Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.[C:26](Cl)(=[O:34])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[C:26](=[O:34])([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:2]([NH2:1])=[N:3][C:4]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:5]=4[C:6]=3[CH:7]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: CCCCCCOC(=O)Cl
Product: CCCCCCOC(=O)Oc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl hexyl carbonate was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedures described for Example 138, but using hexyl carbonochloridate.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C)C=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][C:10](=[O:13])/[C:11](=[CH:16]\[N:17]([CH3:19])[CH3:18])/[CH2:12]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Solvent: CN(C)C=O
Product: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Yield: 90 %

Procedure:
A solution of 13.5 mmol N—BOC-3-pyrrolidone and 13.5 mmol N,N-dimethylformamide-dimethylacetal in 50 ml N,N-dimethylformamide was hold overnight at 60° C. The reaction mixture was quenched by addition of 50 ml water and extracted 3 times with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give the crude title compound as a yellowish oil. Yield=90%. MS (m/e): 241.4 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](S(C)(=O)=O)[N:26]=3)=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:11]3[C:12](=[N:14][N:15]([CH3:17])[CH:16]=3)[N:13]=2)=[CH:4][CH:3]=1.[CH:35]1([CH2:38][NH2:39])[CH2:37][CH2:36]1>>[CH:35]1([CH2:38][NH:39][C:27]2[N:26]=[C:25]([C:9]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:13][C:12]4=[N:14][N:15]([CH3:17])[CH:16]=[C:11]4[C:10]=3[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:30]=[CH:29][N:28]=2)[CH2:37][CH2:36]1
Reactant: Cn1cc2c(-c3ccc(O)cc3)c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc2n1
Reactant: NCC1CC1
Product: Cn1cc2c(-c3ccc(O)cc3)c(-c3ccnc(NCC4CC4)n3)c(-c3ccc(F)cc3)nc2n1

Procedure:
Following a similar procedure to that described in example 128, but starting from 4-[6-(4-fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)-2-methylpyrazolo[3,4-b]pyridin-4-yl]phenol (obtained in section b) and (cyclopropylmethyl)amine, the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].[NH3:36].O>CN(C)C=O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12]([NH2:36])[N:11]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(S(C)(=O)=O)ncc1-c1ccccc1
Reactant: N
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(N)ncc1-c1ccccc1
Yield: 65 %

Procedure:
To a solution of 0.3 g (0.58 mmol) 2-methanesulfonyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 20 ml N,N-dimethylformamide a stream of NH3-Gas was introduced during 10 Min. The reaction mixture was poured onto 100 ml H2O. The aqueous layer was extracted three times with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 140:10:1) to give 0.17 g (65%) 2-amino-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a off-white solid, m.p. 181.5-182.5°.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH3:36]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:35]([CH2:34][CH2:33][O:32][CH3:31])[CH3:36])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: CNCCOC
Agent: Cl
Product: COCCN(C)C(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1

Procedure:
50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 20.1 mg (0.23 mmol) of (2-methoxyethyl)methylamine are reacted together by general method E. 20.5 mg (31.8% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5](=[CH:11][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:13][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1ccc(Cl)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
Ethyl 4-chlorosalicylate (174 mg), 4-chloro-6,7-dimethoxyquinoline (195 mg), and 4-dimethylaminopyridine (320 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed therefrom by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (26 mg, yield 8%).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:13]=[C:12]([CH3:14])[C:9]([CH:10]=[O:11])=[C:8]([CH3:15])[CH:7]=1.[H+].[B-](F)(F)(F)F.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24]>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:27]([O:26][C:22](=[O:25])[CH:23]=[CH:24][C:6]1[CH:13]=[C:12]([CH3:14])[C:9]([CH:10]=[O:11])=[C:8]([CH3:15])[CH:7]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1cc(N)cc(C)c1C=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: O
Product: Cc1cc(C=CC(=O)OC(C)(C)C)cc(C)c1C=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of NaNO2 (102 mg) in water (1 mL) was added to an ice cold mixture of 4-amino-2,6-dimethylbenzaldehyde (Example 5-1, step 3) (220 mg) and 48% HBF4 (0.5 mL). After 30 min at 0° C., tert-butyl acrylate (0.43 mL) and Pd(OAc)2 (10 mg) were added and the mixture was heated to 80° C. (or in a water bath) for 30 min. The suspension was filtered through Celite, washed with CH2Cl2 and the filtrate extracted with CH2Cl2. The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography using hexanes/ethyl acetate (7:1) and gave 3-(4-formyl-3,5-dimethylphenyl)-acrylic acid tert-butyl ester.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:28]([CH2:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:34])[C:29]([O-:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:40])(C)(C)C.[OH-].[Na+]>O.C(O)C>[C:6]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:28]([CH2:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:34])[C:29]([OH:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:40])([OH:41])=[O:5]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)C2(CC(CC(=O)NCCCO)C(=O)[O-])CCCC2)CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)C2(CC(CC(=O)NCCCO)C(=O)O)CCCC2)CCc2ccccc21
Reaction time: 15 h

