Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[C:11]([CH3:16])[CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[C:11]([CH3:16])[CH2:12][C:13]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:15])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COc1ccc(C(C=Cc2ccc(Cl)cc2)=C(C)CC(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: COc1ccc(C(C=Cc2ccc(Cl)cc2)=C(C)CC(=O)N2CCOCC2)cc1OC
Reaction time: 0.17 h

Procedure:
5.38 g (15 mmols) of 5-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-2-methyl-penta-2,4-diene-1-carboxylic acid were dissolved in 30 ml of absolute tetrahydrofuran, and 3.24 g (20 mmols) of 1,1'-carbonyldiimidazole were added in portions thereto. After the evolution of CO2 had ended, 1.74 (20 mmols) of morpholine were added, the mixture was allowed to stand at room temperature for 10 minutes and was then refluxed for 2 hours. The solution was evaporated in vacuo, and the residue was shaken with toluene/water. The toluene phase was again washed with water, then dried and concentrated down to about 20 ml in vacuo. This solution was purified on a chromatography column charged with 30 g of silica gel mixed with toluene. Elution was carried out first with toluene and then with a toluene-acetone mixture (90:10). The fractions containing the substance with an Rf 0.52 (toluene/acetone 70:30 on silica gel plate) were collected and evaporated in vacuo.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][N:21]([CH3:37])[CH2:22][CH2:23][N:24]([CH3:36])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33]>C(Cl)Cl.CO>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([N:24]([CH2:23][CH2:22][N:21]([CH3:37])[CH3:20])[CH3:36])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)=[O:19])=[CH:14][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CN(C)CCN(C)c1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCN(C)c1ccc(NC(=O)Cc2ccc(-n3cnc4ccccc43)cc2)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid (Step 20.1) and 4-[(2-dimethylamino-ethyl)-methyl-amino]-3-trifluoromethyl-phenylamine (Step 6.1). Title compound: ES-MS: 496.0 [M+H]+; single peak at tR=3.00 min (System 1); Rf=0.14 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:9][NH2:10]>CO>[CH3:8][O:7][C:1](=[O:6])[CH:2]=[C:3]([NH:10][CH3:9])[CH3:5]
Reactant: CN
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: CNC(C)=CC(=O)OC
Reaction time: 1 h

Procedure:
To a solution of methyl acetoacetate (29.4 g, 253 mmol) in methanol (30 mL) was added methylamine (33 wt % in EtOH; 48 mL, 385 mmol) dropwise at room temperature. The reaction was stirred for 1 hour, and then concentrated and dried to give the title compound as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=1.[F:9][C:10]1([F:22])[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:11]1>CN1C(=O)CCC1>[F:22][C:10]1([F:9])[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:2]3[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=3)[CH2:18][CH2:17]2)[CH2:11]1
Reactant: FC1(F)CCN(CC2CCNCC2)C1
Reactant: Nc1cnncc1Cl
Solvent: CN1CCCC1=O
Product: Nc1cnncc1N1CCC(CN2CCC(F)(F)C2)CC1
Temperature: 170 °C
Yield: 23.5 %

