Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1.[ClH:28]>C(OCC)(=O)C>[ClH:28].[NH2:18][C@H:15]1[CH2:16][CH2:17][N:13]([C:11](=[O:12])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:26])[F:27])=[CH:9][CH:8]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
t-Butyl ((S)-1-(2-(4-trifluoromethoxyphenyl)ethanoyl)pyrrolidin-3-yl)carbamate (144 g) was suspended in ethyl acetate (300 mL), followed by addition of a solution (278 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred at room temperature for 3 days. The precipitated solids were collected by filtration to obtain the title compound (67 g). The filtrate was concentrated under reduced pressure, followed by addition of hexane and diisopropyl ether, and the precipitated solids were collected by filtration to obtain the title compound (52 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)[CH:7]=1.[CH3:32][C:33]1([CH3:42])[CH2:38][CH:37]([NH2:39])[CH2:36][C:35]([CH3:41])([CH3:40])[NH:34]1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])[C:10]=3[N:11]=[C:12]([NH:39][CH:37]3[CH2:38][C:33]([CH3:42])([CH3:32])[NH:34][C:35]([CH3:41])([CH3:40])[CH2:36]3)[N:13]=2)[CH:7]=1
Reactant: Cc1ccc(N)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: Cc1ccc(N)cc1-c1nc(NC2CC(C)(C)NC(C)(C)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 1 d from 4-(5-amino-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one and 2,2,6,6-tetramethyl-4-piperidinamine: LC-MS m/z 519 (M+H)+, 1.8 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2([CH2:22][S:21][CH2:20][S:19][CH2:18]2)OC1=S)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:12](=[C:11]1[CH2:22][S:21][CH2:20][S:19][CH2:18]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1N(C(=O)OC(C)(C)C)C(=S)OC12CSCSC2
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)=C1CSCSC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of potassium tert.-butylate (5.35 g) in tetrahydrofurane (40 cc) is cooled to -70° C. A solution of 3-tert.-butoxycarbonyl-4-ethoxycarbonyl-2-thioxo-1-oxa-7,9-dithia-3-azaspiro[4.5]decane (9 g) in tetrahydrofurane (40 cc) is added dropwise. The mixture is stirred for a further 3 hours, acetic acid (2.9 g) is then added and the reaction mixture is allowed to warm up to 20° C. The tetrahydrofurane is evaporated off under reduced pressure (20 mm Hg) at 30° C. The residue is dissolved in ethyl acetate (25 cc). The solution is washed with water (25 cc) and then dried over sodium sulphate. The solution is filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg). A solid residue is obtained and treated with petroleum ether (100 cc). The precipitate is filtered off and dried under reduced pressure. Ethyl α-tert.-butoxycarbonylamino-(4,5-dihydro-1,3-dithiin-5-ylidene)-acetate (5.3 g) is thus obtained in the form of a beige solid which melts at 154° C. (Kofler instantaneous m.p.).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][CH2:12][N:11]3[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]([F:26])([F:25])[F:24])=[N:15][CH:16]=[C:10]3[CH2:9]2)=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:26][C:23]([F:24])([F:25])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2=[CH:16][N:15]=1
Reactant: COc1ccc(CN2CCn3c(cnc3-c3ccccc3C(F)(F)F)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1ccccc1-c1ncc2n1CCNC2
Reaction time: 14 h

Procedure:
To a solution of 7-(4-methoxybenzyl)-3-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (Step F, 25 mg) in methanol, at 0° C. and under a nitrogen atmosphere was added palladium hydroxide on carbon (15 mg, 20 wt % Pd-Degussa type, E101) and the contents hydrogenated at 40 psi for 14 hours. The reaction mixture was filtered and the filter cake washed with methanol (2×10 mL). The filtrate was concentrated under reduced pressure and azeotroped with dichloromethane (2×20 mL) and ethyl acetate (2×20 mL). The oil that is obtained g (20 mgs) was used as such for the subsequent step without further purification.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:14]([C:18]1[S:19][C:20]([CH2:23]Cl)=[CH:21][CH:22]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([S:13][CH2:23][C:20]2[S:19][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:22][CH:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(S)cnn(C(C)(C)C)c1=O
