Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@H:24]1[C@@H:30]([NH:31][C:32]([C@@H:34]([NH:39][C:40]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=3[CH:46]=2)=[O:41])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:29][CH2:28][C@@H:27]([CH3:51])[N:26]([S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)(=[O:54])=[O:53])[CH2:25]1.O[C@H]1[C@H](NC([C@@H](NC(C2OC3C=CC=CC=3C=2)=O)CC(C)C)=O)CC[C@H](C)N(S(C2C=CC=CN=2)(=O)=O)C1>C(Cl)Cl>[CH3:37][CH:36]([CH3:38])[CH2:35][C@H:34]([NH:39][C:40]([C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[CH:46]=1)=[O:41])[C:32](=[O:33])[NH:31][C@H:30]1[CH2:29][CH2:28][C@@H:27]([CH3:51])[N:26]([S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)(=[O:53])=[O:54])[CH2:25][C:24]1=[O:23]
Reactant: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)C[C@@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)N[C@@H]1CC[C@H](C)N(S(=O)(=O)c2ccccn2)C[C@H]1O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Dess-Martin periodinane (1.0 g, 2.36 mmol) was added to a solution of benzofuran-2-carboxylic acid {(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide and benzofuran-2-carboxylic acid {(S)-1-[(3R,4R,7S)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide (0.8 g, 1.48 mmol) in CH2Cl2 (20 ml) and was stirred at RT for 45 minutes. The solution was washed with 10% NaHCO3 and brine. Purification by column chromatography (60% ethyl acetate/hexanes) gave the title compound as a mixture of diasteromers (0.75 g, 94%); The diastereomers were separated by HPLC. Diastereomer 1:1H NMR: 8.72 (m, 1H), 8.0 (d, 1H), 8.92 (dd, 1H), 7.65 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.42 (dd, 2H), 7.28 (d, 1H), 7.10 (d, 1H), 5.15 (m, 1H), 4.77 (d, 1H), 4.68 (m, 1H), 4.40 (m, 1H), 3.86 (d, 1H), 2.20-2.08 (m, 2H), 1.78-1.50 (m, 5H), 1.22 (dd, 3H), 0.98 (m, 6H); Electrospray mass spec: M+H+=541.2; Diastereomer 2:1H NMR: 8.68 (m, 1H), 8.04 (d, 1H), 8.92 (dd, 1H), 7.68 (d, 1H), 7.58 (d, 2H), 7.52 (s, 1H), 7.42 (dd, 1H), 7.29 (d, 1H), 7.05 (m, 2H), 5.12 (m, 1H), 4.75-4.68 (m, 1H), 4.43 (m, 1H), 3.83 (d, 1H), 2.25-2.12 (m, 2H), 1.88-1.50 (m, 5H), 0.98 (m, 9H); Electrospray mass spec: M+H+=541.2
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)[C:3]#[N:4].[C:12]([CH2:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13]>C(O)C>[C:12]([C:15]1[C:3]([NH2:4])=[C:2]([C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)[NH:1][C:16]=1[CH3:17])(=[O:14])[CH3:13]
Reactant: Cc1cccc(C(N)C#N)c1
Reactant: CC(=O)CC(C)=O
Solvent: CCO
Product: CC(=O)c1c(C)[nH]c(-c2cccc(C)c2)c1N

Procedure:
Starting from 2-amino-2-(m-tolyl)acetonitrile and acetylacetone, the open-chain intermediate compound is obtained, b.p. 170° C./0.02 mm Hg. The title compound is obtained in a 59% overall yield, m.p. 195°-197° C. (from ethanol).
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14]O)=[CH:13][C:8]=3[N:7]([CH3:16])[C:6]2=[O:17])[CH2:4][CH2:3][CH2:2]1.CS([Cl:22])(=O)=O>ClCCl.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>[Cl:22][CH2:14][C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[C:6](=[O:17])[N:7]([CH3:16])[C:8]=2[CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(C2CCC2)c2ccc(CO)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(C2CCC2)c2ccc(CCl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
1-Cyclobutyl-5-hydroxymethyl-3-methyl-1,3-dihydro-benzoimidazol-2-one (13.79 g, 59.4 mmol) was diluted with dichloromethane (300 mL) and triethylamine (12.4 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (6.9 mL, 89.1 mmol) was added. The mixture was stirred for 1 hour at 0° C. then was diluted with saturated sodium bicarbonate and extraced into dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The resulting oil was filtered through silica gel using ethyl acetate containing 1% triethylamine as eluent to give 11.92 g of 5-Chloromethyl-1-cyclobutyl-3-methyl-1,3-dihydro-benzoimidazol-2-one.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:28])=[C:12]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH3:20])[C:13]([F:17])=[CH:14][C:15]=3[NH2:16])[CH:5]=2)[CH2:3][CH2:2]1.[C:29](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4[C:11]([F:28])=[C:12]([NH:18][C@H:19]([C:21]5[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=5)[CH3:20])[C:13]([F:17])=[CH:14][C:15]=4[N:16]=[CH:29]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1c(F)cc(N)c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1c(F)cc2ncn(-c3cc(C4CC4)[nH]n3)c2c1F)c1ccc(F)cc1

