Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:32])=[C:8]([CH:31]=1)[C:9](=[O:30])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)([OH:3])=[O:2].[Br:33]Br>C(O)(=O)C>[Br:33][C:6]1[CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:31]=[C:8]2[C:7]=1[O:32][C:11]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=1)=[CH:10][C:9]2=[O:30]
Reactant: BrBr
Reactant: O=C(O)c1ccc(O)c(C(=O)C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c2oc(-c3ccc(OCc4ccc5ccccc5n4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
In a solution of 5'-carboxy-2'-hydroxy-4-(2-quinolinylmethoxy)chalcone (1 mmol) in 10 ml of glacial acetic acid, 0.06 ml of bromine was gradually added dropwise. The reaction mixture was stirred at room temperature for 3 hours, and the resulting yellow precipitate was collected and then washed with water. The precipitate was next dissolved in a mixed solvent which was consisted of 8 ml of ethanol and 15 ml of 6% potassium hydroxide. The resulting solution was stirred further for 4 hours. After the reaction mixture was acidified, the resulting precipitate was collected by filtration and then recrystallized from DMF, whereby the title compound represented by the following formula was obtained (yield: 25%). ##STR16##
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1(=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15](=[O:22])[O:14]1>>[CH3:8][C:1]1[CH:2]=[C:3]([CH3:7])[CH:4]=[CH:5][C:6]=1[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:13]([OH:23])=[O:14])=[O:22]
Reactant: Cc1cccc(C)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
An ice/salt cold mixture of m-xylene (114 g, 1073 mmol) was treated with aluminium chloride (59.4 g, 446 mmol) (in three portions), followed by 2-benzofuran-1,3-dione (30 g, 203 mmol) (in three portions). The mixture was warmed to room temperature and stirred for 3 hours after which time the mixture turned to a thick white suspension. The mixture was heated to 55° C. for 2 hours, and cooled to room temperature. The thick mixture was slowly poured into ice cold 20% HCl and collected on filter paper. The filtered material was allowed to dry to give the desired product as a white solid (50 g, 97%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.98-8.07 (m, 1 H) 7.60-7.69 (m, 1 H) 7.51-7.59 (m, 1 H) 7.38-7.45 (m, 1 H) 7.01-7.13 (m, 2 H) 6.86-6.94 (m, 1 H) 2.61 (s, 3 H) 2.33 (s, 3 H); LC/MS (m/z) ES+=255 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][CH2:7][C:8](Cl)=[O:9].[OH-].[Na+]>C(Cl)Cl>[Cl:6][CH2:7][C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: O=C(Cl)CCl
Reactant: C1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)N1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
Pyrrolidine (63.9 g, 0.9 mole) was taken up in CH2Cl2 (640 mL) and cooled to 0° C. in a salt-ice water bath. To the stirred mixture was added chloroacetyl chloride (101.8 g in 450 mL of CH2Cl2, 0.9 mole) dropwise maintaining the internal temperature below 15° C. After adding the chloroacetyl chloride, the mixture was stirred for one hour at 5° C. Sodium hydroxide solution (7 M, 190 mL) was added with vigorous stirring such that the inside temperature did not exceed 20° C. The mixture was stirred for 15 minutes and the aqueous layer was separated. The organic layer was washed with saturated sodium bicarbonate solution (2×200 mL), water (1×200 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was recrystallized from hexane to give 64.5 g (48.6% yield) of white plate crystals; mp 43° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[O:10][C:9](=[O:17])[CH:8]=[C:7]2[CH3:18])[CH:2]=[CH2:3]>S(=O)(=O)(O)O>[CH3:3][CH:2]1[O:14][C:13]2=[C:12]([O:15][CH3:16])[C:11]3[O:10][C:9](=[O:17])[CH:8]=[C:7]([CH3:18])[C:6]=3[CH:5]=[C:4]2[CH2:1]1
Reactant: C=CCc1cc2c(C)cc(=O)oc2c(OC)c1O
Agent: O=S(=O)(O)O
Product: COc1c2c(cc3c(C)cc(=O)oc13)CC(C)O2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A sample of 15.0 g (0.0612 mol) of 6-allyl-7-hydroxy-8-methoxy-4-methylcoumarin was treated with 30 ml of conc. sulfuric acid at 25°. After 10 min, the dark mixture was diluted with 400 ml of ice water and extracted three times with methylene chloride/methanol, 4:1. The organic phases were dried and evaporated; the residue was filtered through 250 g silica, diluting with ethyl acetate/benzene, 1:4 to afford pure 2,5-dimethyl-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]-benzopyran-7-one, m.p. 113°-115°, as a white crystalline solid. Recrystallization from ethanol gave an analytical sample, m.p. 114°-115°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][O:39][NH2:40])=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][O:39][NH:40][C:18]([C:17]2[CH:21]=[CH:22][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:15][CH:16]=2)=[O:20])=[CH:36][CH:35]=1
Reactant: NOCc1ccc(Cl)cc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NOCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Reaction time: 0.33 h
Yield: 21.1 %