Reactant: CC(C)(C)c1ccc(CCl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(SCc2ccc(C(C)(C)C)s2)cnn(C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 2.0 g of 2-t-butyl-5-mercapto-4-methyl-3(2H)-pyridazinone and 1.9 g of 2-t-butyl-5-chloromethylthiophene, and thereto was added under stirring 1.5 g of potassium carbonate at room temperature. After additional stirring for 8 hours at room temperature, the mixture was poured into 50 ml of water and then extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to obtain 3.5 g of a crude product. The crude product was separated and purified through thin layer chromatography (on silica gel; benzene) to give 2.2 g of 2-t-butyl-5-{(5-t-butyl-2-thienyl)-methylthio}-4-methyl-3(2H)-pyridazinone as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:21]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (15.6 g), methyl 4-hydroxyphenylacetate (12.5 g), potassium carbonate (20.8 g) and N,N-dimethylformamide (80 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylacetate (23.8 g, yield 94%) as crystals from an ethyl acetate-hexane (1:4, v/v)-eluted fraction. The crystals were recrystallized from ethyl acetate-hexane to obtain colorless crystals. m.p. 74-75° C.
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][CH:3]=1.O[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:17]1[CH2:18][CH2:19][CH:14]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:15][CH2:16]1
Reactant: OC1CCOCC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
An ice-cold solution of ethyl 4-hydroxybenzoate (0.82 g), 4-hydroxy-tetrahydro-2H-pyran (0.5 g) and triphenylphosphine in THF (50 ml) was treated dropwise with diisopropyl azodicarboxylate (1.69 ml). After 15 min the cooling bath was removed and the reaction stood overnight at rt. The mixture was evaporated, redissolved in toluene and successively washed with 2N sodium hydroxide (2×20 ml), water (2×20 ml) and brine (20 ml). After drying (magnesium sulfate) the solution was loaded directly on to a silica flash column (step gradient 10-30% EtOAc in light petroleum 40-60) to give the title compound (D5) (0.75 g). 1H NMR δ (CDCl3): 7.98 (2H, d, J=8.5Hz), 6.91 (2H, d, J=8.5 Hz), 4.60 (1H, m), 4.35 (2H, q, J=9.8 Hz), 3.98 (2H, m), 3.57 (2H, m), 2.05 (2H, m), 1.80 (2H, m), 1.38 (3H, t, J=9.8 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:31])[CH2:17][CH2:18][N:19]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH2:20][CH2:21][OH:22])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:31])[CH2:17][CH2:18][N:19]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH2:20][CH:21]=[O:22])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)CCN(CCO)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCN(CC=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
To a solution of 1.91 ml (21.77 mmol) of oxalyl chloride in 64 ml CH2Cl2 at −50 to −60° C. was added a solution of 3.22 ml (45.42 mmol) dimethylsulfoxide in 12 ml of CH2Cl2 within 20 min. The solution was stirred for 5 min, then a solution of 6.33 g (18.93 mmol) of 3-[(3,4-dichloro-phenyl)-(2-hydroxy-ethyl)-amino]-propionic acid tert-butyl ester in 43 ml CH2Cl2 was added within 20 min. The mixture was stirred for 15 min and 13.17 ml (94.63 mmol) of triethylamine were added within 20 min. The suspension was stirred for 3 h and slowly warmed to 0° C. The reaction was neutralized with cold aq. 10% KH2PO4 solution (adjusted with solid KH2PO4 to pH 4-5) and extracted with EtOAc (3×). The organic phases were washed with aq. 10% KH2PO4, solution sat. aq. NaHCO3 solution, aq. 10% NaCl solution, dried over Na2SO4 evaporated to yield 6.26 g (99.6%) of the title compound as orange oil. MS: 332.0 (MH+, 2Cl).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].C(CN)O.OCCN1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][CH:27]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[C:15]1=[O:28]>>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][N:1]1[C:15](=[O:28])[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:21]=2[C:22](=[CH:25][CH:26]=[CH:27]3)[C:23]1=[O:24]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCO
