Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:17][CH:16]2[C:33]([OH:35])=O)[CH:12]=[CH:13][CH:14]=1.[NH2:36][CH2:37][CH2:38][CH2:39][OH:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:40][CH2:39][CH2:38][CH2:37][NH:36][C:33]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:17]1)=[O:35]
Reactant: NCCCO
Reactant: CC(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC1NC(C(=O)NCCCO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 40.2 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 31c (0.6 g, 1.1 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU and iPr2NEt in CH2Cl2 at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide as a white solid (0.21 g, 40%).
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:28].[OH-].[K+]>CO>[C:16]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:15])=[O:28])=[N:12][CH:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Dissolve 5 g. of 5-(triphenylmethyl)-2-cyanopyridine in a mixture consisting of 50 ml. of water and 1.0 liter of methanol. Add 4 g. of potassium hydroxide and heat the mixture at reflux for fifteen (15) hours. Remove the methanol under reduced pressure, triturate the residue with water and dry the solids obtained thereby. Crystallize the product from acetonitrile to obtain the product of this example. m.p. 239°-240° C.
Reaction SMILES: OC1C=CC(/C=C/C[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.Br[CH2:33][C:34]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:38][CH2:37][CH2:36][O:35]1>>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[CH2:15][CH2:16][N:11]([CH2:33][C:34]3([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:38][CH2:37][CH2:36][O:35]3)[CH2:12][CH2:13]2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: BrCC1(c2ccccc2)OCCO1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Product: c1ccc(Oc2ccc(C3CCN(CC4(c5ccccc5)OCCO4)CC3)cc2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-bromomethyl-2-phenyl-1,3-dioxolane to produce the above.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH4+].[OH-:9]>[Cu]I.C1COCC1>[O:9]1[CH2:4][CH2:3][CH2:2][CH2:1][CH:6]1[CH2:5][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[OH:7]
Reactant: C1CCC2OC2C1
Reactant: [OH-]
Agent: [Cu]I
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1CCCCC1CC1CCCCO1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirring THF solution of the Grignard reagent (formed from 2-(bromomethyl)tetrahydro-2H-pyran, 16a and powdered magnesium, 20 milligram-atoms) and cooled to -30° C., CuI is added as a bolus. After approx. 10 min., a solution of cyclohexene oxide (10 mmol) is added slowly, maintaining the reaction temperature below -25° C. until the addition is complete. The mixture is then stirred at 0° C. for 2 hours and checked by TLC and/or GC. The reaction is quenched by pouring into concentrated NH4Cl solution (if starting material remains, the reaction may be warmed to r.t. and followed by TLC or GC until no additional starting material is observed). Also, the addition of some concentrated NH4OH solution combined with vigorous stirring may be used to remove suspended CuI from the mixture. This mixture is then extracted with 2 portions of ether or 1:1 EA-hexane. The combined extracts are then washed with brine and dried (MgSO4). The product may be sufficiently pure at this point for use in the next reaction. Otherwise, it may be purified by distillation or flash chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([O-])=O>CCO.CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:17][CH2:18]1)[C:7]([OH:9])=[O:8].[NH2:1][C:4]1[CH:5]=[CH:6][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)O)cc2[N+](=O)[O-])CC1
Solvent: CO
Solvent: CCO
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)O)cc2N)CC1
Product: Nc1ccccc1
Reaction time: 4 h
Yield: 143.4 %

Procedure:
In a mixture of EtOH (100 mL) and MeOH (100 mL) compound acid 3-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (2.0 g, 5.86 mmol) was dissolved and evacuated for 5 min. This was added to a 3-necked flask containing Pd/C (0.2 g of 5 wt %) under nitrogen. The reaction mixture was evacuated and nitrogen purged two times and stirred under a balloon of hydrogen for 4 h. LC-MS indicated the completion of reaction and the contents were evacuated and nitrogen purged and filtered through celite, and concentrated to give the aniline 3-amino-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (1.7 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>O1CCOCC1>[CH2:23]([NH:25][C:26]([NH:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1)=[O:27])[CH3:24]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N)c2s1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(NC(=O)NCC)c2s1
Temperature: 100 °C

