Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].C(O)(=O)C.[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([F:22])[CH:15]=1)(=[O:12])[CH3:11]>O.C(O)C>[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:1][NH:2][C:3]([NH2:5])=[S:4])=[C:16]([F:22])[CH:15]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(C=O)c(F)c1
Reactant: NNC(N)=S
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C=NNC(N)=S)c(F)c1
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
A solution of 0.182 g (0.002 mole) of thiosemicarbazide (Aldrich T3,340-5) in 6 mL of water containing 0.4 mL of acetic acid was added to a solution of 0.36 g (0.002 mole) 4-acetamido-3-fluorobenzaldehyde (20) in 5 mL of ethanol at 70°. The mixture was stirred at this temperature for 30 minutes. A white precipitate developed in the reaction mixture, which was filtered after cooling down to give 0.22 g (44% crude) of white powder which was recrystallized from methanol and dried, yielding 0.12 g (24%) of 17 as white crystals, mp 232-235° (dec.). Infrared (IR) and NMR analysis gave the following results:
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8](I)[C:7]([C:22]#[N:23])=[C:6]([Cl:24])[CH:5]=1)(=[O:3])[CH3:2].[CH3:25][C:26]1(C)C(C)(C)OB(C=C)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([CH:25]=[CH2:26])[C:7]([C:22]#[N:23])=[C:6]([Cl:24])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C#N)c(I)c1OCCNC(=O)OC(C)(C)C
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1c(C#N)c(Cl)cc(C(C)=O)c1OCCNC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of tert-butyl [2-(6-acetyl-4-chloro-3-cyano-2-iodophenoxy)ethyl]carbamate (3.3 g, 7.1 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.81 mL, 10.6 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.3 g, 0.4 mmol) and potassium carbonate (2.9 g, 21 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was degassed with nitrogen. The resulting mixture was heated at 80° C. for 1 h. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The product was purified by FCC on silica gel using ethyl acetate in hexane (0-40%) to give the desired compound tert-butyl [2-(6-acetyl-4-chloro-3-cyano-2-vinylphenoxy)ethyl]carbamate as a crystalline solid (2.2 g. 85%). LCMS calculated for C18H21ClIN2O4Na (M+Na)+: m/z=387.1; found: 387.0.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=[C:2]([OH:1])[C@@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@@H:9]([OH:10])[C:11](=[CH:17][C:16]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:14]([Cl:13])[CH:15]=1)[OH:12]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: OC(=Cc1ccc(Cl)c(Cl)c1)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccc(Cl)c(Cl)c1

Procedure:
Bis(3,4-dichlorobenzylidene)sorbitol was prepared from aqueous sorbitol and 3,4-dichlorobenzaldehyde according to the method of Example 1. The melting point of the product was 270° C.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:24])[CH:13]1[CH:9]([CH2:10][CH:11]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=4)[N:29]=[C:28]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:27]=3)[CH2:12]1)[C:8](=[O:44])[NH:7]2)=[O:5])C.CO.Cl>O1CCCC1.O>[CH3:37][O:36][C:32]1[CH:31]=[C:30]2[C:35]([C:26]([O:25][CH:11]3[CH2:10][CH:9]4[CH:13]([C:14](=[O:24])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:44])[CH2:23]5)[CH2:12]3)=[CH:27][C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:29]2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)C12CC1C=CCCCCNC(=O)C1CC(Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)CC1C(=O)N2
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc2c(OC3CC4C(=O)NCCCCC=CC5CC5(C(=O)O)NC(=O)C4C3)cc(-c3ccccc3)nc2c1
Temperature: 65 °C
Yield: 71.8 %