Procedure:
(S)-N3-(5-Cyclopropyl-1H-pyrazol-3-yl)-2,6-difluoro-N1-(1-(4-fluorophenyl)ethyl)benzene-1,3,4-triamine (Method 101, 0.278 g, 0.718 mmol) and formamidine acetate (0.149 g, 1.44 mmol) in EtOH (10 ml) was heated at reflux for 1 hour. Saturated sodium bicarbonate solution (5 ml) and EtOAc (15 ml) were added. The organic layer was separated, washed with brine (3 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography (Hex-EtOAc=1:1) to give the title compound as off white solid (0.120 g, 42%). 1H NMR (400 MHz) 12.83 (s, 1H), 8.20 (s, 1H), 7.36 (m, 2H), 7.31 (d, J=11.2 Hz, 1H), 7.06 (t, J=8.8 Hz, 2H), 6.15 (s, 1H), 5.15 (d, J=10.4 Hz, 1H), 4.67 (m, 1H), 1.98 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.00 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 397; Found: [M+H]+ 398.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[C:11]3[N:12]=[C:13]([Cl:17])[CH:14]=[C:15](Cl)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[C:11]3[N:12]=[C:13]([Cl:17])[CH:14]=[C:15]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)n2nc(-c3ccc(Br)cc3)cc2n1
Solvent: C1COCCO1
Solvent: O
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccc(Br)cc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 2-(4-bromo-phenyl)-5,7-dichloro-pyrazolo[1,5-a]pyrimidine (217 mg, 0.633 mM), then morpholine (110 μL, 1.27 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture and the residue thus obtained was diluted with water and then extracted with methylene chloride. The extracts obtained were combined together, dried over anhydrous sodium sulfate, the solvent was distilled off and then the resulting solid was washed with methanol to thus give the title compound (240 mg, yield: 96%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]=1.[Cl:9][SiH:10]([Cl:12])[Cl:11].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH3:1][CH:2]1[CH2:7][CH:6]([Si:10]([Cl:12])([Cl:11])[Cl:9])[CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: Cl[SiH](Cl)Cl
Reactant: CC1=CC(C)CCC1
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CC1CC(C)CC([Si](Cl)(Cl)Cl)C1
Yield: 80 %

