Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].CCOC(C)=O.[CH3:19][N:20](C)C=O>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:19]#[N:20])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: CN(C)C=O
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 56.1 %

Procedure:
A mixture of 4-bromo-3-nitrobenzaldehyde (1 g, 4.35 mmol) in dimethylformamide (10 mL) was added cuprous cyanide (584.8 mg, 6.53 mmol). The resultant solution was stirred at 160° C. for 5 hours. After cooling, a standard aqueous/EtOAc workup was followed. Purified by silica gel column chromatography to give product (430 mg, yield 56.1%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].[Cl-].[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:15]=1[CH:16]=[N+:17]([CH3:19])[CH3:18].Cl[C:26]1[CH:33]=[CH:32][CH:31]=[C:30](F)[C:27]=1C=O.CNC>>[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:15]=1[CH:16]([N:17]([CH3:19])[CH3:18])[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:1][CH3:2])[C:4]=1[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:27]=1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CCn1ccc2ccccc21
Reactant: C[N+](C)=Cc1c(F)cccc1Cl
Agent: CNC
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2c(F)cccc2Cl)N(C)C)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethylindole and (2-chloro-6-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-chloro-6-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:19])=O>>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([Cl:19])[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2nc(C)c(C)c(=O)[nH]2)cc1
Product: Cc1ccc(-c2nc(C)c(C)c(Cl)n2)cc1

Procedure:
A mixture of 5,6-dimethyl-2-(4-methylphenyl)-3H-pyrimidin-4-one (6 g) and phosphorus oxychloride (40 ml) was refluxed for 2 hours. Excess phosphorus oxychloride was removed under reduced pressure, ice added to the residue, and the mixture extracted with methylene chloride, the organic layer washed with brine, dried over sodium sulfate, the solvent evaporated under reduced pressure, to yield 6.2 g of 4,5-dimethyl-6-chloro-2-(4-methylphenyl)pyrimidine, m.p. 165° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[NH:13][C:14]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[N:20][N:21]2C(OC)=O)=[O:15].[OH-].[Na+]>O1CCCC1.CO.O>[NH:21]1[C:22]2[C:18](=[C:17]([NH:16][C:14]([NH:13][CH:8]3[C:7]4[C:12](=[C:3]([C:2]([F:1])([F:31])[F:30])[CH:4]=[CH:5][CH:6]=4)[O:11][CH2:10][CH2:9]3)=[O:15])[CH:25]=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCOc4c3cccc4C(F)(F)F)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCOc2c1cccc2C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A solution of Example 37F (0.68 g, 1.56 mmol) in a mixture of 5 ml tetrahydrofuran and 5 ml methanol was treated with sodium hydroxide (5M in methanol, 3 ml, 15 mmol), and the reaction stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water, and the precipitate that formed was collected by filtration. After drying, the solid was purified using reverse-phase HPLC (acetonitrile-water with 0.1% trifluoroacetic acid as eluent) to provide 0.29 g of title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 13.01 (s, 1 H), 8.59 (s, 1 H), 8.03 (s, 1 H), 7.67 (d, J=7.46 Hz, 1 H), 7.62 (d, J=7.80 Hz, 1 H), 7.55 (d, J=7.80 Hz, 1 H), 7.22 (t, J=7.80 Hz, 1 H), 7.04-7.11 (m, 2 H), 6.96 (d, J=7.80 Hz, 1 H), 4.96-5.03 (m, 1 H), 4.41-4.49 (m, 1 H), 4.30 (m, 1 H), 2.18 (m, 1 H), 2.06-2.13 (m, 1 H). MS (ESI) m/e 377 (M+H)+. Calcd. For C18H15N4O2F3.0.15 trifluoroacetic acid: C, 55.87; H, 3.88; N, 14.24. Found C, 55.95; H, 3.82; N, 14.28.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[CH:17])=[CH:13][CH:14]=2)[C:9]([CH3:19])([CH3:18])[CH2:8][C:7]=1[CH3:20])=[O:5])[CH3:2].[CH3:21][O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][C:28]3[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:32])=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)[C:9]([CH3:19])([CH3:18])[CH2:8][C:7]=1[CH3:20])=[O:5])[CH3:2]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)=C2C(=O)OCC
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)OC)cc3)ccc21

