Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:20]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4.[CH3:31][S:32][CH2:33]Cl>CN(P(N(C)C)(N(C)C)=O)C>[CH3:31][S:32][CH2:33][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:20]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4
Reactant: CSCCl
Reactant: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CSCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCc1ccccc1)CC3
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
To Sodium hydride (763 mg of 60% dispersion in mineral oil, 19.1 mmol) in HMPA (15 mL) was added a solution of (+)-3-hydroxy-N-(benzyloxycarbonyl)morphinan (6.00 g, 15.9 mmol) from Example 1 in HMPA (50 mL) at room temperature. The reaction mixture was stirred for 30 min and then chloromethyl methyl sulfide (1.60 mL, 19.1 mmol) was added dropwise. The reaction mixture was stirred vigorously at room temperature overnight. The product was extracted with EtOAc (500 mL). The EtOAc layer was washed with saturated NaHCO3 solution and dried over MgSO4, filtered and evaporated under vacuum to provide the crude product, which was further purified by prep reverse-phase HPLC to afford the title compound (1.78 g, 26%) as a yellow gum.
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1[NH:9][C:10](=O)OC(C)(C)C)=[O:3].C(Cl)Cl>CN(C=O)C>[N:9]1[C:8]2[CH:7]=[CH:6][O:5][C:4]=2[C:2](=[O:3])[NH:1][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccoc1C(N)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2ccoc12
Temperature: 80 °C
Yield: 64.4 %

Procedure:
tert-Butyl 2-(aminocarbonyl)-3-furylcarbamate (Intermediate 82) (3.38 g) was stirred in DMF (25 mL) and DCM (25 mL) for 30 minutes. The solvent was removed and the crude product was heated at 80° C. in triethylorthoformate (20 mL) for 30 minutes. The mixture was cooled, poured into ether (100 mL) collected by filtration and washed with ether to afford a first crop of the title compound as a pale yellow solid (1.31 g, 65%). The filtrate was evaporated and triturated with EtOAc to afford a further crop (296 mg, 15%);
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 12 step B from 6-chloro-4-(2-chloro-benzyl)-2-piperidin-1-yl-quinoline-3-carboxylic acid ethyl ester (50 mg, 0.113 mmol) and 1N NaOH. Pale yellow solid (35 mg, 75%). LC-MS (ESI): 415 (M+H)+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[CH2:35]2.Cl>CN(C=O)C>[O:49]=[C:43]1[CH:42]([N:36]2[CH2:35][C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:8](=[O:10])[C:7]4[CH:6]=[CH:5][C:4]([S:3][CH2:1][CH3:2])=[CH:12][CH:11]=4)[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCSc1ccc(C(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A mixture of 4-(ethylthio)benzoic acid (0.26 g, 1.4 mmol) and CDI (0.24 g, 1.5 mmol) in DMF (30 ml) was stirred at 40° C. for 4 hours. 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) was added and the mixture was stirred at 40° C. for 2 h. 4% Aqueous HCl (30 mL) was added and the resulting precipitate was filtered, washed with water (30 mL) and dried in vacuo providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-ethylsulfanyl-benzamide as a white solid, (0.39 g, 66% yield); mp 217-219° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 35/65 CH3CN/0.1% H3PO4, 5.75 (99.03%); 1H NMR (DMSO-d6) δ 1.26 (t, 3H, J=7.2 Hz), 1.97-2.01 (m, 1H), 2.03-2.45 (m, 1H), 2.57-2.62 (m, 1H), 2.85-2.97 (m, 1H), 3.05 (q, 2H, J=7.2 Hz), 4.30 (d, 1H, J=17.4 Hz), 4.44 (d, 1H, J=17.4 Hz), 4.58 (d, 1H, J=7.8 Hz), 5.11 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 7.37 (d, 2H, J=8.4 Hz), 7.46 (d, 1H, J=7.8 Hz), 7.53 (s, 1H), 7.69 (d, 1H, J=7.8 Hz), 7.85 (d, 2H, J=8.7 Hz), 9.12 (t, 1H, J=5.7 Hz), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 13.9, 22.5, 25.2, 31.2, 42.7, 47.1, 51.5, 122.0, 122.9, 126.3, 127.0, 127.8, 130.3, 130.6, 140.9, 142.3, 143.9, 165.7, 167.9, 170.9, 172.8; LCMS: MH=438; Anal. Calcd for C23H23N3O4S: C, 62.37; H, 5.37; N, 9.49. Found: C, 62.30; H, 5.29; N, 9.60.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH3:14].N>CO.[Ni]>[CH3:14][C:3]1[CH:4]=[C:5]([C:10]([F:13])([F:11])[F:12])[C:6]([CH2:8][NH2:9])=[N:7][CH:2]=1
Reactant: Cc1cc(C(F)(F)F)c(C#N)nc1Cl
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1cnc(CN)c(C(F)(F)F)c1
Yield: 43.7 %

