Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([OH:13])[CH2:5][CH2:4]1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[O:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][CH2:4]1
Reactant: CCOC(=O)CBr
Reactant: OC1CCOc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CCOc2ccccc21
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 173 mg, 4.33 mmol) in THF was added chroman-4-ol (500 mg, 3.33 mmol) at 0° C. After being stirred at the same temperature for 15 min, ethyl bromoacetate (723 mg, 4.33 mmol) was added. After 1 h, the mixture was poured onto water, and the aqueous phase was extracted with EtOAc (twice). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (7:1-4:1) to give 404 mg (51% yield) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([NH:15][CH3:16])[S:13][CH:14]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CI.[CH2:25]([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].Cl>C1C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([N:15]([CH3:25])[CH3:16])[S:13][CH:14]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CI
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminothiazole (415 mg, 1.33 mmol) in benzene (6 ml) was added methyl iodide (370 mg, 2.61 mmol), tetra-n-butyl ammonium hydrogene sulfate (435 mg, 1.33 mmol) and 50% NaOH aq. (3 ml), then the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, then acidified with 2N-HCl to pH 6 and the aqueous solution was extracted with benzene. The extracts were washed with water, dried and then evaporated under reduced pressure to a residue, which chromatographed to afford 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-dimethylaminothiazole (369 mg, 85% yield): NMR(CDCl3)δ1.62(d, 3H), 3.06(s, 6H), 4.09(q, 1H), 6.06(s, 1H), 7.02-7.63(m, 8H) ppm; IR(neat) 2950, 1620, 1550, 1420, 1340 cm-1.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:46]2[CH:47]=[C:42]([Cl:41])[CH:43]=[CH:44][C:45]=2[F:48])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: OB(O)c1cc(F)ccc1Cl
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4cc(Cl)ccc4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-5-fluorophenyl)boronic acid gave 281. 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.12 (dd, J=6.4, 2.7 Hz, 1H), 7.79 (s, 1H), 7.55-7.39 (m, 4H), 5.07 (dd, J=7.0, 4.5 Hz, 1H), 3.99-3.84 (m, 2H), 3.72 (s, 3H), 3.52-3.43 (m, 1H), 3.33-3.24 (m, 1H), 3.15 (s, 3H), 2.33-2.22 (m, 1H), 1.82-1.52 (m, 4H). LCMS (ES+) m/z 495 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][N:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH:7]=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27]
Reactant: COC(=O)c1cc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred brown solution of 5-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester (74.18 g, 180.7 mmol) in methylene chloride (700 mL) was added trifluoroacetic acid (26.2 mL, 352.4 mmol), and the mixture was stirred at room temp overnight. Sat. sodium bicarbonate (400 mL) was added to the solution, and the mixture was stirred for 10 minutes. The organic layer was separated, dried over magnesium sulfate, and evaporated to give 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester as a brown oil (52.5 g, 94% crude yield). The product was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[C:10]1([CH:16]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)=[O:21])[CH2:17][CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:27]2[C:28]3[C:24](=[CH:23][C:22]([C:20]([NH:19][CH:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:17][CH3:18])=[O:21])=[CH:30][CH:29]=3)[CH:25]=[CH:26]2)=[CH:4][CH:5]=1
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Reactant: Clc1ccc(CBr)cn1
Product: CCC(NC(=O)c1ccc2c(ccn2Cc2ccc(Cl)nc2)c1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 1, Example 21, using 5-(bromomethyl)-2-chloropyridine and N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 404 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:14].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:3]1=[O:14]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1OC[C@@H](c2ccccc2)NC1=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@H](C)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (2S,5R)-2-methyl-5-phenylmorpholin-3-one from Step E (90 mg, 0.47 mmol) in DMF (2 mL) at 0° C. was added NaH (20 mg of a 60% dispersion in oil, 0.50 mmol). After 10 min, ethyl bromoacetate (79 mg, 0.47 mmol) was added and the mixture was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (3 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40, to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[O:25]C)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.B(Br)(Br)Br.[NH4+].[Cl-].C([O-])(O)=O.