Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.[CH2:13]([NH2:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.Cl>C(Cl)Cl>[C:15]1([CH2:14][CH2:13][NH:21][C:10](=[O:12])[CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CCc1ccccc1I
Reactant: NCCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(CCc1ccccc1I)NCCc1ccccc1
Reaction time: 72 h
Yield: 120.9 %

Procedure:
To a solution of 2-iodobenzenepropionic acid (8 g, 0.029 mol) and phenethylamine (10.9 g, 0.090 mol) in methylene chloride (200 mL) was added N-ethyl-N-[3-(dimethylamino)propyl]carbodiimide hydrochloride (6.13 g, 0.032 mol) at room temperature. After 3 days, water (100 mL) and 2.5N HCl (50 mL) were added. The organic phase was separated, dried and concentrated to give an oil (13.3 g). The oil was chromatographed on silica gel and eluted with hexane: ethyl acetate (2:1) then hexane: ethyl acetate (1:1) to give a fraction containing a yellow solid 7.6 g (69%). Recrystallization from toluene (15 mL) and petroleum ether (150 mL) afforded 7.1 g of product, mp. 94.5°-95.5° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[I-].[Na+].[C:30]([O:33][CH2:34][C@@H:35]([CH3:38])[CH2:36]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:36][C@H:35]([CH3:38])[CH2:34][O:33][C:30](=[O:32])[CH3:31])[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: CC(=O)OC[C@@H](C)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H](C)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 95 °C
Reaction time: 5 h
Yield: 102.9 %

Procedure:
3.87 g of 2-tert-butyl-4-cyclobutyl-6-piperazin-1-yl-pyrimidine (14.1 mmol) were stirred in 30 ml of dimethylformamide at room temperature. 3.18 g of triethylamine (63.1 mmol), 0.235 g of sodium iodide (1.57 mmol), 2.96 g of (R)-(−)-1-acetoxy-3-bromo-2-methyl-propane (15.2 mmol) were added and the reaction mixture was stirred for 5 h at 95° C. The dimethylformamide was evaporated under reduced pressure. The residue was partitioned between 100 ml of dichloromethane and 100 ml of water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give a brownish oil (5.64 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[N:22]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:36])([F:35])[F:37])=[CH:31][CH:32]=4)[N:22]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)Oc1ccc(-c2cccc(CCl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2cccc(COc3ccc(CCCCn4ccnn4)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
A solution of 37 mg (0.17 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 2.0 ml N,N-dimethylformamide was treated at 0° C. with 7 mg (0.17 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 50 mg (0.17 mmol) 2-Chloromethyl-6-(4-trifluoromethoxy-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 4 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diethylether. The residue was dried at 40° C. to give 15 mg (18%) of the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.C([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])C.C(N(CC)CC)C>C(O)C>[ClH:1].[N+:8]([C:7]1[C:2]([NH:17][C@H:16]([C:15]([OH:19])=[O:14])[CH3:18])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H](Nc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A suspension of 2-chloro-3-nitropyridine (68.6 g, 0.434 mole), (S)-alanine ethyl ester hydrochloride (100 g, 0.651 mole) and triethylamine (103.7 g, 1.03 mole) in 95% ethanol was heated at reflux for 4.5 hours, during which time a dark yellow solution formed. The reaction mixture was stirred at room temperature overnight and then refluxed for an additional 2 hours. The solvents were evaporated under reduced pressure, and the resulting solid was triturated in ethyl acetate, filtered, and rinsed with additional ethyl acetate. The filtrate and washings were combined and washed three times with water, dried over sodium sulfate, filtered, and evaporated to an oil weighing 107 g (quantitative yield). The oil was eluted through 600 g of silica gel, using ethyl acetate as the eluent, and evaporated to an oil. A 3.5-g portion of the oil was dissolved in isopropyl alcohol and acidified with ethereal hydrogen chloride. The mixture was evaporated and redissolved in acetonitrile. Addition of isopropyl ether caused a solid to precipitate. The solid was collected by filtration and its mother liquor was evaporated and the residue was triturated in ethereal hydrogen chloride. A yellow solid formed which was collected by filtration. Upon standing, more solid formed in the mother liquor. This solid was collected by filtration, rinsed with diethyl ether and dried under high vacuum to give 0.14 g of title compound, mp>260° C. (darkens 178°-185° C.).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7]CO)=[N+:2]=[N-:3].S(Cl)(C)(=O)=O.[CH3:15][S:16]([O:19][CH2:20]CN=[N+]=[N-])(=[O:18])=[O:17]>>[CH3:15][S:16]([O:19][CH2:20][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:5][CH2:6][CH3:7])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCCCCO
Agent: CS(=O)(=O)Cl
Product: CCCC(COS(C)(=O)=O)N=[N+]=[N-]

