Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([NH:13][NH:14][C:15]([NH2:17])=[S:16])=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CS(O)(=O)=O>C1(C)C=CC=CC=1>[NH2:17][C:15]1[S:16][C:11]([C:10]2[CH:18]=[CH:19][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=2)=[N:13][N:14]=1
Reactant: CCCCCOc1ccc(C(=O)NNC(N)=S)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCOc1ccc(-c2nnc(N)s2)cc1
Temperature: 10 °C
Yield: 23 %

Procedure:
To a slurry of 1-(4-n-pentyloxybenzoyl)-3-thiosemicarbazide (20 g) in toluene (213.3 ml) at 40° C., was added dropwise over 30 minutes, methanesulfonic acid (6.92 ml). The mixture was refluxed for 12 hours. After cooling to 10° C, the resulting precipitate was filtered and dried. The precipitate was dissolved in water, the solution was adjusted to pH 9 with 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 2-amino-5-(4-n-pentyloxyphenyl)-1,3,4-thiadiazole (4.314 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:22])[C:15](=[CH:18]OCC)[C:16]#[N:17])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:17][C:16]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[N:10]=[CH:18][C:15]=1[C:14]([O:13][CH2:11][CH3:12])=[O:22]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(Cl)c2)c1N
Temperature: 0 °C
Yield: 66.5 %

Procedure:
A solution of 53.7 g of (3-chlorophenyl)hydrazine hydrochloride, 50.8 g of ethyl(ethoxymethylene)cyanoacetate and 41.4 g of potassium carbonate in 500 ml of ethanol was refluxed for 20 hours. The solution was poured into ice water. The precipitated solid was collected by filtration, dried and recrystallized from ethanol/water to provide 53.0 g of 5-amino-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 67%. mp=115°-117° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:30])=[C:20]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[CH3:29])[N:21]=2)=[CH:13][CH:12]=1>>[CH3:30][C:19]1[O:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)=[CH:12][CH:13]=2)=[N:21][C:20]=1[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH3:29]
Reactant: OB(O)c1cncnc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1oc(-c2ccc(-c3cncnc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 5-pyrimidine boronic acid (178 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 40 mg (40%). MS (m/e) 349.3 (M+1)
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].Cl[C:23]1C(CC)=NC=C(C2CC2)N=1>>[CH:9]1([C:6]2[N:5]=[C:4]([NH:11][C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C@@H:13]3[OH:21])[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=2)[CH2:23][CH2:10]1
Reactant: CCc1ncc(C2CC2)nc1Cl
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1ncc(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-5-cyclopropyl-2-ethylpyrazine and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.92–0.95, 1.31–1.35, 1.93, 2.59–2.70, 3.03–3.10, 3.22–3.30, 4.74, 4.91, 5.49–5.52, 7.28–7.32, 7.82; MS (ESI+) for C18H21N3O m/z 296 (M+H)+.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:8]([O:17][CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[CH:7]=1)([O-:5])=[O:4].[BH4-].[Na+].Cl>O1CCCC1>[OH:24][CH:21]1[CH2:22][CH2:23][CH:18]([O:17][C:8]2[CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:11]=[CH:10][C:9]=2[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:19][CH2:20]1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1OC1CCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1OC1CCC(O)CC1
Reaction time: 0.33 h
Yield: 73.5 %

Procedure:
To 8 ml of a mixture of methanol and tetrahydrofuran (1:2) containing 0.23 g of N-[4-nitro-2-(4-oxocyclohexyloxy)phenyl]methanesulfonamide obtained in Example 5 (2) was added 0.01 g of sodium borohydride under ice cooling, and the mixture was stirred for 20 minutes. To the reaction solution was a dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent; n-hexane:dichloromethane:ethyl acetate=1:1:1) and then by recrystallization from dichloromethane-n-hexane to give 0.17 g of N-[2-(4-hydroxycyclohexyloxy)-4-nitrophenyl]methanesulfonamide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10](O)=[O:11]>O1CCCC1>[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[CH2:10][OH:11]
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cccc(Cl)c1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
To a suspension of lithium aluminum hydride (1.1 g, 29.1 mmol) in tetrahydrofuran (150 mL) was added 2-amino-6-chlorobenzoic acid (5 g, 29.1 mmol) at 0° C. The mixture was stirred at room temperature for 16 h. Then, the reaction mixture was quenched with sodium sulfate decahydrate (3 g) and brine (10 ml) and filtrated through a pad of Celite. The organic layer was concentrated in vacuo and the residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:2) to give 2.4 g (52%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][C:20]=1[CH3:27])=O>>[CH3:27][C:20]1[CH:21]=[C:22]([C:24]([OH:26])=[O:25])[NH:23][C:19]=1[CH:17]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)Nc2cccc(-c3ccncc3)c21

