Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:15][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(F)cc1
Yield: 91.5 %

Procedure:
A solution of 4-fluorobenzaldehyde (8.6 mL, 0.081 mol) and carboethoxymethylene triphenylphosphorane (34 g, 0.097 mol) in toluene (400 mL) was heated at reflux for 3 h. After this time the solvent was removed in vacuo and the residue triturated in petrol:Et2O (1:1). The mixture was filtered and the filtrate evaporated. The residue was chromatographed on silica gel, eluting with petrol:Et2O (3:1), to afford the ester (14.4 g, 92%) as a low-melting colourless solid. 1H NMR (major isomer) (250 MHz, CDCl3) δ1.34 (3H, t, J=7.0 Hz), 4.26 (2H, q, J=7.0 Hz), 6.36 (1H, d, J=16 Hz), 7.07 (2H, dd, JHA-HB =8.6 Hz and JHA-F =8.6 Hz), 7.51 (2H, dd, JHB-HA =8.6 Hz and JHB-F =5.3 Hz), 7.65 (1H, d, J=16 Hz).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[C:10]([CH3:12])[NH:9][C:8](=[O:13])[CH:7]=1>>[OH:5][C:6]1[CH:11]=[C:10]([CH3:12])[NH:9][C:8](=[O:13])[C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)cc(=O)[nH]1
Product: Cc1cc(O)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 0 °C
Yield: 80 %

Procedure:
To 70% nitric acid (30 mL), 4-hydroxy-6-methylpyridin-2(1H)-one (10.5 g, 83.9 mmol) was added under ice-cold conditions, and the resultant mixture was stirred at 70° C. for 1.5 hours. The reaction solution was added to ice water (70 mL) under ice-cold conditions. The reaction solution was filtered, washed sequentially with cold water, tetrahydrofuran and diethylether, and then dried. 4-Hydroxy-6-methyl-3-nitropyridin-2(1H)-one (11.5 g, yield 80%) was obtained as a yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([OH:27])=O)=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:32][CH2:31][CH2:30]4)=[O:27])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Reactant: C1CNC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Yield: 73.9 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(2-fluoropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (60 mg, 157 μmol) and azetidine (27.0 mg, 472 μmol) as starting materials. The reaction affords 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(2-fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (48.8 mg, 73.8%) as white solid. mp: >280° C., MS: m/z=421.0 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[N:9]=[C:10](N)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].[OH-].[K+].[Cl:15][CH2:16]C(OC)(OC)OC>COCCO.O>[Cl:15][CH2:16][C:10]1[S:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=2[N:9]=1
Reactant: COC(CCl)(OC)OC
Reactant: CCc1cccc2sc(N)nc12
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: CCc1cccc2sc(CCl)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
A solution of 4-ethyl-1,3-benzothiazol-2-amine (1.0 g, 5.6 mmol, 1 equiv.) and KOH (7.4 g, 112.2 mmol, 20 equiv.) in 2-methoxy-ethanol (9 ml) and H2O (9 ml), was stirred under N2 and under reflux, for 20 h. After cooling at r.t., the mixture was poured into water (150 ml) and extracted with CH2Cl2 (2×40 ml). The aqueous phase was neutralised with conc. HCl and extracted again with CH2Cl2 (3×70 ml). The combined neutral extracts were washed with water (2×60 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The yellow-green semi-solid residue (790 mg) was mixed with 2-chloro-1,1,1-trimethoxy ethane (1.62 g, 10.4 mmol) and the mixture was stirred, under N2, at 60° C., for 4 h. Volatiles were removed by evaporation under reduced pressure and the brown liquid residue was purified by column chromatography on silica, eluted with CH2Cl2/hexane (10% and 50%), to give a yellow liquid (406 mg, 34% yield over two steps). HPLC-MS (method 1): m/z 212 [M+H]+, Rt=5.00 min
Reaction SMILES: O1CCCC1.[N+:6]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH3:18][N:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:34])[N:21]([CH3:35])[C:20]1=[O:36]>C(N(CC)CC)C>[CH3:18][N:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:17][CH:16]=3)[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:34])[N:21]([CH3:35])[C:20]1=[O:36]
