Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=1.Br[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[N:23]3[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[N:27][C:22]3=[N:21][CH:20]=2)=[CH:4][C:3]=1[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: OB(O)c1ccc(F)c(-c2ncccc2F)c1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1ncccc1F

Procedure:
4-Fluoro-3-(3-fluoropyridin-2-yl)phenylboronic acid was coupled with 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 78. Purification by chromatography on silica gel eluting with dichloromethane containing 3.5% methanol and crystallisation from methanol gave 3-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, DMSO) 9.28 (1H, d, J 7), 8.61 (1H, m), 8.31 (1H, s), 7.90-7.99 (3H, m), 7.62 (2H, m), 7.52 (1H, d, J 7); m/z (ES+) 377 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:21]([C:30]2[CH:35]=[CH:34][C:33](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:32]([N+:47]([O-:49])=[O:48])[CH:31]=2)([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:7]=[CH:8][C:9]=1OS(C1C=CC(C)=CC=1)(=O)=O)([O-:3])=[O:2].[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(#N)C>[NH:50]([C:33]1[CH:34]=[CH:35][C:30]([C:21]([C:6]2[CH:7]=[CH:8][C:9]([NH:1][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)([C:26]([F:28])([F:29])[F:27])[C:22]([F:25])([F:23])[F:24])=[CH:31][C:32]=1[N+:47]([O-:49])=[O:48])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C(c3ccc(OS(=O)(=O)c4ccc(C)cc4)c([N+](=O)[O-])c3)(C(F)(F)F)C(F)(F)F)cc2[N+](=O)[O-])cc1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(c2ccc(Nc3ccccc3)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Yield: 218.6 %

Procedure:
In an alternative procedure, 7.3 g (0.01 mol) of 2,2-bis-(3-nitro-4-tosyloxyphenyl)-hexafluoropropane, 11.6 g (0.125 mol) of aniline and 50 ml of acetonitrile are heated under reflux for 24 hours. After the red-orange suspension has been cooled, the solid is removed and washed with acetonitrile. The solvent is removed from the filtrate, and the product is recrystallized twice from ethanol to give 6.3 g of 2,2-bis-(4-anilino-3-nitrophenyl)-hexafluoropropane (65% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH2:8][CH:7](O)[C:6]=2[CH:20]=1.S(=O)(=O)(O)O.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C(O)C2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C=C2

Procedure:
Suspend 14.8 gm of the crude alcohol from Step C in 300 ml of glacial acetic acid and heat the mixture with stirring in an oil-bath at 110°-115° C. Add 50 ml of sulfuric acid in a thin stream. Continue stirring and heating for 15 minutes. Cool and pour into 500 ml of water. Separate the solids by filtration and stir at room temperature in 125 ml of ethylacetate overnight. Separate the solids by filtration to obtain the title product. (m.p. 273°-275° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)nc1
Product: Cc1ccc(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)nc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
0.20 g of 5-(4-chlorophenyl)-6-methyl-4-(5-methyl-2-pyridyl)-2H-pyridazin-3-one and 3.2 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours on an oil bath of 120° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.20 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.18 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(5-methyl-2-pyridyl)pyridazine (hereinafter, described as compound (3) of the present invention.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][NH2:8])[CH:2]=1.[CH2:9]([CH2:11][CH2:12][CH2:13][C:14](CC([O-])=O)=[O:15])[CH3:10]>>[CH2:11]([C:12]1[CH2:13][C:14](=[O:15])[N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1)[CH2:9][CH3:10]
Reactant: NNc1cccnc1
Reactant: CCCCCC(=O)CC(=O)[O-]
Product: CCCC1=NN(c2cccnc2)C(=O)C1

Procedure:
From the reaction of 3-pyridylhydrazine and ethylbutyrylacetate, 2,4-dihydro-5-propyl-2-(3-pyridyl)-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 4-(2-ethylanilinomethylene)-2,4-dihydro-5-propyl-2-(3-pyridyl)-3H-pyrazo 1-3-one, Mp 143.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1ccoc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccoc1-c1cccc(N)c1
Yield: 85.4 %