Procedure:
A one-liter autoclave equipped with a stirrer was charged in a nitrogen atmosphere with 39 grams (0.35 mol) of 1,3-dimethylcyclohexene, 94 grams (0.69 mol) of trichlorosilane and 18 grams (74 mmol) of 1,1'-azobis(cydohexane-1-carbonitrile) and the mixture was reacted at a temperature of 130° C. for 3 days. The resulting reaction mixture was purified by distillation thereby obtaining 69 grams (0.28 mol) of 2,6-dimethyl-4-cyciohexyltrichlorosilane, The structure of the resulting product was Identified by 1H-NMR analysis.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.CO>O1CCCC1>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(F)c(Br)cc1F
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 2 g (8.44 mmol) of 4-bromo-2,5-difluorobenzoic acid (prepared according to the procedure of Ishikawa et al., Kogyo Kagaku Zasshi, pg 972-979, 1970) in 20 mL of tetrahydrofuran was added 40 mL of a 1M solution of borane-tetrahydrofuran complex. The solution was heated under reflux for 64 h, cooled to ambient temperature and 100 mL of methanol was added. The reaction was then heated for a further 2 h, cooled and concentrated in vacuo. Purification by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) afforded 1.6 g of 4-bromo-2,5-difluorobenzyl alcohol. To a solution of 1.3 g (5.6 mmol) of 4-bromo-2,5-difluorobenzyl alcohol in 20 mL of dichloromethane at 0° C. was added 2.27 g (6.7 mmol) of carbon tetrabromide and 1.8 g (6.7 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) to afford 1.5 g of the title compound.
Reaction SMILES: [CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27]C(=O)OC(C)(C)C)=[CH:26][C:20]=4[S:19](=[O:36])(=[O:35])[N:18]=3)[C:7]2=[O:37])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:8]3[C:7](=[O:37])[N:6]([NH:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:18][S:19](=[O:36])(=[O:35])[C:20]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A slurry of the product of Example 464A (1.5 g, 2.85 mmol) in dichloromethane (10 mL) at 0° C. was treated dropwise with 6 mL of trifluoroacetic acid, stirred at 25° C. for 2 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 10% aqueous sodium bicarbonate (3×50 mL), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (1.1 g, 91% yield).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>CN(C)C=O.C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(=O)c2cc(C#C[Si](C)(C)C)ccc2[nH]1
Temperature: 45 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
To a solution of 1.0 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.043 g of bis(triphenylphosphine) palladium (II) chloride and 5.8 mg of copper (I) iodide in 5.0 ml of N,N-dimethylformamide and 5.0 ml of triethylamine is added 0.36 g of (trimethylsilyl) acetylene. The resulting reaction mixture is heated at 45° C. for 1 hour and then 65° C. for 5 hours. Upon cooling, the reaction mixture is concentrated in vacuo and the residue purified by flash chromatography on silica gel, eluting with 1:3 ethyl acetate-hexane to yield 0.75 g of the desired product as a white solid. CI MASS SPEC 299(MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:21]2[C:22]([NH:24][C:25](=[O:26])[C:20]=12)=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][C:19]3[CH:29]=[CH:28][CH:27]=[C:21]4[C:22]([NH:24][C:25](=[O:26])[C:20]=34)=[O:23])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCN3CCC(c4ccc(F)cc4)CC3)cccc21
Temperature: 97.5 °C

Procedure:
A mixture of 4-(4-fluorophenyl)piperidine hydrochloride (5.08 g, 23.2 mmol), 3-bromopropylphthalimide (6.22 g, 23.2 mmol), and potassium carbonate (15 g) in DMF (100 mL) was stirred and heated at 95-100° C. for 12 h. About 80% of the solvent was evaporated at reduced pressure, the residue was diluted with ethyl acetate (200 mL) and washed with brine (3×100 mL) and dried (Na2SO4). Solvent was evaporated and the residue was purified by column chromatography on silica gel using 1/1 hexane-ethyl acetate to 100% ethyl acetate as eluent. This product was crystallized from isopropanol to give a white crystalline solid; m.p. 80-81° C. This material was used in the next step. Concentration of the mother liquor and cooling gave the second crop.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:31][C:32]([CH3:34])=O.[BH4-].[Na+]>C(O)(=O)C.O>[CH:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1)([CH3:34])[CH3:31]
Reactant: CC(C)=O
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCOc1cc(-c2ccc(NC(C)C)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate (3 g) and acetone (0.54 cc) in acetic acid (45 cc), brought to 15° C., is slowly added sodium borohydride (1.14 g) so as to maintain the temperature below 22° C. The mixture is then stirred at room temperature for 4 hours. The reaction mixture is then poured in distilled water (150 cc) and extracted with ethyl ether (2×100 cc). The combined organic phases are washed with distilled water until neutrality, dried over sodium sulphate and concentrated to dryness at 40° C. under reduced pressure. The oily residue obtained is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1 as a yellow oil).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33]>O>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1

Procedure:
To a mixture of ethyl 4-hydroxy-3-methoxybenzoate (15.00 g), potassium carbonate (11.63 g) and N,N-dimethylformamide (2.00 mL) was added 4-chloromethyl-5-methyl-2-phenyl-1,3-oxazole (17.45 g) with stirring, and the mixture was stirred overnight at 80° C. Water was poured into the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoate from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave a pale-brown solid (25.45 g, yield 91%). melting point: 103-104° C.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[C:4]([C:23]([O:25][CH3:26])=[O:24])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[C:9]([C:21]#[N:22])[CH:8]=1.C(N(CC)CC)C>O1CCOCC1.[C].[Pd]>[C:21]([C:9]1[CH:8]=[C:7]([C:6]2[S:5][C:4]([C:23]([O:25][CH3:26])=[O:24])=[C:3]([F:27])[CH:2]=2)[CH:12]=[CH:11][C:10]=1[OH:13])#[N:22]
Reactant: COC(=O)c1sc(-c2ccc(OCc3ccccc3)c(C#N)c2)c(Br)c1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1sc(-c2ccc(O)c(C#N)c2)cc1F