Procedure:
Following General Procedure B and using 6-ethynyl-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 200, 0.106 g, 0.38 mmol), 4-iodo phenyl acetic acid methyl ester (0.106 g, 0.38 mmol), triethyl amine (2 mL), copper(I)iodide (0.02 g, 0.105 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 12-15% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale yellow oil (0.075 g, 47%).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=1.[CH3:17]O>>[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:17])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=1
Reactant: COc1cc(O)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Thionyl chloride (953 μL, 13.1 mmol) was added dropwise to a solution of 4-hydroxy-2-methoxy-benzoic acid (733 mg, 4.36 mmol) in methanol (30 mL) at 0° C. The mixture was stirred at 50° C. overnight. The reaction mixture was concentrated and the residue was dissolved in water (40 mL). The solution was neutralized with saturated sodium bicarbonate solution and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to dryness to give methyl 4-hydroxy-2-methoxy-benzoate (99%). ESI-MS m/z calc 182.1. found 183.1 (M+1)+. Retention time: 0.73 minutes (3 min run).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.O[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Temperature: 0 °C
Yield: 54.5 %

Procedure:
4-(Chloromethyl)benzyl alcohol (4.68 g), methyl 3-(4-hydroxyphenyl)propanoate (5.40 g) and triphenylphosphine (9.20 g) were dissolved in a mixed solvent of toluene (60 mL)-tetrahydrofuran (30 mL), cooled to 0° C. and diethyl azodicarboxylate (40% toluene solution, 15.2 g) was added dropwise with stirring. After completion of the dropwise addition, the reaction mixture was allowed to warm to room temperature and further stirred for 1 hr. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) to give the title compound (5.19 g, yield 54%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[CH3:23][NH2:24].[Cl-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH:24][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CN
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
9.91 ml of triethylamine were added at -40° C. to a solution of 15.03 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 250 ml of dry tetrahydrofuran, and then a solution of 6.81 ml of ethyl chloroformate in 30 ml of dry tetrahydrofuran was added at -30° to -40° C. to the resulting mixture, which was then stirred at the same temperature for 1 hour, 16.82 ml of a 40% by volume aqueous methylamine solution were then added at -30° C., and the temperature of the reaction mixture was allowed to rise to room temperature; the reaction was then allowed to continue for 1 hour. At the end of this time, the reaction mixture was mixed with a small amount of an aqueous solution of sodium chloride and extracted thrice with ethyl acetate. The combined extracts were washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, giving 12.76 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[C:16](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:16][O:9][C:8]([C@H:5]1[CH2:6][CH2:7][C@@H:2]([OH:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cis-4-hydroxy-cyclohexanecarboxylic acid (10.0 g, 69.4 mmol) and a catalytic amount of concentrated sulfuric acid in methanol (700 ml) was heated at reflux over night. After cooling to room temperature the reaction mixture was neutralized by the addition of solid sodium carbonate. The mixture was stirred for 30 min, filtered and concentrated in vacuo. The residue was triturated in ethyl acetate (150 ml). The solids were removed by filtration. The filtrate was concentrated in vacuo to give the crude product (10.3 g, 94%) as colorless oil, which was used in the following steps without further purification. MS m/e: 159 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([C:35]([OH:37])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)#[N:2].[CH3:38]O>C1(C)C=CC=CC=1.CCO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[C:27]([C:35]([O:37][CH3:38])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:23][CH2:24]2)[CH2:15][CH2:14]1)#[N:2]
Reactant: CO
Reactant: Cn1cc([C@H]2CC[C@@H](N3CCN(c4cc(C(=O)O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCN([C@H]3CC[C@@H](c4cn(C)c5ccc(C#N)cc54)CC3)CC2)c2ncccc2c1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To 50 mg (0.1 mmol) of 8-[4-[(cis)-4-(5-cyano-1-methyl-1H-indole-3-yl)cyclohexyl]-1-piperazinyl]-6-quinolinecarboxylic acid in 1 mL of MeOH and 3 mL of C6H5CH3 at 23° C. was added 0.9 mL (0.39 mmol) of a 10% solution of (CH2)3SiCHN2 in hexanes. After stirring at 23° C. for 12 hours, the volatiles were removed by rotary evaporation. The crude product was chromatographed on silica gel eluting with 20:1 CH2Cl2:MeOH. The product fractions were pooled, stripped, and treated with 5 mg (0.05 mmol) of (CO2H)2 in absolute EtOH to give 20 mg (0.04 mmol, a 40% yield) of the oxalate salt of the title compound as a tan crystalline solid. mp: 153-155° C.; MS (ES) m/z: 599 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)[CH3:12].[CH2:24]([O:26][C:27](=[O:36])[C:28](=[NH:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:25]>C(O)C>[CH2:21]([O:20][C:18]([C:16]1[NH:35][C:28]([C:27]([O:26][CH2:24][CH3:25])=[O:36])=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:15]=1[C:14]([O:13][CH2:11][CH3:12])=[O:23])=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: COc1cccc(C=O)c1
Reactant: CCOC(=O)CC(=N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cccc(OC)c2)C(C(=O)OCC)=C(C(=O)OCC)N1