Procedure:
Reaction of 5-azidopentanol (1.1 g, 8.53 mmol) and mesyl chloride (0.98 mL, 12.79 mmol) within 3 h as described for synthesis of 156a gave compound 156d (1.54 g) as a crude colorless oil.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][CH2:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:8][C:7]([C:18]([OH:20])=O)=[N:6]1)[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C(Cl)=O.C[N:28](C=O)C>ClCCl>[CH2:1]([N:5]1[C:9]([CH2:10][CH2:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:8][C:7]([C:18]([NH2:28])=[O:20])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCn1nc(C(=O)O)cc1CCS(=O)(=O)CCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCn1nc(C(N)=O)cc1CCS(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxylic acid (4.00 g, 13.22 mmol) in dichloromethane (66 mL) was added oxalyl chloride (3.5 mL, 39.7 mmol) and a drop of DMF. The solution bubbled vigorously and was stirred at ambient temperature for 30 minutes. The solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (66 mL) and the resulting solution was cooled in an ice bath, then concentrated ammonium hydroxide (66 mL) was added dropwise. After the addition was complete, the ice bath was removed and the mixture was stirred at ambient temperature for 2 hours. The volatiles were removed under reduced pressure to afford a slurry that was extracted with chloroform (2×100 mL). The organic layers were combined and concentrated under reduced pressure to afford 4.0 g of 1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxamide as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][N:12]=1>CN(C)C=O.C(OCC)(=O)C>[I:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1
Reactant: Fc1cc(I)ccn1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1ccnc(Oc2ccccc2)c1
Temperature: 100 °C

Procedure:
Phenol (0.464 g) in N,N-dimethylformamide (5 mL) was treated with sodium hydride (60% in mineral oil, 0.057 g). After the gas evolution ceased, 2-fluoro-4-iodopyridine (0.22 g) was added slowly to the solution. The mixture was heated at 100° C. overnight under nitrogen atmosphere, cooled, diluted with ethyl acetate and washed with aqueous NaOH. The organic layer was concentrated and purified by preparative TLC, eluting with petroleum ether/ethyl acetate (10/1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[CH:33]=1)C1C=CC=CC=1.[CH2:41]([S:43]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:45])=[O:44])[CH3:42]>>[CH2:28]([N:27]1[C:23]([C:12]2[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([N:49]4[CH2:48][CH2:47][N:46]([S:43]([CH2:41][CH3:42])(=[O:45])=[O:44])[CH2:51][CH2:50]4)=[O:39])[CH:33]=3)[CH:11]=2)=[N:24][N:25]=[N:26]1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCS(=O)(=O)N1CCNCC1
Product: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)N3CCN(S(=O)(=O)CC)CC3)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-(1-butyl-1H-tetrazol-5-yl)-biphenyl-3-carboxylic acid and 1-ethylsulfonyl-piperazine as described in general procedure D. LCMS: 514 [M+H].
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1)(=[O:31])=[O:30]
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(O)C3)o2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(C(=O)N3CC(OS(C)(=O)=O)C3)o2)cc1
Reaction time: 7 h
Yield: 177.9 %