Reactant: NCCCCO
Solvent: NCCO
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCO

Procedure:
Following the procedure of example 1(a) and (b) but substituting 4-aminobutanol for the ethanolamine in part (a) one obtains 2-(4-hydroxybutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, 4-methylbenzenesulfonate ester.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl.[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:33]1[CH2:34][CH2:35][N:30]([C:28]2[S:27][N:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:29]=2)[CH2:31][CH2:32]1)=[O:18]
Reactant: O=C(Nc1nc2ccccc2s1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2ccccc2s1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 26.1 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl 1,3-benzothiazol-2-ylcarbamate (240 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 81.4 mg (26.1%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(N(CC)CC)C.[I:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([I:28])=[CH:30][CH:31]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(I)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(6-Chloronaphth-2-ylsulphonyl)piperazine (0.65 g, 2.1 mmol) was dissolved in dichloromethane (50 mL) and triethylamine (2.9 mL, 21 mmol) was added at room temperature. 4-Iodobenzoyl chloride (0.56 g, 2.1 mmol) was added as a solid in one portion and the reaction mixture stirred for one hour at room temperature. The reaction mixture was concentrated in vacuo, then separated between EtOAc (100 mL) and saturated sodium hydrogen carbonate solution (100 mL). The EtOAc layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The resulting white solid was subjected to chromatography (SiO2: 50% EtOAc/Hexane) to yield 1-(6-chloronaphth-2-ylsulphonyl)-4-(4-iodobenzoyl)piperazine as a white solid (097 g); 1H NMR (DMSO-d6) δ=3.05 ppm (s,4H), δ=3.53 ppm (s,4H), δ=7.11 ppm & 7.74 ppm (dd,4H), δ=7.65 to 7.84 ppm (m,2H), δ8.10 ppm to 8.28 ppm (m,3H), δ=8.47 ppm (s,1H); MS (M+H)+ 540.
Reaction SMILES: [F:1][C:2]([F:44])([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([F:43])=[CH:35][CH:34]=1)[CH2:3][NH:4][C:5]1[C:6]([F:32])=[C:7]([CH2:12][C:13]([NH:15][CH2:16][C:17]2[C:18]([CH3:31])=[N:19][C:20]([NH:23]C(OC(C)(C)C)=O)=[CH:21][CH:22]=2)=[O:14])[C:8]([Cl:11])=[CH:9][CH:10]=1.CO.C(Cl)Cl>Cl.C(Cl)Cl>[ClH:11].[NH2:23][C:20]1[N:19]=[C:18]([CH3:31])[C:17]([CH2:16][NH:15][C:13](=[O:14])[CH2:12][C:7]2[C:8]([Cl:11])=[CH:9][CH:10]=[C:5]([NH:4][CH2:3][C:2]([F:1])([F:44])[C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]([F:43])=[CH:35][CH:34]=3)[C:6]=2[F:32])=[CH:22][CH:21]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(N)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 136.6 %

Procedure:
A solution of 2-(3-{[2,2-difluoro-2-(4-fluoronaphthyl)ethyl]amino}-6-chloro-2-fluorophenyl)-N-({6-[(tert-butoxy)carbonylamino]-2-methyl(3-pyridyl)}methyl)acetamide (10 mg, 16 μmol), as prepared in the preceding step, in HCl (0.5 mL, 4.0 M in 1,4-dioxane) was stirred for 2 hours at ambient temperature. A solution of MeOH/DCM (25%, 0.4 mL) was added, and the mixture continued to stir overnight. The solvents were evaporated, and the resulting brown residue was flash chromatographed on silica gel eluting with MeOH/DCM (2.5, 5, and 10%) to give a solid product. It was treated with HCl solution (0.01 mL, 4.0 M in 1,4-dioxane, 40 μmol) in DCM (0.5 mL), stirred for 5 minutes, and the solvents evaporated to give the title compound (6.2 mg, 69% yield) as a white solid. 1H-NMR (400 MHz, CD3OD) δ 8.26 (d, J=8.4 Hz,1H), 8.17-8.14 (m, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.73-7.64 (m, 4H), 7.20 (dd, J=10.0, 8.3 Hz, 1H), 6.82-6.79 (m, 1H), 6.49 (t, J=9.1 Hz, 1H), 4.24 (s, 2H), 4.10-4.02 (m, 2H), 3.66 (d, J=2.3 Hz, 2H), 2.49 (s, 3H). Mass spectrum (LCMS, ESI) calc'd for C27H24ClF4N4O (M+H): 531.1. Found: 531.6.
