Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24](=[O:31])[O:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33]>Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24](=[O:31])[O:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COCN(c1cc(Cl)cnc1C1OC(=O)c2ccccc21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: O=C1OC(c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 4-chloro-N-[5-chloro-2-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide in 3 mL HCl (4 M in dioxane) and 1 mL water was refluxed for 2 h. After cooling to room temperature, the mixture was concentrated and the residue was purified via preparative TLC (50% EtOAc in hexane) to provide 11 mg of 4-chloro-N-[5-chloro-2-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS m/ z 503.3 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[F:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][CH2:18][C:19]([NH:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O)CCOc1ccc(F)cc1
Reactant: COC(=O)C(N)C(=O)OC
Product: COC(=O)C(NC(=O)CCOc1ccc(F)cc1)C(=O)OC
Yield: 80 %

Procedure:
This compound was synthesized from dimethyl aminomalonate according to the procedure for the preparation of example 2 using 3-(4-fluorophenoxy)propionic acid. The crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (80%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:13]([C:23](=O)[CH3:24])[C:12]=2[OH:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:27]([C:29]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1)=[S:30])[NH2:28].CN(C)C=O>Cl.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:14]=[C:13]([C:23](=[N:28][NH:27][C:29]([NH:31][C:32]3[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)=[S:30])[CH3:24])[C:12]=2[OH:26])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1nn(Cc2ccccc2)c(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(Cc2ccccc2)c(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 70.3 %

Procedure:
1-[5-(4-tert-Butylphenyl)-1-benzyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.218 mmol, 76 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.218 mmol, 46 mg) were stirred with dimethylformamide (3.5 mL) and three drops of concentrated hydrochloric acid at room temperature for 22 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (83 mg, yield 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH:38]=O)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:51]1([O:56][C:57](=[O:64])[C@H:58]([CH2:60][CH:61]([CH3:63])[CH3:62])[NH2:59])[CH2:55][CH2:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH2:38][NH:59][C@H:58]([C:57]([O:56][CH:51]3[CH2:52][CH2:53][CH2:54][CH2:55]3)=[O:64])[CH2:60][CH:61]([CH3:62])[CH3:63])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(CC=O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(CCN[C@@H](CC(C)C)C(=O)OC4CCCC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 39.7 %

Procedure:
To a solution of Intermediate F (0.165 g, 0.32 mmol) in dichloroethane (10 mL) was added L-leucine cyclopentyl ester tosylate (0.197 g, 0.52 mmol) and sodium triacetoxyborohydride (0.151 g, 0.71 mmol). The mixture was stirred for 90 minutes, then quenched by addition of saturated ammonium chloride (20 mL). The product was extracted with dichloromethane (3 times 100 mL) and the combined organic extracts were dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, ethyl acetate) to yield the desired product (0.089 g, 53% yield). LC/MS: m/z 701.25 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].[F-].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([Cl:14])[CH:16]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: COc1ccc(B(O)O)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cc(Br)nc(-c2ccc(OC)c(Cl)c2)c1N
Temperature: 80 °C
Yield: 30.2 %

