Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]([CH2:21][CH:22]=[CH:23][CH:24]([O:30]C(=O)C)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)(=[O:3])[CH3:2].[OH-].[Na+]>O.C(O)C>[C:1]([CH:4]([CH2:21]/[CH:22]=[CH:23]/[CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CCCCCC(C=CCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(O)/C=C/CC(CCCCCCC(=O)O)C(C)=O

Procedure:
A solution of diethyl 2-acetyl-2-(4-acetoxy2-nonen-1-yl)azelate (22.9 g., 0.049 mole) and sodium hydroxide (15.7 g., 0.392 mole) in water (150 ml.) and ethanol (150 ml.) is boiled under reflux for 2 hours. Solvents are removed under reduced pressure, the residue is dissolved in water, and the solution extracted with ether. The aqueous layer is acidified with concentrated hydrochloric acid to the Congo Red endpoint. The crude product separates as an oil, weight 18.9 g. 8-Acetyl-12-hydroxy-(E)-10-heptadecenoic acid is isolated in pure condition from the crude product by chromatography on silica gel with 4% methanol in chloroform as the eluant. There is obtained 3.5 g. of yellow oil showing a single spot, Rf 0.63, in thin layer chromatography (silica gel, 1% acetic acid in ether); pmr (CDCl3) δ0.88 (3H,t), 2.10 (3H,s, CH3CH=O), 4.03 (1H,m HCO), 5.50 (2H,m, HC=CH), 6.58 (2H,s COOH, OH).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:3]=1.[C:20]([C:24]1[CH:29]=[C:28](C)[CH:27]=[C:26](C(C)(C)C)[C:25]=1O)(C)(C)[CH3:21].C([Sn](CCCC)(CCCC)C#CC1C=CC=CC=1)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=[C:4]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cc1cc(Br)nc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(C#Cc2ccccc2)nc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 43 %

Procedure:
To a solution of 2-bromo-4-methyl-6-(1-methyl-3-trifluoromethyl-pyrazol-5-yloxy)pyridine (3.0 g, 7.1 mmol), tetrakistriphenyl-phosphine palladium (0.2 g, 1.8 mmol) and 2,6-di-tert-butyl-4-methylphenol (3 crystals) in toluene (40 ml) under a nitrogen atmosphere is added dropwise tributyl-phenylethynyl-stannane (2.9 ml, 7.8 mmol) and the resulting mixture is heated at reflux for 2 hours. After cooling, the reaction mixture is diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and dried. 43% of the product (1.1 g, mp. 56° C.) is obtained by flash chromatography.
Reaction SMILES: O=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C>O1CCOCC1>[N-:9]=[C:4]=[O:3].[CH3:2][O:19][C:18](=[O:20])[C@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:9]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccccc1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of the methyl ester of phenylalanine and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate is fractionally distilled to give phenylalanine methyl ester isocyanate.
Reaction SMILES: [P:1]([CH:5]([CH3:9])[C:6]([OH:8])=[O:7])([OH:4])([OH:3])=[O:2].[CH3:10]O>>[P:1]([CH:5]([CH3:9])[C:6]([O:8][CH3:10])=[O:7])([OH:4])([OH:3])=[O:2]
Reactant: CO
Reactant: CC(C(=O)O)P(=O)(O)O
Product: COC(=O)C(C)P(=O)(O)O

