Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:21])[C:7]3[C:8]([CH:19]=[CH:20][C:4]=2[CH:3]=1)=[N:9][CH:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:12]=3.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>N1C=CC=CC=1>[CH2:24]([NH:26][C:27]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:21])[C:7]3[C:8]([CH:19]=[CH:20][C:4]=2[CH:3]=1)=[N:9][CH:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:12]=3)=[O:28])[CH3:25]
Reactant: CCN=C=O
Reactant: Nc1ccc2c(=O)c3cc(-c4ccccc4)cnc3ccc2c1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc2c(=O)c3cc(-c4ccccc4)cnc3ccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 0° C. solution of 8-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (6.4 mg, 0.021 mmol) in pyridine (0.3 mL) was ethyl isocyanate (0.1 mL, 0.38 M in CH2Cl2) The mixture was then stirred at room temperature for 4 hours followed by heating at 50° C. After 3 hours, more ethyl isocianate (3 μL, 0.038 mmol) was added and the mixture was heated at 70° C. After stirring for 14 hours, a new addition of ethyl isocyanate (9 μL, 0.114 mmol) was followed by heating at 80° C. More ethyl isocyanate (20 μL, 0.253 mmol) was added 2 hours later and heating was continued for 14 hours. The mixture was then concentrated to dryness. The crude residue was purified by flash chromatography (100-85% CH2Cl2/MeOH gradient) and reverse phase HPLC (30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, DMSO-D6) δ 9.24 (d, 1H), 8.69 (d, 1H), 8.14 (d, 1H), 7.85 (d, 2H), 7.80 (d, 1H), 7.67 (dd, 1H), 7.53 (t, 2H), 7.45 (t, 2H), 7.31 (s, 2H), 2.95 (m, 2H), 0.93 (t, 3H). LRMS (APCI) calculated for C23H20N3O2 [M+H]+, 370.1; found 370.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2cc(C(F)(F)F)ccn2)CC1
Yield: 31.9 %

Procedure:
Using the procedure from Example 1A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-4-(trifluoromethyl)pyridine (99 μl, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (49 mg), an off-white solid, in 32% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1nc(N)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N)c([N+](=O)[O-])cc1Cl
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
To stirred conc H2SO4 (70 mL) at 0° C. was added 45 (6.0 g, 41.8 mmol) in portions. To the resulting dark brown solution was added dropwise 70% HNO3 (3.5 mL, 54 mmol) at 0° C. After the addition, the reaction mixture was stirred at 50° C. under N2 for 2.5 h, cooled to room temperature and poured into crushed ice (about 700 g). The mixture was basified to pH 9 by the addition of 40% aq. NaOH dropwise with stirring and cooling (ice-water bath). The precipitate was filtered, washed with water (4×100 mL) and MeOH (3×25 mL), and dried to give 5.28 g (67%) of 46 as a yellow powder, mp 214°-5° C. (lit. 214°-6° C., Cress et al., J. Org. Chem. 93-6 (1976)). 1H NMR (DMSO-d6) δ2.445 (s, 3H), 8.011 (bs, 2H), 8.340 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]3[CH2:25][C:24]([O:26]CC(C)C)=[CH:23][C:22]3=[O:31])[CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CC(C)=O.Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]3[CH2:25][C:24](=[O:26])[CH:23]=[C:22]3[OH:31])[CH:15]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)COC1=CC(=O)C(Cc2cccc(CCNS(=O)(=O)c3ccc(Cl)cc3)c2)C1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C1C=C(O)C(Cc2cccc(CCNS(=O)(=O)c3ccc(Cl)cc3)c2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
A mixture of 32 (0.018 g, 0.04 mmol) in acetone (0.5 mL) and 2 N hydrochloric acid (0.2 mL) was stirred at rt for 6 h. The reaction mixture was diluted with water and the acetone was evaporated under reduced pressure. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by reverse phase preparative HPLC to provide the desired compound as a white solid. Yield: 88%.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][NH2:9].C(N(C(C)C)CC)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][NH:9][S:22]([CH3:21])(=[O:24])=[O:23]
Reactant: NCc1cc(Br)ccc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1cc(Br)ccc1F

Procedure:
Dissolve 5-bromo-2-fluorobenzylamine hydrochloride (500 mg, 2.08 mmol) in dichloromethane (8 mL) and diisopropylethylamine (0.90 mL, 5.20 mmol) and treat with methanesulfonyl chloride (0.19 mL, 2.49 mmol). After 4.5 h dilute with ethyl acetate and wash with 0.5 N hydrochloric acid, an aqueous saturated solution of sodium bicarbonate, and an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate to give the title compound as a pale orange oil, which crystallizes upon standing (573 mg, 98%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-n2cccn2)cc1
Temperature: 130 °C
Yield: 18006.2 %