[Na+]>ClCCl>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:7]2[CH:6]=[CH:5][C:4]([C:15]3[C:16]([OH:25])=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=3)=[CH:3][C:2]=2[F:1])=[N:9][CH:10]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: Nc1cnc(-c2ccc(-c3ccc(C(F)(F)F)cc3O)cc2F)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-[3-fluoro-2′-methoxy-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine (370 mg, 1.02 mmol) in dry dichloromethane (9.8 mL) at −78° Celsius, was added a boron tribromide in dichloromethane (3.1 mL, 1 M). The flask was slowly warmed to rt and stirred overnight. The reaction was poured into sat. NH4Cl and the pH adjusted to 8 with saturated NaHCO3. The resultant mixture was extracted with DCM (3×30 mL) and the combined extracts dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by HPLC to give the title compound. MS (ESI): mass calcd. for C17H11F4N3O, 349.08; m/z found, 350.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.41-8.35 (m, 1H), 8.17-8.10 (d, J=1.5, 1H), 7.99-7.88 (m, 1H), 7.56-7.46 (m, 3H), 7.22-7.19 (m, 1H), 7.19-7.17 (d, J=1.7, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:12]([N:30]=[C:31]=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(C(C)=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH2:10][NH:11][C:31]([NH:30][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:32])=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: NCCSc1ccc(O)cc1
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCSc1ccc(O)cc1
Temperature: 60 °C
Yield: 114.3 %

Procedure:
Into a 200-ml flask equipped with a stirrer and a condenser were charged 10.0 g of 2-(p-hydroxyphenylthio)ethylamine and 120 ml of methyl ethyl ketone, and stirred with heating at 60° C. in a nitrogen stream. Into the resulting solution was slowly dropped 15.3 g of n-octadecyl isocyanate, upon which white crystals were immediately precipiated. The reaction temperature was raised to 90° C. and stirring was continued with heating for 1 hour. The reaction mixture was cooled to room temperature, after which the crystals precipitated were collected by filtration. Recrystallization from chloroform gave 27.5 g of the desired compound. Melting point: 121° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([O:30][CH3:31])[C:24]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[C:23]3[Cl:43])([OH:19])[C:13]2[N:17]([CH3:18])[N:16]=[N:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)=O.Cl>CO>[NH:8]1[CH2:11][CH:10]([C:12]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([O:30][CH3:31])[C:24]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:37][CH:38]=2)=[C:23]3[Cl:43])([C:13]2[N:17]([CH3:18])[N:16]=[N:15][CH:14]=2)[OH:19])[CH2:9]1
Reactant: COc1nc2ccc(C(O)(c3cnnn3C)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: COc1nc2ccc(C(O)(c3cnnn3C)C3CNC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a flask containing tert-butyl 3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidine-1-carboxylate (165 mg, 0.27 mmol, Example 123) was added formic acid (5 mL) at room temperature followed by 6 N aqueous HCl (0.21 mL). The mixture was stirred at room temperature for 40 minutes and then MeOH (5 mL) was added and the mixture was stirred for 20 minutes before concentrating. The resulting oil was chromatographed directly on silica gel (10% 2 M NH3-MeOH-DCM increasing to 12% 2 M NH3-MeOH) to provide the title compound as an off white powder. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J=2.1 Hz, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.1 Hz, 2H), 7.42-7.32 (m, 3H), 4.52-4.34 (m, 2H), 4.33-4.16 (m, 3H), 4.05 (s, 3H), 3.96-3.80 (m, 1H), 3.71 (s, 4H); MS (ESI): mass calcd. Chemical Formula: C25H23ClF3N5O2; Exact Mass: 517.2. m/z found 517.9 [M+H]+.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:18](=O)[CH3:19])=[CH:14][NH:15]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C>C(O)C.[Pd]>[CH2:18]([C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])=[CH:10][CH:11]=2)[NH:15][CH:14]=1)[CH3:19]
Reactant: CC(=O)c1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(6-(Morpholine-4-carbonyl)-1H-indol-3-yl)ethanone (730 mg, 2.68 mmol) in acetic acid (1.53 ml, 26.8 mmol) and ethanol (50 ml) was hydrogenated in the presence of 10% Pd/C (285 mg, 0.27 mmol) for 72 h at room temperature, and then for 3 h at 50° C. After cooling to room temperature, the suspension was filtered over Celite and washed with ethanol. The solvent was evaporated and the residue repeatedly co-distilled with toluene and dichloromethane. White solid. Yield: 228 mg (33% of theory). HPLC-MS: m/z [M+H]+=259
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[Si]([N:36]=[C:37]=[O:38])(C)(C)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([C:37]([NH2:36])=[O:38])[CH2:27][CH2:28]4)[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: O=C(CC1CCNCC1)N1CCC(=C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: O
Product: NC(=O)N1CCC(CC(=O)N2CCC(=C3c4ccc(Cl)cc4SCc4cccnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared by a similar procedure from 4-[2-[4-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]-piperidine (120 mg, 0.265 mmol) in CH2Cl2 (3 ml), to which TMSNCO (200 μl, 170 mmol) was added at 0° C. After 5 minutes at 0° C., the mixture was stirred 3.5 hours at room temperature. The reaction mixture was diluted with water and extracted with CH2Cl2 ; the organic phase was washed with NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was chromatographed on silica in 5%MeOH/CH2Cl2 and eluted with 10%MeOH/CH2Cl2 to afford a white solid (103 mg); HRMS: calc.: 497.1778; found: 497.1766.