Procedure:
A vial containing a mixture of methyl 3-amino-2,6-dibromoisonicotinate (500 mg, 1.613 mmol), 3-chloro-4-methoxyphenylboronic acid (301 mg, 1.613 mmol), cesium fluoride (588 mg, 3.87 mmol), and tetrakis(triphenylphosphine)palladium(0) (112 mg, 0.097 mmol) was flushed with nitrogen. Dimethoxyethane (8 mL) was added and the reaction was heated at 80° C. for 18 hr. It was then partitioned between EtOAc and water and the organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed. Radial silica gel chromatography (step gradient elution with hexane containing 25 to 40% methylene chloride) afforded methyl 3-amino-6-bromo-2-(3-chloro-4-methoxyphenyl)isonicotinate (181 mg) as a yellow solid. MS (ESI) m/z 373.0 (M+H). 1H NMR (CDCl3) δ ppm 7.79 (1H, s), 7.66 (1H, d, J=2.14 Hz), 7.52 (1H, dd, J=8.55, 2.14 Hz), 7.02 (1H, d, J=8.55 Hz), 5.94 (2H, br. s.), 3.95 (3H, s), 3.92 (3H, s).
Reaction SMILES: CC1C(C([O:9][C:10]2[CH:18]=[C:17]3[N:12]([CH2:13][C:14]4([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)[N:22]([C:23]([C:25]5[C:26]([CH3:30])=[N:27][O:28][CH:29]=5)=[O:24])[CH2:21][CH2:20][N:15]4[C:16]3=[O:19])[N:11]=2)=O)=CON=1.[OH-].[Li+]>C1COCC1.CO>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:14]23[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:15]2[C:16](=[O:19])[C:17]2[N:12]([NH:11][C:10](=[O:9])[CH:18]=2)[CH2:13]3)=[CH:36][CH:35]=1
Reactant: COc1ccc(C23Cn4nc(OC(=O)c5conc5C)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C23Cn4[nH]c(=O)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a solution of 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]pyrazin-7-yl 3-methyl-1,2-oxazole-4-carboxylate (120 mg, 0.23 mmol) in THF (1 mL) and methanol (1 mL) was added an aqueous solution of lithium hydroxide (0.1 M, 0.3 mL, 0.3 mmol). The mixture was stirred at room temperature until completion (2 h, monitored by LCMS). The solution was concentrated in vacuo and the residue partitioned between CH2Cl2 and 5% HCl (aq). The organic layer was separated and the aqueous layer further extracted with CH2Cl2. The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography using the Biotage SP4 (12 g cartridge, 0-10% methanol in CH2Cl2, 15 CV) to give 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]-pyrazine-5,7(8H)-dione (155) (36 mg, 38%).
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10](OCC)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O.[NH2:18][NH2:19]>CCO>[N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10]([NH:18][NH2:19])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1ccc(-n2cccn2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(-n2cccn2)cc1
Reaction time: 144 h

Procedure:
To a solution of ethyl 4-(1H-pyrazol-1-yl)benzoate (711 mg, 3.29 mmol) in absolute EtOH (50 mL) was added hydrazine monohydrate (1.6 mL, 32.9 mmol) at room temperature. The reaction mixture was heated to reflux and stirred for 6 d, then concentrated under reduced pressure. The residue was suspended in H2O (30 mL), filtered, washed with H2O (2×20 mL) and EtOH (2×20 mL) to provide the title compound as an off white solid (101 mg, 15%): 1H NMR (400 MHz, CDCl3, δ in ppm) 9.84 (s, 1H), 8.62-8.59 (m, 1H), 7.98-7.90 (m, 4H), 7.81-7.78 (m, 1H), 6.61-6.57 (m, 1H), 4.51 (br d, J=3.3 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)c1ccc(C=O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Hydroxy-4-isopropylbenzaldehyde (6.69 g) and 11.26 g of potassium carbonate were suspended with 100 mL of N,N-dimethylformamide, and 5.33 mL of benzyl bromide was added to the stirred mixture at room temperature. After the mixture was stirred at room temperature for 16 hours, the insoluble material was removed by filtration. To the filtrate were added 10 mL of water and 10 mL of diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. After being washed with brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 10.44 g of 2-benzyloxy-4-isopropylbenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH:22]4[CH2:24][CH2:23]4)(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]1.[H-].[Na+].Br[CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([S:19]([CH:22]4[CH2:24][CH2:23]4)(=[O:20])=[O:21])[CH2:17][CH2:18]3)=[O:12])[N:8]2[CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])=[CH:4][C:3]=1[O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)[nH]c3cc2Br)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)n(CCO[Si](C)(C)C(C)(C)C)c3cc2Br)CC1
Yield: 36 %

Procedure:
The title compound was prepared in analogy to example 12, from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4-cyclopropanesulfonyl-piperazin-1-yl)-methanone (example 17), sodium hydride and (2-bromoethoxy)-tert-butyldimethylsilane in N,N-dimethylformamide, to afford the title compound as a colourless foam (36%).
Reaction SMILES: [NH2:1][OH:2].[C:3]1([CH:9]([N:16]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:17][CH2:18][C:19](OCC)=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C(OCC)C>[OH:2][NH:1][C:19](=[O:20])[CH2:18][CH2:17][N:16]([CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: CCOC(=O)CCN(C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(CCC(=O)NO)C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Freshly prepared hydroxylamine reagent (8 mL; 8 mmol) was added to ethyl 3-[(diphenylmethyl)-(4-methoxybenzene-sulfonyl)-amino]-propionate (563 mg; 1.24 mmol) and the resulting mixture stirred overnight at room temperature. The mixture was poured into 1 N HCl (100 mL) and extracted with CH2Cl2 (2×50 mL). The combined extracts were washed with saturated aqueous NaCl (100 mL), dried over MgSO4, and evaporated under reduced pressure to give crude product. Trituration with diethyl ether afforded 262 mg (48%) of the title compound as a white solid. 300 MHz 1H-NMR (DMSO-d6): δ 1.81 (m, 2H), 3.40(m, 2H), 3.84 (s, 3H), 6.31 (s, 1H), 7.02 (m, 6H), 7.28 (m, 6H), 7.71 (d, 2H), 8.59 (s, 1H), 10.23 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[NH:27][CH2:26]2>>[C:16]([SiH2:15][O:14][C:13]([CH3:21])([CH3:20])[C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]1[CH:7]=[C:2]([N:27]2[CH2:26][C:25]3[C:29](=[CH:30][CH:31]=[C:23]([Cl:22])[CH:24]=3)[C:28]2=[O:32])[CH:3]=[N:4][CH:5]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C1NCc2cc(Cl)ccc21
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1c1cncc(Br)c1
Product: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1c1cncc(N2Cc3cc(Cl)ccc3C2=O)c1