Procedure:
A suspension of 4A (5.45 g, 19. 8 mmol) in dichloromethane (100 mL) was cooled in an ice-bath. Triethylamine (4.4 mL, 31.7 mmol) was added followed by methanesulfonyl chloride (2.3 mL, 29.7 mmol). After the addition, the cooling bath was removed. The mixture was stirred for 7 h. The mixture was transferred to a separatory funnel and was washed with water followed by aqueous NaHCO3 (sat.). The organic solution was dried (phase separator) and evaporated. Dichloromethane (50 mL) and diethyl ether (200 mL) were added and the solid product was filtered. The product was washed twice with diethyl ether and then dried in vacuo. There was obtained 5.03 g (72%) of 4B as a solid. 1H NMR (500 MHz, CDCl3): δ 3.13 (s, 3H), 3.90 (s, 3H), 4.42 (dd, 1H), 4.64 (dd, 1H), 4.86 (dd, 1H), 5.11 (dd, 1H), 5.40 (m, 1H), 7.02 (d, 2H), 8.09 (d, 2H), MS (APCI+) m/z 354 [M+H]+.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:12]=[CH:11][C:10]=1[C:29](=[O:32])[CH2:30][CH3:31])=O)(C)(C)C.[ClH:33]>O1CCOCC1.C(OCC)C>[ClH:33].[NH2:8][C:9]1[C:10]([C:29](=[O:32])[CH2:30][CH3:31])=[CH:11][CH:12]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[N:14]=1
Reactant: CCC(=O)c1ccc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCC(=O)c1ccc(NC2CCCNC2)nc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
380 mg (0.85 mmol) of tert-butyl 3-({6-[(tert-butoxycarbonyl)amino]-5-propanoylpyridin-2-yl}amino)piperidine-1-carboxylate (Example 26A) were dissolved in 10 ml of a solution of hydrochloric acid in dioxane (4 M), and the mixture was stirred at RT for 20 h. After the reaction had gone to completion, the reaction mixture was diluted with diethyl ether (100 ml), and the recipitate was filtered off and washed with diethyl ether (100 ml) and dried. This gave 170 mg (70% of theory) of the product as a solid.
Reaction SMILES: [C-:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](O)=[O:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].P(Cl)(Cl)[Cl:22]>N1C=CC=CC=1.C1C=CC=CC=1>[C-:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([Cl:22])=[O:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: ClP(Cl)Cl
Reactant: O=C(O)c1ccccc1-[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1ccccc1-[c-]1cccc1
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of o-ferrocenylbenzoic acid (1.75 g) and pyridine (3 drops) in 10 cm3 of dry benzene was slowly added 5 cm3 of phosphorous trichloride. The resulting mixture was then stirred for 3 hours at 60° to 70° C. After this time the solution was decanted off and the solvent removed under vacuum. The residue was twice more evaporated from dry benzene and then taken up in light petroleum (40° to 60° ). Removal of the solvent under vacuum afforded 1.54 g (83%) of o-ferrocenylbenzoyl chloride, a dark-red, viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2([CH2:14][C:15]([OH:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2([CH2:14][C:15]([OH:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]
Reactant: O=C(O)CC1(C(=O)c2ccc(Cl)cc2)CCCCC1
Reactant: O=[N+]([O-])O
Product: O=C(O)CC1(C(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CCCCC1

Procedure:
Prepared analogously to Example 189b from [1-(4-chloro-benzoyl)-cyclohexyl]-acetic acid and fuming nitric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:26])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: COCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COCCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with 2-methoxyethylamine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=471.1 [M+H]+.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29].[B:30](OC)([O:33]C)[O:31]C>O1CCCC1>[C:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:13]([B:30]([OH:33])[OH:31])[CH:18]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COCCOCOc1ccc(C(C)(C)C)cc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCOCOc1ccc(C(C)(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
n-Butyllithium in hexane (2.5 M, 4.2 mL, 10.5 mmol) was added dropwise to a solution of give 2-bromo-4-(tert-butyl)-1-((2-methoxyethoxy)methoxy)benzene (3.0 g, 9.46 mmol) and trimethyl borate (1.2 mL, 10.76 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 20 minutes then at 0° C. for an additional 20 minutes. The reaction was then quenched by the addition of water (20 mL) and the mixture extracted with ether (100 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure to give (5-(tert-butyl)-2-((2-methoxyethoxy)methoxy)phenyl)boronic acid (2.61 g, 98% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:12][C:13]1[CH:14]=[C:15]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: Cc1ccc(B(O)O)cc1C
Product: COC(=S)c1cc(Nc2ccc(C)c(C)c2)c(C)s1
Yield: 129.5 %

Procedure:
Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 108 mg (2 equiv, 0.72 mmol) of 3,4-dimethylphenyl boronic acid to give 135.9 mg (32.4%) of methyl 4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ2.24 (s, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 3.88 (s, 3H), 6.11 (bs, 1H), 6.80-6.84 (m, 2H), 7.07 (d, 1H, J=7.9 Hz), 7.71 (s, 1H).
Reaction SMILES: ClC1N2C(=[O:11])NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].ICC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:46][C:45](NCC)(C(N)=O)[CH2:44]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:44][CH:45]([OH:11])[CH2:46]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)=[CH:35][CH:36]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Agent: [Cl-]
Solvent: CCI
Product: CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(N3CC(O)C3)n2c1=O