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[N:11]1.[CH:18](I)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:18]([CH3:20])[CH3:19])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[N:11]1
Reactant: CC(C)I
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(C)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
A mixture of 1-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,4,5-trimethylpyrazole (25.5 g), isopropyl iodide (18.7 g), anhydrous potassium carbonate (14.5 g) and dimethylsulfoxide (200 ml) was stirred at 80° C. for one hour. After cooling, the reaction mixture was admixed with water and toluene to form two layers. The toluene layer formed was separated, washed with water and then dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (31.1 g) as a pale yellow oil, which was then purified through silica gel column chromatography to yield a colorless oil. nD23 =1.5406.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]=4)[CH2:20][CH2:19][C:18]4(OCC[O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]=4)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cccc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCC3(CC2)OCCO3)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCC(=O)CC2)c1

Procedure:
A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-carbomethoxyphenylethynyl)cyclohexane (0.060 g, 0.12 mmol) in tetrahydrofuran (5 mL) containing 3N hydrochloric acid (0.60 mL) under an argon atmosphere was heated at 55°-60° C. for 2 h. The cooled reaction mixture was partitioned between ice cold dilute aqueous sodium carbonate solution and ethyl acetate. The organic phase was washed with water, saturated brine, was dried over sodium sulfate, and was concentrated in vacuo. The residue was chromatographed (silica gel), eluting with 15% ethyl acetate/hexanes, to afford a resin. Anal. (C28H30O5.1/4 H2O) calcd: C 74.56, H 6.82, found: C 74.43, H 6.80. 1H-NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.00 (d-d, J=1.5 Hz;J=6.6 Hz, 1H), 7.65 (d-d, J=1.3 Hz, J=7.7 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.21 (d, J=2.1, 1H), 7.12 (d-d, J=2.0 Hz, J=8.5 Hz, 1H), 6.87 (d, J=8.5 Hz,1H), 4.81 (m, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.04 (d-t, J=6.0 Hz, J=14.2, 2H), 2.50 (d,br, J=14.8, 2H), 2.4-2.2 (m, 4H), 2.0-1.5 (m).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH3:13])[CH:6]=1.C1([Li])C=CC=CC=1.CN(C)[CH:23]=[O:24].S(=O)(=O)(O)O>CCOCC>[Cl:11][C:8]1[C:7]([O:12][CH3:13])=[C:6]([C:5]([OH:4])=[CH:10][CH:9]=1)[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(Cl)c(OC)c1
Agent: O=S(=O)(O)O
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: COc1c(Cl)ccc(O)c1C=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Chloro-3-methoxyphenol methoxymethyl ether (3.1 g, 0.0153 M) in dry ether (3.5 ml) was added dropwise to a solution of phenyllithium (from 0.21 g lithium and 2.4 g bromobanzene) in dry ether (12 ml) under nitrogen and the mixture stirred at room temperature (3 days). A solution of dry dimethylformamide (1.12 g, 0.0153 M) in dry ether (1 ml) was then added dropwise over 15 mins and the mixture stirred at room temperature (1 hr). The reaction mixture was poured into 2 N sulphuric acid (100 ml) and extracted with ethyl acetate. The combined extracts were dried (sodium sulphate) and evaporated. The residue was dissolved in methanol (25 ml), 3 N hydrochloric acid (10 ml) added and the resultant solution stirred at 65° C. for 30 mins. The solvent was removed in vacuo and the residue diluted with water (50 ml) and extracted with ether. The combined extracts were dried (sodium sulphate) and evaporated. The residue was chromatographed on silica (MFC) eluting with chloroform. The fractions were combined and evaporated to give 3-chloro-6-hydroxy-2-methoxybenzaldehyde as an oil which crystallised on standing. (Found: m/e 186.0084. C8H7ClO3 requires M185.0082).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10]CC2C=CC=CC=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19](=O)C(O)=O)([O-])=O>[Pd].C(O)(=O)C>[OH:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:1][CH:19]=[CH:18]2
Reactant: O=C(O)C(=O)Cc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1cccc2cc[nH]c12
Temperature: 220 °C
Reaction time: 0.5 h

Procedure:
Reaction of 2-nitro-3-benzyloxyphenylpyruvic acid (2 g.) with 10% palladium on carbon (2 g.) in acetic acid under hydrogen atmosphere is complete in 30 minutes. The mixture is filtered and the solvent is removed in vacuo. The remaining material is dissolved in glycerol and heated at 220° C. for 20 minutes. The desired product is obtained by sublimation under high vacuum.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]2[C:8]=1[C:9]([CH3:27])=[C:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:11]([CH3:18])=[N:12]2)[CH3:5].[OH-].[Li+]>O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:7]([O:6][CH:4]([CH3:5])[C:3]([OH:28])=[O:2])=[C:8]2[C:13]=1[N:12]=[C:11]([CH3:18])[C:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[C:9]2[CH3:27]
Reactant: COC(=O)C(C)Oc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)ccc(OC(C)C(=O)O)c2c(C)c1Cc1ccc(Cl)cc1