Procedure:
4-(6-cyano-4-(methoxycarbonyl)-3,4-dihydro-2H-chromen-7-yloxy)benzoic acid (from Example 7, Step B) (17 mg, 0.0481 mmol) was diluted with CH2Cl2 (1 mL) followed by the addition of oxalyl chloride in CH2Cl2 (2M in CH2Cl2) (0.0289 mL, 0.0577 mmol) and 1 drop of DMF. This was stirred for 20 minutes followed by the addition of O-(4-chlorobenzyl)hydroxylamine (15.2 mg, 0.0962 mmol) and N,N-diisopropylethylamine (0.0335 mL, 0.192 mmol). After stirring for 30 minutes the reaction was loaded directly onto a Biotage 12i eluting with hexane:ethyl acetate (1:1) to yield the title compound (5 mg, 21.1% yield).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](OS(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2].[N-:70]=[N+:71]=[N-:72].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:70]=[N+:71]=[N-:72])[CH:46]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 70 °C
Yield: 45.2 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(o-nitrophenylsulfonyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (66 mg) in N,N-dimethyl formamide (1 ml) was added an excess of sodium azide (22 mg) and the mixture heated to 70° C. After 2.5 hours the reaction was cooled to room temperature, diluted with ethyl acetate, extracted from half-saturated ammonium chloride, and washed with brine. The combined organics were dried over sodium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (25 mg).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)=[CH:5][C@H:4]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3]1.[BH4-].[Na+].N>FC(F)(F)C(O)=O>[CH3:1][N:2]1[C@H:16]2[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[CH:14]([CH2:15]2)[CH2:13][NH:12]4)=[CH:5][C@H:4]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3]1
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4c3C(CN4)C[C@H]2N(C)C1
Yield: 53.8 %

Procedure:
At -20° C., 19.6 g of 3-(9,10-didehydro-6-methyl-8α-ergolinyl)-1,1-diethylurea is dissolved in 80 ml of trifluoroacetic acid, and 8 portions of respectively 500 mg of sodium borohydride are added at intervals of 3-4 minutes. The mixture is then poured on ice, made alkaline under ice cooling with 90 ml of 26% ammonia solution, and extracted with methylene chloride. The organic phase is dried, concentrated, and chromatographed on silica gel with methylene chloride/methanol, thus isolating 10.6 g of 3-(9,10-didehydro-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea as a mixture of isomers of the 3α and 3β-H-compounds. Crystallization from ethyl acetate yields 6.5 g of the 3β-H-compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:23][CH:24]([C:29]1[S:33][C:32]([CH:34]=[O:35])=[N:31][CH:30]=1)[C:25]([OH:28])([CH3:27])[CH3:26].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[OH:23][CH:24]([C:29]1[S:33][C:32]([C:34](=[O:35])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:31][CH:30]=1)[C:25]([OH:28])([CH3:27])[CH3:26]
Reactant: CC(C)(O)C(O)c1cnc(C=O)s1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(O)C(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Yield: 62.8 %