Procedure:
Compound 92 (95 mg, 0.159 mmol) was dissolved in tetrahydrofuran (10 ml), methanol (5 ml) and water (4 ml) Lithium hydroxide (40 mg, 1.67 mmol) was dissolved in water (1 ml) and added. The reaction mixture was heated to 65° C. After 3 h the reaction mixture was cooled, acidified with aqueous HCl (pH=5), evaporated on silica and purified by silica gel chromatography (10% MeOH in dichloromethane→15% MeOH in dichloromethane) to give the pure title product (65 mg, 72%). MS (M+H+): 569.8
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:22][NH2:23]>>[CH2:13]([C:12]1[C:6]2[C:7](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:8](=[O:9])[NH:23][N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)Cc2ccccc2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(Cc3ccccc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-(phenylacetyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.COC(=O)C(C)(C)CC1N(CC2C=CC(Cl)=CC=2)C2C(C=1SC(C)(C)C)=CC(OC)=CC=2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: COC(=O)C(C)(C)Cc1[nH]c2cc(OCc3ccc4ccccc4n3)ccc2c1Cc1ccc(Cl)cc1
Agent: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Product: CC(C)(Cc1[nH]c2cc(OCc3ccc4ccccc4n3)ccc2c1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared using the conditions described in Step B of Example 1, but substituting the ester from Step D for the ester of Example 1, Step A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:12][C:13]=2[C:14]([O:16]CC)=O)=[CH:5][CH:4]=1.[NH3:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:12][C:13]=2[C:14]([NH2:25])=[O:16])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)nc1-c1ccc(OC)cc1
Reactant: N
Product: COc1ccc(-c2nc(-c3ccccc3)[nH]c2C(N)=O)cc1
Temperature: 150 °C
Yield: 16 %