Procedure:
A solution of 2-phosphonopropionic acid (11.2 g., 0.073 moles) in methanol (150 ml.) is heated at reflux for eighteen hours. The methanol is removed in vacuo. Electrophoresis (0.1 N NH4HCO3, 2000 V, 20 minutes, 7.5 cm) indicates complete conversion to the desired product, methyl 2-phosphonopropionate; yield quantitative.
Reaction SMILES: ClC1C=C2C(CC(=O)N2)=CC=1.COC(C1(OC2C=CC(Cl)=CC=2C=O)CCC1)=O.N1CCCC1.[CH3:35][O:36][C:37]([C:39]1([O:43][C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=2[CH:51]=[C:52]2[C:60]3[C:55](=[CH:56][C:57]([Cl:61])=[CH:58][CH:59]=3)[NH:54][C:53]2=[O:62])[CH2:42][CH2:41][CH2:40]1)=[O:38]>CO>[CH3:35][O:36][C:37]([C:39]1([O:43][C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=2/[CH:51]=[C:52]2\[C:53](=[O:62])[NH:54][C:55]3[C:60]\2=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=3)[CH2:42][CH2:41][CH2:40]1)=[O:38]
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C=C2C(=O)Nc3cc(Cl)ccc32)CCC1
Agent: COC(=O)C1(Oc2ccc(Cl)cc2C=O)CCC1
Agent: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)C1(Oc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CCC1
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (10 g, 60 mmol) and 1-(4-chloro-2-formyl-phenoxy)-cyclobutanecarboxylic acid methyl ester (18 g, 64 mmol) in methanol (100 mL) was added pyrrolidine (4.5 g, 63 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give a mixture of E/Z 1-[4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-cyclobutanecarboxylic acid methyl ester (6 g, 24%).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][C:5]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].Cl>CC(C)=O>[CH:8]1([C:6](=[O:7])[C:5]([CH3:20])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:4][CH:3]=[O:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(CC(C)(C(=O)C1CCCCC1)c1ccccc1)OC
Agent: Cl
Solvent: CC(C)=O
Product: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Yield: 97.6 %

Procedure:
To a solution of 82.65 g (66.29 g, 0.2177 mol) of 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyd dimethyl acetal in 539 mL of acetone was added 539 mL of 3 N HCl (aq) at RT. After reaction completion (2 h), the mixture was concentrated to 426.5 g (or ⅓ volume) of residue (RT-40° C.). The residue contained mostly water (pH=0) and was extracted twice with 300 mL of MTBE. The MTBE extract was washed with 300 mL of 25% NaCl (aq), dried over MgSO4, gravity filtered and concentrated to afford 54.92 g (97.65%) of title compound as a pink oil: 1H NMR (d6-DMSO): δ 9.54 (t, J=2.0 Hz, 1H, —CHO), 7.36-7.45 (m, 2H, phenyl CH), 7.28-7.35 (m, 3H, phenyl CH), 2.95 (dd, J=16.6 Hz, J=1.9 Hz, 1H, CH2CHO), 2.85 (dd, J=16.6 Hz, J=1.7 Hz, 1H, CH2CHO), 2.41-2.49 (m, 1H, cyclohexyl CH), 1.72 (s, 3H, R2C(CH3)Ph), 0.85-1.66 (m, 10H, cyclohexyl —CH2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[N:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:44]CCCl>>[ClH:44].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:28][C:26]4[CH:25]=[N:24][N:23]([CH2:22][CH2:21][OH:20])[CH:27]=4)[CH2:18][CH2:19]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: O=Cc1cnn(CCO)c1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cl
Product: OCCn1cc(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)cn1
Yield: 62 %

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.320 g, 1.24 mmol) in DCE (5 mL). Add 1-(2-hydroxy-ethyl)-1H-pyrazole-4-carbaldehyde (0.243 g, 1.73 mmol), and stir at room temperature. Add sodium triacetoxyborohydride (0.394 g, 1.86 mmol) and stir at room temperature for 18 hr. Purify via SCX chromatography, followed by silica gel chromatography, eluting with 20:80 then 0:100 hexanes:ethyl acetate then 5:95 methanol:ethyl acetate then 10:90 methanol:ethyl acetate, to give the free base of the title compound (296 mg, 62%). Dissolve the free base (0.290 g, 0.760 mmol) in acetonitrile and add 1N aqueous HCl solution (913 μL, 0.913 mmol) and shake at ambient temperature for 30 min. Freeze and lyophilize to give the title compound (315 mg, 99%). MS (ES): m/z=383 [M+H]+.
Reaction SMILES: [NH:1]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:2]([C:18]([O:20]N1C(=O)CCC1=O)=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:38][C@H:39]([C:42]([O:44][CH3:45])=[O:43])[CH2:40][OH:41].Cl.C(N(CC)CC)C>O1CCCC1.CN(C=O)C>[NH:1]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[C@H:2]([C:18]([NH:38][C@H:39]([C:42]([O:44][CH3:45])=[O:43])[CH2:40][OH:41])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 78.8 %

