Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH2:25][CH2:26][CH2:27][CH3:28])[O:7][CH2:8][C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:39]([C@H:8]([O:7][C@H:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH2:27][CH3:28])[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCCCC(OCC(=O)OC(c1ccccc1)c1ccccc1)c1ccco1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCC[C@H](O[C@@H](Cc1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)c1ccco1
Temperature: 0 °C

Procedure:
Benzhydryl 4-(2-furyl)-3-oxaoctanoate (2.0 g, 5.28 mmol) was dissolved in 20 mL freshly distilled THF and cooled to -80°±5° C. under dry argon. Sodium bis(trimethylsilyl)-amide (1.0M in THF, 5.6 mL, 5.6 mmol) was slowly added keeping the temperature at -80°±5° C. After 15 m, freshly distilled and filtered (through basic alumina) benzyl bromide (0.7 mL, 5.81 mmol) in HMPA (4 mL) was added dropwise maintaining the reaction temperature at -75°±5° C. After 15 m, the reaction was allowed to warm to 0° C. for 1 h before quenching with water and extraction with ether. The combined ether extracts were washed with saturated NH4Cl, 5% NaHCO3, brine,dried over MgSO4, and purified by flash silica gel chromatography to give 771.3 mg (31%): [α]25D -65.5°; 1H NMR (300 MHz, CDCl3) δ0.81 (t, 3H, J=7 Hz), 1.22 (m, 4H), 1.80 (m, 2H), 2.91 (m, 2H), 4.12 (dd, 1H, J=9 Hz), 4.30 (t, 1H, J=7 Hz), 5.86 (m, 1H), 6.19 (m, 1H), 6.69 (s, 1H), 7.2 (m, 16H); mass spectrum (FAB): 486 (M+NH4).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]1=[O:15].[N:16]1([C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][N:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[S:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]([N:16]2[CH2:17][CH2:18][N:19]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]3=[O:15])[CH2:20][CH2:21]2)=[N:23]1
Reactant: CC1(C)CC(=O)N(CCCCBr)C(=O)C1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CC(=O)N(CCCCN2CCN(c3nsc4ccccc34)CC2)C(=O)C1
Yield: 64 %

Procedure:
A mixture of N-(4-bromobutyl)-3,3-dimethylglutarimide (4 g., 0.0145 mole) obtained according to the procedure of Example 9, 3-(1-piperazinyl)-1,2-benzisothiazole (3.18 g., 0.0145 mole), anhydrous potassium carbonate (20.04 g., 0.145 mole) and potassium iodide (0.25 g., 0.0015 mole) in 150 ml. of acetonitrile is stirred and refluxed for a period of 12 hr. The reaction mixture is filtered, concentrated in vacuo and residual material triturated with ether. Crystallization of the solid thus obtained from ether affords a 64% yield of analytically pure 1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-4,4-dimethyl-2,6-piperidinedione, m.p. 146°-147° C.
Reaction SMILES: Cl.[C:2]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][NH2:22])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:25](CC)CC)[CH3:24]>C(O)C>[C:2]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][NH:22][C:23](=[NH:25])[CH3:24])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: NCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: Cl
Solvent: CCO
Product: CC(=N)NCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 48 h