Procedure:
A stirred mixture of 1-(7-Amino-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (15 mg, 0.048 mmol), ethyl isocyanate (0.03 ml) and dibutyltindiacetate (2 drops) in anhydrous 1,4-dioxane (2 ml) was heated in a sealed vessel at 100° C. for 16 h. After cooling to ambient temperature, the 1-Ethyl-3-[2-(3-ethyl-ureido)-5-pyridin-3-yl-benzothiazol-7-yl]-urea was isolated by Preparative HPLC as a white solid (5.4 mg, 29%).
Reaction SMILES: [Na].Cl[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:9]=2)[N:4]=1.[CH2:20]([OH:23])[CH2:21][CH3:22]>>[N:15]1([CH2:14][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[C:3]([O:23][CH2:20][CH2:21][CH3:22])[CH:12]=[C:11]3[CH3:13])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CCCO
Reactant: Cc1cc(Cl)nc2ccc(Cn3ccnc3)cc12
Agent: [Na]
Product: CCCOc1cc(C)c2cc(Cn3ccnc3)ccc2n1
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a stirred solution of 2 parts of sodium in 24 parts of 1-propanol was added a solution of 5.2 parts of 2-chloro-6-(1H-imidazol-1-ylmethyl)-4-methylquinoline in 16 parts of 1-propanol at room temperature under nitrogen atmosphere. After stirring for 2 hours at reflux temperature, the mixture was evaporated. The residue was taken up in a potassium carbonate solution and the product was extracted with ethyl acetate. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 1.8 parts (31.9%) of 6-(1H-imidazol-1-ylmethyl)-4-methyl-2-propoxyquinoline; mp. 137.9° C. (compound 35).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1>>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]#[C:5][CH2:4][CH2:3][CH2:2][N:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=[N:13]1.[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]#[C:5][CH2:4][CH2:3][CH2:2][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: BrCCCC#Cc1ccccn1
Product: C(#Cc1ccccn1)CCCn1nc2ccccc2n1
Product: C(#Cc1ccccn1)CCCn1nnc2ccccc21

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(A), from 2-(5-bromo-pent-1-ynyl)-pyridine (298 mg, 0.66 mmol) and benzotriazole (72 mg, 0.60 mmol). The crude product was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 2-(5-(pyridin-2-yl)pent-4-ynyl)-2H-benzo[d][1,2,3]triazole (27 mg, 0.1 mmol) as an orange oil and 1-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d][1,2,3]triazole (27 mg, 0.1 mmol) as an orange solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21]>CC(O)=O>[Br-:13].[CH2:15]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][N+:1]1[CH:2]=[CH:3][CH:4]=[C:5]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:6]=1)[CH3:14]
Reactant: CCOCCOCCBr
Reactant: CN1CCC[C@H]1c1cccnc1
Solvent: CC(=O)O
Product: CCOCCOCC[n+]1cccc([C@@H]2CCCN2C)c1
Product: [Br-]
Yield: 38 %

Procedure:
To a stirred solution of (S)-nicotine (0.67 g, 4.1 mmol) in AcOH (20 ml) was added 1-bromo-2-(2-ethoxy-ethoxy)-ethane (1.97 g, 10.0 mmol). The mixture was heated at reflux for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 0.56 g (38%) of (S)-1-[2-(2-ethoxy-ethoxy)-ethyl]-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide (NONB-3O6O) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 9.65 (1H, d, J=6.0 Hz), 9.26 (1H, s), 8.44 (1H, d, J=7.8 Hz), 7.99 (1H, dd, J=7.8, 6.0 Hz), 5.27 (2H, t, J=4.8 Hz), 4.06 (2H, t, J=4.8 Hz), 3.64 (2H, m), 3.41–3.60 (5H, m), 3.26 (1H, m), 2.43 (2H, m), 2.25 (3H, s), 1.91 (2H, m), 1.60 (1H, m), 1.16 (3H, t, J=6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 145.87, 144.40×2, 144.02, 127.85, 70.83, 69.72, 69.57, 67.17, 66.77, 61.41, 56.91, 40.67, 36.02, 23.41, 15.47; Anal. Calcd for C16H27BrN2.0.5H2O: C, 52.18; H, 7.66; N, 7.61. Found: C, 52.22; H, 7.68; N, 7.50.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH:10]=[C:11]([CH3:22])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][O:17][CH2:18][O:19][CH3:20])C(OC)=O)(=[O:3])[CH3:2].[Cl-].[Na+].O>CS(C)=O>[CH3:22][C:11]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][O:17][CH2:18][O:19][CH3:20])=[CH:10][CH2:9][CH2:4][C:1](=[O:3])[CH3:2]
Reactant: COCOCC(C)=CCCC(C)=CCC(C(C)=O)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCOCC(C)=CCCC(C)=CCCC(C)=O
Temperature: 150 °C
Reaction time: 5 h
Yield: 102.7 %

