Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:28])=O>>[CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([Cl:28])=[O:25])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
After 4'-n-decyl-4-carboxybiphenyl (3.10 g) was heated under reflux for 6 hours together with an excessive amount of thionyl chloride, unaltered thionyl chloride was removed by distillation to give about 3 g of 4'-n-decylbiphenyl-4-carboxylic acid chloride.
Reaction SMILES: C[O-].[Na+].[C:4]([O:10][CH3:11])(=[O:9])/[CH:5]=[CH:6]\[CH2:7][CH3:8].[C:12](OC)(=[O:17])/C=C/CC>CO>[CH3:12][O:17][CH:6]([CH2:7][CH3:8])[CH2:5][C:4]([O:10][CH3:11])=[O:9]
Reactant: CC/C=C/C(=O)OC
Reactant: CC/C=C\C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC(=O)OC)OC
Temperature: 65 °C
Reaction time: 4 h
Yield: 2998.3 %

Procedure:
A solution of 5.4 g of sodium methylate in 64 g of methanol was added to a mixture of 192 g of methyl cis trans-3-pentenoate, 4 g of methyl 2-cis-pentenoate and 28 g of methyl 2-trans-pentenoate, and the mixture was heated to 65° C. and stirred for four hours at this temperature. After the working up procedure described in Example 1, 153.6 g (53% of theory) of methyl 3-methoxyvalerate were obtained.
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[C:12]2[N:8]([CH:9]=[CH:10][CH:11]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[C:20]=1[Cl:32]>C1COCC1>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]2([C:27]([F:30])([F:29])[F:28])[O:1][N:2]=[C:3]([C:4]3[C:12]4[N:8]([CH:9]=[CH:10][CH:11]=4)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=3)[CH2:26]2)[CH:22]=[C:21]([Cl:31])[C:20]=1[Cl:32]
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(/C=N/O)c2cccn12
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2cccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
A solution of crude (E)-ethyl 8-((hydroxyimino)methyl)indolizine-5-carboxylate (1.15 mmol) in THF (20 mL) was added slowly to a stirred solution of DIB (528 mg, 1.64 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (452 mg, 1.64 mmol) in THF (10 mL) at rt. The mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and then Combiflash to give ethyl 8-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylate (130 mg; yield 22% over 2 steps). MS: m/z=506.7 (M+1, ESI+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:12][C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19]([S:21][C:22]3[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=3)[NH:18][C:17]=2[C:29]=1[F:30].[C:31]1(=O)[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:27]([C:25]3[O:26][C:22]([S:21][C:19]4[NH:18][C:17]5[C:29]([F:30])=[C:13]([F:12])[CH:14]=[CH:15][C:16]=5[N:20]=4)=[CH:23][CH:24]=3)[C:32]3[C:33](=[O:37])[CH2:34][CH2:35][CH2:36][C:31]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1ccc(Sc2nc3ccc(F)c(F)c3[nH]2)o1
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3ccc(F)c(F)c3[nH]2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.9 %

Procedure:
A suspension of 148.5 mg (0.96 mmol) of 3-amino-2-ethoxycarbonylpyrrole and 269.9 mg (0.96 mmol) of 5-(6,7-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (obtained from step 2) in 10 mL of n-butanol under argon is stirred at room temperature for 20 minutes. 1,3-Cyclohexanedione (108.0 mg, 0.96 mmol) is then added and the reaction mixture is heated at reflux temperature for 2 h. The mixture is then cooled to room temperature and concentrated under reduced pressure. The residue is taken up in ethanol, cooled to 0° C., triturated, filtered and washed 3 times with ethanol. 127 mg of 9-[5-(6,7-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester are obtained as a light-yellow crystalline powder. mp: 144-148° C. LCMS-DAD-ELSD: 509(−): [M−H]−; 511 (+): [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2O[C:9]([CH3:15])=[C:10](CC#N)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:16].[Na+].Cl.CC[O:21][C:22]([CH3:24])=[O:23]>CCO.O>[CH:1]1([C:7]2[O:16][C:9]([CH3:15])=[C:10]([CH2:24][C:22]([OH:21])=[O:23])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(C2CCCCC2)nc1CC#N
Reactant: CCOC(C)=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1oc(C2CCCCC2)nc1CC(=O)O

