Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3]C=1.C1(C(=O)C(OC2C=CC([Cl:34])=CC=2)=O)C=CC=CC=1>[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:34][C:5]1[CH:4]=[CH:3][C:7]([C:8]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:1][CH:6]=1
Reactant: O=C(Oc1ccccc1)C(=O)c1ccccc1
Reactant: O=C(Oc1ccc(Cl)cc1)C(=O)c1ccccc1
Agent: [Cl-]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Oc1ccccc1)c1ccc(Cl)cc1

Procedure:
The decarbonylation reaction of Example 79 was repeated except that phenyl phenylglyoxylate (PPG) was replaced with 4-chlorophenyl phenylglyoxylate (4-CPPG), and that the amounts of tetraphenylphosphonium chloride and chloroform were changed as set forth in Table 13. The results are set forth in Table 13.
Reaction SMILES: C([O:8][C:9]1[C:10]([N:29]2[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]2)=[C:11]([F:28])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19]CC1C=CC=CC=1)=[C:14]([Br:27])[CH:13]=2)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[Br:27][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:9]([OH:8])[C:10]([N:29]3[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]3)=[C:11]2[F:28])=[CH:16][C:15]=1[OH:19]
Reactant: O=C1CN(c2c(OCc3ccccc3)cc3cc(OCc4ccccc4)c(Br)cc3c2F)S(=O)(=O)N1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CN(c2c(O)cc3cc(O)c(Br)cc3c2F)S(=O)(=O)N1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-(3,6-bis-benzyloxy-7-bromo-1-fluoronaphthalen-2-yl)-1,1-dioxo-[1,2,5]thiadiazolidin-3-one (232 mg, 0.406 mmol) in CH2Cl2 (3 mL) at 0° C. under nitrogen is added BBr3 (0.731 mL, 0.731 mmol). The reaction is stirred at 0° C. for 5 min then the mixture is quenched with 1N HCl (50 mL) and is extracted 3 times with EtOAc, dried over Na2SO4 and washed with brine. The organic layer is concentrated under reduced pressure and purified on reverse phase HPLC using a gradient of 10-20% MeCN/water (0.1% TFA).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]([C:24]#[N:25])=[C:17]2[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1>O1CCCC1>[Br:33][C:29]1[CH:28]=[C:27]([NH:26][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:8](=[O:11])[CH:9]=[CH2:10])[CH:15]=3)[N:20]=[CH:19][C:18]=2[C:24]#[N:25])[CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and acryloyl chloride (0.321 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed and the residue was slurried with water and collected. Recrystallization from ethanol gave 0.580 g of brown solid: mass spectrum (electrospray, m/e): M+H 393, 395.
Reaction SMILES: [C:1]1([CH:11]([N:13]=[C:14]=[O:15])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH2:30][CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)[N:20]=[CH:19][N:18]=[C:17]2[NH:16][C:14]([NH:13][CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])=[O:15]
Reactant: CC(N=C=O)c1cccc2ccccc12
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(NC(=O)NC(C)c3cccc4ccccc34)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Using an analogous procedure to that described in Example 14, 1-(1-naphthyl)ethyl isocyanate was reacted with 4-amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline to give the title compound; NMR Spectrum: (CDCl3) 1.41-1.57 (m, 2H), 1.76 (m, partially obscured by water peak), 1.86-2.05 (m, 5H), 2.02 (s, 3H), 2.91 (s, 2H), 3.87 (s, 3H), 4.02 (d, 2H), 5.95 (s, 1H), 7.19 (s, 1H), 7.23 (s, 1H), 7.39-7.52 (m, 3H), 7.6 (d, 1H), 7.71 (d, 1H), 7.84 (m, 1H), 8.12 (m, 1H), 8.57 (s, 1H), 8.64 (s, 1H), 10.67 (t, 1H); Mass Spectrum: M+H+ 500.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:16][C:15](C(OCC)=O)=[N:14][N:13]=1)=[CH:8]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:16][CH:15]=[N:14][N:13]=1)=[CH:8]2)[S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)c1nnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(-c3nncs3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
A mixture of ethyl 5-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3,4-thiadiazole-2-carboxylate (0.20 g), 8N aqueous sodium hydroxide solution (0.14 mL), tetrahydrofuran (6 mL) and methanol (6 mL) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were dissolved in tetrahydrofuran, treated with activated carbon, and concentrated to give the title compound (0.13 g, yield 78%) as yellow crystals. melting point 270-271° C.
Reaction SMILES: [C:1]1([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:17](=O)([O-])[O-].[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.O1CCCC1>[C:1]1([N:7]([CH3:17])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[C@H](Nc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)[C@@H](C(=O)O)N(C)c1ccccc1
Temperature: 0 °C

