Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:15](=[O:16])[N:9]2[N:10]=[C:11](Cl)[CH:12]=[CH:13][C:8]2=[N:7]1)([OH:3])=[O:2].O.O.[SH-:19].[Na+].Cl.[OH-].[Na+]>O>[C:1]([CH2:4][CH2:5][N:6]1[C:15](=[O:16])[N:9]2[N:10]=[C:11]([SH:19])[CH:12]=[CH:13][C:8]2=[N:7]1)([OH:3])=[O:2]
Reactant: O=C(O)CCn1nc2ccc(Cl)nn2c1=O
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCn1nc2ccc(S)nn2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-carboxyethyl)-6-chloro-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on (567 mg., 2.34 m.moles) and 70% sodium hydrosulfide dihydrate (924 mg., 7.02 m.mole) in water (10 ml.) was stirred at room temperature for 2 hours. The reaction mixture was adjusted successively to pH 1 with c. HCl, to pH 10 with NaOH and then to pH 1 with c. HCl. The resulting precipitate of 2-(carboxyethyl)-2,3-dihydro-6-mercapto-s-triazolo[4,3-b]pyridazin-3-on was collected by filtration and washed with water. Yield: 418 mg. (74%). M.p. 174°-176° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[C:17]([CH2:16][CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[C:6]=1[C:4]([OH:3])=[O:5])([OH:19])=[O:18]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2ccccc12
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)CCc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
Using general procedure B, 3-(2-ethoxycarbonyl-ethyl)-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 372.4 ([M−H]−).
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:25][C:19]1[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:26])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3F)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2cccc(F)c2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 80 %

Procedure:
As described for example 261f, 6-[3-(2,3-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (190 mg, 80%) which was obtained as a white solid. MS: m/e=430.3 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[O:11][CH:10]([CH3:13])[CH2:9][CH2:8][C:7]=2[C:6]([CH3:14])=[CH:5][CH:4]=1)[NH2:2].C(N(C(C)C)CC)(C)C.Cl[C:25]([O:27]C)=[O:26]>C1COCC1>[CH3:13][CH:10]1[CH2:9][CH2:8][C:7]2[C:6]([CH3:14])=[CH:5][CH:4]=[C:3]([NH:1][NH:2][C:25]([OH:27])=[O:26])[C:12]=2[O:11]1
Reactant: Cc1ccc(NN)c2c1CCC(C)O2
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NNC(=O)O)c2c1CCC(C)O2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A stirred mixture of the 1F, 200 ml of THF and 12.4 g of N,N-diisopropyl-N-ethylamine was chilled to 0° C. and 9.1 g of methyl chloroformate was added, drop-by-drop, over five minutes. The mixture was poured over ice water and extracted with ether. The extract was dried (MgSO4) and concentrated to dryness, to give the methyl ester of 2-(3,4-dihydro-2,5-dimethyl-2H-1-benzopyran-8-yl)hydrazinecarboxylic acid (1G), as an amber syrup.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:24])[CH2:7][O:8][C:9]1[CH:22]=[C:21]2[C:12]([CH:13]=[CH:14][C:15]3[O:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]=32)=[CH:11][CH:10]=1)(C)C.S(=O)(=O)(O)O.[CH2:30]([OH:32])[CH3:31]>>[CH2:30]([O:32][C:17](=[O:23])[CH2:18][CH2:19][C:20]1[C:21]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:7][C:6]([O:5][CH2:2][CH3:1])=[O:24])[CH:22]=2)[CH:13]=[CH:14][C:15]=1[OH:16])[CH3:31]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)COc1ccc2ccc3c(c2c1)CCC(=O)O3
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1c(O)ccc2ccc(OCC(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 312 h
Yield: 86 %

Procedure:
To a solution of 2.97 g (9.0 mmol) of [(2,3-dihydro-3-oxo-1H-naphtho[2,1-b]pyran-9-yl)oxy]acetic acid 1,1-dimethylethyl ester from the preceding example, in 120 mL of ethanol, was added 2 mL of concentrated sulfuric acid and the resulting solution was allowed to stir at room temperature for 13 days. Most of ethanol was removed under reduced pressure and the residue was dissolved in ether. The solution was washed with saturated aqueous sodium bicarbonate solution and work-up was completed in the usual manner. The crude product was purified by flash chromatography on 150 g silica gel, eluting with hexane-ethyl acetate (4:1). There was obtained 2.69 g (86.0%) of the title compound as a white solid, mp 112°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH2:16][CH3:17])([CH3:14])[CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC(C)(C)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)N=C=Nc1cc(Cl)cc(Cl)c1
Reaction time: 3 h

