Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10](F)=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7].[CH3:18][O-:19].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10]([O:19][CH3:18])=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(F)c(F)c(OC)c(F)c1C(=O)O
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Into a 100 ml glass reactor equipped with a reflux condenser, a stirrer and a dropping funnel, 20 ml of a methanol solution of 10 g (0.0397 mol) of the 3,4,5,6-tetrafluorophthalic acid-monomethyl ester prepared in Example 14, was charged. Then, 44.9 g (0.0833 mol) of a 10% methanol solution of sodium methoxide was dropwise added thereto. The mixture was stirred for one hour under reflux. After completion of the reaction, the reaction mixture was neutralized with a 10% hydrochloric acid aqueous solution and extracted with ethyl acetate. Then, the solvent was distilled off to obtain 9.14 g of 4-methoxy-3,5,6-trifluorophthalic acid-1-methyl ester. (=5-methoxy-3,4,6-trifluorophthalic acid-2-methyl ester.) The yield was 87.2%.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: Cc1ccc(OCC(=O)O)c(Br)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OCC(=O)N(NC(=O)c2ccccc2)C(C)C)c(Br)c1
Yield: 34.2 %

Procedure:
A solution of (2-bromo-4-methyl-phenoxy)-acetic acid (879 mg, 3.34 mmol) and benzoic acid N′-isopropyl-hydrazide (714 mg, 4.00 mmol) in DMF (20 mL) was treated with diisopropylethyl amine (1.45 ml, 8.35 mmol) and PyBroP (2.33 g, 5.01 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (463 mg, 34%).
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=1.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.FC(F)(F)C(O)=O>ClCCl>[ClH:20].[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:19])[S:12][CH:13]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: BrCc1ccc(Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCN(Cc2ccc(Br)cc2)c2ccc(C#N)cn2)cs1)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained by an operation similar to that of Example 265-1 and using 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 7 and 2-chloro-5-cyanopyridine as starting materials, followed by an operation similar to that of Example 265-2 and using 4-bromobenzylbromide as starting material was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile) to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:16]([OH:19])(=[O:18])=[O:17].Cl.C[O-].[Na+:23]>C(Cl)(Cl)Cl>[S:16]([O-:19])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:18])=[O:17].[Na+:23]
Reactant: CCCCCC(C)CCCCCCO
Reactant: O=S(=O)(O)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C

Procedure:
Into a dried 1 L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical siring and nitrogen outlet is added chloroform (300 ml) and 7-methyldodecanol (100 g, 0.5 mol). Chlorosulfonic acid (60 g, 0.509 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with a ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until an aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added hot ethanol (55° C., 2 L). The mixture is vacuum filtered immediately. The filtrate is concentrated to a slurry on a rotary evaporator, cooled and then poured into 2 L of ethyl ether. The mixture is chilled to 5° C., at which point crystallization occurs, and vacuum filtered. The crystals are dried in a vacuum oven at 50C for 3 hrs. to obtain a white solid (119 g, 92% active by cat SO3 titration).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH3:15][S:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>C(O)CC>[CH3:15][S:16][C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1)=[CH:18][N+:19]([O-:21])=[O:20]
Reactant: COC(=O)C/C=C/c1ccc(N)cc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCCO
Product: COC(=O)C/C=C/c1ccc(NC(=C[N+](=O)[O-])SC)cc1
Yield: 85.5 %

Procedure:
7.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate was dissolved in 120 ml of n-propanol, followed by the addition of 30.28 g of 1,1-bis-(methylthio)-2-nitroethylene. The obtained mixture was heated under reflux for 3 hours and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichloromethane). The obtained solid was washed with ethyl ether to obtain 9.65 g of the title compound as a yellow powder (yield: 86%).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:14])([F:13])[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9]>O.CO.O1CCCC1>[F:4][C:5]([F:14])([F:13])[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)CCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC(F)(F)F
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A solution of lithium hydroxide monohydrate (324 g) in water (1.8 l) was added to a stirred solution of ethyl 4,4,4-trifluorobutyrate (436 g) in methanol (2.0 l) and dry tetrahydrofuran (2.0 l) and the suspension was stirred overnight. After the suspension was partially evaporated, the residue was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 6M hydrochloric acid and extracted with diethyl ether. The combined extracts were washed (brine), dried (MgSO4), and filtered. The filtrate was evaporated and the residue distilled (b.p. 165°-168° C.) to give 4,4,4-trifluorobutyric acid (347 g, 95%); m.p. 27°-30° C.; partial NMR; (300 MHz, CDCl3): 2.33-2.57 (m, 2H, CF3CH2), 2.66 (t, CH2CO2H).
Reaction SMILES: O[C:2]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([CH3:8])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:8][CH:2]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])[CH2:3][CH2:4][CH:5]([CH3:6])[CH3:7]
Reactant: CC(C)CCC(C)(O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CCC(C)c1ccccc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.1 %

