Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[O:25].Cl.[NH:29]1[CH2:32][CH2:31][CH:30]1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][N:14]([C:24]([N:29]3[CH2:32][CH2:31][C@H:30]3[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[O:25])[C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)C1CCN1
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CN(C(=O)N2CC[C@H]2C(=O)OCc2ccccc2)C1=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A slurry of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (0.78 g, 3.54 mmole) in dry dichloromethane was warmed briefly to 50° C. and then cooled to -5° C. Triethylamine (0.354 g, 3.54 mmole) and phosgene (5.7 ml of 12.5% phosgene/toluene) were added and the reaction was stirred at -5° C. for 2 hours. The reaction was concentrated to a residue and fresh dichloromethane was added. After the solution was cooled to -50° C., triethylamine (0.714 g, 7.08 mmole) and azetidine-2-carboxylic acid, benzyl ester hydrochloride (0.8 g, 3.54 mmole) were added. The reaction was stirred at -5° C. for 45 minutes. The reaction mixture was poured into 10% monobasic potassium phosphate and the dichloromethane layer was separated and washed with water and brine. After drying over sodium sulfate the solvent evaporated. The crude oil was flash chromatographed on silica (LPS-1) eluting with ethyl/acetate:hexane (1:1). Fractions containing pure compound were concentrated to give 0.622 g of the title compound.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:12])[O:9][C:8](=[O:10])[CH:7]=[C:6]([CH3:11])[O:5]1.Br.CCOCC.CCCCCC>C(Cl)Cl>[Br:1][C:7]1[C:8](=[O:10])[O:9][C:4]([CH3:12])([CH3:3])[O:5][C:6]=1[CH3:11]
Reactant: BrBr
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: Br
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=C(Br)C(=O)OC(C)(C)O1
Reaction time: 0.25 h
Yield: 74.6 %

Procedure:
Bromine (0.105 mol, 5.38 ml) was added dropwise to a 20° C. solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (TKD, 0.1 mol, 14.2 g) in 100 ml CH2Cl2 over five minutes. The reaction solution was rapidly decolorized and hydrogen bromide evolved. After 15 minutes, the solvent was removed in vacuo to provide 22 g (99%, >95% pure by NMR) of a pale yellow oil which solidified upon refrigeration. Flash chromatography (10% ether/hexane on silica) afforded 16.5 g (75%) of the title compound as colorless plates.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[O:19]([C:26]1[CH:27]=[C:28]([CH2:29][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:31]=[CH:32][CH:33]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(Oc3ccccc3)c2)CCCC1=O
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
40% Methanolic Triton B (1.53 mL, 3.4 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (554.6 mg, 2.28 mM) in 5 mL of DMF at 25° C. After 5 minutes, 3-phenoxybenzyl chloride (748.0 mg, 3.42 mM) was added and the resultant mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed three times with 1N HCl, three times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 563.6 mg (58%) of 9-[(3-phenoxyphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a thick yellow oil. 1H NMR (DMSO-d6) δ7.7 (dd, 1H, J=1 and 8 Hz), 7.4-7.2 (m, 6H), 7.1 (t, 1H, J=8 Hz), 6.95 (m, 2H), 6.8-6.7 (m, 2H), 5.55 (s, 2H), 3.75 (s, 3H), 3.0 (t, 2H, J=6 Hz), 2.45 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CDCl3, cm−1) 3050, 2950, 1725, 1653, 1585, 1487, 1465, 1288, 1252, and 1119. MS (ES) m/e 426.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].C1(C)C=CC=CC=1.Cl>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.CC(C)=O>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (250 g, content: 89.6%, water: 8.6%) and trimethylcetylammonium chloride (0.275 g) was stirred in a mixed solvent of toluene (960 ml) and acetone (24 ml), and 35% conc. hydrochloric acid (30.0 g) was added. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (30.0 g) in acetone (116 g) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 1200 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (850 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by HPLC showed that the solution contained L-ascorbic acid (190.0 g, yield: 93.5%) and 2-keto-L-gulonic acid (2.7 g, residual ratio: 1.2%).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH:15]=[CH2:16])[CH:5]=1)C.C(N(CC)CC)C.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:36])[NH:1][CH2:2][C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:12])=[O:13])=[C:6]([CH:15]=[CH2:16])[CH:5]=2)=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: C=Cc1cc(C(C)N)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)Nc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 39.3 %