Procedure:
A suspension of ethyl 4-(4-methoxyphenyl)-2-phenyl-1H-imidazole-5-carboxylate (0.078 g, 0.23 mmol) in aqueous (28%) ammonia (4.5 ml) was heated in the microwave for 35 minutes at 150° C. The solvent was then removed in vacuo and the residue was purified by preparative HPLC to afford 4-(4-methoxyphenyl)-2-phenyl-1H-imidazole-5-carboxamide (0.0109 g, 0.04 mmol, 16%) as a white solid. 1H NMR (DMSO) δ 3.82 (3H, s), 7.01 (2H, d), 7.10 (1H, br. s), 7.39-7.43 (2H, m), 7.49 (2H, dd), 7.85 (2H, d), 8.10 (2H, m). LCMS (2) Rt: 2.46 min; m/z (ES+) 294.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25](C2C=CC=C(C3N4C=CC(C(O)(C)C)=NC4=NC=3)N=2)=[C:26]([CH:29]=1)[C:27]#[N:28]>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[C:26]([CH:29]=1)[C:27]#[N:28]
Reactant: FC(F)(F)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Reactant: CC(C)(O)c1ccn2c(-c3cccc(-c4ccc(F)cc4C#N)n3)cnc2n1
Product: N#Cc1cc(F)ccc1-c1nccc(-c2cnc3nc(C(F)(F)F)ccn23)n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled to 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (synthesised as in Example 22) by the method of Example 1 to afford 5-fluoro-2-{4-[7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}benzonitrile as a white solid: δH (400 MHz, CDCl3) 7.48-7.53 (2H, m), 7.63 (1H, dd, J 2.5, 8.0), 7.78 (1H, d, J 5.5), 8.39 (1H, dd, J 5.5, 9.0), 8.74 (1H, s), 8.95 (1H, d, J 5.5), 10.67 (1H, d, J 6.7); m/z (ES+) 385 (M++H).
Reaction SMILES: [OH:1][C:2]1[C:7](C(C)(C)C)=[CH:6][C:5]([C:12](C)(C)C)=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1.OC1C(C(C)(C)C)=CC(C)=CC=1N1N=C2C=CC=CC2=N1.OC1C(C(C)(C)C)=CC(C(C)(C)C)=CC=1N1N=C2C=CC(Cl)=CC2=N1.OC1C(C(C)(C)C)=CC(C)=CC=1N1N=C2C=CC(Cl)=CC2=N1.OC1C=C(O)C=CC=1C(C1C=CC=CC=1)=O.OC1C=C(OC)C=CC=1C(C1C=CC=CC=1O)=O.OC1C=C(OC)C(S(O)(=O)=O)=CC=1C(C1C=CC=CC=1)=O.C(SC1N=C(SCCCCCCCC)N=C(NC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)N=1)CCCCCCC.OC1C(C(CC)(C)C)=CC(C(CC)(C)C)=CC=1N1N=C2C=CC(Cl)=CC2=N1.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.C(C1C=C(CCC(OCCOCCOCCOC(=O)CCC2C=C(C)C(O)=C(C(C)(C)C)C=2)=O)C=C(C)C=1O)(C)(C)C.C(C1C=C(CCC(OCCCCCCOC(=O)CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)C=C(C(C)(C)C)C=1O)(C)(C)C.CC1C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=C(C)C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=C(C)C=1CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1.CC(C1C(O)=C(C(C)(C)C)C=C(CN2C(=O)N(CC3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)C(=O)N(CC3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)C2=O)C=1)(C)C>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1
Reactant: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cc(CCC(=O)OCCCCCCOC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(Cn2c(=O)n(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)c(=O)n(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)c2=O)cc(C(C)(C)C)c1O
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
2-(2′-hydroxy-3′,5′-di-tert-butylphenyl) benzotriazol; 2-(2′-hydroxy-3′-tert-butyl-5′-methylphenyl) benzotriazol; 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)-5-chlorobenzotriazol; 2-(2′-hydroxy-3′-(3″,4″,5″,6″-tetrahydrophthalimidomethyl)-5′-methylphenyl) benzotriazol; 2,2-methylene bis (4-(1,1,3,3-tetramethylbutyl)-6-(2H-benzotriazol-2-yl) phenol); 2-(2′-hydroxy-3′-tert-butyl-5′-methylphenyl)-5-chlorobenzotriazol; 2,4-dihydroxybenzophenone; 2,2′-dihydroxy-4-methoxybenzophenone; 2-hydroxy-4-methoxy-5-sulfobenzophenone; bis(2-methoxy-4-hydroxy-5-benzoylphenylmethane); (2,4-bis-(n-octylthio)-6-(4-hydroxy-3,5-di-tert-butylanilino)-1,3,5-triazine; 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)-5-chlorobenzotriazol; 2(2′-hydroxy-3′,5′-di-tert-amylphenyl)-5-chlorobenzotriazol; 2,6-di-tert-butyl-p-cresol; pentaerythrityl-tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate]; triethyleneglycol-bis[3-(3-tert-butyl-5-methyl-4-hydroxyphenyl) propionate]; 1,6-hexanediol-bis[3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate]; 2,4-bis-(n-octylthio)-6-(4-hydroxy-3,5-di-tert-butylanilino)-1,3,5-triazine; 2,2-thio-diethylene bis[3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate]; octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate; N,N′-hexamethylene bis(3,5-di-tert-butyl-4-hydroxy-hydrocinnamide); 1,3,5-trimethyl-2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl) benzene; tris-(3,5-di-tert-butyl-4-hydroxybenzyl)-isocyanurate and the like.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCNCC
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Product: CCN(CC)c1nc2c(Cl)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and diethylamine. Brown foam. MS (ESI): 389.0 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=CC=2F)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]2[CH3:38])[CH:27]=1)=O)(C)(C)C.[C:41](O)([C:43]([F:46])(F)F)=O>C(Cl)Cl>[CH3:38][C:33]1[N:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:39])[NH:21][C:9]4[CH:10]=[C:11]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:41][C:43]=5[F:46])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:36]=[C:35]([CH3:37])[N:34]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1
Solvent: ClCCl
Product: Cc1cn(-c2cccc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)c2)c(C)n1

Procedure:
Prepared from (3-{3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K70) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (92 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccc(F)cc1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccc(F)cc1)C2
Yield: 62.4 %

Procedure:
A mixture of 7-(4-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.2 g), aminoguanidine hydrochloride (0.091 g), concentrated hydrochloric acid (0.2 ml), water (0.2 ml) and ethanol (30 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate and then recrystallized from ethanol-water to give 7-(4-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 77) (0.17 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:23]=[S:20]1(=[O:24])[CH2:21][CH2:22][N:17]([C:2]2[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH2:18][CH2:19]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(N2CCS(=O)(=O)CC2)cnc1N1CCOCC1
Temperature: 25 °C

