Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:42][S:43]([CH2:46][CH2:47][CH2:48][C:49](Cl)=[O:50])(=[O:45])=[O:44]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:25]([NH:31][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][S:43]([CH3:42])(=[O:45])=[O:44])=[CH:26][CH:27]=[CH:28][C:29]=3[CH3:30])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)CCCC(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
{[4-(6′-Amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.500 g, 2.020 mmol), (Example 25: step c), triethylamine (0.153 g, 3.030 mmol), and DCM [30 mL] were added to a flask containing a stirbar. 4-Methanesulfonyl-butyryl chloride (0.013 g, 0.611 mmol) was added slowly while monitoring reaction. Reaction was concentrated in vacuo followed by chromatography (50%–80% EtOAc/Hx). Material was dissolved in a solution of trifluoroacetic acid/dichloromethane (1:1), [4 mL]. This solution stirred at room temperature for 2 hours. Reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to yield title compound (0.138 g, 88%). ESI-MS (m/z): Calcd. for C24H27N3O5S4: 566.75; found 566.1.
Reaction SMILES: C([O:8][C:9](=[O:56])[CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH:21]([N:25]([CH2:32][C:33]3[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=3)[C:26]3[N:27]=[N:28][N:29]([CH3:31])[N:30]=3)[C:20]3[CH:47]=[C:48]([CH3:55])[C:49]([C:51]([F:54])([F:53])[F:52])=[CH:50][C:19]2=3)[CH2:13][CH2:12]1)C1C=CC=CC=1>[OH-].[Na+].CO>[F:45][C:43]([F:44])([F:46])[C:35]1[CH:34]=[C:33]([CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=1)[CH2:32][N:25]([C:26]1[N:27]=[N:28][N:29]([CH3:31])[N:30]=1)[CH:21]1[CH2:22][CH2:23][CH2:24][N:18]([CH2:17][CH:14]2[CH2:15][CH2:16][CH:11]([CH2:10][C:9]([OH:56])=[O:8])[CH2:12][CH2:13]2)[C:19]2[CH:50]=[C:49]([C:51]([F:52])([F:53])[F:54])[C:48]([CH3:55])=[CH:47][C:20]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC1CCC(CC(=O)OCc3ccccc3)CC1)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(CC1CCC(CC(=O)O)CC1)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Yield: 66.3 %

Procedure:
Heat the mixture of (4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cyclohexyl)-acetic acid benzyl ester (0.0340 g, 0.0427 mmol) in 5.0 N NaOH (1 mL) and methanol (1 mL) at 60° C. for 2 h. Evaporate the solvents and re-dissolve in water (10 mL). Adjust to pH=2 by adding 5.0 N HCl. Extract with ethyl acetate (2×10 mL). Combine organic layers, dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (0-50%), to provide the title compound as a colorless oil (0.0200 g, 67%). MS (ES+): MS (ES+): 707 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH3:21])[C:16]=2[C:17]([O:19][CH3:20])=[O:18])=[O:10])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:21][C:15]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[S:13][CH:14]=1
Reactant: COC(=O)c1c(C)csc1NC(=O)Cc1ccc(I)cc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1c(C)csc1NC(=O)Cc1ccc(-c2ccncc2)cc1
Temperature: 25 °C