Procedure:
In analogy to the procedures described for the preparation of example 135, 3-bromo-5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridine (example 135[B]) has been reacted with 5-chloro-2,3-dihydro-isoindol-1-one to give 2-{5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-5-chloro-2,3-dihydro-isoindol-1-one, which was then deprotected with 4M HCl in dioxane to give the title compound as white solid. MS: 344.0 (M+H+).
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][CH2:11][CH2:12]O>C1COCC1>[Cl:3][CH2:12][CH2:11][CH2:10][C:6]1[S:5][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCc1cccs1
Solvent: C1CCOC1
Product: ClCCCc1cccs1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (420 μL, 5.7 mmol) was added to a solution of 3-(2-thienyl)propanol (682.0 mg, 4.8 mmol) in THF (3 mL) at room temperature. The reaction mixture was stirred at 50° C. for 2 hours and then concentrated to dryness to afford the title compound as a brown oil. The product was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([SH:23])[CH:19]=[CH:20][C:21]=1[Cl:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]([S:23][CH2:2][C:3]([C:5]23[CH2:14][CH:9]4[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]4)[CH2:6]2)[CH2:12]3)=[O:4])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CSc1ccc(Cl)c(Cl)c1)C12CC3CC(CC(C3)C1)C2

Procedure:
1-adamantyl bromomethyl ketone (1.3 g.), 1.1 g. of 3,4-dichlorothiophenol and 800 mg. of anhydrous potassium carbonate in 30 ml. of acetone are stirred at reflux overnight. The solvent is then removed and 60 ml. of water is added to the reaction mixture. The product is filtered off, washed with water and recrystallized from methanol to yield 1-adamantyl 3,4-dichlorophenylthiomethyl ketone, M.P. 105°-110.5° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:7]([S:26]([CH3:29])(=[O:28])=[O:27])[N:6]=1)(=O)=O.C([Li])CCC.[CH:35]1([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:35]1([O:41][C:5]2[N:6]=[C:7]([S:26]([CH3:29])(=[O:28])=[O:27])[C:8]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: OC1CCCCC1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Agent: [Li]CCCC
Product: CS(=O)(=O)c1nc(OC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2,4-Bis(methylsulfonyl)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 5) (196 mg, 0.4 mmol) was reacted with 1 equivalent each of n-butyl lithium and cyclohexanol by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 90/10 hexanes/ethyl acetate) afforded 2-cyclohexyloxy-4-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Higher Rf product): 1H-NMR 500 MHz (CDCl3): δ 1.30 (m, 5H), 1.45 (m, 1H), 1.55 (m, 1H), 1.64 (m, 1H), 1.75 (m, 1H), 1.90 (m, 1H), 2.15 (m, 1H), 3.38 (s, 3H), 5.09 (m, 1H), 7.0 (d, J=7 Hz, 1H), 7.18-7.22 (m, 4H), 7.36 (d over m, J=2 Hz, 2H); and 2-methylsulfonyl-4-cyclohexyl-oxy-5-(4chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Lower Rf product): 1H-NMR 500 MHz (CDCl3): δ 0.87-0.9 (m, 1H), 0.95-1.07 (m, 2H), 1.1-1.3 (m, 2H), 1.33 (m, 2H), 1.7-1.82 (m, 4H), 3.40 (s, 3H), 4.37 (d, J=6 Hz, 2H), 7.08 (d, J=8 Hz, 2H), 7.12 (d, J=8 Hz, 1H), 7.22-7.30 (m, 3H), 7.37 (d, J=2 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[C:6]([N:11]2[C:15]([C:16]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[C:27](=O)[C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[O:17])=[CH:14][C:13]([C:36]([F:39])([F:38])[F:37])=[N:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1.C([O-])(=O)C.[Na+]>O.C(O)C>[Cl:4][C:5]1[C:6]([N:11]2[C:15]([C:16]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3/[C:27](=[N:2]/[OH:3])/[C:28]([N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[O:29])=[O:17])=[CH:14][C:13]([C:36]([F:38])([F:37])[F:39])=[N:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: NO
Reactant: CCN(CC)C(=O)C(=O)c1cc(C)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)/C(=N\O)c1cc(C)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C