Procedure:
A mixture of 5-chloropyridazin-4-amine (50 mg, 0.3860 mmol), 4-[(3,3-difluoropyrrolidin-1-yl)methyl]piperidine (197.1 mg, 0.9650 mmol) in NMP (10 mL) were heated under microwave conditions at 170° C. for 7 hours. The reaction was passed through a 10 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures. The solvent was removed in vacuo and the residue was purified by column chromatography (ISCO Companion, 12 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give the sub-title product as a beige solid (27 mg, 23% Yield). 1H NMR (500 MHz, DMSO) δ 8.46 (d, 1H), 8.41 (s, 1H), 5.85 (s, 2H), 3.20 (d, 2H), 2.87 (t, 2H), 2.69 (t, 2H), 2.59 (td, 2H), 2.34 (d, 2H), 2.24 (tt, 2H), 1.83-1.74 (m, 2H), 1.65-1.53 (m, 1H), 1.43-1.30 (m, 2H); 19F NMR (471 MHz, DMSO) δ −90.81; LC-MS ES+: 298.1, ES−: 296.1.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][C:19](OC)=[O:20])[C:12](=[O:23])[N:11]([CH3:24])[C:10]=3[S:9][C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:23])[N:11]([CH3:24])[C:10]=3[S:9][C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:32][CH:33]=1
Reactant: COC(=O)CCn1c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)sc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
To a solution of methyl 3-(5-(4-chlorobenzyl)-6-(4-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (13 mg, 0.0258 mmol) in EtOH (1 mL) was added NaBH4 (2.9 mg, 0.0775 mmol). The reaction was stirred at 50° C. for 18 h, cooled to RT, quenched with aq. HCl (0.1 N, 2 mL) then concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(4-chlorophenyl)-3-(3-hydroxypropyl)-1-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (8.6 mg, 70.1% yield) as a white solid. 1H NMR (CD3OD) δ: 7.43 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H) 4.32 (S, 2H), 4.05 (t, J=7.2 Hz, 2H), 3.55-3.58 (m, 5H), 1.84-1.82 (m, 2H). LCMS: MH+ 475 and TR=3.131 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:16]=[C:17]([CH2:25][CH3:26])[C:18]3[O:22][CH:21]=[C:20]([CH3:23])[C:19]=3[CH:24]=2)[C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1)#[N:2].O[Li].O.C1COCC1>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:15]2[CH:16]=[C:17]([CH2:25][CH3:26])[C:18]3[O:22][CH:21]=[C:20]([CH3:23])[C:19]=3[CH:24]=2)[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCc1cc(C(Nc2ccc(C#N)cc2)C(=O)OC)cc2c(C)coc12
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(Nc2ccc(C#N)cc2)C(=O)O)cc2c(C)coc12
Reaction time: 3 h
Yield: 102.5 %

Procedure:
A mixture of methyl 2-(4-cyanophenylamino)-2-(7-ethyl-3-methylbenzofuran-5-yl)acetate 5 (1.11 g, 3.18 mmol), LiOH.H2O (700 mg, 15.9 mmol), THF (10 mL) and water (5 ml) was stirred vigorously for 3 h. The mixture was partitioned between 1N HCl (100 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (1×125 mL), dried (MgSO4), filtered, and concentrated to yield 1.09 g (98%) of 2-(4-cyanophenylamino)-2-(7-ethyl-3-methylbenzofuran-5-yl)acetic acid 6 as an off-white solid.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:16][NH:17][OH:18]>CO>[CH3:16][N:17]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[OH:18]
Reactant: CNO
Reactant: CCCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(=O)N(C)O

Procedure:
Hexanoylchloride (g, 0.1 mole) is added dropwise with stirring and ice-cooling to a mixture of sodium carbonate (10.6 g, 0.1 mole) and N-methylhydroxylamine hydrochloride (8.35 g, 0.1 mole) in methanol (60 ml), the temperature being kept at less than 5° C. After stirring for a further 30 minutes the mixture is filtered and the solvent is removed using a rotary evaporator. The resultant residue is re-filtered and the residue distilled in vacuo to yield N-methyl-hexanohydroxamic acid as an oil, b.p. 87°-90°/0.1 mm.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10]([CH:7]1[C:5]2[S:6][C:2]([CH3:1])=[CH:3][C:4]=2[CH2:9][CH2:8]1)=[O:12])[CH3:19]
Reactant: CCO
Reactant: Cc1cc2c(s1)C(C(=O)O)CC2
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2cc(C)sc21
Yield: 81 %

Procedure:
A solution of 19.3 g of 2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylic acid and 10 cc of sulfuric acid in 500 cc of ethanol was refluxed for 8 hours then concentrated under reduced pressure to a volume of 100 cc. The residue was diluted with ethyl acetate and stirred with an aqueous solution of sodium bicarbonate. The organic phase was separated, washed with water and dried over sodium sulfate. After evaporation of the solvent under reduced pressure the residue was distilled. 18.2 g (yield=81%) of ethyl-2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylate was obtained. Bp0.7=90° C.
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[C:12]([F:13])=[C:11](F)[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>O>[NH2:2][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:3])[C:12]=1[F:13]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.7 %