Procedure:
To a solution of Z-Lys(Z)OSu (1.50 g, 2.93 mmole) (see Chladek et al. Collect. Czechr. Chem. Commun. 33: 4299 (1968)) in tetrahydrofuran (15 ml), a solution of H-Ser-OMe-HCl (0.46 g, 2.93 mmole) in N,N'-dimethylformamide (10 ml) containing triethylamine (0.41 ml) was added with stirring at 0° C. The mixture was stirred at 0° C. for 2 hr. and at room temperature for 15 hr. After removal of the solvent, the residue was dissolved in three portions of ethyl acetate, which were washed successively with 1N citric acid, sat. NaHCO3 solution and sat. NaCl solution, and dried over Na2SO4. After evaporating, the residue was solidified by addition of ether and reprecipitated from methanol-ether to yield (IV) (1.19 g, 78.8%). RfI 0.88, RfII 0.86 mp 120°-121° C., [α]D29 -7.8 (C=1.03 methanol)
Reaction SMILES: Cl.C([N:4]([CH2:7][CH3:8])CC)C.[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(Cl)(=O)=O>C(Cl)Cl>[C:9]([N:4]1[CH2:7][CH2:8]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.1 %

Procedure:
Amine 182 (2.59 g, 10.2 mmol) was dissolved in 5% HCl/MeOH (30 mL) and the solution was stirred for 3 h at room temperature. Additional 5% HCl/MeOH (10 mL) was added stirring 1 h and the solvent was evaporated to afford 2.52 g of the HCl salt as a tan solid after high vacuum. To a suspension of the HCl salt in CH2Cl2 (50 mL) at 0° C. was added triethylamine (3.55 mL, 25.5 mmol) followed by the addition of solid trityl chloride (5.55 g, 12.8 mmol) in one portion. The mixture was stirred at 0° C. for 1 h and then was warmed to room temperature stirring for 2 h. The reaction was cooled to 0° C., triethylamine (3.6 mL, 25.5 mmol) was added and methane sulfonyl chloride (0.97 mL, 12.5 mmol) was added, stirring the resulting mixture for 1 h at 0° C. and for 22 h at room temperature. The reaction was evaporated and the residue was partitioned between diethyl ether (200 mL) and water (200 mL). The organic phase was washed with water (200 mL) and the combined aqueous phases were extracted with diethyl ether (200 mL). The combined organic extracts were washed with water (100 mL), saturated NaCl (200 mL) and were dried (Na2SO4), filtered, and evaporated. The crude product was purified on silica gel (1/1-hexane/CH2Cl2) to afford N-trityl aziridine 183 (3.84 g, 86%) as a white foam: 1H NMR (CDCl3) δ 7.4-7.23 (m, 16H), 4.32 (m, 1H), 3.81 (s, 3H), 3.06 (dt, 1H, J=1.8, 17.1), 2.94-2.86 (m, 1H), 2.12 (m, 1H), 1.85 (t, 1H, J=5.0).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[CH:15]1[C:20]2[C:21]3[C:32](=O)[C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:22]=3[O:23][C:24](=[O:25])[C:19]=2[CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[O:25]=[C:24]1[C:19]2[C:20](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:21]2[C:22](=[O:23])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:32]=2[N:13]1[CH2:12][C:11]([O:10][CH3:9])=[O:14]
Reactant: COC(=O)CN
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)Cn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Triethylamine (2.7 mL, 19.4 mmol) was added to a stirred solution of glycine methyl ester hydrochloride (1.57 g, 12.5 mmol) in chloroform (30 mL). After 1 h, benz[d]indeno[1,2-b]pyran-5,11-dione (2) (1.24 g, 5.0 mmol) was added to the mixture. The red mixture stirred an additional 4 h before CHCl3 (100 mL) was added and the mixture washed with H2O (3×50 mL) and brine (1×50 mL), dried (MgSO4), and concentrated under reduced pressure to give an orange-red solid (1.48 g, 92%): mp 248-251° C.; IR (thin film) 2956, 1735, 1667, 1609, 1502, 1426, 1227, 981 cm−1; 1H NMR (CDCl3, 300 MHz) δ8.68 (d, 1H, J=8.0 Hz), 8.32 (d, 1H, J=8.2 Hz), 7.73 (td, 1H, J=7.1, 1.3 Hz), 7.61 (m, 1H), 7.47 (td, 1H, J=7.1, 1.1 Hz), 7.37 (m, 2H), 7.26 (m, 1H), 5.34 (s, 2H), 3.79 (s, 3H); CIMS m/z (relative intensity) 320 (MH+, 100). Anal. Calcd for C19H13NO4: C, H, N.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.O>CN(C)C=O>[C:3]1([S:8][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1
Reactant: Sc1ccccc1S
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(Sc2ccccc2Sc2ccc(Cl)cn2)nc1