Procedure:
Methyl 2-(2-(4-iodophenyl)acetamido)-4-methylthiophene-3-carboxylate (420.4 mg, 1.01 mmol), 4-pyridylboronic acid (Aldrich, 167 mg, 1.36 mmol), tetrakis(triphenylphosphine)palladium(0) (123 mg, 0.11 mmol), and potassium carbonate (565 mg, 4.1 mmol) were combined in DME (2 mL) and water (1 mL) in a sealed tube, and heated to 80° C. over 17 h. The reaction mixture was cooled to rt, then partitioned between EtOAc and water. The organic layer was separated, washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. Flash chromatography (EtOAc/hexanes) afforded the titled compound. 1H NMR (CDCl3) δ11.3 (s, 1H), 8.67 (dd, J=4.7, 1.4H, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.60-7.40 (m, 4H), 6.38 (s, 1H), 3.88 (s, 2H), 3.80 (s, 3H), 2.33 (s, 3H); 13C NMR (CDCl3) δ167.7, 166.6, 150.3, 149.9, 147.8, 137.4, 134.8, 134.6, 130.3, 127.7, 121.5, 113.0, 112.3, 51.5, 43.5, 17.8; MH+ 367.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[Br:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][C:17]=1[O:24][CH3:25].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Br:15][C:16]1[N:21]=[C:20]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:19]=[CH:18][C:17]=1[O:24][CH3:25]
Reactant: COc1ccc(C=O)nc1Br
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OC)c(Br)n3)nc2c1
Temperature: 120 °C
Yield: 269.8 %

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (1.23 g, 6.25 mmol) in N,N-dimethylacetamide (100 mL) was added 6-bromo-5-methoxypicolinaldehyde (1.35 g, 1.2 mmol) followed by NaHSO3 (0.98 g, 9.38 mmol) and p-toluenesulfonic acid monohydrate (1.19 g, 6.25 mmol). The resulting mixture was heated at 120° C. for 20 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with saturated Na2CO3. The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol) followed by trituration with ethyl acetate to give 2-(6-bromo-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.27 g, 52%) as a white solid: 1H NMR (400 MHz, DMSO-d6): δ 11.03 (br s, 1H), 8.32 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]O)([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].[Cl-].[NH4+].[Br-:32].[Li+]>ClCCl.C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][Br:32])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1CO
Reactant: [Br-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1CBr
Yield: 22.9 %