Procedure:
To the m-phenoxybenzyl ester of N-phenylvaline (0.25 g) in HMPT (1 ml) and tetrahydrofuran (1 ml), at 24°, is added methyl iodide (0.12 ml) followed by potassium carbonate (0.092 g). The reaction mixture is heated at 60° for 4 days. The reaction is worked up by pouring into ice-water (5 ml) and extracting with ether (3×10 ml). The combined ether extracts are washed with water (2×10 ml) and brine (1×5 ml) and dried over calcium sulfate. The product is isolated and purified by preparative TLC to give the m-phenoxybenzyl ester of N-phenyl-N-methylvaline.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:25])=[O:24])=[C:19]([OH:26])[CH:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:19]1[CH:18]=[C:17]([CH3:16])[CH:22]=[CH:21][C:20]=1[C:23](=[O:24])[CH3:25]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1ccc(C)cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)ccc3C(C)=O)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (116 mg), 2-hydroxy-4-methylacetophenone (300 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (37 mg, yield 6%).
Reaction SMILES: [NH2:1][C@H:2]1[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:14][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:11]([Cl:13])=[CH:12][C:4]=2[CH2:3]1.C(N(CC)C(C)C)(C)C.C1C=CC(O[C:39](OC2C=CC=CC=2)=[N:40][C:41]#[N:42])=CC=1.Cl.[F:51][C:52]1[CH:53]=[CH:54][CH:55]=[C:56]2[C:61]=1[NH:60][C:59](=[O:62])[C:58]([CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[CH:57]2>CN(C)C=O.CO>[Cl:13][C:11]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:14][N:15]([CH2:18][C:19]([F:21])([F:20])[F:22])[C:16](=[O:17])[C@H:2]([NH:1][C:39]([N:66]3[CH2:67][CH2:68][CH:63]([C:58]4[C:59](=[O:62])[NH:60][C:61]5[C:56]([CH:57]=4)=[CH:55][CH:54]=[CH:53][C:52]=5[F:51])[CH2:64][CH2:65]3)=[N:40][C:41]#[N:42])[CH2:3][C:4]=2[CH:12]=1
Reactant: N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#CN=C(N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)N1CCC(c2cc3cccc(F)c3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 34 %