Procedure:
6.43 g ethyl (2“rel1”)-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]-4-oxobutyrate (for preparation see Example 5) was dissolved in 140 ml of a 1:1 (v/v) mixture of water and ethanol, and 4.28 g solid NaOH was added thereto with stirring. After 15 h, the solvent was evaporated at reduced pressure, the residue was taken up in 100 ml EA and washed once with 50 ml aqueous KHSO4 solution. The aqueous phase was extracted twice with 30 ml EA each time. The combined organic phases were washed twice with 30 ml aqueous common salt solution each time and dried over sodium sulfate. Evaporation of the solvent yielded 5.41 g of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1COCC1.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>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[CH:18][C:17]([C:16]3[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:22][CH:21]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(I)c1
Reactant: Nc1ncccc1-c1ccc(B(O)O)cc1
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: C1CCOC1
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2ccc(-c3cccnc3N)cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (8.49 mg) was added to a suspension of 1-iodo-3-methoxybenzene (68.8 mg), 4-(2-aminopyridin-3-yl)phenylboronic acid (52.4 mg) and sodium carbonate decahydrate (210 mg) in DME (5 mL), water (1 mL) and THF (dry) (5 mL). The mixture was stirred at 80° C. under nitrogen overnight. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (49.1 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8](OC)[O:9]C)=[C:6]([O:13][CH:14]([F:16])[F:15])[CH:5]=[CH:4][C:3]=1[F:17]>CC(C)=O.O>[Cl:1][C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]([O:13][CH:14]([F:16])[F:15])[C:7]=1[CH:8]=[O:9]
Reactant: COC(OC)c1c(OC(F)F)ccc(F)c1Cl
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1c(OC(F)F)ccc(F)c1Cl
Yield: 39.9 %

Procedure:
To a solution of crude 2-chloro-4-difluoromethoxy-3-dimethoxymethyl-1-fluorobenzene (181 g, 670 mmol) in acetone (650 mL) and water (150 mL) was added Amberlyst-15 resin (540 g, pre-washed with water) and the mixture was stirred using mechanical stirrer for 40 h at RT. The Amberlyst-15 resin was removed by filtration using celite bed on sintered funnel, and the filtrate was evaporated on a rotary evaporator at RT (Note: aldehyde evaporates at higher temperatures under reduced pressure). The residue was purified by column chromatography on silica gel using ethyl acetate/hexanes (5% to 10%) to obtain the title compound (60 g, 40%).
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:27]([F:30])([F:29])[F:28])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=3)[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1.C(NCC)C.[CH:36]1([C:39]#[CH:40])[CH2:38][CH2:37]1.C1(C)C=CC=CC=1>CN(C=O)C.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.[Cu]I>[NH2:1][C:2]1[O:3][C@H:4]([C:27]([F:30])([F:29])[F:28])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([C:40]#[C:39][CH:36]4[CH2:38][CH2:37]4)=[CH:21][N:20]=3)[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1
Reactant: C#CC1CC1
Reactant: NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(Br)cn3)ccc2F)C[C@@H](C(F)(F)F)O1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(C#CC4CC4)cn3)ccc2F)C[C@@H](C(F)(F)F)O1