Procedure:
N-[4-(1-Amino-ethyl)-2-vinyl-phenyl]-methanesulfonamide (236.7 mg, 0.985 mmol) and triethylamine (274.6 μl, 1.970 mmol, 2 eq) were added in methylene chloride. The reaction mixture was cooled down to 0° C. 4-tert-Butylphenyl isocyanate (192.5 μl, 1.083 mmol, 1.3 eq.) was added into the mixture. The reaction mixture was stirred for 40 min. A reaction solvent was removed in vacuo. The residue was purified with column chromatography (n-Hx:EA=2:1) to yield title compound (155.4 mg, 47%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[CH:22][C:21](Br)=[CH:20][N:19]=1.C([Li])CCC.B(OC)(OC)[O:31]C.OO.FC1C(F)=C(CCCCC)C=CC=1C1N=CC(O)=CN=1>CCCCCC.C1COCC1>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[CH:22][C:21]([OH:31])=[CH:20][N:19]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Reactant: COB(OC)OC
Agent: CCCCCc1ccc(-c2ncc(O)cn2)c(F)c1F
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(-c2ncc(O)cn2)c(F)c1F
Yield: 56.2 %

Procedure:
--Quantities: difluorophenylbromo-pyrimidine 4 (4.30 g, 10.8 mmol), 2.5M butyllithium (4.5 ml, 11.3 mmol), trimethyl borate (2.6 ml, 22.6 mmol), THF (100 ml), hexane (30 ml), 30% hydrogen peroxide (5.4 ml, 44 mmol) ether (200 ml). The experimental procedure was as described for compound 33. The crude product was purified by flash chromatography (10 to 30% ethyl acetate-light petroleum) to give the difluorophenyl-5-hydroxypyrimidine 35 (2.04 g, 56%) [from light petroleum (b.p. 60-80° C.)], m.p. 84-85° C.; νmax /cm-1 (KBr) 3 100br, 2920, 2850, 1620, 1560, 1510, 1475, 1430, 1300, 1285, 1200 and 1085; δ 0.91 (3H, t, Me), 1.19-1.52 (10H, m), 1.32 (2H, quint, OCH2CH2), 4.05(2H, t, OCH2), 6.79 (1H, ddd, J8, 7 and 2, 5'-H), 7.59 (1H, ddd, J8.5, 7 and 2, 6'-H) and 8.38 (2 H, s, 4- and 6-H); m/z 336 (M+), 335, 237, 223, 208, 195 and 155.
Reaction SMILES: C(Cl)Cl.[N:4]1[C:14]2[O:13][C:12]3[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:18][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C1([N:30]=C=NC2CCCCC2)CCCCC1.N>C(O)(=O)C>[N:4]1[C:14]2[O:13][C:12]3[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[C:20]([NH2:30])=[O:21])=[CH:18][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1cccnc1O2
Agent: N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C(N)=O)c1ccc2c(c1)CCc1cccnc1O2
Yield: 44.2 %

Procedure:
To 10 ml of methylene chloride solution containing 50 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]oxepin-8-yl)-propionic acid and 50 mg of dicyclohexylcarbodiimide was added 5 ml of methylene chloride saturated with ammonia, and the mixture was stirred with ice-cooling for 2 hours. To this were added acetic acid and ice and the resulting mixture was extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution, then saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the residue, which was extracted with ethyl acetate and the extract was freed of the solvent. The resulting residue was chromatographed over silica gel, eluted with n-hexane/acetone (4/1-1/1), and there was obtained 22 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]oxepin-8-yl)-propionamide as white crystals. These were recrystallized from ethyl acetate to give colorless crystals having a melting point of 162°-165° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[O:20][CH3:21])=[CH2:12].[C:22]1(SC[Li])C=CC=CC=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[O:20][CH3:21])[CH2:22][CH2:12]1
Reactant: [Li]CSc1ccccc1
Reactant: C=C(c1ccc(C)cc1OC)c1ccccc1OCOC
Product: COCOc1ccccc1C1(c2ccc(C)cc2OC)CC1
Yield: 44 %

Procedure:
The general procedure of Example 34 was followed using 1-(2-methoxymethoxyphenyl)-1-(4-methyl-2-methoxyphenyl)ethene and, initially, 3.3 moles of phenylthiomethyl lithium reagent per mole of olefin. The title compound was obtained as a clear oil in 44 percent yield and its structure was verified by proton NMR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][OH:12])[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH:11]=[O:12])[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1
Reactant: OCc1coc2c(Br)cc(F)c(F)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1coc2c(Br)cc(F)c(F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
The compound obtained in Step 2 (700 mg, 2.66 mmol) was dissolved in dichloromethane (50 mL), and manganese dioxide (1.4 g) was added thereto, and stirred at room temperature overnight. After filtration, the solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[CH2:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33]>>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8]([NH:37][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])=[N:9][CH:10]=1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)Nc1ncc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3ccccc23)n1