Procedure:
Ammonium hydroxide solution (˜30% in water) (35 mL, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 mL water at 0° C. with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 hours, the reaction mixture is cooled to 0° C. and concentrated HCl is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 mL) and extracted with diethyl ether (3×50 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product: MS APCI (−) m/z 217 (M−1) detected.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[CH3:13][NH2+:14][CH3:15].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>C1COCC1>[CH3:13][N:14]([CH3:15])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: C[NH2+]C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
1H-indazole-3-carboxylic acid (45.2 g, 279 mmol) was suspended in THF (500 mL), and to the suspension were added 1-hydroxybenzotriazole dimethylammonium salt (55.7 g, 308 mmol) obtained in a similar manner to the known method [for example, Synthesis, page 285 (1992)] and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58.9 g, 307 mmol), followed by stirring at room temperature overnight. The reaction mixture was added with water, was extracted with ethyl acetate, and the organic layer was sequentially washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from mixed solvent of acetone/water to obtain N,N-dimethyl-1H-indazole-3-carboxamide (37.7 g, 71%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>O>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([S:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:3]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]=2)[CH2:9][CH2:10]1
Reactant: Sc1ccccc1
Reactant: CN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCN(c2cc(Sc3ccccc3)nc(-c3ccccc3)n2)CC1

Procedure:
A mixture of 3.0 g. of the above prepared 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine and 10 ml. of thiophenol is heated under reflux for three hours and then poured into 300 ml. of water. The reaction mixture is basified with 40°/o sodium hydroxide solution. The product which is deposited crystallizes on cooling to afford 3.5 g. of product. Recrystallization from n-heptane affords 4-(4-methyl-1-piperazinyl)-2-phenyl-6-phenylthiopyrimidine, m.p. 125°-128°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[C:16]2/[C:17](=O)[N:18]([CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][CH2:21]/2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C([O-])(=O)C.[NH4+:36]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[C:16]2/[C:17]3[N:18]([CH:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[N:36]=3)[CH2:19][CH2:20][CH2:21]/2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(/C=C2\CCCN(CC(=O)c3ccncc3)C2=O)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C2\CCCn3cc(-c4ccncc4)nc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of 3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}-1-(2-oxo-2-pyridin-4-ylethyl)piperidin-2-one (150 mg) and ammonium acetate (555 mg) in acetic acid (2 mL) was stirred at 120° C. for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system→ethyl acetate-2-propanol) to obtain 121.5 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:29][CH2:28][C:24]3([CH2:27][O:26][CH2:25]3)[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[N:30]1[CH:35]=[C:34]([C:2]2[C:3]([N:22]3[CH2:29][CH2:28][C:24]4([CH2:27][O:26][CH2:25]4)[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:33]=[N:32][CH:31]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC3(COC3)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC3(COC3)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 86 using 5-bromo-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 116.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.35 min, m/z=472.0 [M+H]+, m/z=470.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.00-2.15 (m, 2H) 3.11 (t, J=6.72 Hz, 2H) 3.44 (s, 2H) 4.41-4.45 (m, 2H) 4.45-4.50 (m, 2H) 7.36 (d, J=8.31 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.11 (d, J=2.45 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].[IH:4].[CH2:5]([NH:12][C:13](=[N:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)SC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[IH:4].[NH2:2][NH:3][C:13]([NH:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NN
Reactant: CSC(=NCc1ccccc1)NCc1ccccc1
Agent: I
Solvent: CCO
Solvent: O
Product: NNC(=NCc1ccccc1)NCc1ccccc1

Procedure:
A solution of 6 ml. of hydrazine hydrate and the solution of 1,3-dibenzyl-2-methylthiopseudourea hydroiodide from Example 13 in 500 ml. of absolute ethanol is heated at reflux for 4 hours and then evaporated to dryness under reduced pressure. The residual solid is crystallized from isopropyl alcohol twice giving the desired product as colorless crystals, m.p. 135°-137° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>FC(F)(F)C(O)=O>[NH2:9][C:10]1[C:19]([I:1])=[CH:18][C:17]([Br:20])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)cc(I)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
1-Iodo-pyrrolidine-2,5-dione (10.35 g, 46.0 mmol) was added in one portion to a solution of methyl 2-amino-5-bromo-benzoate (10.35 g, 45.0 mmol) in trifluoroacetic acid (90 mL) at ambient temperature. The reaction was stirred for about 1 hour at ambient temperature then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (150 mL), washed with saturated Na2CO3 solution (2×150 mL) and a 10% aqueous solution of Na2S2O4 (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated to yield methyl 2-amino-5-bromo-3-iodo-benzoate (15.5 g, 97%) as a yellow solid; RP HPLC (Table 1, Method e) Rt=2.45, 1H NMR (DMSO-d6, 400 MHz) δ 3.83 (s, 3H), 7.74 (broad s), 2H), 7.86-7.88 (d, 2H), 8.00-8.02 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.O.[CH2:22](O)[CH3:23]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:22][CH3:23])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CCc1cccc(C(F)(F)F)c1

