Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C@@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=1[CH:20]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][C:19]=1[CH2:20][NH:15][C@H:14]1[CH2:13][CH2:12][CH2:11][NH:10][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(F)(F)F)cc1C=O
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred suspension of Compound 1 (150 mg, 0.60 mmol) and Compound 4 (123 mg, 0.60 mmol) in dry CH2Cl2 (6 ml) was added NaBH(OAc)3 (179 mg, 0.84 mmol) portionwise under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 3.5 hr. This was basified with sat. NaHCO3 aq., extracted with CH2Cl2, dried with MgSO4, and concentrated to give crude (2S,3S)-3-(2-methoxy-5-(trifluoromethyl)benzyl)amino-2-phenylpiperidine as a colorless oil. This was purified with chromatography to give pure (2S,3S)-3-(2-methoxy-5-(trifluoromethyl)benzyl)amino-2-phenylpiperidine as a colorless oil (95 mg). This was diluted with ethyl acetate, added HCl-MeOH, and concentrated. The white solid was recrystallized from MeOH-ether to give Compound 5 as a white crystalline (85 mg, 32.4%)
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[CH:8]=[O:9].[CH3:10][C:11]1[CH:12]=[C:13]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:14]=[CH:15][C:16]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[Br:7][C:6]1[C:2]([C:16]2[CH:15]=[CH:14][C:13]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:12][C:11]=2[CH3:10])=[C:3]([CH:8]=[O:9])[S:4][CH:5]=1
Reactant: O=Cc1scc(Br)c1Br
Reactant: Cc1cc(NS(C)(=O)=O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(NS(C)(=O)=O)ccc1-c1c(Br)csc1C=O
Temperature: 100 °C
Yield: 323.9 %

Procedure:
To the solution of Intermediate 1 (4 g, 15 mmol) in a mixture of DME and H2O (150 mL/50 mL) were added N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (3.6 g, 1.65 mmol) and Na2CO3 (2.8 g, 3.1 mmol), the mixture was degassed with N2, and Pd(PPh3)4 (500 mg) was added, then the mixture was heated to 100° C. under N2 overnight. The reaction solution was concentrated to remove the organic solution, then the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, the residue was purified by column chromatography to give N-(4-(4-bromo-2-formylthiophen-3-yl)-3-methylphenyl)methanesulfonamide (2.0 g, yield 35.7%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:29]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:31]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:15]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:16]=1)=[O:10])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O>[CH2:33]([O:32][C:30]1[CH:29]=[C:8]([CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:31]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:24][CH2:25][CH:26]([CH3:27])[CH3:28])=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:16]=1)=[O:10])[CH:34]([CH3:36])[CH3:35]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cc(OCC(C)C)cc(OCC(C)C)c2)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CC(C)COc1cc(OCC(C)C)cc(C(=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
In 9 ml of ethanol is dissolved 1.74 g of ethyl 3-[5-(3,5-diisobutoxybenzoyl)-2-isobutoxyphenyl]-propanoate. After adding 2 ml of 5 mol/L solution of sodium hydroxide, the mixture thus obtained is stirred at ambient temperature for one hour. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 1.53 g of 3-[5-(3,5-diisobutoxybenzoyl)-2-isobutoxyphenyl]propanoic acid is obtained as a white solid product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:24])([O-])=O.O.NN>C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:5]=1[OH:24]
Reactant: CCCCCCCC[C@H]1CC[C@H](c2ccc(O)c([N+](=O)[O-])c2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCCCCC[C@H]1CC[C@H](c2ccc(O)c(N)c2)CC1
Temperature: 70 °C

Procedure:
Step ii) In a 50 ml-three-necked flask, 1.90 g (5.70 mM) of 2-nitro-4-(trans-4-octylcyclohexyl)phenol, 0.35 g of activated carbon, 0.04 g of FeCl3.6H2O and 15 ml of ethanol were placed and heated to 55°-65° C. under stirring. To the mixture, 1.8 ml of 80% hydrazine hydrate was gradually added dropwise and heated to 70° C., followed by stirring for 20 min at 70° C. After the reaction, the reaction mixture was filtered under heating to remove the activated carbon and the filtrate was cooled to room temperature to precipitate a crystal. The crystal was recovered by filtration and recrystallized from ethanol to obtain 1.49 g of 2-amino-4-(trans-4-octylcyclohexyl)phenol (yield: 86.2%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34]N>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1cc(F)ccc1F
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cc(F)ccc1F