Reactant: Cn1c(N2CCN(CCO)CC2)cc(=O)n(C)c1=O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCOC(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5 ml of tetrahydrofuran were added 0.5 g of 4-nitrobenzoyl chloride, 0.47 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 41) and 1.5 ml of triethylamine, and the resulting mixture was stirred at room temperature overnight. Afterward, the used solvent was distilled off under reduced pressure, and the residue was then dissolved in chloroform. The resulting chloroform solution was washed with water, then dried over anhydrous sodium sulfate, and concentrated to dryness, thereby obtaining a crude product. The latter was then purified through a silica gel column chromatograph (chloroform/methanol=40/1 in terms of volume ratio) in order to obtain 1,3-dimethyl-6-{4-[2-(4-nitrobenzoyloxy)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione. Next, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to prepare 0.84 g of 1,3-dimethyl-6-{4-[2-(4-nitrobenzoyloxy)ethyl]piperazine-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 40).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]4[C:17]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:18][O:19][C:20]=4[CH3:21])[C:11]3=[O:28])[C:9](=[O:29])[N:8]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:5]2=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]4[C:17]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:18][O:19][C:20]=4[CH3:21])[C:11]3=[O:28])[C:9](=[O:29])[N:8]([CH2:30][C:31]([OH:33])=[O:32])[C:5]2=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1CN1CCC2(C1=O)C(=O)N(CC(=O)OC(C)(C)C)c1ccc(Cl)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1CN1CCC2(C1=O)C(=O)N(CC(=O)O)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
An ice-cold solution of tert-butyl [5-chloro-1′-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-2,2′-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetate, intermediate 42 (80.00 mg; 0.15 mmol) in DCM (8.00 ml) was treated with trifluoroacetic acid (2.00 ml). After stirring at room temperature for 5 h, the solvents were removed in vacuo. Toluene was added twice and removed in vacuo to give the titla compound as a white solid in 91% yield (96.3% purity by HPLC). MS (ESI+): 466.3; MS (ESI−): 464.4
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[C:3]1[C:16]2[S:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[Si:18]([CH3:21])([CH3:20])[CH3:19])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C>CC(C)=O>[CH3:1][Si:2]([CH3:23])([CH3:22])[C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[Si:18]([CH3:21])([CH3:20])[CH3:19])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)c1cccc2c1S(=O)c1c(cccc1[Si](C)(C)C)S2
Solvent: CC(C)=O
Solvent: CC(=O)Cl
Product: C[Si](C)(C)c1cccc2c1Sc1c(cccc1[Si](C)(C)C)S2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a stirred solution of 4,6-bis(trimethylsilyl)thianthrene-5-oxide (1.67 g, 4.44 mmole) and acetyl chloride (3.80 mL, 53.2 mmole) in acetone (75 mL), KI (17.00 g, 102.0 mmole) was added. After stirring at room temperature for 2 hrs, solvent was removed in vacuo and the residue was extracted with ether. The extract washed with water and 1 M Na2S2O3 solution, dried with MgSO4, and the solvent was removed in vacuo to afford yellow oil (1.50 g, 86%). The product was eventually crystallized and used without further purification. mp 90˜91° C. (lit. 95˜96° C.). 1H NMR (300 MHz, CDCl3) δ: 7.47 (dd, 2H, J=7.5, 1.5 Hz), 7.42 (dd, 2H, J=7.5, 1.2 Hz), 7.20 (dd, 2H, J=7.5, 7.5 Hz), 0.46 (s, 18H). 13C NMR (125 MHz, CDCl3) δ: 142.4, 139.8, 134.3, 134.0, 129.6, 126.8, 0.52. HR-MS (ESI): calcd. for C18H24S2Si2+Na 383.0750 [(M+Na)+]. Found 383.0747.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[N:39]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]([CH3:50])[CH3:49])=[CH:44][CH:43]=1)=[C:40]=[O:41]>>[CH2:1]([O:3][C:4](=[O:38])[CH:5]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:40]([NH:39][C:42]2[CH:47]=[CH:46][C:45]([CH:48]([CH3:50])[CH3:49])=[CH:44][CH:43]=2)=[O:41])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCCN(CCc1ccc(CC(OCc2ccccc2)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)c1ccc(N=C=O)cc1
Product: CCCCCCCN(CCc1ccc(CC(OCc2ccccc2)C(=O)OCC)cc1)C(=O)Nc1ccc(C(C)C)cc1

Procedure:
Synthesized from 2-benzyloxy-3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-propionic acid ethyl ester using procedures analogous to that used for Example 8 immediately followed by Example 10 and substituting 1-isocyanato-4-isopropyl-benzene in the place of 2,4-dimethoxyphenylisocyanate to give crude 2-benzyloxy-3-(4-{2-[1-heptyl-3-(4-isopropyl-phenyl)-ureido]-ethyl}-phenyl)-propionic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1C[CH2:5][CH2:6][N:7]2[C:12](=[O:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24].BrC1C2[O:33]CCNC=2C=CC=1>>[Br:1][C:2]1[C:3]2[O:33][CH2:5][CH2:6][N:7]([C:12](=[O:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=3[CH3:24])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Brc1cccc2c1OCCN2