Procedure:
A solution of hydroxylamine hydrochloride (50 mg, 0.71 mmol) in water (0.5 mL) was added to a solution of 1-(3-chloro-2-pyridinyl)-N-[2-[(diethylamino)oxoacetyl]-4,6-dimethylphenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (i.e. the title product of Example 2, 124 mg, 0.24 mmol) in ethanol (5 mL) at 25° C. The resulting mixture was treated with a solution of sodium acetate (200 mg) in water (2 mL). The resulting mixture was heated at reflux for 3 days and then cooled to 25° C., diluted with ethanol (30 mL) and concentrated onto silica gel (0.5 g). The residue was purified by flash chromatography on silica gel eluted with 35% ethyl acetate in hexanes to give 50 mg of the title product, a compound of the present invention, as a yellow glassy solid.
Reaction SMILES: [Cl:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C(Cl)Cl.C[OH:16]>>[Cl:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N+:7]([O-:16])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: ClC1CCCc2ncccc21
Reactant: CO
Solvent: ClCCl
Product: [O-][n+]1cccc2c1CCCC2Cl

Procedure:
5-Chloro-5,6,7,8-tetrahydroquinoline from step 2 above was oxidized using the procedure as given in step 3 of Example 3. 5-Chloro 5,6,7,8-tetrahydroquinoline-N-oxide was obtained as a white solid (TLC Rf = 0.24 (97:3 CH2Cl2 : MeOH)).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: NCc1ccccn1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2ccccn2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-(aminomethyl)pyridine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C42H49Cl2N6O3 [(M+H)+] 755.3238, observed 755.3238.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[CH2:5]([NH:9][CH2:10][C:11]([O:13]CC)=O)[CH2:6][CH2:7][CH3:8]>Cl>[CH2:5]([N:9]1[CH2:10][C:11](=[O:13])[NH:3][C:2]1=[O:1])[CH2:6][CH2:7][CH3:8]
Reactant: N#C[O-]
Reactant: CCCCNCC(=O)OCC
Agent: Cl
Agent: [K+]
Product: CCCCN1CC(=O)NC1=O
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
A quantity of 24.4 g (0.30 mole) of potassium cyanate is added portionwise, at room temperature, to a stirred solution of 31.80 g (0.20 mole) of ethyl N-butylglycinate in 220 mL (0.22 mole) of 1N hydrochloric acid. The solution is warmed to ca. 90° C. (at ca. 50° C. an oil separates). After 10 minutes at 90° C., concentrated hydrochloric acid (250 mL) is cautiously added over 2 minutes and the resulting solution is heated at 90°-100° C. for 1/2 hour. The solution is concentrated at reduced pressure to dryness. The last amounts of water are chased by addition and removal of 3×100 mL of absolute ethanol. The residue is extracted with 400 mL 50% ethanolmethylene chloride. The inorganics are filtered and the filtrate is concentrated to dryness. Trituration of the residue with 100 mL of water and filtration gives pure 1-butylhydantoin in 68% yield; mp 90°-92° C.; MS (EI) 156.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](OC(=O)C)(=[O:12])[CH3:11].N1C=CC=CC=1>Cl>[C:10]([O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Cl)c(Cl)c1

Procedure:
A solution of 3,4-dichlorophenol (Alfa Aesar, Ward Hill, Mass.) is treated with acetic anhydride and an appropriate base such as pyridine. When the reaction is complete the reaction mixture is diluted with aqueous hydrochloric acid and extracted with an organic solvent. The organic solvent is washed with water, dried over magnesium sulfate, filtered and rotary evaporated to give crude 1-acetoxy-3,4-dichlorobenzene that may be used with or without further purification in the following reaction.