Procedure:
C-(7-Benzenesulfonyl-chroman-4-yl)-methylamine HCl salt (90 mg, 0.26 mmol) and methyl imidate (acetimidic acid methyl ester, 58 mg, 0.529 mmol) were dissolved in 3 mL of absolute ethanol and 0.362 mL of triethylamine (2.6 mmol) was added. The reaction mixture was stirred at 80° C. for 2 days. It was then cooled, partitioned between EtOAc and water, dried over MgSO4 concentrated and purified using column chromatography (silica gel, MeOH/CHCl3/NH4OH 10:89:1) After formation of the HCl salt, 9 mg (10%) of. N-(7-Benzenesulfonyl-chroman-4-ylmethyl)-acetamidine was collected. MS: 345 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
[4-(Methylsulfonyl)phenyl]boronic acid (0.69 g, 3.40 mmol) was added to a solution of 4-bromophenol (0.5 g, 2.83 mmol) in DME (25 mL), followed by addition of 2M Na2CO3 (25 mL) and Pd(PPh3)4 (0.17 g, 0.14 mmol). The reaction mixture was heated at 90° C. for 3 h, then cooled to ambient temperature, and extracted with ether. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as an off-white solid. The crude product was purified by chromatography on a silica gel column eluted with 50% EtOAc/hexane to give 0.45 g (64%) of 4′-(methylsulfonyl)-4-biphenylol as a white solid. Alternatively, 4′-(methylsulfonyl)-4-biphenylol was prepared from 4-bromophenyl methyl sulfone (2 g, 8.5 mmol), (4-hydroxyphenyl)boronic acid (1.76 g, 12.75 mmol), 2M Na2CO3 (100 mL) and Pd(PPh3)4 (0.1 g, 0.08 mmol) in DME (100 mL) in a manner similar to the conditions above. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H, J=8.6 Hz), 7.71 (d, 2H, J=8.3 Hz), 7.51 (d, 2H, J=8.6 Hz), 6.94 (d, 2H, J=8.5 Hz), 4.92 (s, 1H), 3.08 (s, 3H); LRMS (ESI), m/z 249 (M+H).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([SH:8])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][C:32]=1[Cl:41])=[O:29].O>CN(C=O)C>[Cl:41][C:32]1[CH:33]=[C:34]([S:37](=[O:40])(=[O:39])[NH2:38])[CH:35]=[CH:36][C:31]=1[NH:30][C:28](=[O:29])[CH2:27][S:8][C:5]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:3]([CH2:2][F:1])=[N:7][N:6]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Reactant: Cc1ccc(-n2c(S)nnc2CF)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2c(CF)nnc2SCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
In a solution of 5-fluoromethyl-4-(4-methyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (89 mg, 0.33 mmol), K2CO3 (50.0 mg, 0.36 mmol) in DMF (2.0 mL) was added 2-chloro-N-(2-chloro-4-sulfamoyl-phenyl)-acetamide (93 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (2.0 mL) was added to the reaction and stirred til precipitation occurred and filtered to give solid (126.8 mg, 74% yield). 1H NMR (DMSO, 300 MHz) δ 10.12 (broad s, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.04 (dd, J=4.8, 8.7 Hz), 7.87 (s, 1H), 7.76-7.52 (m, 5H), 7.46 (s, 2H), 7.11 (d, J=8.7 Hz, 1H), 5.35 (dd, J=12.3, 26.7 Hz, 1H), 5.19 (dd, J=11.7, 25.8 Hz, 1H), 4.26 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:22].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]([CH3:22])[C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1C(=O)c2ccccc2N(C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (0.10 g, 0.36 mmol) and iodomethane (0.50 mL, 8.0 mmol) in DMF (4 mL ) was added NaH (60% in mineral oil, 20 mg, 0.50 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc (2×15 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using a 10% mixture of EtOAc and hexane as solvents afforded 90 mg (86%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2,3-trimethyl-4-quinolinone as a colorless oil. The oil (90 mg, 0.32 mmol) was treated with NaBH4 (50 mg, 1.3 mmol) in methanol (5 mL ) for 1 h and the reaction mixture was concentrated. Filtration from the inorganic material through a silica gel pad provided a colorless oil, which was then subjected to hydrogenation over 10% Pd/C (10 mg) in EtOAc (5 mL ) under a hydrogen balloon for 15 h. Filtration from the catalyst through a Celite™ pad followed by removal of solvent gave 70 mg (82%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil. The crude oil (70 mg, 0.26 mmol) was treated with TFA (0.50 mL, 6.5 mmol) in CH2Cl2 for 30 min. and was quenched with 5% NaOH (6 mL). The mixture was extracted with EtOAc (2×15 mL) and was concentrated. Chromatography on silica gel using a 10% mixture of EtOAc and hexane afforded 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil (40 mg, 89%). Data for 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.00-6.91 (m, 2H), 6.60 (t,J=7.3, 1H), 6.45 (d,J=7.3, 1H), 3.61 (br s, 1H), 2.74 (dd,J=16.6, 5.3, 1H), 2.47 (dd,J=16.6, 10.3, 1 H), 1.82 (m, 1H), 1.20 (s, 3H), 1.05 (s, 3H), 0.97 (d,J=7.2, 3H).
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]=1.[N+:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[N:3]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: CCOC(=O)Cn1c(Cl)nc2cccnc21
Reactant: Nc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)Cn1c(Nc2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 150 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A mixture of ethyl (2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)acetate (2.8 g) and 4-nitroaniline (1.6 g) was stirred at 150° C. for 1 h to give the title compound (4.0 g).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:3]1[CH2:17][CH2:18][C:19](O)=[O:20].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C1COCC1.C(Cl)Cl>[O:1]=[C:2]1[O:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@H:3]1[CH2:17][CH2:18][CH:19]=[O:20]
Reactant: O=C(O)CC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=CCC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.4 %