Procedure:
1.900 g of the above prepared (2-cyclohexyl-5-methyl-oxazol-4-yl)-acetonitrile (9.30 mmol) was dissolved in 21 ml EtOH/water=1/1 and treated with 5 eq. of NaOH-pellets (1.86 g). Hydrolysis was allowed to proceed over night at 60° C. After cooling, 25% HCl was added, followed by AcOEt. After separation of the two layers, the aq. phase was again extracted with AcOEt, the combined organic layers washed with water, dried over sodium sulfate, and evaporated to dryness to yield 1.920 g of the title acid as light-brown, waxy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[S:23]1[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([C:25]2[CH:26]=[CH:27][S:23][CH:24]=2)=[O:29])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccsc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 31 h
Yield: 55.4 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) and commercially available 3-thiophenecarboxylic acid (44 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (82 mg) was added, and the admixture was stirred at room temperature for 31 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 41 mg of the title compound (yield: 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([Cl:19])=[C:6]([O:8][C:9]2[C:14]([F:15])=[C:13]([CH2:16]Br)[CH:12]=[CH:11][C:10]=2[Cl:18])[CH:7]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CS(C)=O.CCOC(C)=O>[N:21]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([Cl:18])=[C:9]([O:8][C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:20])[C:5]=2[Cl:19])[C:14]=1[F:15])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cc(Br)cc(Oc2c(Cl)ccc(CBr)c2F)c1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.3 %

Procedure:
2-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-(bromomethyl)-1-chloro-3-fluorobenzene (10.04 g, 22.47 mmol) and sodium azide (1.461 g, 22.47 mmol) were combined in DMSO (50 mL) and stirred 3 days at 25° C. The reaction mixture was diluted with EtOAc, washed 4× with water, dried over MgSO4, filtered and concentrated to dryness to give 1-(azidomethyl)-3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorobenzene (8.3 g, 20.29 mmol, 90% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49-7.66 (m, 3H), 6.80 (s, 1H), 4.61 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH3:22][C@H:23]1[CH2:28][NH:27][CH2:26][C@@H:25]([CH3:29])[NH:24]1>CN(C)C=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH2:26][C@H:25]([CH3:29])[NH:24][C@H:23]([CH3:22])[CH2:28]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In the same manner as described in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, cis-2,6-dimethylpiperazine, and dimethylformamide was stirred at room temperature for 24 hours to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 258°-260° C.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][CH:11](C3C=CC=CC=3C)[N:10]2[CH3:21])=[CH:5][C:4]=1[S:23](=[O:32])(=[O:31])[N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27].[C:33](O)(=O)[CH3:34]>>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:21])[C:11](=[N:10][C:9]3[CH:6]=[CH:5][CH:4]=[CH:3][C:33]=3[CH3:34])[S:12][CH:13]=2)=[CH:5][C:4]=1[S:23](=[O:31])(=[O:32])[N:24]([CH2:25][CH2:26][CH3:27])[CH2:28][CH2:29][CH3:30]
Reactant: CC(=O)O
Reactant: CCCN(CCC)S(=O)(=O)c1cc(C2(O)CSC(c3ccccc3C)N2C)ccc1Cl
Agent: Br
Product: CCCN(CCC)S(=O)(=O)c1cc(-c2csc(=Nc3ccccc3C)n2C)ccc1Cl