Procedure:
13.6 g of 3-methoxybenzaldehyde, 19 g of oxalacetic acid diethyl ester and 18.8 g of iminosuccinic acid diethyl ester in 50 ccs of ethanol are heated to the boil for several hours, and after evaporation a yellow oil is obtained.
Reaction SMILES: C([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[N:25][CH:24]=2)[CH3:22])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[S:27][C:23]([C@@H:21]([NH:20][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([C@@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[CH:19]=[CH:18][N:17]=3)[CH3:22])=[CH:24][N:25]=2)=[CH:29][CH:30]=1
Reactant: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)c1cnc(-c2ccc(Cl)cc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)O)n1)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a round bottom flask containing a stir bar and (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (82 mg, 0.16 mmol) was added DCM (1 mL) followed by the addition of TFA (1 mL). Resulting reaction mixture allowed to stir 30 min at RT. The volatiles were then removed and the residue neutralized by the addition of a saturated solution of NaHCO3. The aqueous mixture was then extracted with DCM. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a brown foam of (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (61 mg, 0.14 mmol, 84% yield) which was used without further purification. LCMS m/z 446.2 (M+H)+, Rt 0.71 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)([N:15]1C=CN=C1)=O.[CH:25]1([CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)CN)[CH2:29][CH2:28][CH2:27][CH2:26]1>C1COCC1>[CH:25]1([CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)[NH:15][C:9](=[O:11])[CH2:8][C:7]2[C:6]([Cl:12])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Reactant: COc1cccc(C(CN)C2CCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(NC(=O)Cc2c(Cl)cncc2Cl)C2CCCC2)c1
Yield: 96.6 %

Procedure:
By working in a way similar to that described in example 30 but using (3,5-dichloro-pyridin-4-yl)-acetic acid (2.06 g, 10 mmoles), carbonyldiimidazole (1.78 g, 11 mmoles), THF (30 ml) and 2-cyclopentyl-2-(3-methoxy-phenyl)-ethylamine (2.19 g, 10 mmoles), obtained as described in example 33, 3.8 g of the title compound were obtained (yield: 98.2%), m.p.: 105-106° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:24])=[C:21]([CH:23]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:24])=[C:21]([NH:22][S:39]([C:33]3[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])(=[O:41])=[O:40])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 0 °C
Yield: 61.8 %

Procedure:
To a solution of 5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (13 g, 36 mmol) in DCM (100 mL) was added pyridine (8.5 g, 107 mmol). The mixture was cooled to 0° C. 2,6-Difluorobenzene-1-sulfonyl chloride (9.1 g, 43 mmol) in DCM (20 mL) was added dropwise to the mixture. The reaction was stirred at rt over night. Then the reaction was washed with water (100 mL), and extracted with DCM (2×200 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:2) to afford the title compound (12 g, 62.2% yield, two batches combined). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95-11.05 (br, 1H), 8.54 (d, J=5.2 Hz, 1H), 7.67-7.79 (m, 1H), 7.45-7.50 (m, 2H), 7.22-7.37 (m, 3H), 7.10 (d, J=5.2 Hz, 1H), 1.42 (s, 9H). MS (ES+): 539 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].[CH3:8][O-:9].[Na+].[CH3:11][C:12]([CH:14]=O)=O>CO>[CH3:8][O:9][C:6]1[C:2]([C:3]([NH2:5])=[O:4])=[N:1][CH:14]=[C:12]([CH3:11])[N:7]=1
Reactant: CC(=O)C=O
Reactant: N#CC(N)C(N)=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cnc1C(N)=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 229 %

Procedure:
Under argon, 6 g (60.5 mmol) of 2-amino-2-cyanoacetamide was initially charged in 67 g of methanol. 1.67 g (9.3 mmol) of sodium methoxide solution (30%) was added and the mixture was stirred at 20° C. for 2 hours. At 0° C., 11.55 g (64.1 mmol) of methylglyoxal solution (40%) was added and the mixture was stirred at 0° C. for 2 hours. The solution was then cooled to −20° C. The product precipitated out. After filtration and drying, 3.56 g of the title product was obtained. The yield was 39 percent. The melting point of the title product was 170° C. to 172° C. Other data concerning the title product was:
Reaction SMILES: [CH3:1][C:2]12[CH2:12][C:6]3([CH3:13])[CH2:7][C:8]([CH3:11])([CH2:10][C:4](C(O)=O)([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:17]([OH:20])(=O)[CH3:18].S(Cl)([Cl:23])=O>CO.CCOC(C)=O.[Pd]>[CH3:1][C:2]12[CH2:12][C:6]3([CH3:13])[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([CH2:18][C:17]([Cl:23])=[O:20])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CC(=O)O
Reactant: CC12CC3(C)CC(C)(C1)CC(C(=O)O)(C2)C3
Reactant: O=S(Cl)Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC12CC3(C)CC(C)(C1)CC(CC(=O)Cl)(C2)C3