Procedure:
To a solution of methyl 2-acetyl-5,9-dimethyl-10-(methoxymethyl)oxy-4,8-decadienate (420 mg, 1.37 mmol) in methylsulfoxide (4 ml) were added sodium chloride (160 mg, 2.74 mmol) and water (0.1 ml), and the mixture was stirred at 150° C. After five hours, the reaction mixture was allowed to cool to room temperature, and water (10 ml) was added thereto. The product was extracted with ether (20 ml×2). The extract was dried over Na2SO4, and concentrated to give a residue, which was then purified with silica gel column chromatography to obtain 6,10-dimethyl-11-(methoxymethyl)oxy- 5,9-undecadien-2-one (358 mg, 67%),
Reaction SMILES: [H-].[Na+:2].[CH3:3][CH:4]([C:10]([CH3:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H].[CH2:15]1[CH2:22][O:21][S:18](=[O:20])(=[O:19])[CH2:17][CH2:16]1>CN(C=O)C>[CH2:8]([O:7][C:5]([C:4]([CH3:3])([C:10](=[O:11])[CH3:12])[CH2:22][CH2:15][CH2:16][CH2:17][S:18]([O-:21])(=[O:20])=[O:19])=[O:6])[CH3:9].[Na+:2]
Reactant: [H][H]
Reactant: O=S1(=O)CCCCO1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCCCS(=O)(=O)[O-])C(C)=O
Temperature: 0 °C

Procedure:
Sodium hydride (60 wt %, 12 g 0.3 mol NaH) was slurried in dry DMF (100 ml). The resulting suspension was cooled with stirring to 0° C. To this was added a solution of ethyl 2-methylacetoacetate (50 g, 0.346 mol) in DMF (25 ml), dropwise so as to maintain the temperature at <10° C. and control effervescence. Once addition was complete and hydrogen evolution ceased, the mixture was warmed in a warm water bath until a clear, pale yellow solution resulted. This was cooled again to 0° C. A solution of 1,4-butanesultone (45 g, 0.33 mol) in DMF (25 ml) was added over 15 mins, maintaining the temperature at <10° C. Once addition was complete, the mixture was heated at 50° C. for 16 hrs. The solvent was then evaporated under vacuum to dryness; the residue was partitioned between water and diethyl ether. The aqueous layer was retained; the organic layer was extracted with fresh water, then discarded. The combined aqueous extracts were washed with fresh ether, then evaporated under vacuum to give the product as a waxy solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)C.[OH-].[Na+]>C(O)C.O>[Cl:21][C:17]1[CH:16]=[C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21

Procedure:
A mixture of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3acetic acid ethyl ester (6.0 g, 0.019 mole), sodium hydroxide pellets (0.9 g, 0.023 mole), and 50 ml of ethanol-water (2:1) was refluxed for 1 hour. The reaction mixture was cooled and the ethanol evaporated in vacuo. The residual aqueous mixture was diluted with water (40 ml) and extracted with diethyl ether (2×25 ml). The aqueous portion was acidified with concentrated hydrochloric acid to a pH of 5-6. After precipitation was complete, the solid was collected by filtration, giving 5.9 g (100%). Recrystallization from ethanol gave 4.7 g of cream colored needles, mp 214°-216° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 38 h

Procedure:
N-(t-Butoxycarbonyl)glycine (8.75 g, 0.05 mole) and benzyl bromide (9.4 g, 0.055 mole) were slurried in 20 ml of dimethylformamide and treated with 6.0 g (0.06 mole) of potassium bicarbonate under argon. After stirring for 38 hours, water was added to give a mass of chunky white solid which was filtered and washed with water. The solid was taken up in ethyl acetate, dried (sodium sulfate), evaporated to a solid, and recrystallized from 600 ml of hot hexane. Cooling to -5° C. for two hours and filtering gave 11.6 g of crystalline flakes, melting point 72°-73° C., in two crops.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:32]C1C=CC(CCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:32][C:7]1[CH:2]=[CH:3][C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:5][CH:6]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2ccc(Cl)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-Chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(4-chloro-phenyl)-propionic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])[N:5]1[CH:9]=[C:8]([C:10]2[C:11]3[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[N:6]1)#[N:2].CN(C=O)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1>O>[N:74]1([C:30]([C:29]2[CH:28]=[C:27]([CH:4]([N:5]3[CH:9]=[C:8]([C:10]4[C:11]5[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:26])[CH3:24])[C:12]=5[N:13]=[CH:14][N:15]=4)[CH:7]=[N:6]3)[CH2:3][C:1]#[N:2])[CH:35]=[CH:34][CH:33]=2)=[O:31])[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cccc(C(=O)O)c4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cccc(C(=O)N5CCOCC5)c4)c3)ncnc21
Reaction time: 0.17 h