Procedure:
(R)-7-Amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (115 mg, 345.6 mmol) was dissolved in N,N-dimethylformamide (5.0 mL). N,N-Diisopropylethylamine (200 μL, 1.1 mmol) was added to the mixture followed by diphenyl N-cyanocarbonimidate (94 mg, 382.7 μmol). Mixture stirred at room temperature for 40 minutes. 8-Fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (121 mg, 427.9 μmol) was added to the vessel with stirring. The mixture was heated to 60° C. and held with stirring for 54 hours. The mixture was warmed to 100° C. and with stirring held for 28 hours. Reaction was diluted with methanol. Mixture was purified by prep HPLC (acetonitrile-water-ammonium acetate). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was diluted with water. Solids were filtered off and washed with water. Air was pulled through the filter cake for 1 hour. Solids were collected and dried in vacuo. Title compound was obtained as tan solid in 34% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.61 (s, 1 H) 11.82 (s, 1 H) 8.35 (s, 1 H) 7.80 (s, 1 H) 7.52 (dd, J=16.48, 7.63 Hz, 2 H) 7.32-7.39 (m, 1 H) 7.29 (s, 1 H) 7.08-7.19 (m, 1 H) 5.57-5.76 (m, 1 H) 5.40 (d, J=18.01 Hz, 1 H) 4.90 (d, J=17.40 Hz, 1 H) 4.59-4.79 (m, 1 H) 4.27 (d, J=12.82 Hz, 2 H) 4.01-4.17 (m, 1 H) 3.32-3.41 (m, 1 H) 2.98-3.25 (m, 4 H) 1.78-2.00 (m, 2 H) 1.42-1.71 (m, 2 H). High resolution MS m/e (M+H)+=629.1788.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH2:17][C@H:18]1[CH2:21][C@H:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:25][CH:24]=2)[CH2:19]1)C(=O)OC(C)(C)C>ClCCl>[CH3:8][NH:9][CH2:17][C@H:18]1[CH2:21][C@H:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:25][CH:24]=2)[CH2:19]1
Reactant: CN(C[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trifluoroacetic acid (8.6 mL, 111 mmol) was added to a solution of compound 9 (5.56 g, 15 mmol) in dichloromethane (50 mL). The reaction mass was stirred at room temperature for 24 h and evaporated in vacuo. The residue was diluted with water (50 mL), and the obtained solution was extracted with CH2Cl2. The organic layer was discarded. The aqueous one was alkalized with 10 N NaOH to pH 12 and extracted with CHCl3 (3×100 mL). The combined extracts were dried and evaporated to afford the title compound (3 g, 74%) as a yellow oil. LCMS-data: M+H 275.2, 276.2 (calc. 274.4). 1H NMR-data (DMSO-d6): 7.16 (d, 2H, Ph, J=8.6); 6.72 (d, 2H, Ph, J=8.6); 4.65-4.78 (m, 1H); 3.46 (s, 2H, CH2); 2.56 (d, 2H, CH2, J=7.6); 2.34-2.41 (m, 4H); 2.28 (s, 3H, NCH3); 2.00-2.30 (m, 5H); 1.60-1.71 (m, 4H).
Reaction SMILES: [Cl:1]C(Cl)(Cl)C=O.C(#N)C=C.[Cl:11][CH:12]([CH2:15][C:16]([Cl:20])(Cl)[CH:17]=O)[C:13]#[N:14]>O>[Cl:1][C:17]1[C:16]([Cl:20])=[CH:15][C:12]([Cl:11])=[CH:13][N:14]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: N#CC(Cl)CC(Cl)(Cl)C=O
Solvent: C=CC#N
Solvent: O
Product: Clc1cnc(Cl)c(Cl)c1

Procedure:
A process for producing 2,3,5-trichloropyridine, which process comprises causing trichloroacetaldehyde to undergo an addition reaction, in the presence of a catalyst, with acrylonitrile, and cyclising the formed 2,4,4-trichloro-4-formylbutyronitrile of the formula I ##STR2## with the splitting-off of water, to give 2,3,5-trichloropyridine.
Reaction SMILES: C([CH:3]([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])C.[NH2:10][C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1C(OC)=O.C(N(CC)CC)C>ClCCl>[CH3:16][C:15]1[C:11]2[NH:10][C:7](=[O:8])[CH2:3][C:4](=[O:5])[C:12]=2[S:13][CH:14]=1
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: COC(=O)c1scc(C)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1csc2c1NC(=O)CC2=O
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Ethyl malonyl chloride (4.29 g, 28 mmol) was added to a solution of methyl 3-amino-4-methylthiophene-2-carboxylate (4 g, 23 mmol) and triethylamine (4.2 mL, 30 mmol) in dichloromethane (50 mL) and the resulting mixture was stirred for 30 minutes. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. To the oily residue was added a freshly prepared ethanolic solution of sodium ethoxyde (0.5 g in 25 mL of EtOH) and the reaction mixture was heated at reflux overnight. The solvent was evaporated under reduced pressure and water (50 mL) was added to the residue, followed by sodium hydroxide (1.5 g). The resulting mixture was heated at reflux overnight, then was cooled and acidified by addition of an aqueous solution of hydrochloric acid (6 M). The solid formed was collected by filtration, washed with water and dried under reduced pressure to afford 2.0 g of 3-methyl-4H-thieno[3,2-b]pyridine-5,7-dione.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+:13].Br[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>O.C(O)(C)C>[CH:17]1([CH2:16][CH2:15][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.[Na+:13]
Reactant: BrCCC1CCCC1
Reactant: O=S(=O)(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=S(=O)([O-])c1ccc(OCCC2CCCC2)cc1