Procedure:
To a solution of 3.0 g of N-(3,5-dichlorophenyl)-N'-t-pentylthiourea produced in Example A-2 in 25 ml of THF were added 2.44 g of DCC and 0.36 g of triethylamine. The mixture was relfuxed for 3 hours and evaporated in vacuo. The residue was extracted with petroleum ether. The extract was evaporated in vacuo to give N-(3,5-dichlorophenyl)-N'-t-pentylcarbodiimide as an oil. To a solution of this oil in 30 ml of THF were added 1.0 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was refluxed for 40 hours and evaporated in vacuo. The residue was recrytallized from diisopropyl ether-ethyl acetate mixture to give 1.9 g of the title compound as colorless needles melting at 151.0°-153.0° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH2:1]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])[CH2:21][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzyl bromide (2.29 mL, 19.3 mmol) was added dropwise to a cooled (0° C.) mixture of commercially available 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoic acid (4.96 g, 19.3 mmol) and K2CO3 (6.67 g, 48.3 mmol) in 40 mL of DMF. The reaction mixture was permitted to warm to rt and stir for 3 days (the reaction was likely complete after only a few h). The reaction mixture was diluted with ether and washed four times with water, then once with brine. The ethereal layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 30% ethyl acetate/hexanes) provided tert-butyl 4-[3-(benzyloxy)-3-oxopropyl]piperidine-1-carboxylate. 1HNMR (CDCl3, 500 MHz): δ 7.38 (m, 5H), 5.14 (s, 2H), 4.09 (br m, 2H), 2.65 (m, 2H), 2.41 (t, J=7.5 Hz, 2H), 1.63 (m, 4H), 1.47 (s, 9H), 1.40 (m, 1H), 1.10 (dq, J=4.0, 12 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:18]=[C:17]([C:19]([OH:21])=O)[O:16][N:15]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34]([O:40][CH2:41][CH3:42])(=[O:39])[CH2:35]C([O-])=O>>[CH2:41]([O:40][C:34](=[O:39])[CH2:35][C:19]([C:17]1[O:16][N:15]=[C:14]([CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH:18]=1)=[O:21])[CH3:42]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)c1cc(C(=O)O)on1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCOC(=O)CC(=O)c1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1

Procedure:
The title compound was prepared from 3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazole-5-carboxylic acid by treatment with carbonyldiimidazole followed by the magnesium salt of mono-ethyl malonate as described in Angew. Chem. Int Ed. Eng., 18 (1979), p. 72.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>>[CH2:28]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[CH2:22][NH:21][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[CH:20][CH:19]=1)[CH3:29]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1
Yield: 98 %

Procedure:
In a manner identical to Example 15, 4-geranyloxybenzoic acid (1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.96 g (98%) of the aimed compound.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][CH:27]=[N:26][C:25]=2[C:29](O)=[O:30])=[CH:20][CH:19]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:29]([C:25]3[N:26]=[CH:27][O:28][C:24]=3[C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[O:30])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: CC(F)(F)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccc(F)cc3)n2)n1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1.C(N(CC)CC)C.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>C(O)CCC>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=4)=[N:3][C:4]4[N:5]([N:17]=[CH:18][N:19]=4)[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCn1ncc2c1ncc1c(Nc3cccc(C(F)(F)F)c3)nc3ncnn3c12

Procedure:
5.8 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]-pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine (0.02 mol.), 3 g. of triethylamine and 3.3. g. of 3-trifluoromethylaniline are refluxed in butyl alcohol for 24 hours with stirring. The solvent is removed in vacuo and the residue treated with 20 ml. of water and filtered off. Recrystallization from alcohol yields 8-ethyl-N-[3-(trifluoromethyl)phenyl]-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidin-5-amine.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][S:15][CH2:14][CH2:13]3)[C:7](=[O:18])[CH:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.IC.[CH3:25]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:13][CH2:14][S:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]3([CH3:25])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCSCC1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC12COCCN1c1nc(Cl)ncc1N(C1CCSCC1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.6 %