Procedure:
N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-bromopicolinamide (Example 52) was transferred to a microwave vial followed by the addition of diethylamine (0.580 ml, 5.55 mmol), tetrakis(triphenylphosphine)palladium (0.053 g, 0.046 mmol), copper(I) iodide (0.021 g, 0.111 mmol), cyclopropylacetylene, 70 wt. % solution in toluene (0.179 ml, 1.480 mmol) and DMF (1.5 mL). The vial was sealed, purged with N2 and heated in microwaved at 90° C. for 45 min. The reaction went to completion, diluted in water (10 mL) and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-3% MeOH/DCM and 0-50% EtOAc/hexanes to afford a light yellow solid as N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-(cyclopropylethynyl)picolinamide. MS m/z=479 [M+H]+. Calculated for C23H19F5N4O2: 478.14
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([OH:11])=O.CCN(C(C)C)C(C)C.[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.Cl>C1(C)C=CC=CC=1.C1COCC1.CN(C=O)C>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:26]([F:25])([F:35])[F:36])=[CH:29][CH:30]=1)=[O:11]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
SOCl2 (2.92 mL, 40.0 mmol) and DMF (0.5 mL) were added dropwise to a suspension of 3-bromo-4-fluorobenzoic acid (1.752 g, 8 mmol) in toluene (20 mL) and the RM was stirred at 80° C. for 1 h. The solvent was evaporated off under reduced pressure and the residue was diluted with THF (15 mL). DIPEA (2.79 mL, 16.00 mmol) was added and the mixture was cooled to 0° C., treated with a solution of 4-trifluoromethoxyaniline (1.181 mL, 8.80 mmol) in THF (5 mL) and stirred for 1 h. The RM was treated with aq. 1 M HCl (50 mL), and extracted with TBME. The combined extracts were washed with aq. 1 M HCl, aq. 1 M NaOH and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue was crystallized from n-heptane/DCM to afford the title compound as a white solid. UPLC-MS (Condition 1) tR=3.18 min, m/z=377.9/379.9 [M+H]+, m/z=375.9/377.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.38 (d, J=8.6 Hz, 2H) 7.56 (t, J=8.7 Hz, 1H) 7.87 (d, J=9.0 Hz, 2H) 8.00-8.06 (m, 1H) 8.32 (dd, J=6.6, 2.2 Hz, 1H) 10.50 (s, 1H).
Reaction SMILES: CCCCC.Cl[SiH](Cl)Cl.[CH3:10][NH:11][CH3:12].[CH2:13]([O:15][SiH:16]([O:18][CH2:19][CH3:20])Cl)[CH3:14]>C(O)C>[CH2:13]([O:15][SiH:16]([O:18][CH2:19][CH3:20])[N:11]([CH3:12])[CH3:10])[CH3:14]
Reactant: CNC
Reactant: CCO[SiH](Cl)OCC
Agent: Cl[SiH](Cl)Cl
Solvent: CCO
Solvent: CCCCC
Product: CCO[SiH](OCC)N(C)C

Procedure:
Following the same general procedure described in Example 1, 2 liters of pentane and 404 mls of trichlorosilane were charged in a 5 L flask. During reflux, 464 mls of anhydrous ethanol was added dropwise. After the alcoholysis was completed, 550 mls of dimethylamine was added to the unisolated diethoxychlorosilane. Distillation yielded 290 g of diethoxy(dimethylamino)silane (b.p. 138°-139° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:14]1(C)C=CC=C[CH:15]=1.S(OCC)(OCC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:7]2[N:8]([CH2:14][CH3:15])[CH2:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S1C=Nc2c(Cl)cccc21
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOS(=O)(=O)OCC
Agent: [Br-]
Solvent: O
Product: CCN1CS(=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
4-Chlorobenzothiazolone (4.64 g, 0.025 mole) was dissolved in a solution of sodium hydroxide (1.60 g, 0.0375 mole) in water (100 c.c.), and tetra-n-butylammonium bromide (0.24 g, 7.5×10-4 mole) and toluene (40 c.c.) were added thereto. Diethyl sulfate (5.78 g, 0.0375 mole) was added dropwise thereto at room temperature, and the mixture was stirred at room temperature for 1 hour, followed by phase-separation. The toluene layer was washed once with water, and the solvent was removed under reduced pressure to obtain 5.24 g of 4-chloro-N-ethylbenzothiazolone as white crystals. Yield 98.1%, purity 98.5%, m.p. 96°-98.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].N12CCCN=C1CCCC[CH2:13]2>CCOC(C)=O.O>[CH3:10][O:9][C:5]1[C:4]([O:11][CH3:13])=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(OC)c1O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(OC)c1OC
Temperature: 90 °C