Procedure:
A solution of 4-hydroxybenzenesulfonic acid (6.5 grams, 28.2 mmole) and sodium hydroxide (2.2 grams, 55 mmole) in water (15 mL) was mixed with a solution of 2-(bromoethyl)cyclopentane (15.0 grams, 84.7 mmole) in isopropanol (40 mL) and the resulting mixture was heated at reflux for 2 days. The isopropanol was removed by evaporation under vacuum. The titled compound, 4.7 grams (57%), was collected by filtration and washed with isopropanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH:23]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30])([CH3:25])[CH3:24]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:30][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:27]=1
Reactant: CC(C)c1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)c1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Reaction time: 16 h

Procedure:
tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (2.0 g, 6.7 mmol) and 3-isopropylbenzylamine hydrochloride (2.5 g, 13.5 mmol) in isopropanol (60 mL) are refluxed 3 h. The reaction is cooled and stirred 16 h. The solution is concentrated under reduced pressure, redissolved in chloroform, washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, 7% methanol/chloroform) gives the title compound in pure form. ESI MS m/z 449.3 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:14]1[CH:37]=[CH:36][C:17]([O:18][C@@H:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@@H:20]2[NH:28][C:29](OC(C)(C)C)=O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CCCC1.C(O)C.C(Cl)(Cl)[Cl:47]>>[ClH:47].[CH2:7]([C:14]1[CH:37]=[CH:36][C:17]([O:18][C@@H:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@@H:20]2[NH:28][CH3:29])=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Cc2ccccc2)cc1
Reactant: ClC(Cl)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Cc2ccccc2)cc1
Product: Cl

Procedure:
The title compound was prepared in a similar manner to Example 12 from LiAlH4 (320 mg, 8.4 mmol), cis-1-(4-benzylphenoxy)-2-tert-butoxycarbonylaminoindane (700 mg, 1.7 mmol) and tetrahydrofuran (40 ml). After a reaction time of 2.5 h the reaction was worked up as previously described and subjected to column chromatography on silica gel eluting with 2% ethanol in chloroform to afford a colourless oil (438 mg) which was converted to the HCl salt and crystallised to afford the title compound as a white solid. m.p. 222° C. dec. (from methanol-diethyl ether).
Reaction SMILES: [CH3:1][CH:2]1OC(C)OC(C)O1.[CH3:10][C:11]1([CH3:34])[O:16][C:15]2C3C(CCC)=[CH:21][C:20](=[O:26])[O:19][C:18]=3[C:27]([C:30](=[O:33])[CH2:31][CH3:32])=[C:28]([OH:29])[C:14]=2[CH:13]=[CH:12]1.CC1C=CC(S([O-])(=O)=O)=CC=1.[CH:46]1[CH:51]=[CH:50][NH+]=[CH:48][CH:47]=1.C(C(O)=O)(F)(F)F.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:48][CH2:47][CH2:46][C:51]1[C:50]2[C:15]3[O:16][C:11]([CH3:34])([CH3:10])[CH:12]=[CH:13][C:14]=3[C:28]3[O:29][C@H:1]([CH3:2])[C@@H:31]([CH3:32])[C:30](=[O:33])[C:27]=3[C:18]=2[O:19][C:20](=[O:26])[CH:21]=1
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Reactant: c1cc[nH+]cc1
Reactant: CC1OC(C)OC(C)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@H](C)[C@@H](C)C3=O
Yield: 27 %

