Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([NH2:26])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[CH3:5].[Li+].[OH-].Cl>C1COCC1.O.O>[NH2:26][C:17]1[CH:16]=[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7]([NH:6][C@@H:4]([CH3:5])[C:3]([OH:27])=[O:2])=[O:8])[CH2:10][CH2:11]2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]=1
Reactant: COC(=O)[C@H](C)NC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (2S)-2-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-propanoic acid-methyl ester (˜50 mg, 0.13 mmol), LiOH (100 mg) in THF-H2O (5 mL, 5:1) was stirred at rt for 3 h. The mixture was diluted with H2O, and acidified with 1.0 N HCl to pH˜5. The crude acid was obtained as a white solid by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:12](O)=O>>[CH3:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: O=CO
Reactant: Cc1ccc(C(N)=O)c(N)c1
Product: Cc1ccc2c(=O)[nH]cnc2c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 2-amino-4-methylbenzamide (20 g, 133 mmol) and formic acid (120 ml, 3129 mmol) was heated to 100° C. After 6 hours, the reaction was cooled down to RT and the volatiles were removed under reduced pressure. The residue was then washed carefully with aqueous saturated sodium bicarbonate and then with water. The tan solid was then dried in a vacuum oven at 45° C. overnight to give 7-methylquinazolin-4(3H)-one. MS (M+H)+ 161.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([S:15]([CH2:18]CO)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.C(O[C:25](=N)[CH2:26][Br:27])C>C(O)C>[Br:27][CH2:26][C:25]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=N)CBr
Reactant: Nc1ccc(-c2ccccc2S(=O)(=O)CCO)cc1N
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1-c1ccc2[nH]c(CBr)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.7 %

Procedure:
A mixture of 2-(3′,4′-diamino-biphenyl-2-sulfonyl)-ethanol (0.140 g, 0.479 mmol) and 2-bromoacetimidic acid ethyl ester hydrochloride salt (0.116 g, 0.575 mmol) in anhydrous ethanol (100%, 6 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to provide 2-bromomethyl-5-(2-methanesulfonyl-phenyl)-1H-benzoimidazole as yellow oil (0.178 g, 94%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:25]([N:26]=[C:27]=[S:28])=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:1]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:27]4[S:28][C:20]5[C:25]([N:26]=4)=[CH:24][CH:23]=[CH:22][N:21]=5)[CH:13]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1cccnc1Cl
Reactant: Nc1cc(Oc2cccc3ncccc23)ccn1
Product: c1cnc2sc(Nc3cc(Oc4cccc5ncccc45)ccn3)nc2c1
Yield: 3.83 %

Procedure:
The title compound was prepared according to the method of Example 180 from 4-(quinolin-5-yloxy)pyridin-2-amine and 2-chloro-3-isothiocyanatopyridine; (0.006 g, 3.83% yield) as a light yellow solid. 1H NMR (d6-DMSO) δ 11.47 (s, 1H), 9.00 (dd, 1H), 8.32 (m, 3H), 8.04 (d, 1H), 7.88 (t, 2H), 7.59 (dd, 1H), 7.51 (d, 1H), 7.38 (dd, 1H), 6.77 (dd, 1H), 6.66 (d, 1H).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[CH:31][N:30]=[CH:29][N:28]=1>>[C:33]([C:32]1[C:27]([NH:26][C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=[N:28][CH:29]=[N:30][CH:31]=1)#[N:34]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Reactant: N#Cc1cncnc1N
Product: CCc1cc2c(C(=O)Nc3ncncc3C#N)cnc(OC)c2o1
Yield: 58.2 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (200 mg) and 4-aminopyrimidine-5-carbonitrile (84 mg). Purification by trituration with ethyl acetate and methanol gave the title compound (110 mg) as an off white solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[CH:26]1>CO.N1CCCCC1>[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[CH:26]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0251 g, 0.0755 mmol) in methanol (2 mL) was added with 1H-indole-3-carboxaldehyde (0.0115 g, 0.0793 mmol) and piperidine (5 drops), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0305 g, 88%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[S:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]([NH2:15])=[N:14][C:5]=2[CH:4]=1.[OH:19][CH2:20][CH2:21][C@H:22]1[CH2:27]N[CH2:25][CH2:24][NH:23]1>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[S:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]([N:15]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH2:21][CH2:20][OH:19])[CH2:27]3)=[N:14][C:5]=2[CH:4]=1
Reactant: Cc1cc2c(s1)Nc1ccc(Cl)cc1N=C2N
Reactant: OCC[C@H]1CNCCN1
Agent: Cl
Product: Cc1cc2c(s1)Nc1ccc(Cl)cc1N=C2N1CCN[C@@H](CCO)C1

