Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]([Cl:14])[CH:7]=1.[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25]O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:14][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[C:2]([Cl:1])[Cl:15])[CH:11]=[C:10]([Cl:12])[C:9]=1[O:13][CH2:25][CH2:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCCCc1ccccc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
To a solution of 0.30 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol, 0.16 g of 4-phenyl-1-butanol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.21 g of diethylazodicarboxylate dissolved in 5 ml of tetrahydrofuran was added dropwise, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.32 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-phenylbutyloxy)benzene (73% yield), nD26.0 1.5716.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([NH2:14])[C:8]2=[CH:7][N:6]=1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21].N1C=CC=CC=1>O1CCOCC1>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([NH:14][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[C:8]2=[CH:7][N:6]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Reaction time: 2 h
Yield: 38.3 %

Procedure:
To 6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-ylamine (60 mg, 0.228 mmol) in 2 mL dioxane was added ethanesulfonyl chloride (22.0 uL, 0.228 mmol) and pyridine (18.5 uL, 0.228 mmol). The reaction mixture was heated to reflux with stirring for two hours, then cooled and chromatographed through silica (0%-40% EtOAc in hexanes) to give 31 mg of ethanesulfonic acid [6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-amide, MP=226.0-226.9° C., MS(M+H)=356.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[CH3:12]I>CS(C)=O>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH3:12]
Reactant: CI
Reactant: COC(=O)C(C)(C)CO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCC(C)(C)C(=O)OC
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a solution of 3.52 g (63 mmol) of powdered potassium hydroxide in DMSO (150 mL) are added 2 mL (16 mmol) of hydroxypivalic acid methyl ester, followed by 3.9 mL (63 mmol) of methyl iodide. The reaction mixture is stirred for 0.5 h, then quenched with water (300 mL). The reaction mixture is extracted with DCM (3×300 mL). The combined organic extracts are washed with water (2×150 mL), brine (50 mL), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to yield 1.76 g of 3-methoxy-2,2-dimethyl-propionic acid methyl ester as a pale yellow oil, which is used in the next step without further purification. Yield: 77%; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.1 (6H, s), 3.2 (3H, s), 3.3 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][CH2:11]3)=[CH:4][CH:3]=1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]2[CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][CH2:11]3)[C:20]([NH:19][CH2:17][CH3:18])=[O:21])=[CH:15][CH:16]=1
Reactant: CCN=C=O
Reactant: Clc1ccc(CNC2CC3CCC2C3)cc1
Solvent: CCCCCC
Product: CCNC(=O)N(Cc1ccc(Cl)cc1)C1CC2CCC1C2
Yield: 85.5 %

Procedure:
24 g of N-4-chlorobenzyl-2-norbornylamine was dissolved in 400 ml of hexane, and with stirring and cooling, a solution of 8 g of ethyl isocyanate in 30 ml of hexane was added dropwise to the solution. After the addition, the temperature of the mixture was gradually raised, and it was stirred for about 3 hours at 40° C. After cooling, the precipitated crystals were suction-filtered, and recrystallized from a mixture of hexane and ethanol to give 26.7 g of the desired 1-(4-chlorobenzyl)-3-ethyl-1-(2-norbornyl)urea. mp. 132°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.[C:19](=O)([O-])[O-:20].[K+].[K+].Br[C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][NH:36][C:35](=[O:38])[CH2:34][O:33]2)=[CH:28][CH:27]=1>CN(C=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[O:20])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[O:33][CH2:34][C:35](=[O:38])[NH:36][CH2:37]2)=[CH:28][CH:27]=1
Reactant: CC1(C)COB(c2cc3cc[nH]c3cc2Cl)OC1
Reactant: O=C([O-])[O-]
Reactant: O=C1COC(c2ccc(Br)cc2)CN1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4CNC(=O)CO4)cc3)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
The mixture of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (150 mg, 0.57 mmol) and N,N-dimethylformiminium chloride (217 mg, 1.70 mmol) in DMF/dioxane (6 mL, 1:5) was stirred at room temperature for 20 minutes. Then 2.0 M potassium carbonate (3 mL), 6-(4-bromophenyl)morpholin-3-one (146 mg, 0.57 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I I) (41 mg, 0.057 mmol) was added to the mixture. The reaction mixture was purged with nitrogen for 3 minutes, heated to 90° C. and stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the title compound (150 mg, 75% yield) as a brown solid that was brought forward without further purification.
