 mmol, 1.5 eq) of 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane was added and the mixture was sparged with argon for 10 minutes. The reaction was then heated to 60° C. in a silicon oil bath and stirred until complete by 1H-NMR (aliquots removed periodically). Upon completion (˜19 hours) the mixture was cooled to room temperature and diluted with Et2O. The solution was then washed with water and the water layer was back extracted with Et2O. The combined Et2O layers were washed with brine and dried over MgSO4. Concentration and silica gel chromatography (hexane/EtOAc) gave 23.1 grams (86%) of 9 as a yellow oil, Rf 0.64 (1:1 hexane:EtOAc). 1H-NMR (500 MHz, CDCl3): 7.81 (1H, d, J=7.1 Hz), 7.75 (1H, d, J=7.8 Hz), 7.47 (1H, d, J=7.6 Hz), 7.24 (1H, d, J=7.4 Hz), 4.73 (1H, q, J=7.1 Hz), 1.45 (3H, d, J=7.1 Hz), 1.36 (6H, s), 1.35 (6H, s), 0.215 (9H, s). 13C-NMR (500 MHz, CDCl3): 150.25, 136.35, 131.64, 126.85, 125.94, 111.34, 85.66, 83.77, 31.52, 26.29, 25.17, 24.93, 0.45. IR (cm−1): 2975 (m), 2165 (m), 1598 (m), 1441 (m), 1380 (m), 1346 (s), 1249 (m), 1145 (m), 842 (s) HRMS (EI) calcd. for C19H29BO2Si: 328.2030. found: 328.2028.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[NH:21][N:20]=2)COCC[Si](C)(C)C)(=[O:9])=[O:8])=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:41][S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:21]2[C:22]3[C:27](=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][CH:23]=3)[C:19]([NH:10][S:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:8])=[N:20]2)=[CH:33][CH:34]=1)(=[O:39])=[O:40]
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1cccc2[nH]nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(S(N)(=O)=O)cc1
Reaction time: 18 h
Yield: 10 %

Procedure:
5-Chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (for a preparation see Intermediate 8) (1.734 g, 3.66 mmol) was dissolved in DMF (2.4 mL) and an aliquot (0.1 mL, 0.15 mmol) added to 4-(bromomethyl)benzenesulfonamide (APAC Pharm) (0.15 mmol) and potassium carbonate (0.15 mmol) added last. The tubes were capped and shaken. Stood at room temperature for 18 h, more potassium carbonate (excess) added and reshaken the tubes. Filtered through alltech tube to remove inorganic solids, and washed tubes with MeOH (1 mL) and blown to dryness under a stream of nitrogen in a Radley's blow down unit. Redissolved in DCM (0.5 mL) and applied to a 10 g silica cartridge, and purified by chromatography on Flashmaster using a gradient of 0-100% DCM-(DCM with 20% EtOAc) over 20 min. The appropriate fractions were combined and evaporated in vacuo using the Genevac. The residue was dissolved in TBAF (1M, 0.5 mL) and heated in a microwave oven (50 Watts, 10 min, at approx 110° C. The sample was purified by MDAP on Atlantis column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo using the Genevac to give the title compound (7.9 mg, 10%) LCMS (System A) RT=0.92 min, ES+ve m/z 513/515 (M+H)+