Reaction SMILES: [NH2:1][C:2](=[O:21])[CH2:3][NH:4]/[C:5](/[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])=[CH:6]\[C:7]([O:9]CC)=O.C[Si]([N:26]=[C:27]=[S:28])(C)C>C(OCCCC)(=O)C.CN(C=O)C>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([C:5]2[N:4]([CH2:3][C:2]([NH2:1])=[O:21])[C:27](=[S:28])[NH:26][C:7](=[O:9])[CH:6]=2)[CH:17]=1
Reactant: CCOC(=O)/C=C(\NCC(N)=O)c1cc(Cl)ccc1OC
Reactant: C[Si](C)(C)N=C=S
Solvent: CN(C)C=O
Solvent: CCCCOC(C)=O
Product: COc1ccc(Cl)cc1-c1cc(=O)[nH]c(=S)n1CC(N)=O
Temperature: 117.5 °C
Reaction time: 8 h

Procedure:
A slurry of (Z)-ethyl 3-((2-amino-2-oxoethyl)amino)-3-(5-chloro-2-methoxyphenyl)acrylate (20 g, 63 mmol) in a mixture of butyl acetate (140 mL) and DMF (38 mL) was treated with trimethylsilyl isothiocyanate (16.8 g, 125 mmol) and the mixture was heated at 115-120° C. for 5-6 hours. The mixture was cooled to 0-5° C., butyl acetate (100 mL) was added and the mixture was slurried for 8 hours. The formed solids were filtered, and the filter cake was washed with butyl acetate (2×100 mL). The solid was dried in a vacuum oven at 50° C. for 12 hours to a tan solid. The solid was dissolved in a 5:1 mixture of DMF and water at room temperature and additional water was added slowly to crystallize the material. The slurry was cooled to 10° C. and stirred for 8 hours, followed by filtration and washing with water. The filter cake was dried in a vacuum oven at 50° C. for 8 hours. The solid was dissolved in a 1:1 mixture of methanol and water and the slurry was heated to 50° C. and held at this temperature for 2 hours. After cooling to 10° C. over 30 minutes, the slurry was held at this temperature for 1 hour, filtered and washed with water and dried in a vacuum oven at 50° C. for 8 hours to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]2[C:20]([C:21]3[CH:33]=[CH:32][O:31][C:22]=3[CH2:23][O:24]2)=[CH:19][CH:18]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:11])=[O:10].C([Sn](CCCC)(CCCC)/[CH:39]=[CH:40]\[CH2:41][OH:42])CCC>O1CCOCC1.O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([N:12]([C:17]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]3[C:20]([C:21]4[CH:33]=[CH:32][O:31][C:22]=4[CH2:23][O:24]3)=[CH:19][CH:18]=2)[C:13]([O:15][CH3:16])=[O:14])(=[O:11])=[O:10])=[C:2](/[CH:39]=[CH:40]\[CH2:41][OH:42])[CH:7]=1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Reactant: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCc1occc1-2
Temperature: 70 °C
Yield: 78.3 %

Procedure:
A mixture of methyl 7-{N-[2-bromo-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 93, 0.200 g) and (Z)-3-tributylstannanyl-prop-2-en-1-ol (Intermediate 1, 0.230 g) in dioxane (9 mL) and water (1 mL) was de-gassed and flushed with nitrogen. tris-(Dibenzylideneacetone)dipalladium (0.034 g) and tri-tert-butylphosphonium tetrafluoroborate (0.022 g) were added and the reaction mixture was heated to 70° C. for 30 minutes. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, pre-equilibrated with ammonia solution in DCM, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-100%. The resultant product was triturated with ether to give methyl 7-{N-[4-fluoro-2((Z)-3-hydroxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (0.150 g) as a cream powder.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[CH2:6][CH2:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20].O>CO>[O:21]=[C:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20])[CH2:7][CH2:6][C:5]([OH:22])=[O:4]