Procedure:
A solution of 2-(3-nitrophenyl)furan-3-carboxylic acid methyl ester (1.0 g) in methanol (60 mL) containing 10% palladium on carbon (2.9 g) was stirred under 1 atmosphere of hydrogen for 1 h. The reaction mixture was then filtered through Celite. Removal of the solvent at reduced pressure gave the title compound as a yellow solid (0.75 g). C12H11NO3: M+Na+ 240
Reaction SMILES: O1CCOCC1.[Cl:7][CH:8]1[C:13](Cl)([NH2:14])[CH:12]=[N:11][CH:10]=[N:9]1.[CH3:16][NH2:17]>O>[Cl:7][C:8]1[N:9]=[CH:10][N:11]=[C:12]([NH:17][CH3:16])[C:13]=1[NH2:14]
Reactant: CN
Reactant: NC1(Cl)C=NC=NC1Cl
Solvent: O
Solvent: C1COCCO1
Product: CNc1ncnc(Cl)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
A 50 mL 3-necked flask fitted with a thermometer was charged with 1,4-dioxane (20 mL) and 4,5-dichloropyrimdine-5-amine (5.00 g, 30.5 mmol). The reaction mixture was then stirred for 30 minutes at room temperature to ensure complete dissolution of the 4,5-dichloropyrimidine-5-amine, after which a solution of methylamine in water (40% by weight, 120 mmol, 9.3 mL) was added over a period of 30 minutes by means of a pressure-equalized dropping funnel. Upon completion of addition, the dropping funnel was replaced with a reflux condenser. The stirred reaction mixture was then heated to 75° C. over a period of 40 minutes, and the progress was monitored by LCMS. The reaction was complete after 16 hours. The resulting mixture was then cooled to 50° C. and poured into 120 mL of ice and water (approximetely 1:1 by volume), which resulted in the rapid precipitation of a solid. The resulting suspension was then for a period of 2 hours. The precipitated solids were collected by vacuum filtration, washed with ice-cold water (20 mL) and dried on the filter to give 4.76 g (98.4% yield) of 6-chloro-N4-methylpyrimidine-4,5-diamine as a light yellow solid. This material was submitted to the next step without further purification. 1H-NMR (400 MHz, DMSO-d6): δ 7.73 (s, 1H), 6.87 (d, 1H), 4.94 (broad s, 2H), 2.86 (d, 3H). MS (EI) for C5H7ClN4: 159 (MH+).
Reaction SMILES: C([O:4][CH:5]1[C:13]2[C:8](=[C:9]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=O)C.[OH-].[K+]>O.C(O)C>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH2:6][CH:5]2[OH:4]
Reactant: CC(=O)OC1CCc2c(-c3cccs3)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC1CCc2c(-c3cccs3)cccc21
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To 3.5 g (0.014 mole) of 4-(2-thienyl)-1-indanyl acetate was added a solution of 1.1 g (0.019 mole) of potassium hydroxide in 19.5 mL of water and 39 mL of ethanol. The reaction mixture was stirred for three hours at 60°-70° C., then for 16 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure to give an oil residue. The oil was slurried in 75 mL of water for one hour, causing the oil to solidify. The solid was washed with water, air dried, then recrystallized from toluene to give, in three crops, 2.4 g of 4-(2-thienyl)-1-indanol, m.p. 101°-103.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:25])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH:10]2O)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:25])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[C:11]([CH3:22])([CH3:23])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-6-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (48 g, 113.2 mmol) and triethylsilane (60 mL) at 25° C. was added trifluoroacetic acid (30 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (23.1 g, 50%) as a white solid: LC/MS m/e calcd for C19H19BrClNO2 (M+H)+: 409.73, observed: 407.9 & 409.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)CCC>[CH3:9][NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][CH2:18]2)[N:7]=1
Reactant: CNc1ccnc(Cl)n1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCCCO
Product: CNc1ccnc(N2CCC(c3ccccc3)CC2)n1
Temperature: 130 °C
Yield: 74.5 %

Procedure:
Two hundred milliliters of n-butanol was added to 3.0 g (0.02 mole) of 2-chloro-4-methylaminopyrimidine and 8.4 g (0.05 mole) of 4-phenylpiperidine, and the mixture was heated at 130° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4.0 g (yield 71%) of the desired compound as an oil.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.B(F)(F)F.[CH3:12][CH2:13][O:14][CH2:15][CH3:16].O1CCOCC1>C(OCC)C>[O:14]1[C:15]2[C:6](=[CH:1][CH:2]=[CH:3][CH:16]=2)[CH2:5][CH2:12][CH2:13]1
Reactant: Oc1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0 h

Procedure:
To a solution of phenol 4 (0.01 mol) and a catalyst, preferably boron trifluoride diethyl etherate (0.016 mol) in an organic solvent, preferably dry dioxane (10 mL), is added vinyl lactone 2 (0.016 mol) in an organic solvent, preferably dry dioxane (5.0 mL) over 1-60 minutes, preferably 60 minutes at 0-150° C., preferably 110° C., under an inert gas. The reaction mixture is stirred for 0 to 8 hours, preferably 0 hours, at the selected temperature, cooled to room temperature, and diluted with an organic solvent, preferably diethyl ether (200 mL). The reaction mixture is then washed with water (100 mL, 2×50 mL), dried over sodium sulfate (Na2SO4), and solvent is removed under reduced pressure to afford a brown oily residue. The residue is dissolved in alcohol, preferably methanol (30 mL), and the alcohol is then removed under reduced pressure. The brown oily liquid or semisolid is further purified by chromatography, preferably on silica gel, to afford pure racemic chroman derivative 5.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:19]([C:21]1[O:25][C:24]([C:26](Cl)=[O:27])=[CH:23][CH:22]=1)#[N:20].CCN(C(C)C)C(C)C>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:26]([C:24]3[O:25][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[O:27])=[C:8]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: Nc1ccc(-n2ccnc2)cc1N1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)Nc2ccc(-n3ccnc3)cc2N2CCCCC2)o1
Yield: 44 %