Procedure:
Paraldehyde One-Step Reaction: To a stirring solution of chromene 4 (350 mg, 1.0 mmol) and PPTS (250 mg, 1.0 mmol) in 1,2-dichloroethane (2 mL) at ambient temperature under N2 was added 3 mL paraldehyde (22.5 mmol). The resulting mixture was refluxed for 7 h. Then, CF3CO2H (1 mL), an additional equivalent of PPTS and 1 mL of paraldehyde were added; the mixture was refluxed overnight. The reaction mixture was neutralized with saturated aqueous NaHCO3 and extracted with ethyl acetate (50 mL×3). The crude product obtained by evaporation under reduced pressure was washed with hexane. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1:2) to afford 100 mg (27% yield) of chromanone 7 and 30 mg (8% yield) of 7a. Chromanone 7 (10,11-trans-dihydro-6,6,10,11-tetramethyl-4-propyl-2H,6H,12H-benzo[1,2-b:3,4-b':5,6-b"]tripyran-2,12-dione) obtained by this method was identical with an authentic sample by comparison of TLC, HPLC and spectroscopic data.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11](Cl)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(Cl)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Reactant: C1CNCCN1
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of Compound 68 (0.8 g, 2.43 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (628 mg g, 7.29 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was then removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 0.9 g (98%) of yellow solids. M.P. 156° C. 1H NMR (DMSO-d6): δ 2.94 (m, 4H), 3.55 (m, 4H), 5.47 (s, 2H), 7.19 (m, 2H), 7.24 (m, 1H), 7.31 (m, 2H), 7.39 (d, J=8.9 Hz, 1H), 7.64 (dd, J=2.6, 8.9 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H). EIMS m/z 379 (M+1).
Reaction SMILES: [CH:1](=[C:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Cl:22])=[C:15]([Cl:21])[CH:16]=3)[NH:11][C:10]=2[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([CH:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Cl:22])=[C:15]([Cl:21])[CH:16]=3)[NH:11][C:10]=2[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=Cc2ccccc2)CCc2c1[nH]c1cc(Cl)c(Cl)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1c2[nH]c3cc(Cl)c(Cl)cc3c2CCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.1 %

Procedure:
To a solution of 2-benzylidene-6,7-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.07 g, 0.20 mmol) in EtOAc (10 mL), 10% Pd/C (10 mg) was added under N2 atmosphere. The reaction mixture was stirred under H2 atmosphere at room temperature for 12 h. The reaction mixture was filtered through a Celite® pad. The Celite® pad was washed with EtOAc (2×20 mL) and the filtrate was concentrated in vacuo to provide the crude material which was purified by silica gel chromatography [EtOAc-hexane (1:9) as eluant] to furnish the title compound as a yellow solid (0.04 g, 57%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.79 (s, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.34-7.31 (m, 2H), 7.25-7.22 (m, 3H), 3.48-3.45 (m, 1H), 3.02-2.97 (m, 1H), 2.86-2.81 (m, 2H), 2.80-2.66 (m, 1H), 2.25-2.21 (m, 1H), 1.95-1.92 (m, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:19][CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([NH:32][CH:17]1[CH2:18][CH2:19][N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:16]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCOc1ccc(S(=O)(=O)N2CCC(OS(C)(=O)=O)C2)cc1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(NCc3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 95.9 %

Procedure:
A solution of methanesulfonic acid 1-(4-butoxy-benzenesulfonyl)-pyrrolidin-3-yl ester (1.51 g, 4 mmol) in tetrahydrofuran (8 ml) was added benzylamine (3.46 g, 32 mmol) and the mixture was stirred at 100° C. for 2 days. After cooling to room temperature the tetrahydrofuran was evaporated, and the residue washed with hexanes. The solid was stirred with 10% sodium carbonate solution (30 ml) and ethyl acetate (40 ml), and the organic solution was washed brine, dried over anhydrous sodium sulfate, and filtered through Magnolsol. The filtrate was evaporated, and the residue was washed with hexanes to give 1.49 g of a white solid; m.p. 99-100° C.; MS (ES) m/z 389.0 (MH+); HRMS (El) Calcd. for C21H28N2O3S (M+): 388.1820, Found: 388.1826.