Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([S:14]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[F:18])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Reactant: Nc1ccccc1F
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To Ethyl 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoate (1.0 g, 3.32 mmol) in N,N-dimethylacetamide (5 mL) was added 2-fluoroaniline (1.48 g, 13.28 mmol) dropwise over 30 seconds at room temperature. The mixture was stirred at room temperature for 2 hours, and then it was diluted with ethyl acetate (33 mL). The organic solution was washed with 1 N HCl (2×13 mL) and saturated NaCl (13 mL). The organic layer was concentrated, ethanol (8 mL) was added, and the mixture concentrated to give ethyl 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: [C:1]1([C:7]2([CH2:17][C:18]#[N:19])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][OH:21].C(OCC)(=O)C.CCCCCC>C(O)C>[OH:21][NH:20][C:18](=[NH:19])[CH2:17][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][C:10]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:15][CH2:16]1
Reactant: NO
Reactant: N#CCC1(c2ccccc2)CCC2(CC1)OCCO2
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N=C(CC1(c2ccccc2)CCC2(CC1)OCCO2)NO
Temperature: 60 °C
Yield: 50.2 %

Procedure:
To a stirred solution of 8-phenyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (264) (1.5 g, 5.83 mmol) in ethanol (30 mL) was added NH2OH (50% aqueous solution, 1.1 mL, 17.49 mmol) and the reaction mixture was heated at 60° C. for 16 h. Silica thin layer chromatography was performed (ethyl acetate:Hexane=1:1, Rf=0.15). The reaction mixture was concentrated in vacuo to yield a crude mixture which was triturated with diethyl ether to obtain pure N-hydroxy-2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetamidine (266) (850 mg, 50.22%) as an off-white solid which was used in the next step without further purification.
Reaction SMILES: CS(C(S(C)(=O)=O)=[N:6][CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH2:32])[C:8](N1C2CC3C(C)(C)C2(CC3)CS1(=O)=O)=[O:9])(=O)=O.Cl.[O:38]1CCCC1>>[NH2:6][CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH2:32])[C:8]([OH:9])=[O:38]
Reactant: C=Cc1ccccc1CC(N=C(S(C)(=O)=O)S(C)(=O)=O)C(=O)N1C2CC3CCC2(CS1(=O)=O)C3(C)C
Reactant: C1CCOC1
Agent: Cl
Product: C=Cc1ccccc1CC(N)C(=O)O

Procedure:
For example, the appropriate 2-(bis-methylsulfonyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo[5.2.1.0 1,5]dec-4-yl)-3-(2-vinyl-phenyl)-propan-1-one derivative of structure (5) is treated with a suitable acid such as aqueous hydrochloric acid in a suitable organic solvent such as tetrahydrofuran. The reaction is conducted at a temperature range of from -10° C. to room temperature and for a period of time ranging from 30 minutes to 20 hours. Evaporation of the solvent followed by treatment with inorganic base such as aqueous lithium hydroxide in a suitable organic solvent, such as tetrahydrofuran. The reaction is conducted at a temperature range of from -10° C. to room temperature and for a period of time ranging from 30 minutes to 10 hours. After acidification, the corresponding 2-amino-3-(2-vinyl-phenyl)-propionic acid derivative of structure (6) was isolated by evaporation of solvents.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:9]=2[N:10]=1.C1C=CC(O[C:38](OC2C=CC=CC=2)=[N:39][C:40]#[N:41])=CC=1.[NH3:49]>C(O)(C)C>[C:38]([NH:39][C:40]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:9]=2[N:10]=1)=[NH:41])#[N:49]
Reactant: N
Reactant: Cc1ccccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Product: Cc1ccccc1-c1nc(NCCNC(=N)NC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 20 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 2-[(2-aminoethyl)amino]-8-(2,6-difluorophenyl)-4-(2-methylphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (20 mg, 0.050 mmol) in isopropanol (2 mL) was added diphenyl cyanocarbonimidate (12 mg, 0.050 mmol) and the mixture was stirred for about 1 hour at about 20° C. A 2M solution of ammonia in isopropanol (2 ml) was added and the mixture stirred at about 20° C. for about 3 days. The solvent was evaporated and the residue redissolved in 2M ammonia in isopropanol (2 mL). The mixture was irradiated with microwave at about 60° C. for about 40 min. The mixture was stored in a sealed tube for 7 days. The solvent was evaporated and the crude product was purified to give the title compound (14 mg, 59%). LC-MS m/z 475 (M+H)+, 2.93 min (ret time).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:9])[CH3:8].CN(C=O)C.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:25]=[CH:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:19][CH:18]=1>COC(C)(C)C>[C:7]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]([O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:25]=[CH:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(=O)Oc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1