Procedure:
The title compound of Example 151 was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 9.15 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 8.34 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.71-7.67 (m, 2H), 7.54 (t, J=7.6 Hz, 1H), 6.92-6.86 (m, 2H), 6.79-6.75 (m, 1H), 3.67 (s, 3H), 3.58 (q, J=7.6 Hz, 2H), 1.39 (t, J=7.6 Hz, 3H). LCMS: 473.0 (M+1)+
Reaction SMILES: [C:1](=[S:3])=S.C(N(CC)CC)C.[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]([CH2:22][O:23][CH2:24][CH3:25])[N:16]=[CH:17]2.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH2:24]([O:23][CH2:22][C:15]1[N:16]=[CH:17][C:18]2[C:13]([CH:14]=1)=[C:12]([N:11]=[C:1]=[S:3])[CH:21]=[CH:20][CH:19]=2)[CH3:25]
Reactant: S=C=S
Reactant: CCOCc1cc2c(N)cccc2cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOCc1cc2c(N=C=S)cccc2cn1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A solution of carbon disulphide (16 cc) and triethylamine (4.5 cc) in pyridine (20 cc) is cooled to -10° C. A solution of 5-amino-3-ethoxymethylisoquinoline (6.5 g) in pyridine (20 cc) is added dropwise in the course of 5 minutes. The mixture is stirred for 3 hours at -10° C. and a solution of dicyclohexylcarbodiimide (6.6 g) in pyridine (20 cc) is then added. Stirring is continued, whilst leaving the reaction mixture to return to a temperature of about 20° C. The mixture is stirred for 24 hours at this temperature and then concentrated to dryness at 50° C. under reduced pressure (20 mm Hg). The residue is taken up in methylene chloride (25 cc). An insoluble material is filtered off and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg). The residue is taken up in diisopropyl ether (200 cc). The isoluble yellow solid is isolated by filtration, washed with diisopropyl ether (20 cc) and dried. 3-Ethoxymethyl-5-isothiocyanatoisoquinoline (7 g), melting at 66° C., is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([C:1](=[N:23][OH:24])[CH3:2])[CH:21]=[CH:20][C:7]=2[CH2:8][CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
7-Acetyl-3-(tert-butyloxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (8.9 g, 30.8 mmol) was dissolved in pyridine (30 ml) and hydroxylamine hydrochloride (2.3 g, 33 mmol) was added and the mixture stirred for 2 h at room temperature. The solvent was evaporated and hexane (300 ml) and water (100 ml) were added and the colourless precipitate was filtered and washed with hexane (3×100 ml). The compound was dried in vacuo to give the title compound (6.23 g, 66%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[NH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1C=CC=CC=1>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:20]([CH2:2][CH2:3][CH:4]=[C:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][CH2:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH2:21][CH2:22]1)[CH3:33]
Reactant: CCOC(=O)CCCC1CCNCC1
Reactant: BrCCC=C1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 120 °C
Yield: 80.7 %

Procedure:
A mixture of 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (5.8 g, 19.8 mmol), ethyl 4-(piperidin-4-yl)butyrate (6.1 g, 29 mmol), potassium carbonate (2.9 g, 21 mmol) and N,N-dimethylformamide (10 ml) was heated at 120° C. for 5 h. After cooling, benzene (50 ml) and water (50 ml) were added and the phases were separated. The organic phase was dried and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (50 g) using mixtures of benzene and chloroform as eluents to give 6.9 g (83%) of 4-(1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)piperidin-4-yl)butyric acid ethyl ester as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32](O)[CH2:33][OH:34]>>[CH3:19][C:18]1([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:11]=3)[N:17]=2)[O:34][CH2:33][CH2:32][O:20]1
Reactant: OCCO
Reactant: CC(=O)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(c2cccc(-c3cnn(-c4cccnc4)c3)n2)OCCO1

