Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][NH:1][CH:2]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: O=C(O)Cc1cc[nH]c1
Product: COc1ccc(N2CCN(C(=O)Cc3cc[nH]c3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using (1H-pyrrol-3-yl)-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting materials. Product as an oil. LC/MS (Method B) 2.66 min, [M+1]+ 460. Potency class ND.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][C:15]=3[N:16]=1)[CH:6]=[CH:5]2.[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH-].[K+].C(O)CCC>O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][C:15]=3[N:16]=1)[CH:6]=[CH:5]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1ccc2oc(-c3ccc4cc(O)ccc4c3)nc2c1
Reactant: CCCCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCOc1ccc2cc(-c3nc4cc(CCCC)ccc4o3)ccc2c1
Yield: 56.6 %

Procedure:
In a 30ml round-bottom flask, 0.47 g (1.48 m mole) of 2-(6-hydroxy-2-naphthyl)-5-butylbenzooxazole, 0.43 g (1.79 m mole) of octyl iodide, 0.12 g (1.82 m mole) of potassium hydroxide and 5 ml of butanol were placed, followed by refluxing for 310 minutes. The reaction mixture was poured into water, extracted from ethyl acetate to obtain an organic layer. The organic layer was washed with water dried with mirabilite and dried under reduced pressure to obtain a resultant. The resultant was recrystallized from ethylacetate to obtain a crystal. The crystal was filtered, purified by silica gel column chromatography (eluent: toluene) and recrystallized from acetone to obtain 0.36 g of 2-(6-octyloxy-2-naphthyl)-5-butylbenzooxazole (Yield: 56.6%). ##STR190##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([C:14]2[S:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=O)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:21][NH2:22]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[N:21][NH:22][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(C)s2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(-c3ccc(C)s3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-(5-methylthiophene-2-carbonyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]([Cl:26])([Cl:25])[C:11]1[N:16]=[C:15](C(Cl)(Cl)Cl)[N:14]=[C:13]([C:21]([Cl:24])([Cl:23])[Cl:22])[N:12]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([NH:8][C:15]1[N:16]=[C:11]([C:10]([Cl:9])([Cl:26])[Cl:25])[N:12]=[C:13]([C:21]([Cl:23])([Cl:24])[Cl:22])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: ClC(Cl)(Cl)c1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: ClC(Cl)(Cl)c1nc(NCc2ccccc2)nc(C(Cl)(Cl)Cl)n1
Reaction time: 72 h
Yield: 84.7 %

Procedure:
Benzylamine (3.21 g., 0.03 mole) is added to 2,4,6-tris(trichloromethyl)-s-triazine (13 g., 0.03 mole) in dry benzene (75 ml.). Triethylamine (3.24 g., 0.03 mole) is then added to the reaction mixture and the solution set aside for 3 days. Evaporation to a residual oil and crystallization from methanol-water (9:1) gives the product 10.7 g., 85%, m.p. 96.5°-97°.
Reaction SMILES: [F:1][CH:2]([F:39])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)=[O:16])[N:12]([CH2:37][CH3:38])[N:11]=2)[CH:7]=[CH:8][CH:9]=1.[ClH:40].C(OCC)C>O1CCOCC1>[ClH:40].[F:39][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:22][CH:23]=3)=[O:16])[N:12]([CH2:37][CH3:38])[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCn1nc(-c2cccc(OC(F)F)c2)cc1C(=O)Nc1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCn1nc(-c2cccc(OC(F)F)c2)cc1C(=O)Nc1ccc([C@H]2CNCCO2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (S)-tert-butyl 2-(4-(3-(3-(difluoromethoxy)phenyl)-1-ethyl-1H-pyrazole-5-carboxamido)phenyl)morpholine-4-carboxylate (27 mg) (prepared in Example 41, b)) in Dioxane (40.8 μl) was added 4M−HCl in dioxane (117 μl, 470 μmol, Eq: 15). The reaction mixture was stirred at 60° C. overnight. To the mixture was added 2 ml of diethyl ether and stirred for 15 min at room temp. The mixture was filtered and concentrated in high vacuum to give the expected hydrochloride as a white solid (15 mg, 63%). MS (ISP): 443.1 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.CC1(C)O[C:22](=[O:24])[CH:21]=[C:20]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:20]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH2:21][C:22](=[O:24])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccs2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccs2)=Nc2ccc(I)cc2N1