Procedure:
1.8 g (6.2 mmol) of 2-((2,6-dinitrophenyl)amino)benzyl alcohol was dissolved in a mixture of 50 ml of dichloromethane with 50 ml of ethyl ether. Under ice-cooling and stirring, 2.2 ml (15.5 mmol) of triethylamine and 0.58 ml (7.4 mmol) of methanesulfonuyl chloride were successively added thereto. After stirring for 30 minutes, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. After concentrating, the residue was dissolved in 150 ml of acetone. Then 2.7 g (31 mmol) of lithium bromide was added and the resulting mixture was heated under reflux for 1 hour. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to thereby give 0.5 g of 2((2,6-dinitrophenyl)amino)benzyl bromide. Thio product was dissolved in 10 ml of dimethylformamide. After adding 216 mg (2.8 mmol) of thiourea, the mixture was stirred at room temperature for 5 hours. Then 10 ml of dimethylformamide, 157 mg (2.8 mmol) of potassium hydroxide and 2 ml of water were successively added thereto and the reaction mixture was heated at 100° C. for 3 hours. After cooling, the reaction mixture was poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. After concentrating, the residue was purified by silica gel column chromatography. Thus 0.22 g of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18](O)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH:18]=[O:19])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CO
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](OC=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a solution of (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (2.45 g: 10 mmole) in tetrahydrofuran (10 ml), formic acid (453 μl: 12 mmole), triphenylphosphine (3.15 g: 12 mmole), and diethyl azodicarboxylate (1.89 ml: 12 mmole) are successively added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 30 minutes at the same temperature to give (2R,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (2.17 g). Yield: 79%. Colorless oil.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].N([O-])=O.[Na+].[CH:14]([CH:16]=[CH2:17])=[O:15]>Cl.O.CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH2:17][CH2:16][CH:14]=[O:15])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: C=CC=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1CCC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a suspension of 2-amino-4-chlorotoluene (1.41 g, 10 mmol) in 24% aq. HCl (5 mL) Was added dropwise NaNO2 (710 mg, 1.03 mmol) in H2O (3 mL) over 30 min at 0° C. The resulting solution was added dropwise to a solution of acrolein (1 mL, 15 mmol) in a mixture of DMF (15 mL) and 20% aq. TiCl3 (20 mL, 26 mmol). After the addition was completed, the mixture was stirred for 30 min at room temperature and extracted with diethyl ether. The extracts was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 5:1 hexane/AcOEt to give 1.11 g of the title compound (60%): 1H NMR (CDCl3) δ9.83 (s, 1H), 7.06~7.12 (m, 3H), 2.90 (t, 2H, J=7.2 Hz), 2.74 (t, 2H, J=7.2 Hz), 2.27 (s, 3H).
Reaction SMILES: [O-:1][S:2]([O-:5])(=O)=[O:3].[Ca+2].[C:7]([OH:18])(=[O:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.OS(O)(=O)=O.O=S(=O)=O.C>O.[Hg]>[S:2]([C:15]1[CH:16]=[C:8]([C:7]([OH:18])=[O:17])[CH:9]=[CH:10][C:11]=1[C:12]([OH:14])=[O:13])([OH:5])(=[O:3])=[O:1]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Ca+2]
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)c(S(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
A 500 ml 3-neck flask equipped with an air condenser (connected to Drierite tube), stirrer and thermometer, was charged with terephthalic acid (100 g), oleum (190 g, 3.76 mol of 27-33%) and mercury (2.7 g). The light brown solution was stirred at 255°-260° C. for 7 hours. The color of the mixture changed to dark brown. The reaction mixture was cooled overnight to room temperature, a precipitate had formed. The mixture was then poured very slowly and portionwise into a beaker of ice cold water, (132 ml), whereupon a homogenous solution was formed. Upon cooling, a precipitate formed and the whole was allowed to stand for 2 hours. The precipitate was filtered. The solid acid thus obtained was dissolved in 750 ml of hot H2O, charcoal was added and the mixture allowed to reflux for 35 minutes. It was then filtered hot, passed through a pad of celite, and the filtrate was cooled in an ice bath. The solution was saturated with gaseous hydrogen chloride (1 hour) and the product precipitated out. The precipitate was collected by filtration, dried over P2O5 in a vacuum dessicator for 48 hours (79 g, 53%), and recrystallized 3 times from acetic acid. Further purification was carried out as follows. The material was dissolved in 200 ml of hot acetic acid and allowed to reflux for 30 minutes. It was then filtered hot and the filtrate was stored in a refrigerator overnight. The precipitate which resulted was filtered and dried at room temperature for several hours and then under high vacuum. The dry pale yellow product (61 g, 41%) melted at 244°-249° C. (Lit 254°-258° C.); Rf=0.35 (1 ml acetic acid: 1 ml H2O: 1.5 ml n-BuOH).
Reaction SMILES: [CH:1]1([CH2:7][C:8](O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClS([N:15]=C=O)(=O)=O.CN(C=O)C>C(Cl)Cl>[CH:1]1([CH2:7][C:8]#[N:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCCC1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC1CCCCC1
Temperature: 0 °C

Procedure:
A solution of the cyclohexylacetic acid (20.0 g, 141 mmol) in CH2Cl2 (80 mL) was heated to reflux and a solution of chlorosulfonyl isocyanate (20.9 g, 148 mmol) in CH2Cl2 (18 mL) was added dropwise over 40 minutes. After the addition was complete, stirring was continued at reflux for 65 minutes. The mixture was cooled to 0° C., and DMF (21.1 g, 288 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred 18 hours. The mixture was poured over ice, the organic layer separated, and the aqueous layer extracted with CH2Cl2 (50 mL). The combined organic layers were washed with water (3×50 mL), brine, dried (Na2SO4), filtered through a plug of Florosil and concentrated. The nitrile was obtained as 14.6 g (85%) of an oil of sufficient purity for use in the next reaction.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][CH:21]=[O:22]
Reactant: COc1ccccc1CCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CCC=O
Yield: 85.4 %