Procedure:
In 100 ml of 1,1,1-benzotrifluoride, 0.13 g (0.49 mmol) of 1-[6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridin-2-yl]ethanone, 0.1 g (0.58 mmol) of 4-toluenesulphonic acid and 1.8 ml (32 mmol) of 1,2-ethanediol were heated under reflux in a reflux apparatus with Soxleth extractor which had been charged with 4 Å molecular sieve for 2 h. The reaction mixture concentrated by evaporation, ethyl acetate, dil. aqueous sodium hydroxide solution, citrate buffer to pH=9 and also aq. NaCl were added to the residue, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried with MgSO4 and concentrated by evaporation. The residue was purified by chromatography on silica gel (petroleum ether/acetone).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH:12]=[C:13]2[CH2:18][CH2:17][C:16]([CH2:22][CH2:23][CH2:24][CH3:25])([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:2]1>C1(C)C=CC=CC=1.ClCCl>[CH3:20][N:19]([CH3:21])[C:16]1([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:18][C:13]2([C:2]3[NH:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]=3[CH2:10][CH2:11][CH2:12]2)[CH2:14][CH2:15]1
Reactant: CCCCC1(N(C)C)CCC(=CCCc2c[nH]c3ccccc23)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCC1(N(C)C)CCC2(CCCc3c2[nH]c2ccccc32)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
p-toluol sulphonic acid (323 mg, 1.7 mmol) was added to a solution 4-[3-(1H-indol-3-yl)propylidene]-1-butyl-N,N-dimethylcyclohexanamine (289 mg, 0.85 mmol) in absolute toluol (10 mL) and stirred for 18 h at 100° C. The reaction solution was then diluted with dichloromethane (30 mL) and washed with 1 N sodium carbonate solution (2×30 mL), water and saturated sodium chloride solution (30 mL each) one after the other, dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (272 mg) was mixed with methanol (100 mL) and stirred overnight at room temperature, during which very little precipitate was formed (light-coloured solid). The 1H-NMR spectrum and the LC-MS data showed that this concerned two isomers, and the 1H-NMR spectrum revealed that these were present in a ratio of approx. 1:1 and olefin side-products were present at most in very small quantity. The reaction solution was concentrated to low volume in a vacuum (259 mg, 90%). The diastereomer mixture was separated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:20]3[CH:19]=[C:18]([O:21][CH2:22][CH:23]4[CH2:28][CH:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH:25]([O:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH3:85])[CH2:24]4)[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C([Br:90])(=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([Br:90])[C:20]3[CH:19]=[C:18]([O:21][CH2:22][CH:23]4[CH2:28][CH:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH:25]([O:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH3:85])[CH2:24]4)[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(O)(c2ccc(Cl)cc2)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: CC(=O)Br
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(Br)(c2ccc(Cl)cc2)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 386.2 %

Procedure:
9-(4-Chlorophenyl)-2-(3,4,5-tris(octadecyloxy)-cyclohexylmethoxy)-9-fluorenol (62.0 mg, 51.2 μmol) was dissolved in chloroform (2 mL), acetyl bromide (13 μmol, 172 μmol) was added, and the mixture was stirred at room temperature for 1 hours. After evaporation of the solvent, acetonitrile was added to the residue to allow crystallization to give 9-(4-chlorophenyl)-2-(3,4,5-tris(octadecyloxy)-cyclohexylmethoxy)-9-bromofluorene (63.9 mg, 50.2 μmol, 98%). δ=0.88 (9H, t, J=6.6 Hz, OC18H37 C18-H) 1.1-1.9 (101H, br, Cyclohexyl C1,2,6-H, OC18H37 C2-17-H) 3.16 (2H, d, J=10.3 Hz, Cyclohexyl C3,5-H) 3.46 (4H, m, 3,5-OC18H37 C1-H) 3.68 (2H, t, J=6.7 Hz, 4-OC18H37 C1-H) 3.82 (2H, m, fl-O—CH2—) 3.92 (1H, s, Cyclohexyl C4-H) 6.90 (1H, d, J=8.3 Hz, fl C3-H) 6.96 (1H, s, fl C1-H) 7.18-7.26 (3H, m,Ph C3,5-H, fl C7-H) 7.34 (1H, t, J=7.1 Hz, fl C6-H) 7.43 (1H, d, J=7.6 Hz, fl C8-H) 7.48 (2H, d, J=8.7 Hz, Ph C2,6-H) 7.57 (2H, m, fl C4,5-H)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]([CH2:7][NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:6]=1.C1CCN2C(=NCCC2)CC1.[C:34](=O)([O-])[O-:35].[K+].[K+]>ClCCl>[CH3:1][C:2]1[N:6]2[C:34](=[O:35])[N:8]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]3)[CH2:7][C:5]2=[C:4]([CH3:22])[N:3]=1
Reactant: Cc1nc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1nc(C)n2c1CN(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Yield: 97 %

Procedure:
tert-Butyl 4-(((2,5-dimethyl-1H-imidazol-4-yl)methyl)amino)-1-piperidinecarboxylate (8.0 g) obtained in Example 88a) was dissolved in dichloromethane (100 ml), DBU (3.6 ml) and N,N′-carbonyldiimidazole (3.9 g) were added thereto. The reaction solution was mixed for 15 hours, and then the reaction solution was poured into an aqueous potassium carbonate solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then the residue was purified with silica gel column to obtain a pale yellow oily title compound (7.8 g, 97%).