Reaction SMILES: C(OCC[C@:7]([OH:49])([C@@H:11]([C:29](=[O:48])[NH:30][C@H:31]([C:44]([O:46][CH3:47])=[O:45])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]#[C:42][CH3:43])=[CH:35][CH:34]=1)/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:8]([OH:10])=[O:9])(=O)C.[CH2:50]1[CH2:60][CH2:59]N2C(=NCCC2)C[CH2:51]1.Br[CH2:62][N:63]1[C:71](=[O:72])[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:64]1=[O:73]>ClCCl>[CH2:40]([O:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C@H:31]([NH:30][C:29]([C@H:11]([C@@:7]([OH:49])([CH2:7][C:8]([O:10][CH2:62][N:63]2[C:71](=[O:72])[C:70]3[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=3)[C:64]2=[O:73])=[O:9])[C:8]([O:10][CH2:59][CH2:60][CH2:50][CH3:51])=[O:9])/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:48])[C:44]([O:46][CH3:47])=[O:45])=[CH:34][CH:35]=1)[C:41]#[C:42][CH3:43]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)O)C(=O)OC)cc1
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)OCN2C(=O)c3ccccc3C2=O)C(=O)OCCCC)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a mixture of No. 5317776 (Compound E; 60 mg, 0.08 mmol), DBU (19 μL, 0.126 mmol) and dichloromethane (0.84 mL) was added 2-bromomethyl-isoindole-1,3-dione (30 mg, 0.126 mmol) commercially available from Aldrich (cat. No. 252611). After the mixture was stirred at room temperature for 6 hours, further 2-bromomethyl-isoindole-1,3-dione (10 mg, 0.04 mmol) and DBU (6.3 μL, 0.04 mmol) were added. Then, 4-(1,3-dioxo-1,3-dihydro-isoindole-2-ylmethyl) 1-butyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate (56 mg, 76%) was obtained (ESI (LC/MS positive mode) m/z 873 (M+H); Rt 3.38 min.).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[N:6]=[CH:5][C:4]=2[CH2:3]1.[CH3:15][C:16](OC(C)=O)=[O:17].[CH3:22][CH2:23][O:24][C:25](OCC)(OCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:16]([N:10]1[C:9]2[CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[N:6]=[CH:5][C:4]=2/[C:3](=[C:25](\[O:24][CH2:23][CH3:22])/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)/[C:2]1=[O:1])(=[O:17])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: COC(=O)c1cc2c(cn1)CC(=O)N2
Solvent: Cc1ccccc1
Product: CCO/C(=C1/C(=O)N(C(C)=O)c2cc(C(=O)OC)ncc21)c1ccccc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
Step-1: To a solution of methyl 2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (10 mg, 0.052 mmol) in toluene (5 mL) was added Ac2O (15 mg, 0.156 mmol) and triethyl orthobenzoate (35 mg, 0.156 mmol) at room temperature. The reaction mixture was heated stirred at 85° C. for 3 h. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography using 5% acetone in dichloromethane to afford (E)-methyl 1-acetyl-3-(ethoxy(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate as yellow solid. 1H NMR (CDCl3, 400 MHz) δ 9.15 (s, 1H), 8.67 (s, 1H), 7.52-7.59 (m, 5H), 4.06 (dd, J=13.9, 7 Hz), 3.89 (s, 3H), 2.45 (s, 3H), 1.37 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)=[C:11]([C:30]#[N:31])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CC(O)=[O:34]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:30]([NH2:31])=[O:34])[C:12]3[NH:15][C:16]4[C:17]([C:13]=3[CH:14]=2)=[CH:18][C:19]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:21]=4)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)O
Reactant: Cc1ccc(-c2ccc(Nc3ccc(C(=O)N4CCOCC4)cc3)c(C#N)c2)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: Cc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)N5CCOCC5)cc4c3c2)cc1C
Temperature: 130 °C

Procedure:
3′,4′-Dimethyl-4-(4-(morpholine-4-carbonyl)phenylamino)biphenyl-3-carbonitrile (320 mg, 0.777 mmol) and Pd(OAc)2 (0.523 g, 2.331 mmol) were mixed with AcOH (10 mL) in a sealed microwave tube and heated at 130° C. for 12 hrs. The mixture was filtered through a pad of CELITE®, then a ACRODISC® PTFE membrane (0.45 um), rinsed with additional 35 ml AcOH. The filtrate was concentrated and purified using preparative HPLC to give 51.8 mg of titled product. MS (ESI) m/z 428.4 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.59 (s, 1H), 8.74 (s, 1H), 8.38 (bs, 2H), 8.3 (s, 1H), 7.76(d, 1H, J=8.2), 7.71 (s, 1H), 7.63 (d, 1H, J=6.3), 7.57 (bs, 1H), 7.48(d, 1H, J=8.2), 7.27(d, 1H, J=7.6), 3.65-3.59 (bm, 8H), 2.35 (s, 3H),), 2.29 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[C:3]([O:5][CH3:6])=[O:4].I[CH3:17]>C(OCC)C.[Ag-]=O>[CH3:17][O:1][CH:2]([C:7]([CH3:15])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CI
Reactant: COC(=O)C(O)C(C)(C)c1ccccc1