Procedure:
A solution of 3-(3-trifluoromethylphenyl)propionic acid (13.6 g) in anhydrous ethanol (25 ml) containing concentrated sulphuric acid (1.5 ml) was heated at reflux for 24 hours and was then poured into water (100 ml). The mixture was extracted with diethyl ether and the ethereal extract was washed with water, with aqueous sodium carbonate solution (2 N), and with water, then dried over magnesium sulphate and evaporated. The resulting residue was distilled, to give ethyl 3-(3-trifluoromethylphenyl)propionate (11.5 g) in the form of a colourless oil, b.p. 133°-135° C./17 mm Hg. [elemental analysis: C, 58.6; H, 5.2%. C12H13F3O2 requires C, 58.5; H, 5.3%. νmax 1125, 1170, 1330 and 1740 cm-1 ].
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:31])[N:3]=1.[OH-].[Na+:33]>O.C(O)(C)(C)C>[Na+:33].[Na+:33].[NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[O:18])=[CH:29][CH:30]=3)[C:5]=2[C:4](=[O:31])[N:3]=1
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1

Procedure:
2.5 grams of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (purity 99.6% HPLC) were dissolved in a mixture of 0.3 L of distilled water and 0.2 L of t-butanol with the addition of 5.849 mL of a 2.0M standard solution of sodium hydroxide in water. The pH of the solution was adjusted to 7.14 by adding a diluted solution of sodium hydroxide in water and a suspension of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid in the same solvent. The obtained solution was dried in a freeze-drier affording the title compound as a white solid (2.7 g, purity 99.6% area by HPLC). Acidimetric titrations of the final product can be used to confirm the absence of residual sodium hydroxide and pemetrexed diacid.
Reaction SMILES: [C:1]([O:5][C:6]([C:9]([C:12]([O:15][CH:16]([C:18]([C:21]([O:23]C)=[O:22])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2].C(O)C.[OH-].[K+:29]>O>[C:1]([O:5][C:6]([C:9]([C:12]([O:15][CH:16]([C:18]([C:21]([O:23][K:29])=[O:22])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2]
Reactant: COC(=O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Reactant: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O[K])C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 40 °C
Reaction time: 6 h

Procedure:
CF3O(CF2)3OCHFCF2COOCH3 (19.6 grams, 50.0 mmol), 15 grams of ethanol, 2.8 grams (50 mmol) of potassium hydroxide, and 2 grams of water were added to a 100-mL, 3-necked flask, equipped with a stirrer, a condenser, and a thermometer. The reaction mixture was heated on a heating mantle and stirred for 6 hours at 40° C. A clear, colorless solution of CF3O(CF2)3OCHFCF2COOK was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH2:19][O:20][C:21]([CH2:23]Br)=[O:22]>CN(C=O)C>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:23][C:21]([O:20][CH2:19][CH3:18])=[O:22])=[CH:7][CH:6]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)CC)cc1
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)propan-1-one (33 g, 0.2200 moles) in DMF (165 mL), potassium carbonate (60.7 gm, 0.4400 moles) and ethyl bromo acetate (40.6 gm, 0.2420 moles) were added and the reaction mixture was srirred at 50° C. for 3 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure to yield 49 gm (94%) of product as thick liquid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8]1)=[O:6])[CH3:3]>C(O)C>[CH2:2]([O:4][C:5]([CH:7]1[NH:12][CH2:11][CH2:10][N:9]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Concentrated hydrochloric acid (5 mL) was added to the above-obtained 1,4-di-tert-butoxycarbonylpiperazine-3-carboxylic acid ethyl ester (5.5 g) in ethanol (50 mL), followed by stirring at room temperature for 3 days. The solvent of the reaction mixture was removed under reduced pressure, to thereby give piperazine-2-carboxylic acid ethyl ester hydrochloride (3.4 g, 95.7%). Under cooling with ice, triethylamine (5 mL) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (4.0 g) were added to the thus-obtained piperazine-2-carboxylic acid ethyl ester hydrochloride (3.4 g) in tetrahydrofuran (30 mL), followed by stirring at room temperature for 16 hours. The reaction mixture was partitioned by use of methylene chloride. The organic layer was dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (methylene chloride-methanol), to thereby give the title compound as an oily product (3.14 g, 49%).