Procedure:
A solution of 6-chloro-5-methyl-3-trifluoromethyl-pyridine-2-carbonitrile (0.300 g, 1.36 mmol) in MeOH (5 mL) was added to a flask charged with Raney Ni (pre-washed with methanol) (˜0.6 g) in MeOH (5 mL). After saturated with NH3 gas the mixture was shaken under H2 (40 psi) for 2 h. The reaction mixture was then filtered through a celite cake, and the filtrate was concentrated by evaporation under vacuum. The residue was purified by flash chromatography on a silica gel column (200:10:1 CH2Cl2/MeOH/NH4OH), affording C-(5-methyl-3-trifluoromethyl-pyridin-2-yl)-methylamine as a colorless oil (0.113 g, 44%). 1H NMR (CDCl3) δ 2.39 (s, 3H), 4.07 (s, 2H), 7.71 (s, 1H), 8.56 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].O.[S-2:13].[Na+].[Na+].O>C(O)C>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[SH:13]
Reactant: [S-2]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(Cl)c1S
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.7 %

Procedure:
Twenty grams of 2,3-dichloronitrobenzene was dissolved in 200 ml of absolute ethanol and the resulting solution added dropwise over three hours to a mixture of 40.0 g of sodium sulfide hydrate in 225 ml of absolute ethanol. The reaction temperature did not exceed 30° C. during the addition. The reaction was allowed to stir for 48 hours at room temperature. Since some of the 2,3-dichloronitrobenzene was still present, as indicated by GLC, an additional 9.0 g of the sodium sulfide hydrate was added at once and the reaction was allowed to stir overnight at room temperature. The ethanol was removed and the concentrate was partitioned between 300 ml of water and 250 ml of ether, the ether extract was discarded, and the aqueous phase made acidic by the dropwise addition of 50 ml of concentrated hydrochloric acid with the evolved gas being scrubbed through a bleach trap. A large amount of solid formed. Water, 100 ml, was added and the aqueous phase extracted with 350 ml of methylene chloride. The organic phase was dried with magnesium sulfate, filtered and concentrated to yield 11.8 g of a tan solid.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=[O:2].S(Cl)(Cl)=O.[C:26]1(C)C=CC=CC=1>>[CH3:26][O:2][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:8]=1)[CH3:5])=[O:3]
Reactant: CC(Oc1ncn(-c2cccc(C(F)(F)F)c2)n1)C(=O)O
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)Oc1ncn(-c2cccc(C(F)(F)F)c2)n1

Procedure:
A 2.5 g portion of the compound of Example 24 was added to 50 ml of toluene, and 3 ml of thionyl chloride was added to the mixture. It was heated under reflux for 2 hours, and was then cooled and evaporated under vacuum. Fifty ml of toluene was added to the residue and was removed under vacuum, and the residue was then taken up in methanol and heated under reflux for 3 hours. The solvent was then removed under vacuum, and the residue was recrystallized from methanol to obtain 2.0 g of the desired product, m.p. 135°-137°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=3[F:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: COc1cccc(B(O)O)c1F
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cccc(OC)c3F)c(F)ccc2c1N
Yield: 28.9 %