Procedure:
Meanwhile, a solution of 760 mg of dimethyl sulfoxide in 2 ml of methylene chloride was added dropwise to a solution of 740 mg of oxalyl chloride in 12 ml of methylene chloride at -60° C., with stirring, and the mixture was stirred at the same temperature for 10 minutes. At the end of this time, a solution of 640 mg of 3-(2-methoxyphenyl)propanol (prepared as described above) in 3 ml of methylene chloride was added dropwise to the mixture, and the mixture was stirred for a further 10 minutes. 1.96 g of triethylamine were then slowly added dropwise to the mixture at the same temperature. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 30 minutes and then mixed with water. The methylene chloride layer was separated, dried over anhydrous magesium sulfate, and concentrated by evaporation under reduced pressure. The oily residue thus obtained was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 540 mg of 3-(2-methoxyphenyl)propanal as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[C:3]=1[N+:18]([O-:20])=[O:19].[CH2:21]([N:23]([CH:26](OC)OC)[CH2:24][CH3:25])[CH3:22]>C(N(CC)C=O)C>[CH2:21]([N:23]([CH2:24][CH3:25])[CH:26]=[CH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[C:3]=1[N+:18]([O-:20])=[O:19])[CH3:22]
Reactant: Cc1ccc2c(c1[N+](=O)[O-])C(=O)c1ccccc1C2=O
Reactant: CCN(CC)C(OC)OC
Agent: CCN(C=O)CC
Product: CCN(C=Cc1ccc2c(c1[N+](=O)[O-])C(=O)c1ccccc1C2=O)CC

Procedure:
42.0 g (0.16 mol) of 2-methyl-1-nitroanthraquinone (0.16 mol) and 46.2 g (0.32 mol) of diethylaminodimethoxymethane (0.32 mol) in 150 g of diethylformamide are refluxed for 7 hours. After all the volatiles have been distilled off, the residue is slurried in water and filtered with suction, and the filter residue is dried under reduced pressure. This gives 49.6 g (90.0%) of 2-(2'-diethylaminoethenyl)-1-nitroanthraquinone; melting point: 235°-241° C. (with decomposition).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10].O[C:18]12[CH2:25][CH2:24][N:21]([CH2:22][CH2:23]1)[CH2:20][CH2:19]2.C(N(CC)CC)C>CN(C)C=O.C(Cl)(Cl)Cl>[N:21]12[CH2:24][CH2:25][C:18]([O:10][C:9](=[O:11])[C:8](=[O:7])[C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)([CH2:23][CH2:22]1)[CH2:19][CH2:20]2
Reactant: OC12CCN(CC1)CC2
Reactant: O=C(O)C(=O)c1cccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(OC12CCN(CC1)CC2)C(=O)c1cccs1
Temperature: 25 °C