Reactant: COC(=O)CCC(=O)c1ccc(OC)c(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)CCC(=O)O)c(OC)c1OC
Temperature: 25 °C
Yield: 88.4 %

Procedure:
5.95 g of sodium hydroxide was dissolved in 200 mL of methanol in a 500 mL round bottom flask. The reaction mixture was cooled to room temperature and 55 (6.78 g, 22.90 mmol) was added followed by 20 mL of water and 100 mL of methanol and the reaction mixture was refluxed for 30 min. The solvent was evaporated under reduced pressure and the reaction mixture was neutralized with dilute hydrochloric acid and the reaction mixture was extracted with ether (100×3) and the combined organic phases were washed with water and dried over sodium sulfate and solvent evaporated under reduced pressure. The crude product was purified by column chromatography (20:80 EtOAc:Hexanes) to yield 5.43 g of 56 as tan colored solid (94%).
Reaction SMILES: O[CH2:2][C:3]1(C)[CH:11]2[CH:7]([CH2:8][NH:9][CH2:10]2)[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])([OH:12])[CH2:5][CH2:4]1.N1C2C(=CC=CC=2)C(CC(O)=O)=C1>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:6]1([OH:12])[CH2:5][CH2:4][CH:3]([CH3:2])[CH:11]2[CH:7]1[CH2:8][NH:9][CH2:10]2
Reactant: COc1ccccc1C1(O)CCC(C)(CO)C2CNCC21
Agent: O=C(O)Cc1c[nH]c2ccccc12
Product: COc1ccccc1C1(O)CCC(C)C2CNCC21

Procedure:
By working in an identical manner to Example 1, 1.5 g of (3aRS,4RS,7SR,7aRS)-7-(hydroxymethyl)-4-(2-methoxyphenyl)-7-methyl-4-perhydroisoindolol and 0.88 g of 3-indoleacetic acid are used. After concentration, the crude residue is recrystallized in acetonitrile and, after drying at 40° C. and 15 Pa, 0.7 g of (3aRS,4RS,7SR,7aRS)-7-(hydroxymethyl)-2-(3-indolylacetyl)-4-(2-methoxyphenyl)-7-methyl-4ethyl)-4-(2-methoxyphenyl)-7-methyl-4-perhydroisoindolol is obtained, in the form of a white solid melting at 170-180° C. (pasty melt).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29].[C:30]1([N:40]=[C:41]=[O:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH2:25]([C:6]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23][CH3:24])=[O:22])=[CH:13][CH:14]=2)[C:3]([CH2:2][NH:1][C:41]([NH:40][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[O:42])=[C:4]([Cl:29])[N:5]=1)[CH2:26][CH2:27][CH3:28]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Solvent: ClC(Cl)Cl
Product: CCCCc1nc(Cl)c(CNC(=O)Nc2cccc3ccccc23)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 55.2 %

Procedure:
5-Aminomethyl-2-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole (1.00 g, 2.4 mmol, 1 eq) and 1-naphthyl isocyanate (0.35 mL, 2.4 mmol, 1 eq), were mixed and stirred in chloroform at room temperature for 3 days. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel in 1:1 hexane/ethyl acetate to yield 770 mg of a white glass. NMR (200 MHz, CDCl3) δ 7.83 (d, 3H, J=6 Hz); 7.67 (d, 1H, J=6 Hz); 7.56-7.18 (m, 9H); 6.97 (d, 2H, J=7 Hz); 6.74 (s, 1H); 5.27 (s, 2H); 4.74 (s, 1H); 4.39 (d, 2H, J=7 Hz); 3.58 (s, 3H); 2.60 (t, 2H, J=7 Hz); 1.43-1.21 (m, 4H); 0.85 (t, 3H, J=7 Hz).