Procedure:
Obtained by a procedure analogous to that indicated in Example 1(b), from 4-(4-chloro-3-dipropylsulfamoylphenyl)-3-methyl-2-(2-methylphenyl)-thiazolidin-4-ol hydrobromide, by boiling in glacial acetic acid for 2 hours. The reaction mixture is concentrated, water is added to the residue and the crystals are filtered off. Melting point 218°-220° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:22][C:23]2[CH:27]=[C:26]([C:28]3[S:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[O:25][N:24]=2)[CH:7]=[C:8]([C:10](=[O:21])[NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:9]=1)=[O:4].C(O)(C(F)(F)F)=O>C1COCC1.O>[Cl:33][C:30]1[S:29][C:28]([C:26]2[O:25][N:24]=[C:23]([CH2:22][N:6]3[CH:7]=[C:8]([C:10](=[O:21])[NH:11][CH:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)[CH:9]=[C:5]3[C:3]([OH:4])=[O:2])[CH:27]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1cc(C(=O)NC2CCN(C(C)C)CC2)cn1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCC(NC(=O)c2cc(C(=O)O)n(Cc3cc(-c4ccc(Cl)s4)on3)c2)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a solution of 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid methyl ester (example 16, 60 mg) in 15 mL of THF/water(3:1) was added LiOH monohydrate (50 mg) The mixture was stirred for 2 h at 45° C. whereupon it was cooled to RT, acidified with TFA and concentrated. 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid (33 mg) was obtained after HPLC purification (CH3CN/H2O gradient+0.05% TFA) of the crude product. MS (ESI+): m/e=477 [M+H]+, chloro pattern.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[CH:16][N:15]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14]=2[CH:31]=1)=[O:8])([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[CH:16][N:15]([CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14]=2[CH:31]=1)=[O:8]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3cccc([N+](=O)[O-])c3)cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3cccc(N)c3)cc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-{6-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (231 mg, 504 μmol) in a mixture of ethanol and water (4:1, 10 mL), was added palladium on carbon (46 mg, 10% w/w Pd) and ammonium formate (191 mg, 3.03 mmol). The suspension was heated to reflux for 3 hours, and was then cooled to room temperature, and filtered through a pad of Celite®. The filtrate was evaporated in vacuo to afford the title compound, 1H NMR: (CD3OD), 8.43 (s, 1H), 8.14 (d, J=1.46, 1H), 7.65 (d, J=8.79, 1H), 7.47 (dd, J=8.79, 1.83, 1H), 7.30 (br, 8H), 6.92-6.90 (m, 1H), 6.11 (dd, J=9.52, 6.22, 1H), 4.04 (q, J=7.32, 2H), 3.62 (dd, J=16.11, 9.52, 1H), 3.46 (dd, J=16.11, 6.22, 1H), 1.08 (t, J=7.32, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1.Cl.[CH2:21]([NH:23][CH2:24]/[CH:25]=[CH:26]/[C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][C:29]([CH3:31])([CH3:32])[C:28]#[C:27]/[CH:26]=[CH:25]/[CH2:24][N:23]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH:4]=1)[CH2:21][CH3:22]
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)c1
Reactant: CCNC/C=C/C#CC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(N2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
6.0 g of N-(3-bromomethylphenyl)phthalimide [synthesized by brominating N-(m-tolyl)phthalimide with N-bromosuccinimide in carbon tetrachloride] was dissolved in 100 ml of dimethylformamide, and 3.82 g of (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 7.87 g of potassium carbonate were added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate-water and the organic layer was separated, and the solvent was evaporated, and then the residue was washed with a small amount of ethyl ether to give 5.5 g (yield 72%) of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-phthalimidobenzylamine, m.p. 96°-98 ° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:33])([F:32])[F:31])[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=3)[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37]>C(Cl)(Cl)Cl.O>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:33])([F:32])[F:31])[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH:37][CH2:36][C:35]([F:39])([F:38])[F:34])=[O:26])=[CH:23][CH:22]=3)[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: O=C(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Reactant: NCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(NCC(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Yield: 73.9 %