Procedure:
A mixture of methyl 4-fluorobenzoate (2 g, 0.0130 mol), pyrazole (1.33 g, 0.0195 mmol) and potassium carbonate (3.59 g, 0.0260 mol) in dry 1-methyl-1-pyrrolidinone (20 mL) was heated to 130° C. for 44 hours. The cooled reaction mixture was then partitioned between ethyl acetate (200 mL) and 2 M sodium hydroxide (200 mL). The organic phase was separated, washed with 2 M sodium hydroxide (200 mL), 2 M hydrochloric acid (2×200 mL), water (200 mL), and brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a white solid (0.71 g). Recrystallization from hexane (40 mL) gave the title compound (0.533 g, 20%) as a white crystalline solid, m.p. 115° C.
Reaction SMILES: N[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:21]>O>[OH:21][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCc1ccc2c(c1)Cc1cc(N)ccc1-2
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(=O)CCc1ccc2c(c1)Cc1cc(O)ccc1-2

Procedure:
Diazonium salt was prepared by the same way as in Example 6 using 6.47 grams of 4-(7-amino-2-fluorenyl)-butan-2-one. The diazonium salt was dropped into a refluxing and stirring mixture of 9 ml of concentrated sulphuric acid and 150 ml of water. After being stirred for 2 hours, the mixture was cooled and crystals separated out therefrom were collected by filtration. They were washed until the washing became neutral and dried with air. The resulting crystals were subjected to a silica gel column chromatography, eluted with a 4:1 mixture of n-hexane and ethyl acetate, and the resulting crystals were recrystallized from methanol to give 4.96 grams of 4-(7-hydroxy-2-fluorenyl)-butan-2one, pale yellow crystals, m.p. 170°-170.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14]C)[C:3]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19]>C(#N)C.O>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([O:10][CH3:11])=[C:5]([O:12][CH3:13])[C:4](=[O:14])[C:3]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19]
Reactant: COc1c(Cl)c(/C=C(\C)C(=O)O)c(OC)c(OC)c1OC
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(/C=C(\C)C(=O)O)=C(Cl)C1=O
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
Following a modified procedure of Flader et al.,22 22 (0.124 g, 0.391 mmol) was dissolved in acetonitrile (10.0 mL) at room temperature, then ceric ammonium nitrate (0.970 g, 1.77 mmol) dissolved in water (8.0 ml) was added at room temperature. The reaction was stirred for 30 minutes and then extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, filtered, and condensed. The red oil was then purified by either flash column chromatography (1:1 Et2O:hexanes 0.5% AcOH) or recrystallization from Et2O/hexanes to afford 23 (0.026 g, 0.091 mmol, 22%) as a red solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC>CN(C=O)C.O>[CH2:18]([O:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc(-n2cccn2)nc1O
Reactant: ClCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 60 °C
Yield: 42 %

Procedure:
To a solution of ethyl 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylate, 3-a, (0.62 g, 2.7 mmol) in DMF (7 ml) were added benzyl chloride (0.5 g, 3.99 mmol) and Et3N (0.8 g, 7.97 mmol). The resulting mixture was then heated at 60° C. for 12 hours. Then the mixture was cooled to room temperature and diluted with water followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel column with the eluent of ethyl acetate/petroleum ether=1/1 (Rf=0.7) to afford the compound, 3-b, (0.36 g, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][CH:16]=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12].C(N(CC)CC)C.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][CH:39]=1.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]([OH:43])[C:16]([NH:15][CH2:14][CH2:13][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]#[CH:12])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:17])=[CH:40][CH:39]=1
Reactant: C#CCOc1ccc(CCNC=O)cc1OC
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)cc2)cc1OC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-formamide (34 g, 0.14 mol) and triethylamine (34 g, 0.34 mol) are dissolved in dichloromethane (120 ml). Bis(trichloromethyl) carbonate (triphosgene, 16 g, 55 mmol) in dichloromethane (80 ml) is added at +5° C. The mixture is stirred for 4 hours at +5° C. and then cooled to −78° C. A solution of titanium tetrachloride (28 g, 0.15 mol) in dichloromethane (150 ml) is added and the mixture is stirred for 2 hours at −40° C. 4-Chlorobenzaldehyde (20 g, 0.14 mol) in dichloromethane (70 ml) is added dropwise and the mixture is stirred for 17 hours at room temperature. The mixture is hydrolyzed with 5N HCl (80 ml), stirred 30 minutes at room temperature and washed with water. After evaporation of the organic layer the residue is submitted to flash-chromatography (ethyl acetate/hexane) to give 2-(4-chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy -phenyl)-ethyl]-acetamide. 1H-NMR (300 MHz, CDCl3, δ(ppm)): 2.54 (t, 1H, CO≡CH), 2.72 (t, 2H, CH2CH2), 3.53 (t, 2H, CH2CH2), 3.84 (s, 3H, OCH3), 4.78 (m, 2H, OCH2), 4.98 (s, 1H, CHOH), 6.07 (bs, 1H, NH), 6.53–7.38 (m, 7H, CH arom.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:25][NH:26][C:27](=[O:34])[CH:28]([CH2:32][CH3:33])[C:29](O)=[O:30]>>[F:21][C:22]1[CH:23]=[C:24]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:25][NH:26][C:27](=[O:34])[CH:28]([CH2:32][CH3:33])[C:29]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:30]
Reactant: CCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CCC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=505.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-ethyl-malonamic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].S(Cl)(Cl)=O.[NH2:19][C@H:20]1[CH2:25][C:24]2[C:26]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[CH:27][CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:36][N:33]1[CH2:34][CH2:35][N:30]([C:26]2[C:24]3[CH2:25][C@H:20]([NH:19][C:9](=[O:11])[C:8]4[CH:7]=[CH:6][C:5]([C:3]([N:2]([CH3:1])[CH3:14])=[O:4])=[CH:13][CH:12]=4)[CH2:21][O:22][C:23]=3[CH:29]=[CH:28][CH:27]=2)[CH2:31][CH2:32]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: CN(C)C(=O)c1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(=O)N(C)C)cc2)CO3)CC1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 54 %