Procedure:
Oxalyl chloride (1.5 ml, 0.017 mol) was added to a solution of oxothien-2-yl-acetic acid (2.24 g, 0.014 mol) and dimethylformamide (one drop) in 30 ml of chloroform (ethanol free) at 0° C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was dissolved in CHCl3 (30 ml) and added to a suspension of 1.1 g (0.009 mols) of 4-hydroxy-1-azabicyclo[2.2.2]octane, 1.8 ml of triethylamine (0.013 mols), 0.6 g (0.9 mmols) of N-(methylpolystyrene)-4-(methylamino) pyridine at 70° C. The mixture was refluxed for 1 hour, cooled, filtered and washed with water. The title product was extracted with a solution of diluted HCl, washed with CHCl3, basified with K2CO3 and extracted again with CHCl3. After removal of the solvent 1.47 g (45%) of a solid was obtained. 1H-NMR (dmso): δ 2.0 (m, 6H), 2.9 (m, 6H), 7.35 (m, 1H), 8.05 (m, 1H), 8.3 (m, 1H).
Reaction SMILES: C(O)(C)C.[Cl:5][C:6]1[N:7]=[C:8]([N+:17]([O-:19])=[O:18])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:11]=1Cl.[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][NH:23][C:24]([CH3:30])=[CH:25][C:26]([O:28][CH3:29])=[O:27]>C(N(CC)CC)C>[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][NH:23][C:24]([CH3:30])=[C:25]([C:11]1[C:6]([Cl:5])=[N:7][C:8]([N+:17]([O-:19])=[O:18])=[C:9]([NH:13][C:14]([CH3:15])=[O:16])[N:10]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C=C(C)NCC(O)CO
Reactant: CC(=O)Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)C(=C(C)NCC(O)CO)c1nc(NC(C)=O)c([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 50 ml isopropanol is added 2.0 g (0.008 m) N-(5,6-dichloro-3-nitropyrazinyl)acetamide (8), 1.32 g (0.007 m) methyl 3-(2,3-dihydroxypropyl) amino-2-butenoate (3), and 0.81 g (0.008 m) triethylamine. This dark solution is stirred at room temperature for five days. The solvents are then removed on the rotary evaporator and the residue is chromatographed on silica gel and is eluted with 8% methanol/chloroform. Material with Rf =0.5 is collected. This material is a reddish brown solid and is further purified by high pressure liquid chromatography to afford 9 as a brown solid, m.p. 70°-73°.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([O:6][CH3:7])[C:4]=1[Cl:11].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].Cl>ClCCCl>[Cl:11][C:4]1[C:3]([OH:2])=[C:10]([CH:9]=[CH:8][C:5]=1[O:6][CH3:7])[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]([F:12])([F:23])[F:24])=[O:17]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: COc1cccc(OC)c1Cl
Agent: Cl
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccccc2C(F)(F)F)c(O)c1Cl
Reaction time: 18 h

Procedure:
To a solution of 1.7 g of 2-chlororesorcinol dimethyl ether and 2.08 g of o-trifluoromethyl benzoyl chloride in 50 ml of 1,2-dichloroethane at 5°-7° C., 1.6 g of ferric chloride is added gradually. The mixture is brought to room temperature and allowed to stand 18 hours. The reaction mixture is refluxed 30 minutes and poured into 5% HCl and ice. The aqueous phase is extracted with additional organic solvent. The combined organic extracts are washed with water, dried over Na2SO4 and evaporated to give 3-chloro-2-hydroxy-4-methoxy-2'-trifluoromethylbenzophenone, mp 101°-102° C.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCC1CC1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1N(CC2CC2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 214° C. and MS: m/e=424.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and bromomethylcyclopropane.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO.B(F)(F)F.[CH3:21]COCC.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:21])=[O:5]
Reactant: CCOCC
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(F)(F)F)cc1N
Reaction time: 0.25 h

Procedure:
2-Amino-4-trifluoromethyl-benzoic acid (141.2 g.), methanol (1.51 liters) and boron trifluoride etherate (506 cc.) are heated to the reflux temperature for 99 hours. The solution obtained is added to sodium carbonate (350 g.) in iced water (2.8 kg.). The mixture is stirred for 15 minutes and is then extracted with ethyl ether (3 liters). The ether layer is washed with water (250 cc.) and then dried over anhydrous magnesium sulphate (30 g.). After filtration and concentration, methyl 2-amino-4-trifluoromethyl-benzoate (137 g.) melting at 64° C is obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:25]([O:24][C:22](=[O:23])[CH2:21][O:15][CH:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C

Procedure:
Tetrabutylammonium bromide (275 mg; 0.85 mmol) is added to a solution of the crude 1-(4-trifluoromethyl-phenyl)-piperidin-4-ol (627 mg, prepared in accordance with Example 9) in toluene (8 mL). The reaction mixture is cooled to 0° C. and aq. 35% sodium hydroxide (8 mL) is added followed by a drop wise addition of tert-butyl bromoacetate (749 mg; 3.84 mmol).