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Product: Cc1cccc(OCCCC(=O)N2CCOc3c(Br)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that 5-bromo-1,2,3,4-tetrahydroquinoline, HCl salt was replaced by 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine. LCMS, [M+H]+=404.1. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.0 Hz, 1H), 7.26-7.21 (m, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.78-6.71 (m, 2H), 6.64 (d, J=8.1 Hz, 1H), 4.36-4.28 (m, 2H), 3.98 (t, J=5.8 Hz, 2H), 3.95-3.90 (m, 2H), 2.80 (t, J=7.2 Hz, 2H), 2.24 (s, 3H), 2.19 (dt, J=13.1, 6.4 Hz, 2H), 2.02 (s, 3H).
Reaction SMILES: [CH2:1]([C:7]1[CH:11]=[CH:10][S:9][C:8]=1[CH:12]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:15]O>N1C=CC=CC=1.C(O)C>[C:12]([C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])#[N:15]
Reactant: CCCCCCc1ccsc1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCCCc1ccsc1C#N
Temperature: 80 °C
Yield: 64.7 %

Procedure:
To a solution of 3-hexylthiophene-2-carboxaldehyde (7.8 g, 40 mmol) in pyridine/ethanol (60 mL, 1/1, v/v) was added hydroxylamine hydrochloride salt (4.2 g, 60 mmol). The solution was stirred with refluxing at 80° C. overnight. After cooling, the solution was rotary evaporated to remove the solvent. The residue was taken up with chloroform (100 mL) and the resulting solution was washed twice with distilled water (50 mL), dried over anhydrous magnesium sulfate, and rotary evaporated to remove the solvent. The viscous liquid residue was then dissolved in acetic anhydride (30 mL) containing 0.2 g of potassium acetate, and the resulting mixture was refluxed at 140° C. for 3 h. After cooling down to room temperature, the solution was poured into 100 mL H2O and extracted three times with hexanes (50 mL). The organic extracts were combined and washed until neutral, dried over anhydrous magnesium sulfate, and rotary evaporated to remove the solvent. The yellow liquid residue was subjected to silica-gel column chromatography (EtOAc/Hex=8/92, v/v, Rf=0.4) to yield a light yellow liquid product (5.0 g, 65% yield). 1H NMR (400 MHz, acetone-d6) δ (ppm): 7.85 (d, 1H, J=5.2 Hz); 7.19 (d, 1H, J=5.2 Hz); 2.80 (t, 2H, J=7.8 Hz); 1.68 (m, 2H); 1.28-1.38 (m, 6 H); 0.88 (m, 3H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:13](=[O:14])[C:12]2C(C(O)=O)=[C:16]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[S:17][C:11]=2[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:9]1=[O:36].CN(C)C=O>ClCCl>[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[C:1]([C:2]([Cl:4])=[O:3])=[C:16]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[S:17][C:11]=2[N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:9]1=[O:36]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3cccc4ccccc34)sc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)Cl)c(Cc3cccc4ccccc34)sc21
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.092 ml) was added to a solution of 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid (Example 15a, 222 mg) and dimethylformamide (0.01 ml) in anhydrous dichloromethane (5 ml) at room temperature. After 2 hours, the solution was evaporated under reduced pressure to give 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carbonyl chloride as an oil. A solution of this oil (58 mg) in anhydrous dichloromethane (2 ml) was added to a stirred mixture of glycine methyl ester hydrochloride (29 mg) and triethylamine (0.037 ml) in anhydrous dichloromethane (1 ml) at room temperature. After 1 hour, ethyl acetate (25 ml) and 2M hydrochloric acid were added. The organic layer was washed with water then with saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure The residue was dissolved in a mixture of tetrahydrofuran (4 ml), methanol (2 ml) and 1M sodium hydroxide solution (1 ml). After 2 hours, water (20 ml) was added and the solution was extracted with ether (20 ml). The aqueous layer was acidified with hydrochloric acid and then extracted with ethyl acetate (3×20 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallised from ethyl acetate:isohexane to give the title compound (42 mg).