Procedure:
In a solution of 0.29 g of 2,2,2-trifluoroethylamine and 0.37 g of triethylamine in 20 ml of chloroform, 1.81 g of the crude 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] benzoic acid chloride dissolved in 10 ml of chloroform was added dropwise with cooling with ice and with stirring. After the completion of addition dropwise, the mixture was continued to stir at room temperature further for 30 minutes. After the completion of the reaction, the reaction mixture was poured in 100 ml of water, and extracted with chloroform (20 ml×3), the organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and passed through a glass filter packed with silica gel, and then the solvent was distilled off under reduced pressure. The residual solid was washed with hexane to obtain 1.05 g of the aimed product as white crystal.
Reaction SMILES: N1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2N=N1.S(Cl)(Cl)=O.[OH:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:16]=1[C:17]([OH:19])=O.[CH2:28]([N:30](CC)[CH2:31]C)[CH3:29]>C1COCC1.C(Cl)Cl.C1COCC1>[OH:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:16]=1[C:17]([N:30]1[CH2:28][CH2:29][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:31]1)=[O:19]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: c1ccc2[nH]nnc2c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(O)c(C(=O)N2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 1H-benzotriazole (9.11 g, 76.5 mmol) in mixed solvents (CH2Cl2/THF; 50 mL/50 mL) at room temperature was added thionylchloride (3.03 g, 25.5 mmol). After stirring for 30 min at room temperature, the mixture was treated with a solution of 2-hydroxy-5-(methoxycarbonyl)benzoic acid (5.0 g, 25.48 mmol) in THF (20 mL THF). The formation of a white precipitate was observed and the mixture was stirred for additional 1 h. The precipitate was allowed to settle and the supernatant was added to a mixture of 1,2,3,4-tetahydroisoquinoline (5.1 g, 38.3 mmol) and triethylamine (5.5 mL, 38.2 mmol) in THF (10 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrate in vacuo, and the resulting crude compound was dissolved in EtOAc, washed with water, followed by 1N HCl and then brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give crude product. The crude material was purified by flash chromatography (gradient from 0% to 30% EtOAc/hexanes) to provide the title compound (5.0 g, 63%). 1H NMR (DMSO-d6, 3:1 mixture of amide rotamers) δ 10.84 (s, 1H), 7.88 (dd, J=8.8, 2.4 Hz, 1H), 7.75 (br s, 1H), 7.30-7.15 (m, 3.5H), 7.01 (d, J=8.4 Hz, 1.5H), 4.78 (br s, 1.5H), 4.41 (br s, 0.5H), 3.85-3.84 (m, 0.5H), 3.80 (s, 3H), 3.44 (br s, 1.5H), 2.86-2.80 (m, 2H); MS(ESI+) m/z 312.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([C:20]#[CH:21])=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.I[C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:19]([C:20]#[C:21][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:18][C:5]([C:6]([N:8]=[S:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Reactant: Oc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=NC(=O)c1cnc(N)c(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of (S)-6-amino-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (60 mg, 0.2 mmol), 3-iodophenol (66 mg, 0.3 mmol), triethylamine (0.07 mL, 0.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02 mmol), triphenylphosphine (1.3 mg, 0.005 mmol) in 1.8 mL DMF at room temperature was degassed using a H2/N2 (1:1) mixture and then copper(I) iodide (2 mg, 0.01 mmol) added. The reaction was heated at 60° C. for 15 minutes and then partitioned between EtOAc and saturated NaHCO3. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to a brown oil. Before chromatography a different lot of product (23 mg) was added and the combined lots were purified by chromatography (silica gel, EtOAc/EtOH) to the title compound as an off-white solid (91 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CN(C1C=CC=CN=1)C>ClCCl>[Cl:1][C:2]1[C:7]([N:8]([CH3:9])[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CN(C)c1cccc(CO)c1Cl
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cccc(COS(C)(=O)=O)c1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(2-Chloro-3-dimethylamino-phenyl)-methanol (0.50 g, 2.69 mmol) was placed in a round bottomed flask with dichloromethane (10 mL) and cooled to 0° C. Triethylamine (0.68 g, 6.73 mmol), methanesulfonylchloride (0.23 mL, 2.97 mmol), and dimethylaminopyridine (0.02 g) were added and the reaction was allowed to warm and stir at rt over 3 h. The reaction was diluted with dichloromethane (20 mL) and washed with 1N Hydrochloric acid (10 mL), 10% aqueous sodium bicarbonate (10 mL), and water (10 mL). The organics were dried (MgSO4) and concentrated to afford methanesulfonic acid 2-chloro-3-dimethylamino-benzyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][CH2:17][CH3:18])([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]S(O)(=O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][CH2:17][CH3:18])([C:14]([NH2:15])=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CCNC1(C#N)CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CCNC1(C(N)=O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 1-benzyl-4-ethylaminopiperidine-4-carbonitrile I-1A-1e (0.58 g, 2.38 mmol) in methylene chloride (2 ml) cooled in an ice bath was treated with H2SO4 (1.8 ml, 33 mmol), dropwise, while keeping the internal temperature below 20° C. The reaction was then warmed to room temperature and stirred for 19 hours. After stirring was discontinued, the thick pale orange H2SO4 bottom layer was separated, cooled in an ice bath and then carefully quenched with concentrated NH4OH keeping internal temperature below 55° C. The aqueous layer was extracted with methylene chloride (2×10 ml), the combined organic layers were washed with brine (20 ml), dried (Na2SO4), and then concentrated, in vacuo, to afford I-1A-1f as a pale orange oil that solidified to a peach colored solid upon standing (0.54 g, 87%): +APcI MS (M+1) 262.2; 1H NMR (400 MHz, CD2Cl2) δ 7.34–7.30 (m, 4H), 7.29–7.21 (m, 1H), 7.16 (br s, 1H), 3.48 (s, 2H), 2.71–2.68 (m, 2H), 2.47 (q, J=7.0 Hz, 2H), 2.17–2.02 (m, 4H), 1.62–1.58 (m, 2H), 1.41 (br s, 1H), 1.09 (t, J=7.0 Hz, 3H).
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C1OCCOCCOCCOCCOCCOC1.I[CH2:39][CH2:40][CH2:41][OH:42]>C(#N)C>[OH:42][CH2:41][CH2:40][CH2:39][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: OCCCI
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(OCCCO)cc2)cc1
Temperature: 25 °C

Procedure:
The potassium salt of 4-hydroxy-4'-nitrostilbene from Example 4 (280 g, 1 m), acetonitrile (2 liters) and the catalyst 18-Crown-6 (1 g) were charged into a 4 liter 3 necked flask equipped with a reflux condenser, mechanical stirrer, a heating mantle, and an addition funnel, and provided with argon atmosphere. The mixture was kept gently refluxing and stirring, while 3-iodopropan-1-ol (223 g, 1.2 m) was added dropwise over a period of about 3 hours. The reaction mixture was refluxed for about 24 hours. About a liter of the solvent was then distilled off at atmospheric pressure, and the reaction mixture was allowed to cool to ambient temperature. The yellow solid was filtered, dried, and recrystallized from toluene to yield yellow crystals of compound of Formula 28. Yield 210 g (70%).