Procedure:
To a mixture of 2-chloro-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (83.6 mg, 0.245 mmol) and iodomethane (0.077 ml, 1.226 mmol) in DMSO (3 ml) at 0° C. was added sodium 2-methylpropan-2-olate (47.1 mg, 0.491 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water (containing Na2S2O3), dried and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 1:1) to afford 2-chloro-6a-methyl-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (9.4 mg, 0.026 mmol, 11% yield) as a colorless oil. MS [M+H] found 355.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH3:23]I>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([N:7]=[C:8]2[N:13]([CH3:23])[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[S:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: CI
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(N=c2sc3ncccc3c(=O)n2C)cc1

Procedure:
The reaction procedure of Example 11 was followed except that 428 mg of 2-(4-methoxyanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.094 ml of methyl iodide were used. As a result, 200 mg of 2-[(4-methoxyphenyl)imino]-3-methyl-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 35 mg of 2-[N-(4-methoxyphenyl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13]C=C)=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)[CH:7]=[CH:6]2.[CH2:24]([C:33]([CH2:44][CH2:45][CH2:46][C:47]([F:53])([F:52])[C:48]([F:51])([F:50])[F:49])([C:39]([O:41]CC)=[O:40])C(OCC)=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH:33]([CH2:44][CH2:45][CH2:46][C:47]([F:52])([F:53])[C:48]([F:49])([F:50])[F:51])[C:39]([OH:41])=[O:40])=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH:7]=[CH:6]2
Reactant: C=CCc1c(-c2ccc(OC)cc2)ccc2cc(OC)ccc12
Reactant: C=CCCCCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Product: O=C(O)C(CCCCCCCCCCc1c(-c2ccc(O)cc2)ccc2cc(O)ccc12)CCCC(F)(F)C(F)(F)F

Procedure:
Starting with 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene and separately prepared diethyl 2-(8-nonenyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate, the same procedures as shown in Examples 1, 2 and 3 were repeated to give 12-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoic acid.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[Cl:30])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:29].[NH2:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[Cl:30])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2Cl)cc1
Reaction time: 2 h

Procedure:
To (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(2′,5′-dichlorobiphenyl-4-yl)butanoate (1.09 g, 2.33 mmol) is added a solution of 4 M HCl in 1,4-dioxane (5.81 mL, 23.3 mmol) at room temperature. After stirring for 2 hours, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 3-amino-4-(2′,5′-dichlorobiphenyl-4-yl)butanoate hydrochloride. Next, a solution of the product, succinic anhydride (280 mg, 2.80 mmol) and DIPEA (0.489 mL, 2.80 mmol) in dichloromethane (15 mL) is allowed to stir for 2 hours. The reaction is quenched with 1 M aqueous HCl and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(2′,5′-dichlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (553 mg) as a white solid; HPLC retention time=1.02 minutes (condition B); MS (m+1)=452.14; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.2 Hz, 3H) 2.47-2.67 (m, 6H) 2.89 (A of ABX, Jab=13.7 Hz, Jax=7.8 Hz, 1H) 3.00 (B of ABX, Jab=13.7 Hz, Jbx=6.7 Hz, 1H) 4.12-4.24 (m, 2H) 4.49-4.57 (m, 1H) 6.53 (br d, J=8.8 Hz, 1H) 7.23-7.26 (m, 3H) 7.32-7.40 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH3:19])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH2:34])[CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2([C:6]3[N:5]=[C:4]([CH3:19])[N:3]=[C:2]([NH:34][C:24]4[CH:25]=[CH:26][C:27]([N:28]5[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]5)=[C:22]([O:21][CH3:20])[CH:23]=4)[CH:7]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:13][CH:14]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1nc(Cl)cc(C2(c3ccc(Cl)cc3)CCC2)n1
Product: COc1cc(Nc2cc(C3(c4ccc(Cl)cc4)CCC3)nc(C)n2)ccc1-n1cnc(C)c1
Yield: 81 %

Procedure:
The title compound was prepared in analogous manner as described in example 62 from 4-chloro-6-[1-(4-chloro-phenyl)-cyclobutyl]-2-methyl-pyrimidine and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine Obtained as a pale-yellow solid in 81% yield after column chromatography of the crude product on silica gel using dichloromethane/methanol (19:1 v/v) as eluent.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:5]=1[CH2:6]O)([O-:3])=[O:2].S(Cl)([Cl:18])=O>>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:5]=1[CH2:6][Cl:18])([O-:3])=[O:2]
Reactant: COc1cc(CO)c([N+](=O)[O-])cc1OC
Reactant: O=S(Cl)Cl
Product: COc1cc(CCl)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 86.4 %