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]([C:12]#N)=[C:5]([C:10]#N)[C:6](=O)[C:7]=1Cl.[OH:15][C:16]1C=C2C(=C[C:25]=1[O:26][CH3:27])CCCC2>O1CCOCC1>[OH:15][C:16]1[CH:10]=[C:5]2[C:4](=[CH:12][C:25]=1[O:26][CH3:27])[C:3](=[O:14])[CH2:2][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1O)CCCC2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1cc2c(cc1O)CCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
A solution of 231 mg of 2,3-dichloro-5,6-dicyanobenzoquinone in 2 mL of dioxane was added dropwise over a period of 3 minutes to a stirred solution of 89 mg of 6-hydroxy-7-methoxytetralin dissolved in 5% aqueous dioxane under an atmosphere of nitrogen. The resulting solution was stirred at 25° C. under nitrogen for 3 hours. Thereafter the reaction mixture was filtered through a sintered glass funnel and the solid residue of 2,3-dichloro-5,6-dicyanodihydrobenzoquinone was washed with 2 mL of dioxane. The residue wash solution was combined with the filtrate. Thereafter the dioxane was evaporated from the combined filtrate at reduced atmospheric pressure. The resulting residue was chromatographed on a column of silica gel eluted with a solution of ethyl acetate and hexane in ratio of 1 to 1 to obtain 68 mg of known 6-hydroxy-7-methoxytetralin-1-one having m.p. 117-119° C. (lit. 117-119° C. Grethe, G. et al J Org. Chem, 1968, 33 504-508.)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[N:10]([CH3:21])[C:9]=2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[F:23]C1C=CC(C=O)=CC=1>>[F:23][C:7]1[CH:6]=[CH:5][C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[N:10]([CH3:21])[C:9]=2[CH3:22])=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc2c(=O)n(C)c(C)c(-c3cccc(F)c3)c2c1
Product: COc1ccc2c(=O)n(C)c(C)c(-c3ccc(F)cc3)c2c1

Procedure:
Following the procedure for 4-(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one, using (in Step A) 4-fluorobenzaldehyde in place of 3-fluorobenzaldehyde, the title compound was synthesized.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:22])[CH:17]=[CH:18][C:19]=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:19]2[CH:18]=[CH:17][C:16]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:15][C:14]=2[Cl:13])[CH:7]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2Cl)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the is product from example 18 step (iv) and the product from step (i).
Reaction SMILES: N1C=CC=CC=1.Cl.[N+:8]([C:11]1[C:16]([OH:17])=[C:15]([O:18]C)[CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[C:12]=1[CH2:23][CH2:24][C:25]([OH:27])=[O:26])([O-:10])=[O:9]>O>[OH:17][C:16]1[C:11]([N+:8]([O-:10])=[O:9])=[C:12]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:13]([N+:20]([O-:22])=[O:21])=[CH:14][C:15]=1[OH:18]
Reactant: COc1cc([N+](=O)[O-])c(CCC(=O)O)c([N+](=O)[O-])c1O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)CCc1c([N+](=O)[O-])cc(O)c(O)c1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
Pyridine (16 ml) and concentrated hydrochloride acid (16.6 ml) were heated at 150° C. until the evaporation of water was ceased. 3-(2,6-Dinitro-3-hydroxy-4-methoxyphenyl)propanoic acid (2.3 g) was added and the resulting mixture heated at reflux for two minutes. The product mixture was cooled to about 150° C. and poured to ice water. The mixture was extracted with ethyl acetate and the product finally recrystallized from acetic acid. Yield: 0.93 g, melting point 165-166° C. NMR-data identical to that of example 11.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:24]4=[C:25]([C:27](=[O:37])[C:28]([CH2:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:29][N:23]4[C:22]4[CH:21]=[C:20]([Br:38])[CH:19]=[CH:18][C:17]3=4)[CH:26]=2)[CH:9]=[N:10][CH:11]=1)(=O)C.[OH-].[Na+]>CO.O>[Br:38][C:20]1[CH:19]=[CH:18][C:17]2[C:16]3[C:24]4=[C:25]([C:27](=[O:37])[C:28]([CH2:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:29][N:23]4[C:22]=2[CH:21]=1)[CH:26]=[C:14]([O:13][CH2:12][C:8]1[CH:9]=[N:10][CH:11]=[C:6]([CH2:5][OH:4])[CH:7]=1)[CH:15]=3
Reactant: CC(=O)OCc1cncc(COc2cc3c(=O)c(Cc4cccnc4)cn4c5cc(Br)ccc5c(c2)c34)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(OCc4cncc(CO)c4)cc1c32
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
2-(5-acetoxymethyl-3-pyridylmethyloxy)-9-bromo-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (200 mg) produced in Example 106 was suspended in methanol (10 ml), and to the suspension was added a solution of sodium hydroxide (85 mg) in water (0.8 ml). The mixture was stirred at room temperature for 10 minutes, and the crystals precipitated were recovered by filtration, and washed with methanol and ether in succession to obtain the title compound (170 mg, 92%).