Procedure:
After 2.7 g (13.1 mols) of the 2-(1-hydroxy-1,4-dimethylpentyl)aniline obtained in Example 3-1 was diluted with toluene, p-toluenesulfonic acid monohydrate (225 mg) was added thereto, and the resulting mixture was dehydrated with refluxing over a period of 3 hours by the use of a Dean-Stark trap. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in ethanol, followed by adding thereto 5% palladium-carbon (100 mg), and the resulting mixture was stirred under a hydrogen atmosphere at room temperature for 12 hours. The reaction mixture was filtered through Celite and the residue was concentrated under reduced pressure to obtain 2.2 g of 2-(1,4-dimethylpentyl)aniline.
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:10][C:9](=S)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CCCCCC.[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>CN(C)P(=O)(N(C)C)N(C)C>[CH3:27][O:28][C:29]([CH2:30][C:9]1[S:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)=[O:32]
Reactant: COC(=O)CBr
Reactant: S=C1N=C(c2ccccc2)C(c2ccccc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 0 °C

Procedure:
The starting material can be produced, for example, in the following manner: 6 g of 4,5-bis-phenylthiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and, while stirring, sodium hydride (0.89 g of a 50% strength suspension in mineral oil, de-oiled with hexane) is added. The mixture is stirred for 30 minutes at room temperature, 3.57 g of bromoacetic acid methyl ester are slowly added dropwise, the mixture is then stirred for 1 hour at room temperature, poured into 500 ml of ice-water, extracted by shaking twice with 300 ml of ethyl acetate each time, washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation under reduced pressure. The remaining oil is dissolved in toluene and purified by chromatography over 50 g of silica gel. The eluate with toluene/ethyl acetate (95:5) is concentrated by evaporation under reduced pressure. 2-Methoxycarbonylmethyl-4,5-bis-phenylthiazole having a melting point of 65°-67° is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[CH2:8])[C:5]([OH:7])=[O:6])[CH3:2].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[CH2:8])[C:5]([O:7][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:2]
Reactant: C=C(OCC)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(OCC)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
To a solution of 2-ethoxyacrylic acid B-43a (1 g, 8.61 mmol) in DMF (10 mL) under a nitrogen atmosphere was added (bromomethyl)benzene (1.620 g, 9.47 mmol) followed by potassium carbonate (1.309 g, 9.47 mmol) and stirred for 12 h at 25° C. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×100 mL). The combined organic layer was washed with water (3×50 mL) followed by brine solution (50 mL) and dried over anhyd. Na2SO4. It was filtered and concentrated under reduced pressure. The crude was purified by Combiflash (Silica gel, 12 g, Redisep, EtOAc/petroleum ether, 10:90) to obtain benzyl 2-ethoxyacrylate B-43b (550 mg, 2.67 mmol, 31.0% yield) as a colorless liquid. 1H NMR (CDCl3, 6=7.26 ppm, 400 MHz): δ 7.39-7.31 (m, 5H), 5.36 (d, J=2.8 Hz, 1H), 5.25 (s, 2H), 4.61 (d, J=2.4 Hz, 1H), 3.82 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[N:15]=2)[CH:5]=[C:6]([O:11][CH2:12][CH3:13])[C:7]=1[O:8][CH2:9][CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:5]=[C:6]([O:11][CH2:12][CH3:13])[C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1cc(-c2nc(-c3cccc4c(CCC(=O)OC)c[nH]c34)no2)cc(Cl)c1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOc1cc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc(Cl)c1OCC
Temperature: 20 °C
Reaction time: 4 h
Yield: 20.6 %