Procedure:
By using a method similar to Example 258, using 7-chloro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride and (S)-2-(2-hydroxy-ethyl)-piperazine gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH:14][CH3:15])[C:10]([O:12]C)=O)[CH:6]=[CH:7][CH:8]=1.[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[CH:21][C:22]=1[Cl:23]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[C:10](=[O:12])[CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:14]([CH3:15])[C:25]2=[O:26])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CNC(C(=O)OC)c1cccc(OC)c1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: COc1cccc(C2C(=O)N(c3ccc(Cl)c(Cl)c3)C(=O)N2C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3 g of methyl 2-(3-methoxyphenyl)-2-methylaminoacetate were introduced into a 250 mL Woulff bottle at ambient temperature. 2.7 g d of 3,4-dichlorophenyl isocyanate in 50 mL of THF were added and the mixture was stirred for 30 min at ambient temperature. The insoluble matter was filtered, washed with isopropyl ether and dried to yield the product in the form of a white solid (3.9 g; Yd=75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=1.[CH:22](O)=[O:23]>O>[CH:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=1)=[O:23]
Reactant: O=CO
Reactant: CC(C)(C)c1cccc(-c2cc(C(C)(C)C)ccc2N)c1
Solvent: O
Product: CC(C)(C)c1cccc(-c2cc(C(C)(C)C)ccc2NC=O)c1
Yield: 82 %

Procedure:
Added 2-amino-3′,5-di-t-butyl biphenyl (2.0 g, 7.11 mmol) to a solution of formic acid and heated to reflux for 16 hours. After cooling, water (25 mL) was added the product and the precipitate collected by vacuum filtration. The crude product was dissolved into ethyl acetate, washed with water. The organics were dried over magnesium sulfate and concentrated and purified by column chromatography using 10% ethyl acetate and hexanes as the eluants to give the pure N-formyl-2-amino-3′,5-di-t-butyl biphenyl (1.8 g, 82% yield) as determined by GCMS.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24](Cl)=[O:25])=[CH:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[N:4]1.[NH2:27][OH:28]>>[OH:28][NH:27][C:24](=[O:25])/[CH:23]=[CH:22]/[C:19]1[CH:20]=[CH:21][N:17]([S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH:18]=1
Reactant: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)Cl)c3)cc2)cn1
Reactant: NO
Agent: Cl
Product: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NO)c3)cc2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The above prepared solution of (E)-3-{1-[4-(1-Methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acryloyl chloride hydrochloride was added to an aqueous hydroxylamine solution (50%, 105 mL, 1.78 mol) at 10-20° C. over a period of 20 min. After stirring for 90 min, the suspension was filtered and dried. The crude product (48.4 g) was suspended in a mixture of isopropanol (480 mL) and water (480 mL) and stirred at reflux for 1 h. After cooling to room temperature, the suspension was filtered and dried. The title compound was obtained as beige solid (28.1 g).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C([O:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24])(=O)C.[CH3:37][C:38]1[O:42][C:41]([CH2:43]O)=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[OH:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:43][C:41]3[O:42][C:38]([CH3:37])=[CH:39][CH:40]=3)[CH:31]=2)=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: Cc1ccc(CO)o1
Reactant: COc1ccc(/C=C/C(=O)Nc2cccc(O)c2)cc1OC(C)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)Nc2cccc(OCc3ccc(C)o3)c2)cc1O
Reaction time: 16 h
Yield: 1.7 %