Procedure:
A solution of 27 g (92.7 mmol) of the crude acid (43c) in 200 mL of THF is cooled to 0° C. and 13 mL (10.7 g, 141 mmol) of borane-methyl sulfide complex is added dropwise via an addition funnel. The reaction is allowed to warm gradually to room temperature and stirred for 12 h. The resulting mixture is concentrated in vacuo to give a white glassy material which is taken up in 500 mL of methylene chloride and treated with of pyridinium chlorochromate (61 g, 281 mmol) at 0° C. in the presence of 3 -- molecular sieve. The mixture is allowed to warm to room temperature and stirred for 3 h. The mixture is filtered through diatomaceous earth with ether (200 mL) then concentrated. The residue is taken up in ether and filtered again through diatomaceous earth with ether then concentrated to give 13.22 g of the crude aldehyde as a light green oil: NMR δ9.80 (br s, 1H), 7.40 (m, 5H), 5.55 (br s, 1H), 5.20 (m, 3H), 4.38 (t, J=6.0 Hz, 1H), 2.6-2.1 (m, 4H).
Reaction SMILES: [Cl:1]C1C(F)=CN=C(C)C=1.[Cl:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[CH:12]=1>>[Cl:1][C:12]1[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][CH:15]=[C:16]([F:17])[C:11]=1[Cl:10]
Reactant: CCCc1cc(Cl)c(F)cn1
Reactant: Cc1cc(Cl)c(F)cn1
Product: CCCc1ncc(F)c(Cl)c1Cl

Procedure:
By following the procedures described in Example 67 and replacing 4-chloro-5-fluoro-2-picoline (the product of Example 66) with 4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70), the title compound can be prepared.
Reaction SMILES: C(O)(C)C.[Cl:5][C:6]1[N:7]=[C:8]([N+:17]([O-:19])=[O:18])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:11]=1Cl.[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][NH:23][C:24]([CH3:30])=[CH:25][C:26]([O:28][CH3:29])=[O:27]>C(N(CC)CC)C>[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][NH:23][C:24]([CH3:30])=[C:25]([C:11]1[C:6]([Cl:5])=[N:7][C:8]([N+:17]([O-:19])=[O:18])=[C:9]([NH:13][C:14]([CH3:15])=[O:16])[N:10]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C=C(C)NCC(O)CO
Reactant: CC(=O)Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)NCC(O)CO)c1nc(NC(C)=O)c([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 50 ml isopropanol is added 2.0 g (0.008 m) N-(5,6-dichloro-3-nitropyrazinyl)acetamide (8), 1.32 g (0.007 m) methyl 3-(2,3-dihydroxypropyl) amino-2-butenoate (3), and 0.81 g (0.008 m) triethylamine. This dark solution is stirred at room temperature for five days. The solvents are then removed on the rotary evaporator and the residue is chromatographed on silica gel and is eluted with 8% methanol/chloroform. Material with Rf =0.5 is collected. This material is a reddish brown solid and is further purified by high pressure liquid chromatography to afford 9 as a brown solid, m.p. 70°-73°.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:3][CH:2]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:15][C:1]1[CH:2]=[CH:3][C:4]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[CH:5][CH:6]=1
Reactant: CCOP(=O)(OCC)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)c1ccc(CBr)cc1
Temperature: 10 °C

Procedure:
To the suspension of diethyl p-tolylphosphonate (0.73 g, 3.2 mmol) was added a small amount of azobisisobutyronitrile (0.016 g, 0.1 mmol, in portions) and N-bromosuccinimide (0.57 g, 3.2 mmol) in anhydrous CCl4 (30 mL). The mixture was refluxed for 4 h, then cooled to 10° C. and filtered to remove succinimide. The filtrate was washed with water (30 mL) and brine (30 mL) and then dried over anhydrous Na2SO4. After filtration, the crude product was obtained via evaporation of solvent and purified by chromatography on silica gel (hexene/ethyl acetate: 2/l as eluent) to provide diethyl 4-(bromomethyl)phenylphosphonate as a colorless oil. 1H NMR (500 MHz, CD3Cl): δ 7.79-7.83 (m, 2H), 7.50-7.52 (m, 2H), 4.51 (s, 2H), 4.09-4.18 (m, 4H), 1.33-1.36 (t, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:24]Cl>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:24][C:23]2[CH:26]=[CH:27][C:28]([F:29])=[C:21]([F:20])[CH:22]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: Fc1ccc(CCl)cc1F
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(Cc3ccc(F)c(F)c3)n2)ccc1F
Yield: 66.7 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3,4-difluorobenzyl chloride were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1(7) to yield the title compound as a pale yellow solid (66.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[S:14])[S:10][CH:11]=1)=[O:5])[CH3:2].[CH2:33](O)[CH3:34].O1CCOCC1.Cl>O>[CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([O:31][CH2:33][CH3:34])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[S:14])[S:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=S)Nc2ccccc2)n1
Reactant: CCO
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CN1C(=O)C(=C(C(=O)OCC)c2csc(NC(=S)Nc3ccccc3)n2)SC1=S
Reaction time: 108 h