Procedure:
Using method A, 4-amino-7-fluoro-8-iodo-N-propyl-cinnoline-3-carboxamide (250 mg, 0.67 mmol) and (2-fluoro-3-methoxyphenyl)boronic acid (193.4 mg, 1.136 mmol) were reacted to afford the title compound (72.0 mg, 29% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.49 (bs, 1H), 7.94 (d×d, J=4.9 Hz, J=9.2 Hz, 1H), 7.55 (t, J=8.5 Hz, 1H), 7.21 (m, 1H), 7.03-7.10(m, 2H), 3.94 (s, 3H), 3.44 (q, J=6.7 Hz, J=13.4 Hz, 2H), 1.64 (apparent sextet, J=7.3 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H). MS APCI, m/z=373 (M+H) HPLC 2.72 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH2:26].CCN(CC)CC>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:26][CH2:25][S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: C=CS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)CCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 130 °C
Yield: 57.7 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 210 mg; 0.62 mmol), methyl vinyl sulfone (654 mg; 6.16 mmol) and Et3N (0.26 mL; 1.85 mmol) in methanol (15 mL) was heated at 130° C. for 0.5 h in a microwave reactor. The reaction mixture was cooled to r.t., concentrated to give a residue which was triturated with MeOH (2 mL) to afford 160 mg (58%) of the title product as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:34])[C:14]1[CH:19]=[C:18]([CH:20]=[N:21][OH:22])[C:17]([F:23])=[C:16]([F:24])[C:15]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=1[F:33])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:24][C:16]1[C:15]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[C:14]([CH:19]=[C:18]([CH:20]=[N:21][OH:22])[C:17]=1[F:23])[C:13]([NH:12][O:11][CH2:10][CH2:9][OH:8])=[O:34]
Reactant: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=NO)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NOCCO)c1cc(C=NO)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-(hydroxyiminomethyl)-benzamide (a mixture of two geometric or atropisomers ) (5.0 mg, 46%) prepared in Process C was dissolved in THF (1 ml), tetrabutylammonium fluoride (1 M solution in THF, 30 μl, 30 μmol) was added thereto, and the mixture was stirred at room temperature for five hours. Water (8 ml) was added to the reaction solution, which was extracted with ethyl acetate (8 ml×3). The organic layers were combined, washed with 0.1 N hydrochloric acid (8 ml) and saturated brine (8 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with preparative thin layer chromatography (Silicagel 60 F254, 0.5 mm thickness, Merck & Co., Inc., CH2Cl2/MeOH (10:1)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(hydroxyiminomethyl)-benzamide (Compound 3) (3.9 mg, 96%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[O:30]1[CH2:36][CH2:35][CH2:34][NH+:33]([CH2:37][B-](F)(F)F)[CH2:32][CH2:31]1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:37][N:33]5[CH2:34][CH2:35][CH2:36][O:30][CH2:31][CH2:32]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: F[B-](F)(F)C[NH+]1CCCOCC1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCCOCC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and ([1,4]oxazepanium-4-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=0.94 min; Mass spectrum (ESI+): m/z=506 [M+H]+.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5]Cl)=[CH2:2].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K].CN(C=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:1]([O:3][CH2:4][CH2:5][C:16]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:10]([NH:11][C:7](=[O:17])[C:8]=12)=[O:12])=[CH2:2]
Reactant: C=COCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C=COCCc1cccc2c1C(=O)NC2=O

Procedure:
2-Vinyloxy Ethyl Phthalimide was prepared via reacting 2-chloroethyl vinyl ether (25 g, 0.24 mol) and potassium phthalimide (25 g, 0.135 mol) in 100° C. DMF (75 ml) using tetra n-butyl ammonium bromide (0.5 g) as the phase transfer catalyst. This solution was heated for 6 h and then crashed out in water and filtered. This solid was then recrystallized twice from methanol to give white crystals.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[Cl:9][C:10]([Cl:16])=[CH:11][CH:12]=[C:13]([CH3:15])[CH3:14]>S([O-])([O-])(=O)=O.[Cu+2]>[CH3:14][C:13]1([CH3:15])[CH:12]([CH:11]=[C:10]([Cl:16])[Cl:9])[CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)=CC=C(Cl)Cl
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C

Procedure:
Thus, for example, in Pesticide Science (1974) 5, 791-799 it is shown that the reaction between ethyl diazoacetate and 1,1-dichloro-4-methylpenta-1,3-diene in the presence of copper sulfate to produce ethyl 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylate, results in a product which is contaminated with up to 20% of ethyl fumarate and maleate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:20][O:21]C(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.ClCCl>[CH3:1][O:2][C:3](=[O:33])[CH:4]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:20][OH:21]
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1COC(C)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1CO)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (1.85 g, 4.0 mmol) in methanol (40 mL) was added potassium carbonate (560 mg, 4.0 mmol) at room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane (150 mL), washed with 1.0 M aqueous hydrogen chloride and dried (Na2SO4) to give the pure 3-(4-benzyloxy-2-hydroxymethyl-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester in almost quantitative yield. To the alcohol (800 mg, 1.93 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride (0.18 mL, 2.3 mmol) followed by triethylamine (0.38 mL, 2.70 mmol) at 0° C. and then brought to room temperature. After 1 h, the reaction mixture was washed with aqueous sodium hydrogencarbonate, dried (Na2SO4). The solvent was removed, dissolved the crude product in anhydrous THF (20 mL) followed by addition of 2.0 M solution of methylamine in THF (10 mL) in a sealed tube. The sealed tube was heated at 80° C. for a period of 12 h and then removed the solvent. The crude product was purified by flash chromatography using 30% ethyl acetate in hexane to give (8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamic acid tert-butyl ester in 39% overall yield. 1H NMR (500 MHz, CDCl3): in δ 7.40-7.31 (m, 5H), 7.01-7.00 (m, 1H), 6.83-6.82 (m, 1H), 6.66 (s, 1H), 5.91-5.90 (m, 1H), 5.13-5.01 (m, 4H), 3.50-3.46 (m, 1H), 3.03 (s, 3H), 2.85-2.78 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[NH:18][C@@H:17]2[C:21]([N:23]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH3:24])=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:42][C@@H:43]([N:50]=[C:51]=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[N:18]([C:51]([NH:50][C@@H:43]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:42])=[O:52])[C@@H:17]2[C:21]([N:23]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH3:24])=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: CN(C(=O)[C@H]1NC(=O)[C@@H]1Cc1ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1)S(=O)(=O)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)N1C(=O)[C@H](Cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)[C@H]1C(=O)N(C)S(=O)(=O)c1ccc(F)cc1)c1ccccc1
Reaction time: 20 h