Procedure:
Prepared from (2-amino-4-iodo-phenyl)-carbamic acid tert.-butyl ester (Example G1) and 2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (Example J1) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (30 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[NH:14])[NH:12][NH2:13])=[N:9][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:5]2=[N:6][CH:7]=1.[CH3:24][C:25]([CH3:36])([C:30](=O)[C:31](OC)=[O:32])[C:26]([O:28][CH3:29])=[O:27]>>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:30]([C:25]([CH3:36])([CH3:24])[C:26]([O:28][CH3:29])=[O:27])=[C:31]([OH:32])[N:14]=3)=[N:9][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(C(=N)NN)c3cc(F)cnc32)cc1
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccc(OC)cc3)c3ncc(F)cc23)nc1O

Procedure:
4.89 g (15.557 mmol) of the compound from Example 32A were reacted analogously to the procedure of Example 28A with 4.391 g (23.336 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124(14), 3680-3691; 2002). After the reaction had gone to completion, a solid was filtered off, which was washed with ethanol and then dried under high vacuum. This gave 6.04 g (85% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:12](OCC)=O)=[C:7]([CH3:11])[C:8]=1[CH2:9][CH3:10])[CH2:2][CH3:3].[CH:17](=O)[CH2:18]C>>[CH2:1]([C:4]1[NH:5][C:6]([CH2:12][CH2:17][CH3:18])=[C:7]([CH3:11])[C:8]=1[CH2:9][CH3:10])[CH2:2][CH3:3]
Reactant: CCCc1[nH]c(C(=O)OCC)c(C)c1CC
Reactant: CCC=O
Product: CCCc1[nH]c(CCC)c(CC)c1C

Procedure:
2-n-propyl-3-ethyl-4-methyl-5-carbethoxy-pyrrole was reductively alkylated with propionaldehyde to yield 2,5-di(n-propyl)-3-ethyl-4-methylpyrrole. ##STR103##
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:12]([CH2:23]O)=[CH:11]2>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:12]([CH2:23][Cl:3])=[CH:11]2
Reactant: OCc1cc2cccc(Cl)c2nc1-c1ccccc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccccc1-c1nc2c(Cl)cccc2cc1CCl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Thionyl chloride (0.850 mL, 11.6 mmol) was added to a stirring solution of (8-chloro-2-(2-fluorophenyl)quinolin-3-yl)methanol (0.670 g, 2.33 mmol) in CH2Cl2. The reaction mixture was stirred at room temperature. After 2.5 h, the crude product was purified by column chromatography on a 40 g Redi-Sep™ column using 0% to 100% gradient of CH2Cl2-MeOH—NH4OH (89:9:1) in CH2Cl2 to give 8-chloro-3-(chloromethyl)-2-(2-fluorophenyl)quinoline: LC-MS (ESI) m/z 306.0 [M+H]+.
Reaction SMILES: C1([C@@H]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]3)[CH2:10]2)C)C=CC=CC=1.CC(O)=O.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[C@H:16]12[NH:9][CH2:10][C@H:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2
Reactant: C[C@@H](c1ccccc1)N1C[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Yield: 75 %