Procedure:
Potassium carbonate (0.075 g) and acetyl chloride (0.035 ml) were added to DMF (3 ml) solution of phenyl N-(4-hydroxyphenyl)-3-(phenoxy)acrylimidate (0.15 g) at room temperature and stirred for two hours at the same temperature and for three hours at 50° C. t-Butyl methyl ether (80 ml) was added to the reaction solution, and it was successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain phenyl N-(4-acetoxyphenyl)-3-(phenoxy)acrylimidate (0.11 g) as colorless oil.
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH3:5].[OH-:9].[Na+].[Mn]([O-])(=O)(=O)=[O:12].[K+].CCO>O>[F:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[C:5]([OH:12])=[O:9]
Reactant: CC(=O)C(C)(C)CF
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(CF)C(=O)C(=O)O
Reaction time: 0.25 h
Yield: 44.7 %

Procedure:
To a vigorous stirring mixture of 4-fluoro-3,3-dimethylbutan-2-one (4.1 g, 34.7 mmol) in water (50 mL) and NaOH (7 mL, 70.0 mmol) cooled in an ice-acetone bath was added portionwise potassium permanganate (9.87 g, 62.5 mmol). The inner temperature was controlled between −3 to 2° C. during the addition process. Upon the completion of the addition, the reaction mixture was stirred in the ice-acetone bath for 6 hrs and then allowed to warm up. EtOH (5 mL) was added and the reaction mixture was stirred for another 15 min. The reaction mixture was filtered and the solid was washed with water (˜80 mL). The filtration was acidified with 6 N HCl, and extracted with EtOAc. The combined extracts were washed with 1N HCl, sat. NaCl, dried (Na2SO4), filtered and concentrated to yield 4-fluoro-3,3-dimethyl-2-oxobutanoic acid (2.3 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:14]([O:16][CH2:17][CH3:18])=[CH2:15])CCC.[F-].[K+]>CN(C=O)C.CCOCC.O.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>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:14]([O:16][CH2:17][CH3:18])=[CH2:15])=[CH:7][N:6]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ncc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: C=C(OCC)c1cnc(Cl)nc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (12.5 g, 64.62 mmol) in dry DMF (175 mL) under N2 was added tributyl(1-ethoxyvinyl)tin (21.8 mL, 64.62 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2.27 g, 3.23 mmol). The mixture was heated at 100° C. for 3 h before being allowed to stir at room temperature for 16 hr. The mixture was then diluted with ether (200 mL) and treated with aqueous KF soln (55 g of potassium fluoride in 33 mL of water). The two phase mixture was stirred vigorously for 1 h at room temperature before being filtered through diatomaceous earth (Celite®). The Titrate was washed with sat'd NaHCO3 soln and brine prior to drying (Na2SO4). The original aqueous phase was extracted with ether (2×) and the organic phase was treated as above. Repetition on 13.5 g of 5-bromo-2-chloropyrimidine and combined purification by Biotage™ flash chromatography on silica gel (gradient elution on a 65M column using 3% ethyl acetate in hexanes to 25% ethyl acetate in hexanes with 3.0 L) afforded the title compound as a white, crystalline solid (18.2 g, 73%).
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([C:6]1[CH:38]=[CH:37][C:9]([C:10]([C:12]2[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=2[O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]3=[O:32])[CH2:19][CH2:18]2)=[O:11])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[BH4-].[Na+].O>C(O)C>[CH2:39]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:10]([C:12]2[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=2[O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]3=[O:32])[CH2:21][CH2:22]2)[OH:11])=[CH:37][CH:38]=1)=[O:5])[CH3:40]
Reactant: CCN(CC)C(=O)c1ccc(C(=O)c2ccccc2OCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(C(O)c2ccccc2OCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
The 1-[2-[2-(4-diethylcarbamoylbenzoyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine (39 mg) obtained in Example 23 was dissolved in ethanol (1 ml), added with sodium borohydride (1 mg) with ice cooling and stirred at room temperature for 30 minutes. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: ethyl acetate:methanol=10:1) to obtain 27.2 mg of the title compound. Yield: 70%.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:17](=[O:22])[CH2:18][N:19]([CH3:21])[CH3:20])[CH2:4][CH2:3]1.CO.[H][H]>C(OCC)(=O)C.O.[Pd]>[CH3:21][N:19]([CH2:18][C:17]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH2:14])[CH:7]=2)[C:2]([CH3:23])([CH3:1])[CH2:3][CH2:4]1)=[O:22])[CH3:20]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CCC2(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1N)N(C(=O)CN(C)C)CCC2(C)C
Yield: 88.9 %