Procedure:
To 4-(N,N-dimethylaminocarbonyl)benzoic acid (110 mg, 0.56 mmol; described in: U.S. Pat. No. 3,607,918, 1971) was dropwise added thionyl chloride (500 μL, 6.9 mmol). The reaction mixture was stirred at ambient temperature for 1 min and then concentrated in vacuo. The excess of thionyl chloride was co-evaporated with toluene in vacuo. The crude acid chloride was dissolved in methylene chloride (8 mL) and dropwise added to a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.80 mmol) in methylene chloride (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for an additional 30 min. The solvent was evaporated in vacuo giving 300 mg of a crude product. Purification by preparative TLC on silica using chloroform/ethanol (saturated with ammonia) 10:1 as the eluent afforded 120 mg (54% yield) of the title compound as a white solid: mp 219° C. (dec); EIMS (70 eV) m/z (relative intensity) 422 (47, M+); [α]22D −12° (c 0.42, chloroform).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
1.00 g of 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid was dissolved in dichloromethane (q.s.), then 2 drops of anhydrous N,N′-dimethylformamide were added. Then 2 ml of oxalyl chloride was added dropwise to the mixture. The reaction mixture was reacted at room temperature for 5 h, and concentrated to provide the product.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[F:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>C(O)CC(C)C>[F:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: Fc1cccc(N2CCNCC2)c1
Solvent: CC(C)CCO
Product: O=c1[nH]c(N2CCN(c3cccc(F)c3)CC2)nc2c1CCCC2

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-(3-fluorophenyl)piperazine (82.6 μl; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 and worked up; yield: 54 mg (32%), crystals;
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O1CCCCC1OC1CCCCO1.[CH3:43][C:44]([CH:48]=O)([CH2:46][OH:47])[CH3:45].C([Li])CCC>CCCCCC.CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[CH3:43][C:44]([CH3:45])(/[CH:48]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:46][OH:47]
Reactant: CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)CO
Agent: C1CCC(OC2CCCCO2)OC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCC/C=C\C(C)(C)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A 5.6 g (11.9 mmoles) sample of (n-nonyl)triphenylphosphonium bromide was coupled with 1.86 g (10 mmoles) of the tetrahydropyranyl ether of hydroxypivaldehyde using the Wittig reaction conditions described in the previous examples (THF:HMPT, 2:1; 7 ml of 1.6 M n-butyllithium in hexane; -78° C.). The crude product (3.4 g) was chromatographed on silica gel. Hexane-ether (7:3) eluted 2.8 g (95%) of (Z)-2,2-dimethyl-3-dodecen-1-ol tetrahydropyranyl ether, which was dissolved in 28 ml of methanol and subsequently treated with 0.3 ml of 2 N HCl. After stirring for 3 hours at room temperature, most of the solvent (about 20 ml) was removed in vacuo, and the residue was extracted with ether. The ethereal solution was washed with brine, saturated NaHCO3 solution, brine, dried over MgSO4, and the solvent was evaporated under reduced pressure. The crude alcohol (2.2 g) was chromatographed on silica gel to afford 1.8 g (85%) of (Z)-2,2-dimethyl- 3-dodecen-1-ol as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:8]2[C:9](=[O:26])[N:10]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:7]=2[N:6]([CH3:27])[C:5]=1[C:28]([NH:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:29].C(N(CC)CC)C.[C:45]([O:48][CH2:49][C:50](Cl)=[O:51])(=[O:47])[CH3:46]>C1COCC1.C(=O)([O-])O.[Na+]>[C:45]([O:48][CH2:49][C:50]([N:35]1[CH2:34][CH2:33][CH:32]([CH2:31][NH:30][C:28]([C:5]2[N:6]([CH3:27])[C:7]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]([CH2:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:9](=[O:26])[C:8]=3[C:4]=2[O:3][CH3:2])=[O:29])[CH2:37][CH2:36]1)=[O:51])(=[O:47])[CH3:46]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1c(C(=O)NCC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C(=O)NCC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of the compound of Example 542 (400 mg, 0.76 mmol) and triethylamine (0.29 mL, 2.1 mmol) in THF (17 mL) was added acetoxyacetyl chloride (0.10 mL, 0.95 mmol) under ice-cooling, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate, and filtered through aminosilica gel. The filtrate was concentrated, and the residue was recrystallized from ethanol-hexane to give the title compound (321 mg, 71%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:24])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=C(Cl)C=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)Nc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nc2ccccc2o1
Reaction time: 48 h
Yield: 42.3 %