Procedure:
570 g of 2-nitro-4,5-dimethoxybenzyl alcohol was added over 1 hour to 733 ml of thionyl chloride at 0° C. The solution was heated to 25° C. over 2 hours and to 50°-56° C. for 2 hours. The solution was cooled to 5° C. and the mixture was poured onto 12 l of ice water with stirring. The supernatant was poured off and the solid washed with water. The oily solid was blended with ice and water, filtered, and dried in a 40° C. vacuum oven to yield 535 g, 86.4% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[C:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:24]([O:23][C:21](=[O:22])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:13]2[CH:14]=[CH:15][C:10]([C:9](=[O:20])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:33][CH:34]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A solution of the product of Example 49A (5.132 g, 14.45 mmol) in anhydrous N,N-dimethylformamide (50 mL) was treated with N-Boc-4-hydroxyaniline (3.024 g, 14.45 mmol) and potassium carbonate (3.994 g, 28.90 mmol) at room temperature, then heated at 80° under a nitrogen atmosphere for 4.5 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with water (4×50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give the product as a dark yellow solid (7.38 g, 13.97 mmol, 97%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6](Cl)[N:5]=[C:4]([CH3:11])[N:3]=1.[NH2:12][NH2:13]>>[Cl:1][C:2]1[N:3]=[C:4]([CH3:11])[N:5]=[C:6]2[NH:12][N:13]=[CH:8][C:7]=12
Reactant: NN
Reactant: Cc1nc(Cl)c(C=O)c(Cl)n1
Product: Cc1nc(Cl)c2cn[nH]c2n1
Reaction time: 0.25 h
Yield: 5.86 %

Procedure:
The resulting solution of 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde was treated dropwise with a solution of anhydrous hydrazine (1101 μL, 35071 μmol) at −78° C. The mixture was stirred for 15 min, and then the cooling bath was removed and the mixture stirred at RT for 1 h. The mixture was concentrated and partitioned between water (110 mL) and EtOAc (110 mL). The organic layer was washed with saturated aqueous NaHCO3 (100 mL), separated, dried (MgSO4), treated with activated charcoal and filtered through a plug of silica, washing with EtOAc. The filtrate was concentrated and purified by flash chromatography on silica eluting with 5% acetone/DCM to 25% EtOAc/hexane. The residue was suspended in DCM (3 mL), cooled in a freezer, and filtered to give 4-chloro-6-methyl-1H-pyrazolo[3,4-d]pyrimidine (330 mg, 5.86% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 14.25 (bs, 1H); 8.35 (s, 1H); 2.68 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[NH:12][CH3:13])[CH3:2].[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:15])[CH:8]=[C:7]([F:11])[C:6]=1[NH:12][CH3:13])[CH3:2]
Reactant: CCOC(=O)c1cccc(F)c1NC
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Cl)cc(F)c1NC
Temperature: 25 °C
Reaction time: 3 h
Yield: 124 %

Procedure:
To a solution of 3-fluoro-2-methylaminobenzoic acid ethyl ester (124 mg, 0.63 mmol) in acetic acid (4 ml) was added 1,3-dichloro-5,5-dimethylhydantoin (93 mg, 0.47 mmol). The reaction mixture was stirred at RT for 3 h. The mixture was diluted with ethyl acetate and then washed with sat. NaHCO3. The organic phase was then washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography to give 5-chloro-3-fluoro-2-methylaminobenzoic acid ethyl ester (135 mg, 93%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): 7.67 (dd, J=2.5, 1.5 Hz, 1H), 7.52 (brds, 1H), 7.09 (dd, J=13.5, 2.5 Hz, 1H), 4.31 (q, J=7.0 Hz, 2H), 3.11 (m, 3H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: S[C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1>C(O)C.[Ni]>[NH:6]1[CH:2]=[N:3][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5]1
Reactant: CCOC(=O)Cc1n[nH]c(S)n1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)Cc1nc[nH]n1
Temperature: 80 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
A suspension of ethyl (5-mercapto-1H-1,2,4-triazol-3-yl)acetate obtained in Reference Example 13 (2.00 g, 10.7 mmol) and Raney-nickel (5.00 g) in ethanol (20 mL) was stirred at 80° C. for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. To a suspension of the residue in ethyl acetate was added activated carbon, and the mixture was filtered. the filtrate was concentrated under reduced pressure to give the title compound as a pale-green powder (900 mg, 54%).