Procedure:
{2-[4,4-dimethyl-6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-2-oxoethyl}dimethylamine (assumed 2.8 mmol) was dissolved in a mixture of ethyl acetate (50 mL) and water (5 mL) and transferred to a Fischer Porter apparatus. 10% Palladium on carbon (500 mg, Aldrich) was added followed by methanol (5 mL) and the mixture stirred under 60 psi hydrogen pressure for 2 h. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 1-[(dimethylamino)acetyl]-4,4-dimethyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (724 mg, 2.49 mmol, 89% over three steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 6 H), 1.62-1.68 (m, 2 H), 2.20 (s, 6 H), 3.17 (s, 2 H), 3.62-3.69 (m, 2 H), 3.75 (s, 3 H), 4.58 (bs, 2 H), 6.56-6.94 (s at 6.71 on top of a very broad singlet caused by amide rotomers, 2 H); ESIMS (M+H)+=292.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:9]2[C:8]3[C:13](=[CH:14][C:15]([F:16])=[C:6]([NH:5][CH2:4][C:3]4[C:2]([CH3:1])=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:32])[CH:7]=3)[N:12]=[C:11]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:10]=2)[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cccc(C)c1CNc1cc2c(NC3CC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C24H23FN6O2, 446.2
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5]C(S(O[C@H](C#C)C)(=O)=O)=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C[C@H](O)C#C.[NH2:32][OH:33].Cl.[O:35]([C:37]#[N:38])[K]>CO.C(N(CC)CC)C>[OH:33][N:32]([C@@H:1]([C:6]#[CH:5])[CH3:15])[C:37]([NH2:38])=[O:35]
Reactant: N#CO[K]
Reactant: C#C[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Reactant: NO
Agent: C#C[C@H](C)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C#C[C@@H](C)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 46047.3 %

Procedure:
To a solution of (S)-O-p-toluenesulfonyl-3-butyn-2-ol (11.2 g, 50.0 mmol), prepared by addition of p-toluenesulfonyl chloride and triethylamine to (S)-3-butyn-2-ol, in methanol (100 mL), was added 55% aqueous hydroxylamine (30 mL, 0.50 mol) and the reaction mixture was stirred at ambient temperature for 40 hours. The reaction mixture was cooled to 10° C. and concentrated HCl (50 mL) was added dropwise. The reaction mixture was concentrated in vacuo and the residue was partitioned between H2O (50 mL) and ethyl acetate (200 mL). The 2-phase mixture was cooled to 10° C. and taken to pH 8 with 50% aqueous NaOH solution (60 mL). After stirring for 15 min the layers were separated and the aqueous phase was extracted twice with 200 mL of ethyl acetate. The combined ethyl acetate extracts were cooled to 10° C. and a solution of KOCN (8.1 g, 0.10 mmol) in H 2 O (30 mL) was added, followed by dropwise addition of 11 mL of concentrated HCl, and the reaction mixture was stirred for 30 min. The ethyl acetate layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 5.9 g (92% yield) of (R)-N-hydroxy-N-(3-butyn-2-yl)urea. mp 129° C. [α]D24 =+53.3° (c=0.58, CH3OH). 1H NMR (DMSO-d6, 300 MHz) 67 1.25 (d, 3H, J=7 Hz), 3.05 (d, 1H, J=2.5 Hz), 4.85 (dq, 1H, J=2.5, 7 Hz), 6.50 (br s, 2H), 9.24 (s, 1H). 13CNMR (DMSO-d6, 75 MHz) δ18.43, 45.14, 72.81, 83.87, 161.51. IR (KBr) 3455, 3330, 3290, 3215, 1658, 1637, 1585 cm-1. MS (DCI/NH3 ) m/e 146 (M+NH4)+, 163 (M+NH4.NH3)+. Anal. Calc for C5H8N2O2 : C, 46.87; H, 6.29; N, 21.86. Found: C, 46.78; H, 6.34; N, 21.72.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:25])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH:3]=[O:4].C(Br)(C)C.[Mg].[C:31]([O:34][C:35](C)(C)[CH3:36])(=[O:33])[CH3:32].[Cl-].[NH4+]>CCOCC>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:25])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH:3]([OH:4])[CH2:32][C:31]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC(C)Br
Product: CCOC(=O)CC(O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Yield: 66 %

Procedure:
To a mixture of ether (344 ml) and 2,6,10,14,18-pentamethyl-5,9,13,17-nonadecatetraenal (34.4 g), Grignard reagent (prepared by adding portionwise isopropyl bromide (18.5 g) to a mixture of ether (100 ml) and metallic magnesium (3.7 g), adding further t-butyl acetate (17.4 g) thereto while cooling with ice and then stirring the resultant mixture for 1 hour) is dropwise added while cooling with ice. The resultant mixture is stirred at room temperature for 3 hours, and the reaction mixture is poured into an aqueous saturated solution of ammonium chloride. The ether layer is separated, washed with water, dried and evaporated. The residual material is chromatographed on silica gel (500 g) using a mixture of benzene and ethyl acetate (9.5:0.5 by weight) to give ethyl 3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen-2-ol-1-carboxylate (28.5 g) as a pale yellow oil. IR: 3480, 1030 cm-1 (OH); 1720, 1180 cm-1 (COO).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30]([S:33](Cl)(=[O:35])=[O:34])[C:29]([CH3:37])=[N:28]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:33]([C:30]3[C:29]([CH3:37])=[N:28][N:27]([CH3:26])[C:31]=3[CH3:32])(=[O:34])=[O:35])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)c3c(C)nn(C)c3C)CC2)nc1N