Procedure:
(RS)-2-[(2-Hydroxy-phenylcarbamoyl)-methyl]-piperidine-1-carboxylic acid tert butyl ester (1.25 g), 4-toluenesulphonic acid (0.07 g) and 4-N,N-dimethylaminopyridine (0.023 g) were combined in 1,3-dichlorobenzene (30 ml) and the mixture boiled for 48 h. The mixture was diluted with dichloromethane and washed with water. The organic phase was dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 0→1% methanol in dichloromethane) to give the title compound (0.50 g)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([C:13](Cl)=[O:14])[C:3]=1[Cl:16].O1CCCC1.[O:22]1CC[O:25][CH2:24][CH2:23]1.[CH2:28]([OH:31])[CH2:29][OH:30]>N1C=CC=CC=1>[OH:30][CH2:29][CH2:28][O:31][C:8](=[O:9])[C:7]1[C:2]([Cl:1])=[C:3]([Cl:16])[C:4]([C:13]([O:22][CH2:23][CH2:24][OH:25])=[O:14])=[C:5]([Cl:12])[C:6]=1[Cl:11]
Reactant: C1COCCO1
Reactant: O=C(Cl)c1c(Cl)c(Cl)c(C(=O)Cl)c(Cl)c1Cl
Reactant: OCCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(OCCO)c1c(Cl)c(Cl)c(C(=O)OCCO)c(Cl)c1Cl
Reaction time: 24 h

Procedure:
A mixture of 34 grams of tetrachloroterephthaloyl chloride in 85 ml. of tetrahydrofuran and 100 ml. of dioxane are charged to a 500 ml. flask. About 75 grams of ethylene glycol is added dropwise to the solution. This is followed by dropwise addition of 20 grams of pyridine over a period of one hour. The reaction mixture is stirred for 24 hours, and then the volume concentrated by distillation up to a temperature of about 120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9])[NH2:5].[F:11][C:12]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17]([NH:16][C:14](=[O:15])[C:13]2[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:12]=2[F:11])=[O:18])[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3,4,5-trichloro-aniline (19.7 g) and 2,6-difluorobenzoyl isocyanate (18.3 g) were dissolved in toluene (200 ml) at 50° C., and the solution was allowed to stand at this temperature for five hours. After cooling the solution to room temperature, the title compound was isolated by suction filtration and dried.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[C-:18]#[N:19]>C(Cl)Cl.C(=O)(O)[O-].[Na+].O>[C:12]1([CH2:11][N:8]2[CH2:9][CH2:10][C@H:6]([C:18]#[N:19])[CH2:7]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#C[C@H]1CCN(Cc2ccccc2)C1
Temperature: 60 °C
Yield: 109.3 %

Procedure:
(3R)-1-(phenylmethyl)-3-pyrrolidinyl methanesulfonate (12.9 g, 50.6 mmol) and tertrabytulamonium cyanide (25 g, 93.3 mmol) was mixed in DCM (20 mL) and refluxed at 60° C. for 6 h. The resulting solution was cooled down to room temperature and diluted with saturated sodium bicarbonate solution in water. The aqueous phase was extracted several times with toluene. The organic fractions was combined, washed with brine and concentrated to provide the title compound as an oil (10.3 g, quantit.) which was used without further purification: LC/MS (ES) m/e 187 (M+H)+.