Procedure:
A solution of 2-[8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yloxy]propionic acid methyl ester (0.092 g), tetrahydrofuran (2.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.25 mL) was stirred at room temperature for 30 minutes. The tetrahydrofuran was removed under reduced pressure and pH of the residue was adjusted to 2 by the addition of 1.0 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting solid washed with pentane to afford title compound, 0.080 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[N+:17]([O-])=O)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH2:17])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
N-(4—Chlorophenyl)-5-chloro-2-nitrobenzamide (13.2 g, 42.4 mmol) and tin(II) chloride dihydrate (48 g, 213 mmol) were combined in ethyl acetate (90 mL) and the mixture was heated at 70° C. under a nitrogen atmosphere. After 15 minutes, the mixture was cooled to ambient temperature, then poured onto water (750 mL) and ethyl acetate (750 mL). The aqueous layer was adjusted to pH 8 with by addition of 1 N NaOH and a saturated NaHCO3 solution, and the layers were separated. The aqueous layer was further extracted with 500 mL of ethyl acetate. The combined organic extracts were washed with water (1 L), then brine (500 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 11.6 g (97% yield) of N-(4-chlorophenyl)-2-amino-5-chlorobenzamide as an off-white solid; NMR (CDCl3) 7.7 (br s, 1), 7.2-7.5 (m, 6), 6.7 (d, 1), 5.5 (br s, 2) ppm.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:9]=[C:8]2[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:42]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][N:7]4[CH:11]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:9]=[C:8]4[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)=[CH:34][CH:35]=3)=[CH:40][CH:41]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: O=C1CN(c2ccc(-c3nc(-c4ccc(Cl)cc4Cl)cn3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-c3nc(-c4ccc(Cl)cc4Cl)cn3Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[1-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (41 mg, 0.2 mmol) to give 5-{4-[1-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1.[CH2:15]1[C:19]2([CH2:24][NH:23][CH2:22][CH2:21][N:20]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:18][CH2:17][CH2:16]1>C(O)C>[OH:13][C@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:23]1[CH2:24][C:19]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:22]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: CC(C)(C)OC(=O)N1CCNCC12CCCC2
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(C(=O)OC(C)(C)C)C3(CCCC3)C2)ccc2c1COC2=O

Procedure:
A solution of 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one (INTERMEDIATE 2) (38 mg, 0.20 mmol) in 2 mL ethanol was added to tert-butyl 6,9-diazaspiro[4.5]decane-6-carboxylate (42 mg, 0.20 mmol). The reaction mixture was microwaved at 140° C. for 55 minutes. The solvents were removed in vacuo to provide tert-butyl 9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-6,9-diazaspiro[4.5]decane-6-carboxylate which was carried on without further purification.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:12].N1C=CC=CC=1>C(OCC)(=O)C>[C:5]([NH:12][C:11]1[CH:13]=[CH:14][C:15]([CH3:16])=[C:9]([Cl:8])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: Cc1ccc(N)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C)c(Cl)c1
Reaction time: 0.33 h
Yield: 65.3 %