Procedure:
To a solution of (1R,6S)-tert-butyl 8-((S)-1-phenylethyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.5 g, 75%) in EtOH (50 mL) was added AcOH (1.5 mL). The resulting mixture was cycled through an ThalesNano H-Cube containing a 20% Pd(OH)2/C catalyst cartridge at 50° C. and 100 bar of hydrogen pressure. After 16 hours the resulting mixture was removed from the ThalesNano H-Cube and poured over a saturated sodium carbonate solution (100 mL). The aqueous layer was extracted with DCM (50 mL) four times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (755 mg, 75%) which was used in the next step without purification. MS (ESI) mass calcd. for C11H20N2O2, 212.2; m/z found, 213.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 4.18-4.00 (m, 1H), 3.85-3.57 (m, 3H), 3.44-3.34 (m, 1H), 3.28 (dt, J=13.1, 6.5 Hz, 1H), 3.24-3.13 (m, 1H), 2.82-2.72 (m, 1H), 1.93-1.83 (m, 1H), 1.82-1.70 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].[CH3:20]OC(OC)N(C)C>C(Cl)(Cl)Cl>[CH3:20][N:14]1[C:15](=[O:16])[C:17]([CH3:18])=[CH:19][N:11]([C@@H:6]2[O:7][C@H:8]([CH2:9][OH:10])[C@@H:4]([N:1]=[N+:2]=[N-:3])[CH2:5]2)[C:12]1=[O:13]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: COC(OC)N(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(C)c1=O

Procedure:
3'-Azido-3'-deoxythymidine (0.5 g; 1.9 mMol) and N,N-dimethylformamide dimethylacetal (Zemlicka, Coll. Czech. Chem. Comm. 35, 3572 (1972)) (0.9 mL; 7.5 mMol) were refluxed in 20 mL CHCl3 for 48 hours. The solvent was removed in vacuo and the material placed on a silica solumn. Elution with EtOAc/CHCl3 (1:1 v/v) resulted in pure material as a viscous oil: 0.26 g (0.9 mMol, 47%).
Reaction SMILES: [OH:1][NH2:2].[C:3]1(=[O:10])[O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4]1>C1C=CC=CC=1.C(N(CC)CC)C>[C:3]([OH:9])(=[O:10])[CH2:4][CH2:5][CH2:6][C:7]([OH:1])=[O:8].[NH2:2][OH:1]
Reactant: O=C1CCCC(=O)O1
Agent: NO
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This example that demonstrates how this method could be performed. Part 1: To a solution of 2 g hydroxy amine in 100 ml dry benzene and 20 ml triethyl amine, 9.4 g glutaric anhydride is added and the reaction mixture stirred at room temperature for 2 h and refluxed for 2 h. The solvent is evaporated under vacuum and the residue is purified by flash chromatography using silica gel.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:33][C:30]2([CH2:29][C:28]3[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=3[O:26][CH3:25])[CH2:32][CH2:31]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1CC1(N)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: COc1ccccc1CC1(NCC(O)c2ccc(O)c3c2OCC(=O)N3)CC1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 177 mg (1 mmol) 1-(2-methoxy-benzyl)-cyclopropylamine. Yield: 100 mg (20%, trifluoroacetate); mass spectroscopy: [M+H]+=385.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19].[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:31])[CH2:29][CH3:30])[C:25](O)=[O:26])(=[O:22])[CH3:21]>>[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:31])[CH2:29][CH3:30])[C:25]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19])=[O:26])(=[O:22])[CH3:21]
Reactant: CC[C@H](C)[C@H](SC(C)=O)C(=O)O
Reactant: CCOC(=O)CN1C(=O)C(N)CCc2ccccc21
Product: CCOC(=O)CN1C(=O)C(NC(=O)[C@@H](SC(C)=O)[C@@H](C)CC)CCc2ccccc21
Yield: 48.3 %

Procedure:
By using 0.525 g (2.00 mmol) of 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one and 0.418 g (2.20 mmol) of (2S,3S)-2-acetylthio-3-methylpentanoic acid obtained in the Synthesis Example C-2, the treatment of Example C-1 was repeated. Thus, 0.420 g of the title compound was obtained as a colorless amorphous product (yield 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[S:12]([OH:14])=[O:13].O.[OH-].[Na+].[CH3:18]I>CO>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:12]([CH3:18])(=[O:14])=[O:13])=[CH:4][C:5]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc(S(=O)O)c(Cl)cc1Cl
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Yield: 56 %