Procedure:
(4-Benzyloxy-3-cyanophenyl)boronic acid and methyl 4,5-dibromo-3-fluorothiophene-2-carboxylate were dissolved in a mixed solution of toluene and a 1 M aqueous sodium carbonate solution and the whole was heated at 110° C. for 2.5 days in the presence of tetrakis(triphenylphosphine)-palladium to obtain methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate. Methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate and triethylamine were stirred at room temperature in 1,4-dioxane under a hydrogen atmosphere at normal pressure in the presence of palladium-carbon to obtain methyl 5-(3-cyano-4-hydroxyphenyl)-3-fluorothiophene-2-carboxylate. FN: 276.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(O[C:16]([N:18]1[CH2:22][CH2:21][C@@H:20](COS(C)(=O)=O)[CH2:19]1)=O)(C)(C)C>C1(C)C=CC=CC=1>[OH:9][CH2:8][CH:7]([NH:10][CH2:16][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Solvent: Cc1ccccc1
Product: OCC(NCN1CCCC1)c1ccccc1
Yield: 126.8 %

Procedure:
A solution of (R)-(-)-phenylglycinol (2.20 g, 16.1 mmol) and (3R)-N-tert-butyloxycarbonyl-3-methylsulphonyloxymethylpyrrolidine (Intermediate 1 part b; 1.0 g, 3.58 mmol), in toluene (20 ml), was heated at 150° C. for 6 h in a sealed pressure tube (Aldrich). The solvent was then removed under vacuum and the residue taken up into ethyl acetate (200 ml) and washed with water (×4). The organic was dried (MgSO4) and evaporated and the crude product chromatographed on silica gel eluting with CH2Cl2 /MeOH (97:3) to give the title-α-(hydroxymethyl) benzylaminomethylpyrrolidine (1.0 g, 87%), δ (360 MHz,CDCl3) 1.45 (9H, s, OC(Me)3), 1.52-2.60 (5H, m, CH2 and CH), 2.90-3.76 (7H, m, 3 of CH2 and CH), 7.25-7.39 (5H, m, Ar--H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1Cl
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using method analogous to those described for the synthesis of intermediates 1 to 3, the intermediate below was synthesised according to the method described below. 2-piperazinone (2.51 g, 25.07 mmol, commercially available e.g. from Sigma-Aldrich) and triethylamine (4.19 mL, 30.1 mmol) were dissolved in Dichloromethane (DCM) (50 mL). 2,3-dichloro-4-fluorobenzoyl chloride (I33)(6.28 g, 27.6 mmol) dissolved in Dichloromethane (DCM) (50 mL) was added dropwise at 0° C. and the solution allowed to stir to room temperature overnight. The mixture was diluted with Dichloromethane (200 mL) and washed with saturated sodium bicarbonate solution (100 mL). The aqueous phase was extracted with Dichloromethane (3×100 mL) and the combined extracts were washed with water (2×100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated to a crude solid that was triturated with hexane to afford product in 6.94 g. The product was recrystalised from ethanol (Note: slow to come out of solution) to afford the desired product in 5.08 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:24]([Cl:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[ClH:33]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[ClH:32].[ClH:33].[C:24]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][CH2:10]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-aminopropyl)-4-benzhydrylpiperazine (1.2 g) in a mixture of pyridine (2 ml) and chloroform (15 ml) was dropwise added a solution of benzoyl chloride (0.55 ml) in chloroform (3 ml) at ambient temperature with stirring, which was continued for 1.5 hours. The reaction mixture was washed successively with aqueous sodium bicarbonate and water. The chloroform layer was separated, dried and evaporated in vacuo to give an oil. According to a conventional manner, the oil was converted to hydrochloric acid salt, which was recrystallized from a mixture of methanol and diethyl ether to afford 1-(3-benzoylaminopropyl)-4-benzhydrylpiperazine dihydrochloride (1.0 g) as white crystals. mp: 235°-237° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Br[CH2:68][CH:69]1[CH2:72][CH2:71][CH2:70]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH2:68][CH:69]2[CH2:72][CH2:71][CH2:70]2)=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: BrCC1CCC1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N(CC2CCC2)C(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) was reacted with bromomethyl cyclobutane and K2CO3 in DMF afforded (S)-2-({(S)-7-[2-(acetyl-cyclobutylmethyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure O. This product (20 mg) was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 979.