Procedure:
3,5,7-trimethyl adamantane-1-carboxylic acid was converted to it's acid chloride per the procedure described for 3,5-dimethyl-adamantan-1-yl)-acetic acid. It was then homologated to the corresponding benzyl ester via the procedure described in Tetrahedron Letters, 1980, 21, 4461-4462. The benzyl ester was converted to the acid by standard hydrogenation conditions of 10% Pd/C in MeOH/EtOAc::1:1. The acid was then converted to the acid chloride via standard treatment with thionyl chloride at reflux for 1 to 2 hours. Excess reagent was azeotropically removed with hexanes and the resulting acid chloride was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:18])[CH3:17].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:16]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])[CH3:17]
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Reaction time: 6 h

Procedure:
A mixture of 2-phenylindole (193.3 mg, 1.0 mmol) and acetyl chloride (92 μL, 1.3 mmol) in CH2Cl2 is treated with tin tetrachloride (97.4 μL, 1.9 mmol) at room temperature, shaken for 6 h, quenched with saturated NaHCO3 and extracted with ethyl acetate. The extracts are combined and concentrated in vacuo to afford the 3-acetyl-2-phenylindole intermediate. A suspension of the thus-obtained 3-acetyl-2-phenylindole (47 mg, 0.2 mmol) in isopropanol and concentrated HCl (5 μL) is treated with aminoguanidine bicarbonate, heated at 80° C. for 2 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product, 21.0 mg (36% yield), identified by HPLC1 and mass spectral analyses, (M+H) 292, retention time 3.9 min.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[CH:15]=[CH:14][S:13][C:12]=2C(O)=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1[CH2:23][O:22]CC1.[N-:24]=[N+]=[N-].[Na+]>C1C=CC=CC=1.O>[CH:15]1[C:11]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C:23](=[O:22])[NH:24][C:12]=2[S:13][CH:14]=1
Reactant: C1CCOC1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1sccc1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=c1[nH]c2sccc2c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
0.08 ml of thionyl chloride were added to a solution of 3-phenylthiophen-2-carboxylic acid (6) (0.138 g, 0.68 mmol) in 2 ml of anhydrous benzene and the mixture was refluxed for 2 hrs. The solvent and the excess thionyl chloride were removed under vacuum and the residue was taken up using 3 ml of THF, and NaN3 (0.066 g, 1.02 mmol) in 1 ml of water was added rapidly to this stirred solution at 0° C. The mixture was left for 1 hr at room temperature with stirring, poured into 10 ml of crushed ice and water and extracted with ethyl ether (4×10 ml) and the separated organic layer was washed, dried and evaporated under vacuum. The residue was dissolved in 1 ml of o-dichlorobenzene and then added dropwise to 3 ml of boiling o-dichlorobenzene with stirring. The mixture was refluxed for 5 hrs, then cooled and evaporated. The mixture was subjected to flash chromatography, elution with 90:10 petroleum ether-ethyl acetate giving the end compound (7) (0.061 g, 0.3 mmol, 44% yield) as a pure solid (M. Pt. 266–268° C.); IR: 2849, 1647 cm−1 (NHCO).
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14](C(=O)C)[CH:13]=1)(=O)[CH3:10].[CH2:21](O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[C:1]1([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH2:10])[CH:24]=2)=[CH2:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cccc(C(C)=O)c1
Reactant: Cl[Mg]c1ccccc1
Reactant: CCCCCCCCO
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1cccc(C(=C)c2ccccc2)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
A Grignard reaction mixture was prepared by contacting 100 mL of 2M phenylmagnesium chloride in tetrahydrofuran with 0.1 mole m-diacetyl benzene. 100 mL of n-octanol were added to the Grignard reaction mixture. The tetrahydrofuran was removed by distillation during which the pot temperature rose to 175° C. in 2 hours. Gas chromatograph analysis showed that the alcohol had been dehydrated to m-bis-(1-phenylethenyl) benzene. Product yield was about 95%
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([N:18]([CH2:20][CH3:21])[OH:19])[CH3:17].[OH-].[Na+]>C1COCC1>[CH:10]1([NH:9][C:8](=[N:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[O:19][N:18]([CH2:20][CH3:21])[CH2:16][CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCN(O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)OC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 50 h
Yield: 89.6 %

Procedure:
To a solution of dicyclohexylcarbodiimide (10.3 g, 50 mmol) and N,N-diethylhydroxylamine (6.7 g, 75 mmol) in THF (30 ml) is added finely powdered NaOH (0.2 g) and the mixture is stirred at room temperature for 50 hours. The reaction mixture is then filtered and the filtrate is evaporated on the rotary evaporator below 45° C. to afford 13.24 g of the title compound as a light yellow oil.