Reaction SMILES: O[CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:16]3[CH:15]=[N:14]2)[O:4]1.ClC(Cl)C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:52]([O:54][P:55]([CH:60]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:57][CH2:58][CH3:59])=[O:56])[CH3:53]>CS(C)=O.O.CO>[C:23]([NH:22][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([C@H:5]3[C@@H:6]4[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]4[C@@H:3](/[CH:2]=[CH:60]/[P:55](=[O:56])([O:57][CH2:58][CH3:59])[O:54][CH2:52][CH3:53])[O:4]3)[N:14]=[CH:15][C:16]=12)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOP(=O)(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCC
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ncc2c(NC(=O)c3ccccc3)ncnc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(Cl)Cl
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: CCOP(=O)(/C=C/[C@H]1O[C@@H](n2ncc3c(NC(=O)c4ccccc4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)OCC
Reaction time: 8 h
Yield: 27 %

Procedure:
Compound 22.3 (2.03 g, 4.93 mmol) in anhydrous dimethyl sulfoxide (25 mL, 0.2 M) was treated with dichloroacetic acid (400 μL, 4.93 mmol) and DCC (2.04 g, 9.67 mmol). The solution was stirred at room temperature for 2 h. [(Diethoxyphosphinyl)methylidene]triphenylphosphorane (2.0 g, 4.93 mmol, J. Org. Chem. 1996, 61, 7697-7701) was added and the mixture was stirred overnight. MeOH (25 mL) and H2O (25 mL) were added and the mixture was filtered over a plug of SiO2 and washed with MeOH (3×25 mL). The solvent was removed in vacuo and residue was suspended in CH2Cl2 and filtered over a plug of SiO2, and the solvent removed in vacuo. The residue was subjected to a column chromatography eluting with 0-100% EtOAc-hexanes, followed by 0-20% MeOH—CH2Cl2 to afford compound 22.4 (734 mg, 27% yield, E/Z ratio not determined) as a white solid (data for major isomer): 1H NMR (CDCl3, 300 MHz) 9.73 (br s, 1H), 8.71 (s, 2H), 7.91 (d, J=7.8 Hz, 2H), 7.50 (m, 1H), 7.35 (t, J=7.5 Hz, 2H), 6.89 (m, 1H), 6.15 (br s, 1H), 5.95 (m, 1H), 4.78 (m, 1H), 4.62 (m, 1H), 4.36 (m, 1H), 4.01 (m, 4H), 1.23 (m, 12H); 31P NMR (DMSO-d6, 121.4 MHz) 15.9; MS (ESI) m/z 544 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH2:16][C:17]3[NH:21][C:20]4[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:19]=4[N:18]=3)[CH3:15])=[O:13])[C:6]=2[CH:28]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Br[CH2:41][CH2:42][O:43][CH2:44][O:45][CH3:46]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH2:16][C:17]3[N:18]([CH2:41][CH2:42][O:43][CH2:44][O:45][CH3:46])[C:19]4[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:20]=4[N:21]=3)[CH3:15])=[O:13])[C:6]=2[CH:28]=1
Reactant: COCOCCBr
Reactant: CN(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)C(=O)Cn1c(=O)oc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOCCn1c(CN(C)C(=O)Cn2c(=O)oc3ccc(Cl)cc32)nc2cc(Cl)c(Cl)cc21
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-(5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-[(5,6-dichloro-1H-benzimidazol-2-yl)methyl]-N-methylacetamide (150 mg) and DMF (4.5 mL) were added K2CO3 (94 mg) and 1-bromo-2-(methoxymethoxy)ethane (80 μL), followed by heating and stirring at 70° C. for 5 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=50/50-0/100) to obtain 2-(5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-({5,6-dichloro-1-[2-(methoxymethoxy)ethyl]-1H-benzimidazol-2-yl}methyl)-N-methylacetamide (110 mg).