Procedure:
The title compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone, Example 59, and 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (Maybridge) by the procedure described in Example 152. HR-MS (ES, m/z) calculated for C23H28FN7O4S [(M+H)+] 518.1981, observed 518.1986.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH:38][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30]
Reactant: NCc1cccc(Cl)c1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1cccc(Cl)c1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 3-chlorobenzylamine (16 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 56 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.N1CCCCC1.[C:14]([C:18]1[CH:19]=[C:20]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31](C=O)[CH:30]=[CH:29]3)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25])([CH3:17])([CH3:16])[CH3:15].[S:38]1[CH2:42][C:41](=[O:43])[NH:40][C:39]1=[O:44]>C(O)(=O)C>[C:14]([C:18]1[CH:19]=[C:20]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([N:40]2[C:41](=[O:43])[C:42](=[CH2:1])[S:38][C:39]2=[O:44])[CH:30]=[CH:29]3)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25])([CH3:15])([CH3:17])[CH3:16]
Reactant: O=C1CSC(=O)N1
Reactant: Cc1ccccc1
Reactant: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1C(C)(C)C
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: C=C1SC(=O)N(c2ccc3cc(-c4ccc(OC)c(C(C)(C)C)c4)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A solution of toluene (2.5 mL), piperidine (0.003 mL), acetic acid (0.003 mL), 6-[3-(t-butyl)-4-methoxyphenyl]-2-naphthaldehyde (0.124 g, 0.31 mmol) and 2,4-thiazolidinedione (0.036 mg, 0.31 mmol) was heated at reflux for 16.5 hours under an argon atmosphere. The resulting suspension was filtered and the solid was stirred at room temperature in EtOH. After 3 hours, the solid was filtered and dried under high vacuum to afford 0.037 g (28%) of 6-[3-(t-butyl)-4-methoxyphenyl]-naphthalen-2-yl-methylene-2,4-thiazolidinedione, mp 274–276° C. 1H NMR (300 MHz, DMSO-d6): δ 1.40 (s, 9H), 3.86 (s, 3H), 7.11 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.66 (t, J=8.1 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.92 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.17 (brs, 2H), 12.60 (brs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1(CCN)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:20][CH2:21][N:22]=C=NCCCN(C)C>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:22]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:21][CH3:20])=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: NCCC1CCCCC1
Reactant: CCN=C=NCCCN(C)C
Product: CCN(C(=O)c1ccc(Br)nc1)C1CCCCC1
Reaction time: 288 h
Yield: 14 %

Procedure:
Compound 26 was obtained according to general procedure II, method A, starting from 6-bromonicotinic acid, cyclohexylethylamine (5.0 equiv.) and using EDCI (4.5 equiv.) as coupling agent. The reaction was stopped after 12 days at R.T. and 12 Hrs at 80° C. Purification by flash-chromatography (AcOEt 20% in cyclohexane) afforded the product in 14% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O.[C:25]1(C)[CH:30]=[CH:29][C:28](S(O)(=O)=O)=[CH:27][CH:26]=1.C1(C)C=CC=CC=1.COC1CCCCC=1>C(Cl)Cl>[C:25]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Agent: COC1=CCCCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCOC2=CCCCC2)c1
Yield: 74.8 %

Procedure:
A solution of the compound 1 (33.4 mg, 0.1 mmol) and p-toluenesulfonic acid hydrate (20.0 mg, 0.105 mmol) in a mixture of methylene chloride (1 mL) - toluene (0.1 mL) was concentrated under reduced pressure. The residue was dissolved in a mixture of dioxane (2 mL) - benzene (0.5 mL), to which was added 1-methoxycyclohexene (112 mg, 1.00 mmol). The reaction mixture was heated under reflux, and concentrated to a small volume over 1 hour. A drop of triethylamine was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Hexane was added to the residue, the mixture was filtered to remove the insoluble matter, and the filtrate was purified by chromatography on an alumina column (eluate: hexane - ethyl acetate (2:1)) to give the same compound 6 (31 mg, 75%) as oil. Rf 0.62 (Al2O3 60, Type E, 2:1 hexane -EtOAc).