Procedure:
In 50 ml of stirred dimethylformamide, a mixture of 3.0 grams (0.02 mole) dimercaptobenzene, 7.0 grams potassium carbonate, and 7.0 grams of 2,5-dichloropyridine is heated at 80° for 5 hours. Thereafter pouring into excess H2O, the mixture is extracted with ethyl ether (200 ml) and washed with H2O, saturated NaHCO3, and brine, dried (MgSO4), and evaporated to yield the crude product which can be recrystallized from 1-chlorobutane.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([OH:29])=[CH:21][CH:20]=1.O>CN(C=O)C>[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-methoxy-1-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracted with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-methoxynaphthalen-1-yloxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]([CH:12]=[O:13])=[C:10](Br)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]#[N:16])[CH:8]=2)[O:3]1.P(Br)(Br)Br.[NH:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]1=[O:28].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1([CH3:17])[C:11]([CH:12]=[O:13])=[C:10]([N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]2=[O:28])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]#[N:16])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C(Br)=C1C=O
Reactant: O=c1cccc[nH]1
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2ccc(C#N)cc2C(n2ccccc2=O)=C1C=O
Reaction time: 1 h

Procedure:
A mixture of 1.4 g of 2,2-dimethyl-3-formyl-4-bromo-6-cyano-3-chromene (m.p. 124°-125°; obtainable by dropwise addition of a solution of 2,2-dimethyl-5-cyano-5-chromanone in chloroform to a mixture of equal volume parts of DMF and PBr3 in chloroform and subsequent boiling for 11 hours), 0.9 g of 1H-2-pyridone, 3 g of K2CO3 and 20 ml of DMF is stirred at 60° for 1 hour. The mixture is diluted with ethyl acetate and filtered, and customary working up of the filtrate gives 2,2-dimethyl-3-formyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromene ("A") m.p. 190°-192° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NC(C)CC[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1>>[OH:1][C@@H:2]([CH2:3][N:11]([C:23]1[CH:24]=[CH:25][C:26]([C:27](=[O:28])[NH2:29])=[CH:30][CH:31]=1)[CH2:10][CH:18]([CH3:6])[CH3:17])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(N)CCc1ccc(C(N)=O)cc1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(C(N)=O)cc1

Procedure:
Titled compound was prepared substantially in accordance with Example 114 from (S)-4-(oxiranylmethoxy)-9H-carbazole (0.479 g, 2 mmol) and 4-[3-amino-3-methylpropyl] benzamide (580 mg, 3 mmol) to yield product after purification. MS(m+1) 432.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[C:18]3[C:13]([N:14]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:15](=[O:27])[NH:16][C:17]3=[O:26])=[N:12]2)=[CH:2]1.N12[CH2:42][CH2:41]CN=C1CCCCC2.BrCCBr.CS(C)=[O:49]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[C:18]3[C:13]([N:14]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:15](=[O:27])[N:16]([CH2:41][CH2:42][OH:49])[C:17]3=[O:26])=[N:12]2)=[CH:2]1
Reactant: CS(C)=O
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3cccn3C)n(Cc3csc4ccccc34)nc21
Solvent: BrCCBr
Product: CC(C)Cn1c(=O)n(CCO)c(=O)c2c(-c3cccn3C)n(Cc3csc4ccccc34)nc21
Temperature: 80 °C