Procedure:
To a solution of methyl 3-(7-{5-[3-chloro-4,5-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D70) (20 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (9 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. for 4 h. The organic solvent was evaporated off and the mixture was acidified with HCl (1 M) solution to pH around 1. Extracted with EtOAc (60 mL), the organic layer was separated and the organic solvent was evaporated off. The residue was purified by Mass Directed Auto Prep to afford 3-(7-{5-[3-chloro-4,5-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E45) (4 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.34 (3H, t), 1.43 (3H, t), 2.63 (2H, t), 3.00 (2H, t), 4.19 (2H, q), 4.27 (2H, q), 7.21 (1H, t), 7.27 (1H, d), 7.80-7.84 (2H, m), 7.95 (1H, d), 8.01 (1H, d), 10.81 (1H, s), 12.09 (1H, br s). MS (ES): C23H22ClN3O5 requires 455; found 456.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:7][CH:6]=2.[Br:30]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:30][CH2:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:7][CH:6]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 100 °C

Procedure:
To a suspension of methyl 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.66 g, 6.28 mmol) in carbon tetrachloride (41.9 mL) was added N-bromosuccinimide (1.454 g, 8.17 mmol) and benzoyl peroxide (0.152 g, 0.628 mmol). The resulting mixture was heated at 100° C. for 18 h. The mixture was cooled to room temperature and concentrated in vacuo to afford methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:11]([Cl:23])=[C:10]([O:12][CH:13]([F:14])[F:15])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1nc(-n2ncc([N+](=O)[O-])c2N)cc1OC(F)F
Solvent: ClCCl
Product: Cn1nc(-n2ncc([N+](=O)[O-])c2N)c(Cl)c1OC(F)F
Reaction time: 0.17 h

Procedure:
1.5 g (5.5 mmole) 5-Amino-4-nitro-1-(1-methyl-5-difluoromethoxy-3-pyrazolyl)pyrazole in 30 ml methylene chloride was treated with 0.74 g (5.5 mmole) sulfuryl chloride and the mixture stirred for 10 minute sat room temperature. It was then concentrated and the residue was recrystallised from diisopropyl ether/ethyl acetate. The mother liquor was concentrated and chromatographed (SiO2 /hexane/ethyl acetate 3:1).
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: Oc1nc2ccccc2s1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1sc2ccccc2n1CCCCl
Temperature: 55 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a solution of 2-hydroxybenzothiazole (2.0 g, 13.2 mmol) and potassium carbonate (2.74 g, 19.8 mmol) in N,N-dimethylformamide (20 mL), was added 1-bromo-3-chloropropane (3.92 mL, 39.7 mmol, d=1.6). After stirring at 55° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4 and concentrated to obtain 3-(3-chloropropyl)benzo[d]thiazol-2(3H)-one (2.86 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][NH:12]2)[CH2:10][CH2:9]1.CO.C=O.[C:28]([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][N:12]2[CH3:28])[CH2:9][CH2:10]1
Reactant: COc1cc2c(cc1C)CCNC2C1(c2ccccc2Cl)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2c(cc1C)CCN(C)C2C1(c2ccccc2Cl)CC1
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
A mixture of 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline (6.2 g), methanol (160 ml) and 37-40% aqueous formaldehyde solution was stirred for 15 minutes. Sodium cyanoborohydride (5.13 g) was added and the mixture was stirred for a further 10 minutes. The reaction was then neutralised with acetic acid and stirred for 45 minutes. The methanol was removed in vacuo and the residue treated with aqueous sodium hydroxide solution. The product was extracted with ethyl acetate. The extracts were washed with aqueous ammonia solution, water and brine, then dried over magnesium sulphate. Concentration yielded 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinoline as a gum (5.02 g).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:23][C:24](=[O:38])[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([O:32][CH2:33][CH2:34][CH2:35][NH2:36])=[CH:27][C:26]=1[Cl:37])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[NH2:36][CH2:35][CH2:34][CH2:33][O:32][C:28]1[CH:27]=[C:26]([Cl:37])[C:25]([C:24]([NH:23][C@@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[CH:10][CH:11]=2)[C:3]([OH:39])=[O:2])=[O:38])=[C:30]([Cl:31])[CH:29]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(OCCCN)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.4 %