Agent: O=[Ag-]
Solvent: CCOCC
Product: COC(=O)C(OC)C(C)(C)c1ccccc1
Temperature: 40 °C
Reaction time: 26 h

Procedure:
To a solution of methyl 2-hydroxy-3-methyl-3-phenylbutanoate (0.50 g, 2.4 mmol, from Reference Example 37) in diethyl ether (11 mL) is added silver (I) oxide (4.3 g) and iodomethane (8.7 mL). The reaction mixture is stirred in a 40° C. oil bath under nitrogen atmosphere for 26 hours. The reaction mixture is combined with that from a previous run conducted under the same conditions and filtered through a plug of diatomaceous earth. The filtrate is concentrated under reduced pressure and then purified by flash chromatography (silica gel, hexanes/ethyl acetate) to furnish 0.52 g of a clear, colorless liquid (68% combined yield). MS (ES+): (M+H)=222.9
Reaction SMILES: [OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[C:4]([CH3:12])([CH3:11])[CH2:3]1.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][C:41]1=[O:45].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O>[OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([NH:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])=[O:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: NCCCN1CCCC1=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)NCCCN4CCCC4=O)C(C)(C)C3)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (102 mg, 0.20 mmol), N-(3-aminopropyl)-2-pyrrolidinone (85 μL, 0.60 mmol), EDC (58 mg, 0.30 mmol), and HOBt (46 mg, 0.30 mmol) was added N,N-dimethylformamide (2 mL) and triethylamine (140 μL, 1.01 mmol). The mixture was stirred at room temperature for 16 h, quenched with 1:1 water:brine, and extracted with EtOAc. The organic layer was washed with 1:1 water:brine (3×). The organic layer was dried over magnesium sulfate, filtered and purified by reverse phase HPLC(C-18, eluting with a 45:55 to 80:20 gradient of acetonitrile:water+0.1% TFA). The combined fractions were diluted with ethyl acetate and dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to afford the title compound (97 mg, 0.15 mmol, 76% yield) as a white solid. MS ESI: [M+H]+ m/z 631.2. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J=4.9, 1H), 7.93 (s, 1H), 7.92 (s, 1H), 7.68 (t, J=5.6, 1H), 7.46 (s, 1H), 7.28 (d, J=4.9, 1H), 7.14 (s, 1H), 5:86 (s, 1H), 3.29 (s, 1H), 3.24-3.12 (m, 2H), 3.12-3.03 (m, 1H), 2.99-2.88 (m, 1H), 2.31 (s, 3H), 2.19 (m, 2H), 2.02 (m, 2H), 1.86 (m, 5H), 1.66-1.50 (m, 3H), 1.40 (m, 1H), 1.11 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[N:15]1([CH2:20][CH2:21][OH:22])[CH:19]=[CH:18][N:17]=[N:16]1.O>CN(C=O)C>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:22][CH2:21][CH2:20][N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5]
Reactant: OCCn1ccnn1
Reactant: C=CCOc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(COCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
197 mg 8.21 mmol) 95% sodium hydride were given at −50° C. to a solution of 1.00 g (5.47 mmol) 1-allyloxy-4-chloromethyl-benzene and 619 mg (5.47 mmol) 2-(1H-[1,2,3]-triazol-1-yl)-ethanol in 9.0 ml DMF. The mixture was allowed to warm slowly to r.t., stirred overnight and 10 ml water added. The formed oil was collected with 10 ml dichloromethane, the aqueous phase extracted with 10 ml dichloromethane and the combined organic phases dried over Na2SO4.
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28]1([Mg]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[OH:15][C:14]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:2]2[N:1]=[CH:6][C:5](=[O:7])[NH:4][C:3]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1cnc2c([nH]1)-c1ccccc1C2(O)c1ccccc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione (2 g) was dissolved in dry THF (50 ml). Triethylamine (1.6 ml) was added and trimethylsilyl chloride (1.4 ml) dissolved in THF (10 ml) was added dropwise at room temperature. The mixture was stirred overnight and the precipitate filtered off. Phenylmagnesium bromide (20 mmol) in THF (10 ml) was subsequently added dropwise under nitrogen, and the resulting mixture stirred at room temperature for 3 days. Subsequent evaporation followed by addition of water and addition of HCl (1N) to slightly acidic solution resulted in precipitation of yellow crystals (2.7 g). The precipitate was purified on silica gel column using methylene chloride/methanol (9/1) as eluent resulting in 1.2 g pure title compound. M.p.>270° C. The MS showed the molecular ion 276. 1H-NMR (DMSO-d6, δ): 6.39 (s, 1H), 7.15-7.5 (m, 8H), 7.82 (s+m, 2H), 12.6 (s, 1H).