Procedure:
The product of Step A is placed in a three-liter flask to which is added water (300 ml.), methanol (500 ml.) sufficient 10N sodium hydroxide to attain a pH of 9 and methyl iodide (520 g.; 3.66 moles). The reaction mixture is refluxed for 36 hours with the occasional addition of 10N sodium hydroxide to maintain pH 9. The alcohol is distilled at reduced pressure and the reaction solution is acidified with hydrochloric acid. The product is filtered, washed with water, dried and recrystallized from ethanol (800 ml.) to give 150 g. (yield 56%) 2,4-dichloro-5-methylsulfonylbenzoic acid, m.p. 210°-211° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>C(N(CC)CC)C>[C:9]([C:5]1[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(=O)c1n[nH]c(C(=O)c2ccccc2)n1

Procedure:
To a cooled, stirred mixture of 3 g. of 1,2,4-triazole-3-carboxamide and 4 g. of benzoyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 18 hours. The heterogeneous mixture is filtered and washed successively with diethyl ether, cold water and then diethyl ether and dried in vacuo for 4 hours yielding 4 g. of colorless solid. This solid is extracted with hot, dry acetonitrile and cooled yielding a solid product which is collected, washed with acetonitrile and dried in vacuo, yielding 1 g. of product, m.p. 174°-178° C. (dec.).
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[CH:24][C:10]3[S:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:14][C:13]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C[O:32][B:33](OC)[O:34]C>O1CCCC1>[C:18]1([C:15]2[CH:16]=[C:17]([B:33]([OH:34])[OH:32])[C:12]3[S:11][C:10]4[CH:24]=[CH:25][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:8][C:9]=4[C:13]=3[CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COB(OC)OC
Reactant: c1ccc(-c2ccc3sc4ccc(-c5ccccc5)cc4c3c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(-c2ccccc2)cc2c1sc1ccc(-c3ccccc3)cc12
Temperature: -78 °C

Procedure:
2,8-diphenyldibenzo[b,d]thiophene (6.0) was dissolved in anhydrous tetrahydrofuran (80 mL) under nitrogen atmosphere and the solution was then cooled to −78° C. 20.0 mL of n-butyl lithium (1.6 M solution) was added dropwise into the reaction mixture and continuously stirred to equilibrate to room temperature. The reaction mixture was then cool to −60° C. and trimethyborate (5.67 mL) was added and the reaction was allowed to stir overnight. The reaction was then quenched with 20% aqueous hydrochloric acid, and extracted the organic layer with ethyl acetate; ethyl acetate layer was then washed thoroughly with water and dried over anhydrous sodium sulfate, and was evaporated to dryness to yield 4.5 g of 2,8-diphenyldibenzo[b,d]thiophene-4-boronic acid.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=[O:4].[CH2:25](O)[CH3:26].CC1C=CC(S(O)(=O)=O)=CC=1>CC1C=CC=CC=1C>[CH3:25][CH2:26][O:4][C:3]([CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[N:14]=[C:15]([CH3:22])[N:16]([CH:19]([F:20])[F:21])[C:17]2=[O:18])[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])=[O:5]
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(Cl)Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Yield: 93 %

Procedure:
To a flask was added 140 g of the 2-chloro-3-{2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorophenyl}propionic acid, obtained according to the Example 1, 140 g of ethanol, 1.9 g of 4-methylbenzenesulfonic acid and 400 g of dimethyl benzene. The mixture was refluxed for 15 hours to remove water. The excess ethanol was recovered by distillation. At room temperature the mixture was washed with 200 g of water, with 200 g of a 4% (wt/wt) aqueous solution of sodium hydroxide and finally with water. The solvent was completely removed under reduced pressure to give carfentrazone-ethyl as a faint yellow transparent and viscous liquid in a yield of 93% with a purity of 99%. A HNMR spectrum of the carfentrazone-ethyl is showed in FIG. 1 and a mass spectrum thereof is showed in FIG. 2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14]3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH:13]1[S:12][C:8]1[C:6]2[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SC3Cc4ccccc4C3)c2n1
Product: c1ccc2c(c1)CC(Sc1ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc13)C2