Procedure:
To a solution of 3-(2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)benzoic acid (40 mg, 0.00008 mol) in DMF (1 mL, 0.01 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (36 mg, 0.000095 mol) and DIPEA (30 μL, 0.0002 mol) were added. The reaction was stirred for 10 minutes and then morpholine (10 mg, 0.00012 mol) was added and the resulting mixture was stirred for 3 hours. Water was added and the product was extracted with ethyl acetate. The combined organic extracts were washed with 1N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give 3-[3-(morpholine-4-carbonyl)phenyl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]propanenitrile as a crude (40 mg, 88%) product. MS (ES): 558 (M+1).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18]([NH:20][C@H:21]([C:31]([C:33]([O:35][CH3:36])=[O:34])=[O:32])[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl>[NH2:1][C@H:2]([C:18]([NH:20][C@H:21]([C:31]([C:33]([O:35][CH3:36])=[O:34])=[O:32])[CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1.[F:47][C:46]([C:44]([OH:50])=[O:45])([F:49])[F:48]
Reactant: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Boc-Tyr(OBn)-Ser(OBn)-CO2Me (from Step 1 above, 2.64 g, 4.69 mmol) was dissolved in CH2Cl2 (15 mL), cooled to 0° C. and TFA (5 mL) was added. The solution was warmed to room temperature and stirred for 4 hours. The solution was concentrated, taken up in CH2Cl2 and reconcentrated twice. The resulting oil was triturated with ether to provide 2.7 g of the title compound as a white solid.
Reaction SMILES: O[C:2]1([C:12]([OH:14])=[O:13])[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]1[OH:11]>S(=O)(=O)(O)O>[OH:11][C:3]1[CH:4]=[C:5]([C:8]([OH:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)C1=CC(O)C(O)(C(=O)O)C=C1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(C(=O)O)c(O)c1

Procedure:
A solution of 100 mg of 1,2-dihydroxycyclohexa-3,5-diene-1,4-dicarboxylic acid in 5 mL of 5% sulfuric acid is heated at 85° C. for 60 minutes. The solid which forms is collected (by filtration or centrifugation). The filtrate shows the absence of the 270 nm absorbance. The solid is dissolved in 1 N sodium hydroxide, filtered, and the filtrate acidified with acetic acid. The solid is collected and dried to yield 2-hydroxybenzene-1,4-dicarboxylic acid. m.p. >300° C. 1NMR (d6 -DMSO) δ 7.42 (1H), 7.45 (1H), 7.88 (1H). UVmax =311, 247 nm (pH 7.0), ε311 =4.1 mM-1 cm-1.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.NC(N)=O.O.N.[CH3:17][N:18]1CCC[C:19]1=[O:23]>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]=[N:18][C:19](=[O:23])[NH:10]2)=[CH:5][CH:4]=1
Reactant: CN1CCCC1=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Agent: N
Agent: NC(N)=O
Solvent: O
Product: O=c1ncn(-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C

Procedure:
A mixture of 4-bromophenylhydrazine hydrochloride (5.g, 22.4 mmol) and urea (8.1 g, 134 mmol) was heated to 80° C. overnight in 1-methyl-2-pyrrolidinone (25 mL). The reaction was poured into water (250 mL) and concentrated ammonia was added until basic pH. The solution was cooled on an ice bath and the semicarbazone filtered off. The semicarbazone (1.0 g, 4,4 mmol) was stirred in triethyl orthoformiate (B mL) at 90° C. for three days. The reaction mixture was cooled to room temperature and the crude material filtered off. Re-crystallisation from methanol afforded the desired product.
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([C@@H:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F:34][C:35]1[CH:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][CH2:49][CH2:50][O:51][CH3:52])=[N:40]2>>[F:17][C:18]1[CH:19]=[C:20]([C@H:26]([NH:27][C:45]([C:43]2[CH:42]=[C:41]3[C:36]([CH:37]=[N:38][C:39]([NH:48][CH2:49][CH2:50][O:51][CH3:52])=[N:40]3)=[C:35]([F:34])[CH:44]=2)=[O:46])[C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COCCNc1ncc2c(F)cc(C(=O)O)cc2n1
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Product: COCCNc1ncc2c(F)cc(C(=O)N[C@@H](c3ccc(OC)c(F)c3)c3cnn(C)c3)cc2n1

Procedure:
5-Fluoro-2-(2-methoxy-ethylamino)-quinazoline-7-carboxylic acid [(S)-(3-fluoro-4-methoxy-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide (I-58) was prepared analogously except 32b was replaced with 40f and 84b was replaced with 87a.