Procedure:
2-(1-benzothien-3-ylmethyl)-7-isobutyl-3-(1-methyl-1H-pyrrol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione was dissolved in anhydrous dimethylsulfoxide and 1,8-diazabicyclo[5.4.0]undec-7-ene was added. 1,2-dibromoethane was added and the mixture was heated at 80° C. for 18 h. The crude reaction product was purified by semi-prep RPHPLC eluting with water/acetonitrile/trifluoroacetic acid mixtures. 477 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C#N)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5 g (37.0 mmol) of (4-fluorophenyl)acetonitrile are added dropwise to a suspension of 1.62 g of 60% NaH in 50 ml of DMF cooled to 0° C. After stirring for 30 minutes at 0° C., 4.62 mmol (37.0 mmol) of bromopentane are added dropwise. The reaction medium is stirred for 16 hours at ambient temperature and then treated with ice and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. An orangey-yellow oil is obtained and used as it is in the next stage.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:18]([O-])([O-])[O:19][CH2:20][CH3:21].C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([C:6](=[CH:18][O:19][CH2:20][CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Br
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Br
Temperature: 150 °C
Yield: 79.7 %

Procedure:
A mixture of ethyl (2-bromo-4,5-difluorobenzoyl)acetate (52.0 g), ethyl orthoformate (36.6 g) and acetic anhydride (41.6 g) is heated at 150° C. for 2 hours. After the reaction, the reaction mixture is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:n-hexane=2:1) to give ethyl 2-(2-bromo-4,5-difluorobenzoyl)-3-ethoxyacrylate (49 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([O:10][CH3:11])[CH:3]=1.[C-:12]#[N:13].[Na+]>C1(C)C=CC=CC=1.O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:12]#[N:13])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: [C-]#N
Reactant: COc1cc(Cl)ccc1CBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Cl)ccc1CC#N
Yield: 68 %

Procedure:
269 g of 4-chloro-2-methoxybenzyl bromide in 214 ml of toluene are reacted with 68.2 g of sodium cyanide in 69 ml of water and 1.8 g of Aliquat 336. 141 g of colorless oil are obtained (b.p. 107° C./0.08 mbar).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2C=CN1[S:11]([C:14]1[CH:19]=[CH:18][N:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16](=[O:26])[C:15]=1[N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:13])=[O:12].C(O)(=O)C.C1C(=O)[N:50]([Cl:53])[C:48](=O)C1>C(O)C.C(Cl)Cl.[Zn]>[Cl:53][S:11]([C:14]1[CH:19]=[CH:18][N:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16](=[O:26])[C:15]=1[N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:13])=[O:12].[S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:50]=[CH:48]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cn1ccc(S(=O)(=O)N2C=Cc3ccccc3S2)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)Cn1ccc(S(=O)(=O)Cl)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1=O
Product: c1ccc2scnc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Zinc powder (6.93 g, 106 mmol) was added to a stirred mixture of 4-(2-benzothiazinylsulfonyl)-3-(N,N-di-t-butoxycarbonylamino)-1-ethyloxycarbonylmethyl-2-pyridinone (3.94 g, 6.48 mmol) and acetic acid (8.73 mL) in ethanol (63 mL). After 16 h, the reaction mixture was filtered and evaporated in vacuo at rt. NCS (0.952 g, 7.13 mmol) was added to a stirred mixture of this residue in methylene chloride (100 mL) at -5° C. After 15 min the reaction was warmed to rt and after a further 40 min the reaction was filtered through celite and evaporated in vacuo to give the title compound contaminated with benzothiazole (1 equivalent) as a yellow solid;
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH3:1][NH:2][C:3]([CH:5]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9][CH2:8][N:7]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=2)[CH2:6]1)=[O:4]
Reactant: CNC(=O)C1CNCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CNC(=O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using N-methyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carbamide and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 9.49 (1H, br s), 7.35 (3H, m), 7.24 (1H, m), 7.14 (4H, m), 4.30 (2H, m), 4.19 (1H, m), 3.69 (2H, m), 3.07 (1H, m), 2.91 (1H, m), 2.78 (3H, br s); MS (ES): 366.2 (MH+).