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with the requisite amine, followed by alkylation with iodoethane, in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=4.173 min, [M+H]30 =456.
Reaction SMILES: [CH3:1][C:2]1[C:3](N=NC2C=CC=CC=2O)=[C:4]([OH:15])[CH:5]=[C:6]([CH3:14])[C:7]=1C1C=CC=CC=1.O.[NH2:26]N>CO.[Ni]>[CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([CH3:14])[C:7]=1[NH2:26]
Reactant: Cc1cc(O)c(N=Nc2ccccc2O)c(C)c1-c1ccccc1
Reactant: NN
Agent: [Ni]
Solvent: CO
Solvent: O
Product: Cc1cc(O)cc(C)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
3,5-Dimethyl-4-phenylazophenol (132.0 g, 0.583 mol) was dissolved in methanol (500 mL) and pure (100%) hydrazine hydrate (113 mL, 2.33 mol), and Raney nickel [50% slurry in water (Aldrich), (2.5 mL)] was added to give an exothermic reaction. The mixture was stirred for one hour at ambient temperature and then heated to gentle reflux for three hours. The solution was filtered hot and cooled to room temperature. The crystals which formed were collected by filtration and dried to afford 3,5-dimethyl-4-aminophenol (42.4 g, 60% yield) as a white solid; m.p. 180.5-182.5; 1H-NMR (DMF-d7). δ 2.10 (s, 6H, CH3), 5.32 (s, 2H, NH2), 5.32 (s, 1H, OH), 6.45 (s, 2H, aromatic).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][NH2:25])=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][NH:25][C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Product: CC(C)(C)OC(=O)N1CCCC1CNc1cccn2nc(Cl)nc12

Procedure:
2-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (475.0 mg, 2.372 mmol) in a manner analogous to Example 2d. Product isolated as a yellow viscous oil (0.411 g, 54%). MS=374, 376 (MH)+.
Reaction SMILES: [ClH:1].FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C(NC[C@H]3CCNC3)=O)SC=12.[F:41][C:42]1[CH:76]=[C:75]([NH:77][C:78]([NH:80][C:81](=[O:89])[CH2:82][C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[S:79])[CH:74]=[CH:73][C:43]=1[O:44][C:45]1[CH:50]=[CH:49][N:48]=[C:47]2[CH:51]=[C:52]([C:54]3[CH:59]=[CH:58][C:57]([N:60]4[CH2:65][CH2:64][N:63](C(OC(C)(C)C)=O)[CH2:62][CH2:61]4)=[CH:56][CH:55]=3)[S:53][C:46]=12>>[ClH:1].[ClH:1].[F:41][C:42]1[CH:76]=[C:75]([NH:77][C:78]([NH:80][C:81](=[O:89])[CH2:82][C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)=[S:79])[CH:74]=[CH:73][C:43]=1[O:44][C:45]1[CH:50]=[CH:49][N:48]=[C:47]2[CH:51]=[C:52]([C:54]3[CH:55]=[CH:56][C:57]([N:60]4[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]4)=[CH:58][CH:59]=3)[S:53][C:46]=12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc4nccc(Oc5ccc(NC(=S)NC(=O)Cc6ccccc6)cc5F)c4s3)cc2)CC1
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)NC[C@H]4CCNC4)sc23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(N5CCNCC5)cc4)sc23)c(F)c1
Yield: 21 %

Procedure:
Following the procedure described above for the synthesis of compound 137a (scheme 25, example 97) but substituting compound 135b for the compound 158, title compound 159 was obtained in 21% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.48(s, 1H), 11.84 (s, 1H), 9.26(bs, 1H), 8.62(d, J=5.6 Hz, 1H), 8.05(d, J=12.0 Hz, 1H), 7.94 (s, 1H), 7.81(d, J=8.8 Hz, 2H), 7.62-7.55 (m, 2H), 7.37-7.31 (m, 4H), 7.31-7.24 (m, 1H), 7.10(d, J=8.8 Hz, 2H), 6.85(d, J=5.6 Hz, 1H), 3.83 (s, 2H), 3.58-3.51 (m, 4H), 3.26-3.18 (m, 4H). LRMS (M+1) 597.2 (100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].ClCC#CC[N:32]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[C:33](=[O:35])[O-:34]>>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:7][CH2:8][N:9]([CH2:4][C:6]#[C:7][CH2:8][O:34][C:33]([NH:32][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)=[O:35])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C([O-])N(CC#CCCl)c1cccc(Cl)c1
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(CC#CCOC(=O)Nc3cccc(Cl)c3)CC2)cc1
Yield: 128.3 %

Procedure:
Ethyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-(4-{[(3 chloroanilino)carbonyl]oxy}-2-butynyl)-4-piperidinecarboxylate was prepared according to the general method as outlined in Example 37 (step 1). Starting from 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (0.291 g,0.7 mmol) and 4-chloro-2-butynyl-(3-chlorophenyl)carbamate (0.19 g, 0.735), 0.27 g (64%) of the desired product was isolated as pale yellow oil. Electrospray Mass Spec: 601.3 (M+H)+