Procedure:
Using a procedure similar to Example 3, step (d), 4-imidazol-1-yl-2-piperidin-1-yl-phenylamine (69 mg, 0.28 mmol, as prepared in the previous step) was allowed to react with 5-cyano-furan-2-carbonyl chloride (56 mg, 0.36 mmol) in the presence of DIEA (138 μL, 0.790 mmol) to afford 44.9 mg (44%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 9.65 (br s, 1H), 8.57 (d, 1H, J=9.3 Hz), 7.84 (s, 1H), 7.34 (d, 1H, J=3.7 Hz), 7.28-7.27 (m, 2H), 7.22-7.20 (m, 3H), 2.93-2.90 (m, 4H), 1.88-1.85 (m, 4H), 1.72 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C20H19N5O2, 362.1 (M+H), found 362.2.
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[N:12]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(=O)[nH]1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nc2ccccc2c(=O)n1CCOc1ccc(C=O)cc1
Yield: 27 %

Procedure:
The title compound (5.0 g, 27%) was prepared from 2-ethyl-4-oxo-3,4-dihydroquinazoline (9.2 g, 57.5 mmol) and 4-(2-bromoethoxy)benzaldehyde (14.5 g, 69.0 mmol) in the presence of K2CO3 (14.6 g, 115.0 mmol) as base, by a similar procedure to that described in preparation 1.
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14]C)=[O:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH3:16][O-:17].[Na+]>CN(C=O)C.O>[CH3:16][O:17][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc2c(cc1Br)OCCO2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1C(=O)O)OCCO2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
In a 2 mL microwave vial, methyl 7-bromo-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (273 mg, 1 mmol) and CuBr (14.3 mg, 0.1 mmol) were dissolved in dry DMF and was placed in ice bath. Sodium methoxide (540 mg, 10 mmol) was added into the reaction mixture dropwise while stirring at 0° C. The reaction was warmed to room temperature and stirred for 45 minutes. The reaction was then placed in a microwave reactor for 5 minutes at 135° C. The reaction mixture was dissolved in water and washed with ethyl acetate. The water layer was collected and acidified to pH 4 with 1M HCl. The product was extracted using ethyl acetate then dried over sodium sulfate. The solvent was evaporated under vacuum to give the desired intermediate of 7-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid which was used directly without further purification. Yield 57%. MS M+H calculated 211.1, found 211.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[N-:13]=[N+:14]=[N-:15].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:13]=[N+:14]=[N-:15])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NS(=O)(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 15.0 g (0.61 mole) 2,6-dichlorobenzenesulfonyl chloride in 100 ml ethanol was added a solution of 5.2 g (0.79 mole) of sodium azide dissolved in a minimum amount of water. The solution was stirred 30 minutes and then poured into a 2 liter Erlenmeyer flask containing 500 ml of ice water. The resultant white solid was recrystallized from ethanol; yield 14.29 g (93% of theory). The purified product melted at 63°-64° C. (lit. 63°-64° C.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8](=[O:36])[C@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])=[CH:24][CH:23]=1)[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[Cl:19].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:36])[C@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])=[CH:24][CH:23]=1)[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([N:18]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:13]=1[Cl:19]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(N)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
MeSO2Cl (24 μL) was added to a solution of N-(4-amino-2-chlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (56.0 mg) in anhydrous CH2Cl2 (1 mL) containing DIEA (66.6 μL). The resulting mixture was stirred at room temperature under N2 for 3 h and diluted with CH2Cl2, washed with 1N HCl, water, dried (MgSO4) and evaporated. The residue was purified through a silica gel column using CH2Cl2 as an eluent to give N-[2-chloro-4-(N,N-dimethanesulfonylamino)benzoyl]-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (59.4 mg). ESMS: m/z 595 (MH+).
Reaction SMILES: C([N:5](CCC)[S:6]([CH:9]1[CH2:11][CH2:10]1)(=[O:8])=[O:7])(C)(C)C.[CH3:15][C:16]1(S(N)(=O)=O)C[CH2:17]1>>[CH2:15]([C:9]1([S:6]([NH2:5])(=[O:7])=[O:8])[CH2:10][CH2:11]1)[CH2:16][CH3:17]
Reactant: CCCN(C(C)(C)C)S(=O)(=O)C1CC1
Reactant: CC1(S(N)(=O)=O)CC1
Product: CCCC1(S(N)(=O)=O)CC1
Yield: 80 %