Procedure:
A stirred solution of 4-(5-chloro-3-nitropyridin-2-yl)morpholine (500 mg, 2.05 mmol), thiomorpholine 1,1-dioxide (333 mg, 2.46 mmol), Pd2dba3 (94 mg, 0.10 mmol), X-Phos (98 mg, 0.20 mmol), sodium tert-butoxide (394 mg, 4.1 mmol) in toluene (19.7 mL, 184.7 mmol) was heated at reflux for 14 h. After this time the reaction was cooled to rt and partitioned between EtOAc (100 mL) and NaHCO3 (satd aq. solution, 50 mL). The separated organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. Column chromatography (hexanes:EtOAc, 1:0 to 1:1) gave 4-[5-(1,1-dioxidothiomorpholin-4-yl)-3-nitropyridin-2-yl]morpholine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.C(OC([N:28]1[CH2:33][CH2:32][C:31]2([CH2:38][CH2:37][C:36]3[CH:39]=[C:40]([C:43](O)=O)[CH:41]=[CH:42][C:35]=3[O:34]2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:43]([C:40]3[CH:39]=[C:36]4[C:35](=[CH:42][CH:41]=3)[O:34][C:31]3([CH2:30][CH2:29][NH:28][CH2:33][CH2:32]3)[CH2:38][CH2:37]4)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCc3cc(C(=O)O)ccc3O2)CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc5c(c4)CCC4(CCNCC4)O5)nc23)[C@H]2C=C[C@@H]1C2
Temperature: 50 °C
Yield: 79.9 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and N-tert-butoxycarbonyl-6-carboxy-3,4-dihydrospiro[2H-1-benzopyran-2,4′-piperidine] (75.4 mg, 0.228 mmol) were reacted. The crude reaction was concentrated, then taken up into 4N HCl/dioxane and heated at 50° C. for 4 hours. The reaction mixture was then concentrated and chromatographed on Gilson HPLC 0-45% CH3CN/H2O. The desired fractions were lyophilized to produce 65 mg (47%) of the title compound as the TFA salt. mp: lyophilate, 1H NMR (300 MHz, DMSO-d6): 13.19 (s, 1H), 8.59 (m, 1H), 8.42 (m, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.89 (d, 1H), 7.76 (s, 1H), 7.25 (s, 2H), 7.00 (d, J=8 Hz, 1H), 6.38 (s, 2H), 5.19 (t, J=8 Hz, 1H), 3.23 (m, 2H), 3.14 (m, 2H), 2.88 (m, 3H), 2.78 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.96-1.85 (m, 4H), 1.39 (d, J=8 Hz, 1H). MS: 551 (M+H), HPLC: 1.94 min (G method).
Reaction SMILES: C(OC(=O)C)(=[O:3])C.CCN(CC)CC.[N+:15]1([O-])[C:16](=[CH:20][CH:21]=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])C(O)=O>C(Cl)(Cl)(Cl)Cl>[OH:3][C:16]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][N:15]=1
Reactant: O=C(O)c1ccc(C(=O)O)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(O)nc1
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
20.4 g of acetic acid anhydride (0.2 mole), 20.2 g of Et3N (0.2 mole) and 50 ml of CCl4 were put up in a flask. 18.3 g of isocinchomeronic acid-N-oxide (0.1 mole) was added by portions to this solution. The temperature rose to 50° C. After completion of the reaction the solvents were distilled off. About 100 ml of 20 percent KOH was added drop by drop to the viscous residue and the acetate was saponified over a 15 minute period at 80° C. After removal of the Et3N by extraction, the aqueous solution was acidified with concentrated HCl. The precipitate was sucked off, washed with water and dried under a vacuum. 11.0 g of 6-hydroxy nicotinic acid was obtained, which was pure according to NMR. The crude yield was about 79 percent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:11]([F:22])([F:21])[F:10])[CH:17]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: FC(F)(F)c1cccc(Oc2cc(Br)cc(Br)c2)c1
Reaction time: 168 h