Procedure:
To a solution of 99 in DMF (0.75 mL) was added (R)-α-methylbenzylisocyanate (6 uL, 2.0 eq.) and TEA (8.5 uL, 3.0 eq.). The reaction was stirred under an atmosphere of argon for 20 hours. The reaction was then concentrated in vacuo and taken on to the next step without further purification.
Reaction SMILES: [ClH:1].[CH3:2][C:3]([CH3:15])([CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:4]([OH:6])=[O:5].[CH3:16][C:17]1([CH3:40])[C:22]2[CH2:23][S:24][CH2:25][C:21]=2[C:20]2[C:26](O)=[CH:27][C:28]([CH:30]([CH:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH3:31])=[CH:29][C:19]=2[O:18]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:1].[CH3:40][C:17]1([CH3:16])[C:22]2[CH2:23][S:24][CH2:25][C:21]=2[C:20]2[C:26]([O:5][C:4](=[O:6])[C:3]([CH3:15])([CH3:2])[CH2:7][CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:27][C:28]([CH:30]([CH:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH3:31])=[CH:29][C:19]=2[O:18]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CSC1
Reactant: CC(C)(CCN1CCCCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)C(C)(C)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CSC1

Procedure:
2,2-Dimethyl-4-piperidinobutyric acid hydrochloride is reacted with 1,3-dihydro-4,4-dimethyl-7-(3-methyl-2-octyl)-9-hydroxy-4H-thieno[3,4-c][1]benzopyran in methylene chloride in the presence of dicyclohexylcarbodiimide to produce 1,3-dihydro-4,4-dimethyl-7-(3-methyl-2-octyl)-9[2,2-dimethyl-4-(piperidino)butyryloxy]-4H-thieno[3,4-c][1] benzopyran hydrochloride.
Reaction SMILES: [NH2:1][CH:2]([C:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[Br:11].C(N(CC)CC)C.[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>C(#N)C>[Br:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:2]1[C:12]2[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=2[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)[C:37](=[O:38])[NH:1]1)[C:7]#[N:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCCC2=O)c(Br)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{Amino-[6-oxo-2-(3-trifluoromethyl-phenylamino)-cyclohex-1-enyl]-methyl}-3-bromo-benzonitrile (INTERMEDIATE 21, 16.5 g, 33 mmol) is suspended in acetonitrile (150 mL) and triethylamine (3.47 mL, 24.7 mmol) and 1,1′-carbonyldiimidazole (6.7 g, 41.2 mmol) are added. The mixture is stirred at room temperature for 1 h. The solvent is evaporated under reduced pressure and water is added. The product precipitates; the precipitate is filtered off, washed with water and dried. Yield: 14 g. ESI mass spectrum: [M+H]+=490 (bromine isotope pattern); Retention time HPLC: 0.64 min (X012_S02).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(F)cc1
Yield: 21.9 %

Procedure:
Using 1.00 g of (4-fluorobenzyl)malononitrile, 15 ml of N,N-di-methylformamide, 0.23 g of sodium hydride (60% in oil), and 1.02 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.34 g of 2-(4-fluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (16)).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[C:20]1(C)[CH:25]=CC(S(O)(=O)=O)=C[CH:21]=1>CC(C)=O>[CH3:21][C:20]1([CH3:25])[O:8][C@@H:7]2[CH2:6][CH2:5][CH2:4][C@@H:3]([N:9]3[C:10](=[O:19])[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:17]3=[O:18])[C@@H:2]2[O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCC[C@@H](O)[C@H]1O
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2[C@H](N3C(=O)c4ccccc4C3=O)CCC[C@H]2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of 2-[(1R,2S,3R)-2,3-dihydroxycyclohexyl]-1H-isoindole-1,3(2H)-dione (19) (50.0 g, 191.4 mmol) and 2,2-methoxypropane (500 mL, 4.07 mol) in acetone (500 mL), a catalytic amount of p-toluenesulfonic acid was added and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated Na2CO3 solution to adjust the pH to 10 and the solvent was removed. Water (750 mL) was added to the residue and extracted with ethyl acetate (2×750, 500 mL). The organics were combined, dried over Na2SO4 and concentrated to give the desired product as a white solid (55.8 g, 96.8% yield). LC/MS [Method B: rt: 6.16 min; m/z: 302 (M+1)].