Procedure:
Acetic anhydride (78 ml, 0.825 mol) was added in portions (using a dropping funnel) during a 45 min period to a stirred, cooled in an ice-bath solution of 3-chloro-4-methylaniline (106.2 g, 0.75 mol) in ethyl acetate (550 ml, dried over MgSO4 prior to use) and anhydrous pyridine (66.6 ml, 0.825 mol) under argon. During the reaction the temperature of the reaction mixture varied between 10-20° C. Stirring was continued for 20 min; then the ice-water bath was removed and the reaction mixture was stirred for 18 h at room temperature. The solvents were removed in vacuo and the light brown solid residue was triturated with ether (350 ml) and left to stand in a fridge overnight. The solid was collected by filtration, washed with cold ether (100 ml) and hexanes (100 mL), dried over P2O5 to afford a white solid (90 g). The filtrate was concentrated in vacuo, triturated with ether to afford an additional 28.1 g of the product. Total yield 118.1 g (86%); mp 105-106° C.; 1H-NMR (CDCl3) 2.17, 2.32 (2×s, 6H, 4-CH3, CH3CO), 7.14 (d, J=8.22 Hz, 1H, 6-H), 7.25 (2×dd, J=1.9, 6.5 Hz, 1H, 5-H), 7.58 (d, J=1.8 Hz, 1H, 3-H); MS (FAB, m/z) 184, 186 [(M+H)+ 100%, 30% respectively; Cl isotopic pattern].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)[CH2:4][CH2:3]1.O.NN>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:4][CH2:3]1
Reactant: CN1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CCN(CCCN)CC1
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a solution of N-[3-(4-methyl-1-piperazinyl)propyl]phthalimide (502 g) in ethanol (3.0 l) was added 100% hydrazine hydrate (187.6 g). The nesulting mixture was refluxed with stiving for 1.5 hours. The reaction mixture was cooled and then filtered. The filter cake was washed with ethanol (1 l). The filtrate and washing were combined and evaporated, under reduced pressure. The residual oil was distilled under reduced pressure to give 3-(4-methyl-1-piperazinyl)propylamine (146.6 g), bp 34 mmHg/127° to 128° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([C:13]#[N:14])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9](=[O:15])[NH:10][C@H:11]([CH3:12])/[C:13](/[NH2:14])=[N:17]/[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](C#N)NC(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)OCc1ccccc1)/C(N)=N/O
Temperature: 75 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of benzyl[(1R)-1-cyanoethyl]carbamate (2.52 g, 12.3 mmol) in ethanol (30 ml) was added hydroxylamine hydrochloride salt (0.90 g, 13.0 mmol) and triethylamine (3.43 ml, 24.6 mmol) and the mixture heated to 75° C. After 16 h, the solution was concentrated and the residue was dissolved in 200 mL of dichloromethane. The mixture was washed with 100 mL of saturated aqueous sodium bicarbonate (2×) and brine (100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give benzyl[(1R,2Z)-2-amino-2-(hydroxyimino)-1-methylethyl]carbamate (2.9 g). MS 238.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]([CH2:15][CH3:16])[CH2:10][C:11](=O)[CH2:12][CH3:13]>>[CH2:12]([CH:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH:9]([CH3:8])[CH2:15][CH3:16])[CH3:13]
Reactant: CCC(=O)CC(C)CC
Reactant: Nc1ccccc1
Product: CCC(C)CC(CC)Nc1ccccc1

Procedure:
N-(1-Ethyl-3-methylpentyl)aniline was prepared from aniline and 5-methylheptan-3-one using the same method as in Example 2i).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11](OC)OC)=[CH:5][CH:4]=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:9][CH:10]=[CH:11][C:7]=2[CH:8]=1
Reactant: COc1ccc(OCC(OC)OC)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2occc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
To a suspension of polyphosphoric acid (38.3 g) in toluene (400 ml) was added 4-methoxy-(2,2-dimethoxy)ethoxybenzene (38.0 g), and the mixture was stirred at 100° C. overnight and cooled. To the mixture was added water, and the mixture was separated. The organic layer was washed with 1N sodium hydroxide solution and then washed with saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give brown oil of 5-methoxybenzofuran (6.5 g).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu](C#N)[C:14]#[N:15]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1[C:14]#[N:15]
Reactant: N#C[Cu]C#N
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(C(F)(F)F)ccc1N
Reaction time: 0.08 h

Procedure:
In a 20 mL microwave vial, 2-bromo-4-(trifluoromethyl)aniline (238 mg, 1 mmol) and copper cyanide (90 mg, 1 mmol) were dissolved in N-methylpyrrolidone (NMP) (10 mL). The reaction was placed in a microwave reactor for 5 minutes at 200° C. The crude was dissolved in ethyl acetate and the precipitate was removed by filtration. The clear solution was washed with water. The organic layer was collected, dried over sodium sulfate, and evaporated under vacuum. The residue was purified by Varia HPLC (10% acetonitrile/water) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH3:17])[C:11]=2[N+:18]([O-])=O)=[CH:5][CH:4]=1)#[N:2]>ClCCl.C(O)C.[Pd]>[NH2:18][C:11]1[C:12]([CH3:17])=[N:13][C:14]([CH3:16])=[CH:15][C:10]=1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: Cc1cc(Nc2ccc(C#N)cc2)c([N+](=O)[O-])c(C)n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(Nc2ccc(C#N)cc2)c(N)c(C)n1
Yield: 94.8 %

Procedure:
A solution of 4-(4-cyanophenyl)amino-2,6-dimethyl-3-nitropyridine (5.00 g, 18.6 mmol) in a mixture of dichloromethane (20 ml) and ethanol (100 ml) was hydrogenated at 20° C over 10% palladium on charcoal (500 mg) at 138 kPa (20 p.s.i.) for 3 hours. The catalyst was filtered off and the solvents were removed under reduced pressure to give the title compound as a brown solid (4.20 g, 94%).