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2-indanyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 202°-205° C.) and piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[CH3:22][C@@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1.CN1C(=O)CCC1>CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@H:23]2[CH3:22])[N:3]=1
Reactant: C[C@@H]1COCCN1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1ccc(F)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOC[C@H]2C)nc(Cl)c1C(=O)NCc1ccc(F)cc1
Temperature: 180 °C
Yield: 19.3 %

Procedure:
A mixture of 6.0 g (19.2 mmol) 2,6-dichloro-N-(4-fluorobenzyl)-4-methyl-pyridine-3-carboxylic amide (synthesized according to the methods described in section a) of example 2), 3.9 g (28.7 mmol) (R)-3-methylmorpholine hydrochloride, 13.0 ml (76.6 mmol) and NMP (18.4 ml) was heated in the MW to 180° C. for 16 h. After cooling to RT the mixture was partiotionated between EtOAc and a 2M aq. NaOH sol. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 1.4 g (3.7 mmol, 20%) 2-chloro-N-(4-fluorobenzyl)-4-methyl-6-[(3R)-3-methylmorpholino]-pyridine-3-carboxylic amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])N.Cl.N([O-])=O.[Na+].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([CH3:22])=[O:21]>O.CC(C)=O>[CH3:22][C:20]([C:16]1[O:15][C:19]([C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:18][CH:17]=1)=[O:21]
Reactant: CC(=O)c1ccco1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reaction time: 1 h
Yield: 35.3 %

Procedure:
A mixture of 81 g (0.50 mole) of 3,4-dichloroaniline, 100 ml of water and 75 ml of conc. HCl was heated on a steam bath to ca. 70°, and 150 ml of conc. HCl was added. White crystals separated and the mixture was cooled to 0°. A solution of 35 g (0.50 mole) of sodium nitrite in 150 ml of water was added at 0°-5° over 25 min and stirring was continued at 0°-5° for 1 hour. A solution of 55 g (0.50 mole) of methyl 2-furyl ketone in 50 ml of acetone was added quickly followed by the dropwise addition over 10 minutes at 4°-5° of a solution of 10 g (0.06 mole) of cupric chloride dihydrate in 20 ml of water. The cooling bath was removed, and the green solution was stirred overnight at ambient temperature. The solid which was deposited was collected by filtration and washed with water. Recrystallization from ca. 800 ml of MeOH gave 45 g (35%) of 5-(3,4-dichlorophenyl)-2-furyl methyl ketone A. Two additional recrystallizations from MeOH gave an analytical sample, m.p. 114°-117°.
Reaction SMILES: ClCCl.[C:4]([O:8][C:9](=[O:25])[NH:10][C@H:11]1[CH2:24][C:14]2[NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]#N)=[CH:20][C:21]=3[C:13]=2[CH2:12]1)([CH3:7])([CH3:6])[CH3:5].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=[O:37].[Na+].[Na+]>C(OCC)(=O)C>[C:4]([O:8][C:9](=[O:25])[NH:10][C@H:11]1[CH2:24][C:14]2[NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]=[O:37])=[CH:20][C:21]=3[C:13]=2[CH2:12]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1Cc2[nH]c3ccc(C=O)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine dichloromethane (15 ml) and (R)-[7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid tert-butyl ester (2 g, 6.73 mmol) and stir for 10 min under nitrogen at room temperature. Add diisobutylaluminum hydride (1 M solution in methylene chloride, 14.1 ml; 14.1 mmol) dropwise over 15 min. Add ethyl acetate (30 mL) to the reaction mixture and stir at room temperature for 1 h. Add a 20% aqueous solution of sodium tartrate (30 mL) and stir for 1 h at room temperature. Separate the organic layer and extract the aqueous layer with ethyl acetate (2×15 mL). Combine and dry (Na2SO4) organic layers, filter and concentrate to give 2.2 g [(R)-7-formyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid tert-butyl ester. Purify by chromatography on silica gel using methylene chloride/acetone (95/5) to give 1.3 g (64%). MS (m/z): 301 (M+1).