Procedure:
A mixture of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.50 g), 5-(1,2-dihydroxy-2-methylpropyl)-1,3-thiazole-2-carbaldehyde (0.32 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43 mg), triethylamine (0.09 mL), tetrahydrofuran (6 mL) and ethanol (6 mL) was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, the residue was subjected to basic silica gel column chromatography, and eluted with tetrahydrofuran, and the fraction was concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.51 g, yield 61%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 524 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:16]([OH:17])[C:15]4[S:18][CH2:19][CH2:20][S:21][C:14]=4[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:25]([N:28]1[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1)(=[O:27])[CH3:26]>CN(C)C=O.O.C(Cl)(Cl)Cl>[C:25]([N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:17][CH:16]2[N:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[C:13](=[O:22])[C:14]3[S:21][CH2:20][CH2:19][S:18][C:15]2=3)=[O:35])[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(=O)N1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Temperature: 2 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
6-(7-Chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (2.5 g.) is added, at 0° C., to a suspension of sodium hydride (0.20 g.) in anhydrous dimethylformamide (10 cc.). The reaction mixture is stirred for 1 hour at 2° C., and then a solution of 1-acetyl-4-chlorocarbonylpiperazine (2.85 g.) in anhydrous dimethylformamide (20 cc.) is added. After 18 hours at 2° C., the reaction mixture is diluted with distilled water (100 cc.). The precipitate formed is filtered off, washed with distilled water (10 cc.) and dried in air. The product obtained (3.5 g.) is dissolved in chloroform (50 cc.), and the solution is filtered through silica gel (50.0 g.) contained in a column of diameter 4.1 cm. Elution is carried out using a mixture of chloroform and methanol (98-2 by volume; 400 cc.), and the eluate is discarded. Elution is continued using a similar mixture (400 cc). This eluate is evaporated to dryness under reduced pressure (20 mm.Hg). The chromatographed product is purified by recrystallisation from a mixture of dimethylformamide and ethanol (50-50 by volume; 20 cc.). 5-(4-Acetylpiperazin-1-yl)carbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (1.40 g.), which melts at 271° C., is obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:22])=[CH:18][N:17]=1
Reactant: NN1CCOCC1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NN1CCOCC1)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added 4-aminomorpholine (31 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (96 mg, 0.30 mmol) and N,N-diisopropyl ethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4) and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (41 mg, 47%) as a colorless oil. MS: m/e=412.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:23]2[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: NS(=O)(=O)c1ccc(O)cc1
Product: N#Cc1ccc(N(CCOc2ccc(S(N)(=O)=O)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-hydroxybenzenesulfonamide: MS (APCI) m/z 468 (M+1).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(=O)([O-])O.[Na+].[NH2:16][C:17]1[C:22]([C:23]([OH:25])=[O:24])=[C:21]([CH3:26])[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:19]([CH3:32])[CH:18]=1.Cl>C(O)C.O>[ClH:2].[ClH:1].[CH2:30]([O:29][C:27]([C:20]1[C:21]([CH3:26])=[C:22]([C:17]([NH:16][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:18][C:19]=1[CH3:32])[C:23]([OH:25])=[O:24])=[O:28])[CH3:31]
Reactant: ClCCN1CCCCC1
Reactant: CCOC(=O)c1c(C)cc(N)c(C(=O)O)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C)cc(NCCN2CCCCC2)c(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.6 %