Procedure:
A mixture comprising 10 g of 5-{1-ethoxycarbonyl-1-[2-(3-phenylthioureido)thiazol-4-yl]methylene}rhodanine-3acetic acid 20 g of ethanol and 150 ml of a 4N dioxane solution of hydrogen chloride was left to stand at room temperature for 4.5 days. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and then with aqueous sodium chloride solution, and was then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography, using as eluent a 1:1 by volume mixture of hexane and ethyl acetate. The resulting crystalline product was recrystallised from a 1:5 by volume mixture of hexane and ethyl acetate, giving a yellow powder having the following physical properties.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:22]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(C=O)c1
Yield: 87.4 %

Procedure:
(E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (3.0 g, 10.52 mmol), 3-hydroxybenzaldehyde (1.41 g, 1.1 eq) and potassium carbonate (3.0 g, 3.0 eq) were together refluxed for 15 hours in acetonitrile (CH3CN, 30 mL)/H2O (5 mL). Concentration at a reduced pressure removed the reaction solvent. The residue was stirred in water (50 mL) and the aqueous layer was extracted twice with 50 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to remove the solvent. The concentrate was purified by silica gel chromatography to give (E)-methyl 2-(2((3-formylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (3.0 g, yield 87%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:10]([CH3:12])[CH3:11])[CH2:7][NH:6]1)=O.[NH3:13]>CO>[CH3:11][N:10]([CH3:12])[C@H:8]1[CH2:7][NH:6][C@H:5]([C:3]([NH2:13])=[O:2])[CH2:9]1
Reactant: N
Reactant: COC(=O)[C@@H]1C[C@@H](N(C)C)CN1
Solvent: CO
Product: CN(C)[C@H]1CN[C@H](C(N)=O)C1

Procedure:
A solution of (2S,4R)-4-dimethylamino-pyrrolidine-2-carboxylic acid methyl ester (Stage B.1, 225 mg) and 7 M ammonia in MeOH (7 mL) was stood for 18 h at it in a sealed vessel. Evaporation and trituration with Et2O gave the title compound as a white solid.
Reaction SMILES: CC1(C)C[O:36][C:5]2([CH2:9][C@@H:8]([CH2:10][C@H:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:12](N([C@H](C)[C@H](O)C3C=CC=CC=3)C)=[O:13])[CH2:7][CH2:6]2)OC1.S(=O)(=O)(O)[OH:40]>O1CCOCC1.O>[O:36]=[C:5]1[CH2:6][CH2:7][C@H:8]([CH2:10][C@H:11]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:12]([OH:40])=[O:13])[CH2:9]1
Reactant: O=S(=O)(O)O
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](C[C@H]1CCC2(C1)OCC(C)(C)CO2)c1cccc(C(F)(F)F)c1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Temperature: 110 °C
Yield: 73 %

Procedure:
A solution of (R)-3-((R)-8,8-dimethyl-6,10-dioxa-spiro[4.5]dec-2-yl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-trifluoromethyl-phenyl)-propionamide (250 mg, 0.47 mmol) in dioxane (2.5 mL) was treated with a 9 N aqueous sulfuric acid solution (1.5 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (50 mL) and extracted with a chloroform/methanol solution (3:2, 2×25 mL) and then concentrated. The resulting residue was then dissolved in acetonitrile and concentrated with silica gel (2 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 60% ethyl acetate/hexanes) to afford (R)-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (102 mg, 73%) as a pale yellow oil: [α]22589=−86.1° (c=0.18, methanol); ES-HRMS m/e calcd for C15H15O3F3 (M+Na)+ 323.0865, observed 323.0865; 1H NMR (400 MHz, CDCl3) δ 1.55 (m, 1H, CH), 1.82-2.47 (m, 8H, 4×CH2), 3.73 (t, J=7.8 Hz, 1H, ArCHCO), 7.47-7.61 (m, 4H, Ar).
Reaction SMILES: [C:1]([CH:3]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=1)C(OC)=O)#[N:2].[Cl-].[Na+]>CS(C)=O.O>[Cl:14][C:13]1[C:8]([CH2:3][C:1]#[N:2])=[N:9][CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: COC(=O)C(C#N)c1ncc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ncc(Cl)cc1Cl
Temperature: 130 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
Methyl 2-cyano-2-(3,5-dichloropyridin-2-yl)acetate (120 mg, 0.490 mmol) was diluted with DMSO (1 mL) and water (40 uL) followed by the addition of sodium chloride (14.3 mg, 0.245 mmol). The reaction was heated to 130° C. and stirred for 3 hours. The reaction was allowed to cool, loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to yield the desired compound (70 mg, 0.374 mmol, 76.4% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].I[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:31][CH:30]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: ICCCc1ccc(CCCCCOc2ccccc2)cc1
Product: COC(=O)c1ccc(OCCCc2ccc(CCCCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 1-(3-iodopropyl)-4-(5-phenoxypentyl)benzene.