Procedure:
Diethylazodicarboxylate (1.13 mL 5.83 mmol) was added dropwise to a solution of (E)-3-(3-acetoxy-4-methoxy-phenyl)-N-(3-hydroxy-phenyl)-acrylamide (0.763 g, 2.33 mmol), (5-methyl-furan-2-yl)-methanol (0.392 g, 3.5 mmol) and triphenylphosphine (1.53 g, 5.83 mmol) in dry THF (20 mL) at 0° C. The resulting solution was allowed to reach RT and stirred for 16 hrs. The reaction mixture was then diluted with DCM and washed with water, aqueous hydrochloric acid, and brine. The organic layer was then dried over sodium sulphate and evapored. The resulting raw material was taken up, without further purification, with a 3N methanolic solution of hydrochloric acid (5 mL-15 mmols) and stirred at RT for 16 hrs, concentrated under reduced pressure, taken up with solvent an re-evaporated (3 times with MeOH and once with acetone) to give a residue that was purified by silica gel column chromatography (eluant DCM/MeOH 98/2) to obtain 15 mg of the title (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-[3-(5-methyl-furan-2-ylmethoxy)-phenyl]-acrylamide.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl-].[OH:8][NH3+:9].[C:10]([C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])[CH3:13])#[N:11]>O.C(O)C>[NH2:11]/[C:10](=[N:9]\[OH:8])/[C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])[CH3:13]
Reactant: CC(C)(C#N)NC(=O)OC(C)(C)C
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)/C(N)=N/O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
Potassium carbonate (3.64 g) was dissolved in water (12 mL) and hydroxylammonium chloride (CAN: 5470-11-1, 1.7 g, mmol) was added. A solution of tert-butyl 2-cyanopropan-2-ylcarbamate (4.84 g, 26 mmol) in ethanol (42 mL) was added and the resulting reaction mixture was stirred for 18 h at ambient temperature. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (20 mL). The mixture was filtered and the filtrate was concentrated to yield the crude product (5 g, 87.6%) as yellow solid. MS: m/e=218.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=1[CH3:15])=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC.C(Cl)(Cl)Cl>[OH:13][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([CH3:15])[CH:9]=1)[NH:6][C:4](=[O:5])[CH2:3][CH2:2]2
Reactant: COc1ccc(NC(=O)CCCl)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCCCCCC
Product: Cc1cc(O)cc2c1NC(=O)CC2
Temperature: 110 °C
Reaction time: 96 h
Yield: 42.7 %

Procedure:
A suspension of 3-chloro-N-(4-methoxy-2-methylphenyl)propaneamide (0.50 g, synthesized from 3-chlorobutyryl chloride and 4-methoxy-2-methylaniline) and aluminum chloride (1.4 g) in n-heptane (4.0 mL) was stirred at 110° C. for 4 days. The reaction mixture was diluted with chloroform, followed by addition of ice-cold water under ice cooling. After stirring at room temperature for 1 hour, the organic layer and the aqueous layer were separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform/methanol=10/0 to 97/3) to give the titled compound (0.166 g, 39%) as a light-brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>C(OCC)C.CCCCCC.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1nc2ccccc2s1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc2ccccc2s1
Yield: 37.1 %

Procedure:
The title compound (1.2 g) after column chromatography (silica gel, 5% diethyl ether/hexane-diethyl ether eluant) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and 2-chlorobenzothiazole (1.58 g) according to the method of D2.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:13](O)([CH3:16])([CH3:15])[CH3:14].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 4-acetylbenzoic acid (3.9 g) in anhydrous methylene chloride (120 ml) are added 4-dimethylaminopyridine (1.5 g), t-butyl alcohol (4.6 ml), N-methylmorpholine (3.4 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.0 g) under ice cooling. The mixture is stirred under ice cooling for six hours and under water cooling overnight. The reaction mixture is concentrated under reduced pressure, water is added to the concentrate, and the whole is extracted with ether. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 3.13 g (59%) of t-butyl 4-acetylbenzoate as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[C:10]([SH:15])[CH2:9]1.Cl[CH2:17][C:18](=[O:20])[CH3:19].[O-]CC.[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[C:10]([S:15][CH2:17][C:18](=[O:20])[CH3:19])[CH2:9]1
Reactant: O=C1C=C(S)CC(c2ccccc2Cl)C1
Reactant: CC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)CSC1=CC(=O)CC(c2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.5 %

Procedure:
To a solution of 5-(2-chlorophenyl)-3-mercapto-2-cyclohexen-1-one (1.8 g) and chloroacetone (0.7 g) in ethanol (20 ml) was added a solution of 20% sodium ethoxide in ethanol (0.48 g), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and to the residue was ethyl acetate. The mixture was subjected to extraction, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give 5-(2-chlorophenyl)-3-(2-oxopropylthio)-2-cyclohexen-1-one (2.3 g).
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2].[C:26](OC(C)=C)(=[O:28])[CH3:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([O:23][C:26](=[O:28])[CH3:27])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(OC(C)=O)=CC[C@H]3[C@@H]1CC2