Procedure:
1-(2-Chloroethyl)piperidine hydrochloride (0.85 g) and sodium hydrogen carbonate (1.5 g) were added to a solution of 6-amino-3-ethoxycarbonyl-2,4-dimethylbenzoic acid (1.0 g) in ethanol (10 ml) and water (10 ml). The mixture was stirred at room temperature for 24 hours and then its pH was adjusted to 4-5 by addition of 10% hydrochloric acid. The solution was concentrated under reduced pressure, and the resulting residue was extracted with CHCl3. The CHCl3 extracts were combined, washed with water, and dried over anhydrous MgSO4. The solvent was evaporated, and the residue was recrystallized from ethanol/diethyl ether to give 3-ethoxycarbonyl-2,4-dimethyl-6-(2-piperidinoethylamino)benzoic acid dihydrochloride (1.2 g, 68%). MS: m/e, 348(M+), 304, 303, 259. NMR: δ (ppm CDCl3), 1.37 (3H, t), 1.75 (6H, b), 2.25 (3H, s), 2.41 (3H, s), 3.00 (6H, b), 3.65 (2H, b), 4.36 (2H, q), 6.33 (1H, s), 8.20 (2H, b).
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+].[S:8](=[O:11])(=[O:10])=[O:9].S([O-])(O)(=O)=O.[Na+]>O>[S:1]([O:5][S:8]([O-:11])(=[O:10])=[O:9])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+:6]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=S(=O)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])OS(=O)(=O)[O-]

Procedure:
As the gaseous and solid streams flow counter current to each other, they undergo the reactions shown in equations 3 and 6. Beginning at the far right, the combustion gases are sufficiently hot to decompose sodium pyrosulfate to produce sodium sulfate and sulfur trioxide. The sodium sulfate is discharged from the kiln through a port at the far right end, and the sulfur trioxide enters the gas stream which is moving to the left. Somewhere towards the middle of the kiln, sodium hydrogen sulfate is decomposed to give sodium pyrosulfate and water vapor. The solid pyrosulfate moves toward the right while the water vapor flows with the combustion gases upwards towards the left. In the left hand section of the kiln, water vapor and sulfur trioxide combine to form sulfuric acid. This acid for the most part is lost with the product gases since the temperature of the flue gases at the exit exceeds the boiling points of lower concentrations of sulfuric acid. Acid in the feed combines with the salt to form hydrogen chloride and sodium hydrogen sulfate. The solid sodium hydrogen sulfate moves to the right while the hydrogen chloride escapes with the combustion gases through the vent in the left end of the kiln.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33]>>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Fc1ccccc1OCCCBr
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.753 g of 1-(3-bromopropoxy)-2-fluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.53 (2:1 EtOAc-heptane); Rt=5.10.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[N+]([O-])=O)[C:12]([N+:20]([O-])=O)=[CH:11][C:10]=1[O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])C1C=CC=CC=1>CO.[C].[Pd]>[CH3:28][O:27][CH2:26][CH2:25][CH2:24][O:23][C:10]1[CH:11]=[C:12]2[C:13]([CH:15]=[CH:16][NH:20]2)=[CH:14][C:9]=1[OH:8]
Reactant: COCCCOc1cc([N+](=O)[O-])c(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCCOc1cc2[nH]ccc2cc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 34 %

Procedure:
10% Palladium-carbon (water content, 50%) (8 g) was added to a solution of (E)-1-(benzyloxy)-2-(3-methoxypropoxy)-4-nitro-5-(2-nitrovinyl)benzene described in Production Example 32-4 (19.6 g, 50.5 mmol) in methanol (300 mL) at room temperature. The liquid mixture was stirred under hydrogen atmosphere at room temperature for 6 hours. The reaction liquid was filtered through celite and then the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=2:1-1:1) to obtain the title compound (3.81 g, 34%).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH:12]1[C:24]2[NH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([N:23]3[C:24]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:6]=2[CH:7]=1
Reactant: Clc1ccc2scc(Br)c2c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1ccc2scc(-n3c4ccccc4c4ccccc43)c2c1
Yield: 129.4 %

Procedure:
In a 250 mL 2-neck round flask 3-bromo-5-chlorobenzothiophene (2 g, 8.1 mmol), carbazole (0.675 g, 4.05 mmol), CuI (0.46 g, 24.3 mmol), trans-1,2-dicyclohexane-diamine (0.92 g, 2.43 mmol), K3PO4 (3.43 g, 16.2 mmol), and 150 mL of 1,4-dioxane were poured, and refluxed and stirred. After the reaction, the solid matter was filtered. And after the organic solvent was distilled in vacuum and removed, column chromatography (Hex:E.A=9:1) is performed, the solution was distilled in vacuum, giving 1.75 g of white solid (65% yield).