Procedure:
3,5-Dibromophenol (4.1 g; 16.2 mmol), 3-(trifluoromethyl)-phenylboronic acid (6.2 g; 32.4 mmol), Cu(II) acetate (2.9 g; 16.2 mmol), TEA (5.6 mL; 40.5 mmol) and dichloromethane (150 mL) and molecular sieves (2 ml) was added to a reaction flask the reaction mixture was stirred for 7 days. Further 3-(trifluoromethyl)-phenylboronic acid (6.2 g; 32.4 mmol) was added and the reaction mixture stirred for 1 day. Further 3-(trifluoromethyl)-phenylboronic acid (6.2 g; 32.4 mmol) and TEA (5.6 mL; 40.5 mmol) was added and the reaction mixture stirred for 1 day. 5% Aqueous citric acid (150 mL) was added and the two phases were separated. The aqueous phase was extracted with dichloromethane (50 mL×2) and the organic phases were pooled, dried and evaporated to dryness. The crude product purified by flash chromatography (heptane→ethyl acetate:heptane 1:9). Yield: 1.86 g; HPLC-MS: m/z: 397. (M+H)+; Rt: 2.78 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[C:34]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])[CH2:35][CH3:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:41]3[CH:42]=[CH:43][C:38]([C:34](=[O:37])[CH2:35][CH3:36])=[CH:39][CH:40]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CCC(=O)c1ccc(B(O)O)cc1
Product: CCC(=O)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(NCC(=O)OC)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.8 g, 3.3 mmol) was coupled with 4-propionyl-phenyl boronic acid (712 m g, 4.0 mmol) according to general procedure G to give {4-[4-(2,4-dichloro-phenyl)-2-(4′-propionyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][C:5]2([S:9]C=[N:7][CH:6]2[C:10]([O:12]CC)=[O:11])[CH2:4][CH2:3]1.C.[ClH:18]>>[ClH:18].[ClH:18].[NH2:7][CH:6]([C:5]1([SH:9])[CH2:4][CH2:3][N:2]([CH3:1])[CH2:16][CH2:15]1)[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C1N=CSC12CCN(C)CC2
Agent: Cl
Product: CN1CCC(S)(C(N)C(=O)O)CC1
Yield: 81 %

Procedure:
A solution of 113 g (0.466 mole) of ethyl 8-methyl-1-thia-3,8-diazaspiro-[4.5]dec-2-ene-4-carboxylate in 5 liters of approximately 6 N hydrochloric acid is heated under reflux for 4 hours. The solution is decolorized with activated charcoal and evaporated to dryness. Traces of water are eliminated by entrainment with benzene and isopropanol. The residue is then dissolved in 1.5 liter of ethanol, concentrated to a volume of approximately 400 ml and allowed to crystallize. In this way, 104.7 g of alpha-amino-4-mercapto-1-methyl-4-piperidine-acetic acid dihydrochloride is obtained; Yield: 81%; M.P. 201°-202° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[NH2:16][C:17]1[N:21]=[C:20]([SH:22])[NH:19][N:18]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:11]([CH2:12][S:22][C:20]2[NH:19][N:18]=[C:17]([NH2:16])[N:21]=2)=[N:10][C:9]2[C:4]([N:3]=1)=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2
Reactant: ClCc1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: Nc1n[nH]c(S)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1n[nH]c(SCc2nc3cc(Cl)c(Cl)cc3nc2Cl)n1
Reaction time: 8 h

Procedure:
2,6,7-Trichloro-3-chloromethylquinoxaline (105 mg, 0.37 mmol) and 3-amino-5-mercapto-1,2,4-triazole (48 mg, 0.41 mmol) were dissolved in DMF (3 ml). Triethylamine (0.2 ml, 1.1 mmol) was added and the dark brown solution was allowed to stand at room temperature overnight. After evaporation of the solvent under reduced pressure, the residue was taken up in ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were concentrated in vacuo, and the residue was purified by flash column chromatography using ethyl acetate to afford the title compound.