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])OC(Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=[CH:15][CH:14]=1.O1CCC[CH2:20]1>>[ClH:1].[CH2:14]([NH:13][CH2:18][CH2:2][O:5][C:6](=[O:12])[CH3:20])[CH3:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccncc1
Reactant: C1CCOC1
Product: CCNCCOC(C)=O
Product: Cl

Procedure:
To a solution (30 mL) of bis(trichloromethyl)carbonate (0.59 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 10 min., 2-(ethylamino)ethylacetate hydrochloride (0.67 g) obtained in Reference Example 20 was added. A solution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was dropwise added and the mixture was stirred at room temperature for 1 hr. After concentration under reduced pressure, water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The layer was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred overnight at 60° C. After concentration under reduced pressure, water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=3:7, then ethyl acetate) to give the title compound (1.58 g) as a yellow amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:27]=[C:28]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)[CH:29]=[CH:30][CH:31]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:50]1(B(O)O)[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=1>>[C:50]1([C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:27]=[C:28]([N:32]6[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:46])[CH3:44])[C:34](=[O:47])[CH2:33]6)[CH:29]=[CH:30][CH:31]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:48][CH:49]=3)=[CH:4][CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)c2)S1(=O)=O
Reactant: OB(O)C1=CCCCC1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5=CCCCC5)nn4)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (38 mg, 0.05 mmol) was treated as described in general procedure G using 1-cyclohexen-1-yl-boronic acid (13 mg, 0.1 mmol) to give 5-{3-[2-[4-(6-cyclohex-1-enyl-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(OC)C=CC=CC=1.[Cl:20][S:21](O)(=[O:23])=[O:22]>ClCCCl>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[S:21]([Cl:20])(=[O:23])=[O:22]
Reactant: COc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)Cl
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: COc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of 4-nitroanisole (3.1 g; 20 mmol) in 1,2-dichloroethane (20 mL), 2 mL of chlorosulfonic acid was added at 0° C. The resulting reaction mixture was gradually warmed to room temperature and then heated to reflux for 2 h at which time all the anisole had been consumed. The reaction mixture was then cooled to room temperature and diluted with chloroform (30 mL). The contents were then transferred to a separatory funnel, washed with water (50 mL), and the layers were separated. The aqueous layer was then extracted with chloroform (30 mL). The combined organic layers was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue obtained was purified by silica gel flash column chromatography using ethyl acetate/hexanes as eluant (1:5 to 1:1 gradient) to afford 2-methoxy-5-nitrobenzenesulfonyl chloride as a dark brown solid. 1H NMR (CDCl3, 400 MHz): δ 4.21 (s, 3H), 7.28 (d, 1H), 8.59 (dd, 1H), 8.88 (d, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][N:24]=[C:25]=[O:26].[CH:27]([NH2:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][NH:24][C:25]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:26]
Reactant: CC(C)N
Reactant: CC1=C(CN=C=O)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC1=C(CNC(=O)NC(C)C)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of the isocyanate from Step 1 in toluene was added 1.2 equivalent of isopropylamine. The reaction mixture was kept under reflux for 1 h. After having been cooled to room temperature, the mixture was diluted with n-hexane to form a yellow precipitate, which was filtered off, and was recrystallized from CH2Cl2, to give the title compound as a yellow solid (75%), mp: 217° C.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[Cl:13][CH2:14][CH2:15][CH2:16]Br>CN(C)C=O>[Cl:13][CH2:14][CH2:15][CH2:16][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:3][C:4]1=[O:12]
Reactant: ClCCCBr
Reactant: O=c1[nH]c2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc2ccccc2n1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a stirred suspension of sodium hydride (7.8 g, 160 mmol, ether-washed) in dimethylformamide (75 ml) was added dropwise under nitrogen, 2-benzoxazolinone (20.0 g, 150 mmol) dissolved in dimethylformamide (150 ml). After complete addition the reaction was stirred at ambient temperature for 30 min, and then it was cooled to -5° C. with an ice-acetone bath. A solution of 3-chloro-1-bromopropane (46.6 g, 300 mmol) in dimethylformamide (50 ml) was added dropwise (temperature never exceeded 0° C.). The reaction was allowed to reach ambient temperature and was stirred for 16 hours. The reaction was poured into waiter, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4), and the extract concentrated to afford 21.9 g of a brown solid. The solid was recrystallized from toluene-hexane to afford N-(3-4chloropropyl)-2-benzoxazolinone as large needles, 15.6 g, m.p.=264°-266° C.