Procedure:
Step 29b) This compound was made from Compound 29a in 80% yield (25.15 g) from N-tert-butyl-(1-propyl) cyclopropylsulfonamide (42.2 g, 193 mmol) according to the procedure of Steps 3Id (Example 2) described in the synthesis of 1-methylcyclopropylsulfonamide. The compound was recrystallized from EtOAc/hexanes as a white solid: 1H NMR CHLOROFORM-D) δ ppm 0.85 (m, 2H), 0.94 (t, J=7.32 Hz, 3H), 1.36 (m, 2H), 1.47 (m, 2H), 1.87 (m, 2H), 4.42 (s, 2H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[NH2:15][CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18]>>[CH3:20][N:19]([CH3:21])[C:17](=[O:18])[CH2:16][NH:15][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: CN(C)C(=O)CN
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Product: COC(=O)c1cccc2oc(NCC(=O)N(C)C)nc12

Procedure:
Following general procedure GP-A, a mixture of methyl 2-chlorobenzoxazole-4-carboxylate and 2-amino-N,N-dimethylacetamide provided methyl 2-(2-(dimethylamino)-2-oxoethylamino)benzoxazole-4-carboxylate. 1H NMR and MS consistent.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: C1CNCCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCCNCC2)cc1
Yield: 82.7 %

Procedure:
A solution of hexahydro-1H-1,4-diazepine (0.20 mol) and 1-fluoro-4-nitro-benzene (0.10 mol) in DCM (300 ml) was stirred at room temperature for 24 hours under nitrogen atmosphere. Yellow crystals precipitated. The precipitate was collected on filter, washed with ether and dried. The residue (21.1 g, 87%) was taken up in water and treated with a 3 N NaOH solution. This mixture was extracted with DCM (3×500 ml), dried (Na2SO4), filtered, and the solvent was removed under reduced pressure and dried under vacuum at room temperature for 16 hours, yielding 18.3 g of hexahydro-1-(4-nitrophenyl)-1H-1,4-diazepine (interm. 1), melting point 115-116° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H:36]([CH3:39])CO)[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N[C@H:44](C)[CH2:45][OH:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([CH2:36][CH2:39][O:4][CH2:44][CH2:45][OH:46])[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H](C)CO)c4)cc23)CC1
Reactant: C[C@@H](N)CO
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCOCCO)c4)cc23)CC1
Yield: 38.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting 2-[(2-aminoethyl)oxy]ethanol (1.20 mmol) for (2R)-2-amino-1-propanol to afford 17.2 mg of the title compound (38.7%).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:35]2[C:36]([C:41]3C=CC=CC=3F)=[N:37]OC=2C)=NC=1.C(N)(C)C>>[CH:36]([NH:37][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1)([CH3:41])[CH3:35]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccccc2)nc1
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2conc2-c2ccccc2)nc1
Yield: 81 %

Procedure:
As described for example 84f, 6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (67 mg, 0.21 mmol) was converted, instead of [6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (59 mg, 81%) which was obtained as an off white solid. MS: m/e=338.2 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[CH:32]=[CH:31][C:8]([C:9](=[O:30])[CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[C:20]2[C:21]([NH:25][CH2:26][CH2:27]C#N)=[N:22][O:23][N:24]=2)=[CH:7][CH:6]=1)C(C)=O.[C:33](=[O:36])(O)[O-:34].[Na+]>Cl.O>[NH2:1][C:5]1[CH:32]=[CH:31][C:8]([C:9](=[O:30])[CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[C:20]2[C:21]([NH:25][CH2:26][CH2:27][C:33]([OH:34])=[O:36])=[N:22][O:23][N:24]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(C(=O)Cn2c(-c3nonc3NCCC#N)nc3ccccc32)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1ccc(C(=O)Cn2c(-c3nonc3NCCC(=O)O)nc3ccccc32)cc1

Procedure:
A solution of 4-[1-(4-acetaminophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine (0.061 g) in aqueous hydrochloric acid (5 ml, HCl conc.) is heated at reflux for two hours. The mixture is diluted with water and neutralized by addition of sodium bicarbonate. Extraction with ethyl acetate, drying over sodium sulphate, filtering and evaporation of the resulting filtrate to dryness gives the title compound in pure form, m.p. 174-177° C. 1H-NMR (400 MHz, d6-DMSO): 12.40 (s, 1H); 7.84 (m, 4H); 7.38 (m, 3H); 6.65 (m, 2H); 6.28 (S, 2H); 6.17 (s, 2H); 3.57 (m, 2H); 2.66 (t, 2H).