Reaction SMILES: [Cl:1][CH:2]([F:10])[CH:3]([Cl:9])[O:4][C:5]([F:8])([F:7])[F:6]>[Zn]>[Cl:1][C:2]([F:10])=[C:3]([Cl:9])[O:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(Cl)C(Cl)OC(F)(F)F
Agent: [Zn]
Product: FC(Cl)=C(Cl)OC(F)(F)F
Temperature: -75 °C
Yield: 83 %

Procedure:
In a 1 l three necked flask, equipped with magnetic stirrer, thermometer, dropping funnel, and connected through a Vigreux column and a condenser to a trap maintained at -75° C., 80.0 g of zinc powder, activated by washing with HCl3N, 550 ml of DMF and 50 mg of KI were charged under nitrogen atmosphere. The internal temperature was brought to 80° C. and 102.0 g of 1,1,2,2-tetrachloro-1-fluoro-2-trifluoromethoxyethane (377m moles), were added dropwise. During the addition, he temperature increased up to 90° C. When the addition was over, the reaction mixture was stirred for 1 additional hour a 90° C. In the cold trap 62.8 g (315 mmoles) of 1,2-dichloro-1-fluoro-2-trifluoromethoxyethane (cis/trans 50%/50%) condensed. The 1,2-dichloro-1-fluoro-2-trifluoromethoxyethene (trans+cis) yield was 83%.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][C:28](=[O:30])[O:27][N:26]=2)=[C:21]([Cl:31])[CH:20]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>ClCCl>[Cl:31][C:21]1[CH:20]=[C:19]([O:18][CH2:17][C:16]2[S:15][C:14]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:34][CH:33]=3)=[N:13][C:12]=2[CH2:11][CH2:10][CH2:9][OH:8])[CH:24]=[CH:23][C:22]=1[C:25]1[NH:29][C:28](=[O:30])[O:27][N:26]=1
Reactant: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCOCc3ccccc3)cc2Cl)no1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCO)cc2Cl)no1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 10.6 %

Procedure:
To a solution of 200 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-4H-[1,2,4]oxadiazol-5-one in 6 ml of dichloromethane cooled to −70° C. was added 0.8 mL of a 1 M solution of boron tribromide in dichloromethane. After stirring for 45 minutes at −60° C., the solution was poured into a mixture of methanol and a saturated aqueous solution of sodium hydrogenocarbonate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 90/10) then crystallized from dichloromethane/diisopropylether to give 18 mg of 3-{2-chloro-4-[4-(3-hydroxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: C(O)(C)C.C[O-].[Na+].[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[CH2:13]1[CH2:18][CH2:17][C:16](=[C:9]2[CH:8]=[CH:12][CH:11]=[CH:10]2)[CH2:15][CH2:14]1
Reactant: C1=CCC=C1
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: C1=CC(=C2CCCCC2)C=C1

Procedure:
To a flask containing isopropyl alcohol (500 ml) and 25% sodiummethylate solution (10 g) are added a mixture of cyclopentadiene (150 g) and cyclohexanone (200 g) over a period of two hours. When addition is complete, the mixture is mixed with water and the organic layer extracted into hexane.