Procedure:
A solution of 1-acetoxy-3-methoxyestra-1,3,5(10)-trien-17-one (8.84 g, 26 mM), isopropenyl acetate (132 g, 1320 mM) and p-toluenesulfonic acid monohydrate (1.34 g, 7 mM) is heated at 120° in a distilling flask equipped with a 5 inch Vigreaux column to insure slow distillation. After heating at 120° for 16 hrs, 5 ml of distillate is collected. The temperature is increased to 140° and after 45 mins an additional 60 ml of isopropenyl acetate is collected. The residue is poured into 750 ml of ether and the ether solution is extracted with saturated NaHCO3 solution and H2O. The ether extract is dried over MgSO4 and evaporated in vacuo to give a residue containing the enol acetate and recovered starting material as the major components. The residue is chromatographed on 300 g of neutral silica gel and the column is eluted with 0.5% acetone:petroleum ether to give 1,17-diacetoxy-3 -methoxyestra-1,3,5(10),16-tetraene, yield 6.1 g (61%); m.p. 118° (petroleum ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:23][NH2:24].O>C1(C)C=CC=CC=1>[NH2:23][NH:24][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[N:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: NN
Reactant: O=C(Nc1ccccc1Cl)c1ccncn1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NNC(=Nc1ccccc1Cl)c1ccncn1

Procedure:
To a suspension of N-(2-chlorophenyl)pyrimidine-4-carboxamide 3 (0.2 g, 0.86 mmol) in 20 mL of PhMe was added 0.65 g of PCl5. The mixture was stirred at reflux for 3 h. To this solution was added 3 mL of NH2NH2.H2O. The mixture was stirred at ambient temperature for 2 h. After removal of all solvent, the residue was purified by column (2:1 of hexane/ethyl acetate) to give N-amino-N′-(2-chlorophenyl)pyrimidine-4-carboxamidine 5 as a solid. Yield: 0.15 g, 70%.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:3]1.O[N:31]=[C:32]([NH2:34])[CH3:33]>>[CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]3[O:28][N:34]=[C:32]([CH3:33])[N:31]=3)[CH2:11]2)=[O:9])[CH2:3]1
Reactant: CC1(C)CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCO1
Reactant: CC(N)=NO
Product: Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOC(C)(C)C3)C2)n1

Procedure:
250 mg (0.410 mmol, 68% pure) of 1-[(2,2-dimethylmorpholin-4-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid and 33.4 mg (0.451 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Yield: 117 mg (62% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]=[N:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[C:8]=2[CH3:13])[N:3]=1>O1CCCC1.O>[CH3:13][C:8]1[C:9]2[C:10]([NH2:12])=[N:11][C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=[CH:6][C:7]=1[CH2:14][NH:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1
Reactant: COc1cc(N=Cc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OC

Procedure:
The method of claim 21 wherein step (c) comprises heating the 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyphenylimino)methyl]quinazoline in a mixture of tetrahydrofuran and water in the presence of a reducing agent to produce a crude trimetrexate base, and converting the crude trimetrexate base to trimetrexate acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11](OCC)=[O:12])=[O:5])[CH3:2].[BH4-].[Na+].O.Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncsc1C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ncsc1CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.3 %

Procedure:
4,5-Diethoxycarbonylthiazole (7.13 g) was dissolved in 100 ml of ethanol, 2.20 g of sodium borohydride was added to the solution in an argon atmosphere under ice cooling, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction solution, the mixture was adjusted to pH 4.5 by the addition of 1 N aqueous hydrochloric acid, and the organic solvent was removed by distillation under the reduced pressure. The remaining aqueous solution was extracted five times with chloroform, was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. Ethyl acetate and hexane were added to the concentrate, and the resultant solid was collected by filtration to give 2.29 g of 4-ethoxycarbonyl-5-hydroxymethylthiazole.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[CH2:25](OC(OCC)OCC)C.O.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[N:17]=[C:18]4[NH:23][CH:25]=[N:22][C:19]4=[CH:20][CH:21]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN(c1ccc(N)c(N)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CN(c1ccc2nc[nH]c2n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
A solution of (R)—N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine-2,5,6-triamine (35 mg, 0.11 mmol), triethoxymethane (0.58 mL, 3.45 mmol) and 4-methylbenzenesulfonic acid monohydrate (62 mg, 0.33 mmol) in methanol (3.0 mL) was stirred at 150° C. for 5 min in an Initator™ Biotage microwave reactor. The volatiles were removed and the residue is purified by chromatography to give the title product. MS (m/z): 335 (M+H)+.