Procedure:
To a solution of (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester (5.8 g, 7.98 mmol,) in THF (200 mL) was added a solution of lithium hydroxide (2.4 g, 100 mmol) in water (30 mL) at room temperature. The mixture was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, the solvent was removed by rotary evaporation and the residue was purified by an HPLC method to obtain 3.7 g (65% yield) of (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid as a white solid. ES(+)-HRMS m/e calcd. for C26H23Cl4N3O5 (M+H)+ 598.0465, obsd. 598.0465.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][C:21](OC)=[O:22])=[C:10]1[C:25]([O:27][CH3:28])=[O:26].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][C:21]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:22])=[C:10]1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(C)N1
Reactant: C1CNCCN1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(CC(=O)N2CCNCC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of dimethyl 4-(2,6-dichlorophenyl)-2-methoxycarbonylmethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate(13.9 g, 30 mmol) , piperazine(39.2 g, 460 mmol), and dimethylformamide(30 ml) was heated to 100° C. (becomes a solution) and stirred for 1.5 h (longer reaction times result in decomposition). The reaction mixture was cooled briefly, poured into water(800 ml), and extracted with ethyl acetate. The extract was washed thoroughly with water, dried over sodium sulfate, and concentrated to give 12.2 g (84%) of an orange color oil, suitable for use in succeeding steps. It can be purified by column chromatography on silica gel using dichloromethane/methanol: 2/1 as eluent.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[C:7](OCC)(=[O:12])[CH2:8][C:9]([CH3:11])=O.[OH-].[K+]>CO>[C:1]([C:3]1[C:4]([OH:5])=[N:6][C:7]([OH:12])=[CH:8][C:9]=1[CH3:11])#[N:2]
Reactant: N#CCC(N)=O
Reactant: CCOC(=O)CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O)nc(O)c1C#N
Temperature: 25 °C
Yield: 76.6 %

Procedure:
Cyanoacetamide (8, 34 g, 0.40 mol) and ethyl acetoacetate (9, 52 g, 0.40 mol) were dissolved in methanol (250 mL) at room temperature, a solution of potassium hydroxide (28 g, 0.42 mol) in methanol (200 mL) was slowly added, and the resulting mixture was heated to reflux for 12 h. The reaction mixture was cooled to room temperature and the white amorphous precipitate was filtered and washed with methanol (2×50 mL). The solid product was redissolved in hot water. The solution was carefully acidified and the off-white precipitate was allowed to form. The precipitate was filtered and washed with water and methanol to yield 110 (46 g, 75%): mp>300° C. (dec) [lit. (J. Org. Chem. 1960, 25, 560-564.) mp 315-320° C. (dec)]. 1H NMR (300 MHz, DMSO-d6) δ 5.58 (s, 1H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@:11]1([C:26]#[CH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@@:11]1([C:26]#[CH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[O:25][S:29]([CH3:28])(=[O:31])=[O:30])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Reaction time: 6 h
Yield: 78.2 %

Procedure:
To a pyridine (3.5 mL) solution of 4 (110.9 mg, 0.30 mmol) was added MsCl (0.12 mL, 1.5 mmol) at 0° C. under Ar atmosphere, and the mixture was stirred for 6 h. The reaction mixture was partitioned between CHCl3/sat. aqueous NaHCO3. Silica gel column chromatography (1.5% MeOH in CH2Cl2) of the organic layer gave 5 (105.2 mg, 78%) as a foam: 1H NMR (CDCl3) δ1.92 (3H, d, JMe,6=1.2 Hz, Me-5), 2.43 (1H, dd, J1′,2′a=3.6 and J2′a,2′b=16.0 Hz, H-2′a), 2.72 (1H, s, C≡CH), 3.07 (3H, s, SO2Me), 3.23 (1H, ddd, J1′,2′b=8.2, J2′b,3′=5.2 and J2′a,2′b=16.0 Hz, H-2′b), 4.72 (1H, d, J5′a,5′b=11.2 Hz), 4.76 (1H, d, J5′a,5′b=11.2 Hz), 5.37 (1H, d, J2′b,3′=5.2 Hz, H-3′), 6.56 (1H, d, J1′,2′a=3.6 and J1′,2′b=98.2 Hz, H-1′), 7.36 (1H, d, JMe,6=1.2 Hz), 7.47-7.51, 7.60-7.64 and 8.07-8.10 (5H, each as m, Ph), 8.32 (1H, br); FAB-MS (m/z) 449 (M++H).