Procedure:
To a solution of 2,6-dimethoxyphenol (1.0 g, 6.49 mmol) in DMC (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)(0.99 g, 6.49 mmol) was added and the resulting solution was heated to reflux (90° C.) for 4.5 hours. The reaction was cooled to ambient temperature and diluted with EtOAc (50 mL) and H2O (40 mL). The organic layer was separated and washed in sequence with H2O (40 mL), 2M HCl (2×40 mL), 2M NaOH (2×40 mL) and H2O. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give trimethoxybenzene as a solid. The yield of trimethoxybenzene as deteremined by HPLC was 99%.
Reaction SMILES: C(N)C1C=CC=CC=1.[NH2:9][NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[NH:12].[Cl:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:23]=1[CH:24]=O.CO>C(O)C>[Cl:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:23]=1[CH:24]=[N:9][NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[NH:12]
Reactant: N=C(NN)NCc1ccccc1
Reactant: COc1ccc(C=O)c(Cl)c1OC
Solvent: CO
Solvent: NCc1ccccc1
Solvent: CCO
Product: COc1ccc(C=NNC(=N)NCc2ccccc2)c(Cl)c1OC
Temperature: 25 °C

Procedure:
536 mg (5 mmol) benzylamine and 1.17 g (5 mmol) S′-methylthiosemicarbazide hydroiodide was mixed in 10 ml of ethanol. The reaction mixture was refluxed for 5 minutes after which it was cooled down to room temperature and the residue filtered off. The crude product of N-amino-N′-benzylguanidine was reacted with 1.0 g (5 mmol) 2-chloro-3,4-dimethoxybenzaldehyde under reflux for 5 h, after which the solvent was removed under vacuum to give a white solid. The product was obtained by recrystallisation from methanol. Yield of title compound 1, was 1.65 g (77%). M.p. 0.223–225° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:47]=[CH:46][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:27][CH:26]=4)=[CH:20][C:19]=3[N:37]([CH3:45])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:48].O1CCOCC1>>[ClH:48].[CH3:45][N:37]1[C:19]2[CH:20]=[C:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][CH:30]=3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:47][CH:46]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-phenylphenoxy)phenyl}-N-methylcarbamate (2.39 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at room temperature for 21 hours. The solvent of the reaction mixture was evaporated to dryness and to the residue was added ethyl acetate and insoluble product was isolated by filtration and washed with ethyl acetate to give the title compound (1.90 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:20]([C:28](O)=[O:29])[NH:19][C:18]2=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:55]1([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:20]([C:28]([N:58]3[CH2:57][CH2:56][N:55]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:60][CH2:59]3)=[O:29])[NH:19][C:18]2=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1[nH]c(=O)n(C2CCCN(C(=O)OCc3ccccc3)C2)c1-c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2[nH]c(=O)n(C3CCCN(C(=O)OCc4ccccc4)C3)c2-c2ccccc2)CC1
Yield: 76.2 %

Procedure:
Dissolved 16E (3.0 g, 7.118 mmol) prepared in the previous step in 30 mL of DMF and added EDC (2.39 g, 12.46 mmol) and HOBt (1.65 g, 12.01 mmol). The mixture was stirred for at least 15 minutes. Next, DIEA (2.76 mL, 21.35 mmol) was added along with tert-butyl piperazine-1-carboxylate (1.39 g, 7.47 mmol). This reaction mixture was then stirred at RT for about four hours. After the disappearance of 16E, this mixture was poured into 300 mL of water, a white precipitate was formed. The white solid was filtered, rinsed with water and dried under vacuum to provide tert-butyl 4-(1-(1-(benzyloxycarbonyl)piperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate (16F) (3.2 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 9H) 1.40 (s, 2H) 1.65-1.80 (m, 4H) 2.34 (br. s., 1H) 2.83 (br. s., 4H) 3.13-3.19 (m, 4H) 3.94-4.07 (m, 2H) 5.03 (s, 2H) 7.23-7.50 (m, 10H) 10.73 (s, 1H). ESI-MS: m/z 590.1 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3,4-dichlorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.37 (dd, J=8.2, 2.1 Hz, 1H), 3.80-3.84 (m, 4H), 3.72 (s, 2H), 3.08-3.11 (m, 4H); MS (ESI−) M/Z 431 (M−H)−.