Reaction SMILES: [NH2:1][S:2]([N:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19](=[O:27])[O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:13][C:12]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:6][C:7](OC)=[O:8])(=[O:4])=[O:3].CC(C)([O-])C.[K+]>C1COCC1>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][C:19](=[O:27])[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:5]2[CH2:6][C:7](=[O:8])[NH:1][S:2]2(=[O:4])=[O:3])=[C:12]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:13]=1
Reactant: COC(=O)CN(c1ccc(OCC(=O)OCC[Si](C)(C)C)cc1OCc1ccccc1)S(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)COc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl N-(aminosulfonyl)-N-(2-(benzyloxy)-4-{2-oxo-2-[2-(trimethylsilyl)ethoxy]ethoxy}phenyl)glycinate in THF is added potassium t-butoxide (1.1 equivalent) in THF dropwise. The mixture is stirred at RT for 18 h. The solvent is removed under reduced pressure to afford the title compound which is used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([CH3:7])=[C:4]([C:8]([N:10]([CH3:12])[CH3:11])=O)[NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>N1C=CC=CC=1.O>[O:1]=[C:2]1[NH:6][C:5]([CH3:7])=[C:4]([C:8](=[S:14])[N:10]([CH3:12])[CH3:11])[NH:3]1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)N(C)C
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: Cc1[nH]c(=O)[nH]c1C(=S)N(C)C

Procedure:
A suspension of 3.4 g (20 mmol) of 2,3-dihydro--N,N,5-trimethyl-2-oxo-1H-imidazole-4-carboxamide (prepared in example 3) and 4.4 g cf phosphorus pentasulfide in 100 ml of dry pyridine is stirred at reflux temperature for 6 hours. The mixture is allowed to cool overnight and is diluted with water. The precipitate is collected and recrystallized from 50% aqueous ethanol to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.C(N(CC)CC)C.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>C(Cl)(Cl)Cl>[C:26]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)(=[O:27])[CH2:25][C:24]([CH3:23])=[O:28]
Reactant: O=C1CCc2c(cccc2OCCO)N1
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)OCCOc1cccc2c1CCC(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2 Grams of 5-(2-hydroxyethoxy)-3,4-dihydrocarbostyril and 2 ml of triethylamine were added to 50 ml of chloroform, then 1 g of diketene was added dropwise thereto, and the whole reaction mixture was stirred at room temperature for 2 days. The insoluble matter formed in the reaction mixture was removed by filtration, and the filtrate was concentrated, then the residue obtained was purified by silica gel column chromatography (eluant: chloroform), the eluate obtained was concentrated and the residue was recrystallized from chloroform-ether to yield 1.5 g of 5-(2-acetoacetoxyethoxy)-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. Melting point: 134.5°-135.5° C.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.S(Cl)(Cl)=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][NH2:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(N(CC)CC)C>C(OCC)(=O)C.O.O1CCCC1.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][NH:31][C:12](=[O:14])[CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: O=C(O)Cc1ccc2c(c1)CCCC2
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CCNC(=O)Cc2ccc3c(c2)CCCC3)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A mixture of 3.60 g (18.9 mmol) of (5,6,7,8-tetrahydronaphthalen-2-yl)acetic acid, 3.38 g (28.4 mmol) of thionyl chloride and 40 ml of toluene was stirred at 50° C. for 30 minutes and then 80° C. for 2.5 hours, cooled and concentrated under reduced pressure. The residue was added to a mixture of 3.43 g (18.9 mmol) 2-(3,4-dimethoxyphenyl)ethylamine, 2.30 g (22.7 mmol) of triethylamine and 40 ml of tetrahydrofuran at 0° C. and kept at 0° C. for 30 minutes and at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture and precipitated solid was collected with filtration. The obtained solid was dried to give 5.78 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH:33]([CH3:35])[CH3:34])[C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH:33]([CH3:34])[CH3:35])[C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCC(=O)N(CCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCCCCC(=O)N(CCCCCO)C(C)C
Yield: 101.2 %

Procedure:
A solution of 5 (4.75 g, 9.02 mmol) and p-toluenesulfonic acid in MeOH (50 mL) was stirred at rt for 12 h, then quenched with solid NaHCO3 and filtered. The filtrate was evaporated under vacuum and the residue was dissolved in ethyl acetate (50 mL). The ethyl acetate layer was washed with water (2×50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using 50-60% ethyl acetate/hexane as eluent to afford alcohol 6 (2.35 g, 93%) as a colorless, viscous liquid. TLC: EtOAc/hexanes (1:1), Rf˜0.30; 1H NMR (400 MHz, 55/45 mixture of rotamers) δ 4.58-4.66 and 3.96-4.08 (m, 1H, rotamers), 3.56 and 3.70 (t, J=5.4 Hz, 2H, rotamers), 3.02 and 3.16 (t, J=5.2 Hz, 2H, rotamers), 2.38 and 2.26 (t, J=6.3 Hz, 2H, rotamers), 1.50-1.64 (m, 6H), 1.22-1.40 (m, 8H), 1.13 and 1.09 (d, J=7.5 Hz, 6H, rotamers), 0.84 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, 55/45 mixture of rotamers) δ 172.81, 62.66, 62.60, 48.41, 45.55, 43.56, 41.04, 34.08, 34.0, 32.46, 32.43, 31.86, 31.57, 29.40, 25.87, 25.70, 23.77, 23.73, 22.75, 21.57, 20.72, 14.26.