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (2,5-difluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=435.0 (M+H)+
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:37](I)[CH3:38]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:31]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:37][CH3:38])[C:21](=[O:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:12][CH2:11]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1)C(=O)CCc1cccnc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
0.79 g (26.3 mmol) 80% sodium hydride are suspended in 30 ml DMF and 10.0 g (22.0 mmol) N-[4-(1-diphenylmethyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-propionamide (substance 54) are added. The mixture is warmed to ca. 30° C. and, after addition of 0.2 g tetrabutyl ammonium iodide, this is stirred for one hour. Subsequently, 2.0 ml (24.1 mmol) ethyl iodide is added at RT (foam development) and the orange-brown suspension is stirred at RT overnight. Excess sodium hydride is destroyed by addition of 1 ml water and the mixture is concentrated under vacuum to a large extent. The residue is dispersed between 50 ml water and 100 ml dichloromethane. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified three times over silica gel with CHCl3/CH3OH (97/3 and 100/0 to 97/3 and 98/2) and crystallized from 10 ml 1-chlorobutane/petroleum ether (3/7) after drawing off the solvent. Beige colored crystals with an MP of 72-74° C.; yield 3.6 g (34%).
Reaction SMILES: C([O:8][C:9](=[O:41])[CH2:10][CH2:11][C@H:12]([C:38](=[O:40])[NH2:39])[NH:13][C:14](=[O:37])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29](=[O:30])[C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26](=[O:35])[C:25]=1[CH3:36])C1C=CC=CC=1>CO.O.[Pd]>[CH3:32][O:31][C:28]1[C:29](=[O:30])[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([NH:13][C@@H:12]([C:38](=[O:40])[NH2:39])[CH2:11][CH2:10][C:9]([OH:41])=[O:8])=[O:37])=[C:25]([CH3:36])[C:26](=[O:35])[C:27]=1[O:33][CH3:34]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)N[C@H](CCC(=O)OCc2ccccc2)C(N)=O)=C(C)C1=O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)N[C@H](CCC(=O)O)C(N)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
10-(2,3-Dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-D-isoglutamine benzyl ester (3.42 g, 6 mmol) was dissolved in methanol (12 ml) and, the solution was hydrogenated with palladium black at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in methanol (25 ml). A solution of ferric chloride (2.43 g, 15 mmol) in water (5 ml) was added and the mixture was stirred at room temperature for 10 minutes. The solvent was then distilled off and the residue was dissolved in ethyl acetate (30 ml), washed with water (15 ml×4) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was chromatographed on a silica gel column. Elution with chloroform-methanol (9:1, v/v), chloroform-acetone-methanol (10:3:2, v/v) and chloroform-methanol-acetic acid (18:2:1, v/v) in that order gave a crude product. The product was recrystallized from ethanol-ethyl ether-petroleum ether to give 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-D-isoglutamine (1.61 g), melting at 136°-137° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](Br)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:30]3[CH:38]=[CH:37][C:33]([C:34](=[O:35])[NH2:36])=[CH:32][CH:31]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccc(C(N)=O)cc3)cn2)CC1

Procedure:
To a degassed solution of 4-(5-bromo-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.80 mmol, 1.0 equiv; intermediate C13/step 1) in dimethoxyethane (15 mL) was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1.38 g, 5.60 mmol, 2.0 equiv; commercially available from CSIRO Molecular Science, Australia), tetrakis(triphenylphosphine)palladium(0) (97.0 mg, 0.08 mmol, 0.03 equiv) and an aqueous solution of 2 M sodium carbonate (5.6 mL) and the reaction mixture heated by microwave irradiation under Ar to 130° C. for 30 min. The crude reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases washed with a sat. solution of sodium chloride (2×50 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol providing 0.31 g (28%) of the title compound. MS (ISP): 398.4 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1I
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1I

Procedure:
22 g of 2-iodotoluene, 100 ml of carbon tetrachloride, 19.67 g of N-bromo succinimide and 1 g of benzoyl peroxide are mixed together and heated to reflux for 8 hours. After filtering, the insoluble part is rinsed with carbon tetrachloride and the filtrate is distilled off, firstly under atmospheric pressure, then under reduce pressure. The expected product is obtained, and used just as it is for the continuation of the synthesis.
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19]1([C:25]2[C:26]3[CH:27]=[CH:28][C:29]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[CH:30][C:31]=3[N:32]3[CH2:38][C:37]([C:39]([O:41]C)=[O:40])=[CH:36][C:35]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:34]=4[C:33]=23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>CO.C1COCC1>[C:52]([O:51][C:49]([C:29]1[CH:28]=[CH:27][C:26]2[C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:33]3[C:34]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:35]=4[CH:36]=[C:37]([C:39]([OH:41])=[O:40])[CH2:38][N:32]3[C:31]=2[CH:30]=1)=[O:50])([CH3:55])([CH3:53])[CH3:54]
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Yield: 118 %

Procedure:
Tetrabutylammonium hydroxide (40% in water, 14.4 mL, 22 mmol) was added to a slurry of 10-tert-butyl 6-methyl 13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (5.0 g, 10 mmol) in MeOH (40 mL) and THF (40 mL) and the reaction was stirred at rt ON (complete by LCMS). The reaction mixture was neutralized with 1N HCl (aq) (24 mL) and concentrated to remove the organic solvents. The sludge was diluted with water, stirred and the solids were collected by filtration. The wet solids were dissolved into EtOAc (˜250 mL), washed with brine (100 mL), dried (MgSO4), filtered and concentrated to yield 10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (5.73 g, 11.8 mmol, 118% yield) as a bright yellow solid. The product appears to be mixed with a tetrabutylammonium by-product. The material was used without further purification. 1HNMR (300 MHz, CDCl3) δ ppm 1.14-2.13 (m, 10H), 1.60 (s, 9H), 2.73-2.86 (m, 1H), 3.89 (s, 3H), 4.03-4.26 (m, 1H), 5.49-5.80 (m, 1H), 6.98 (d, J=2.6 Hz, 1H), 7.07 (dd, J=8.4, 2.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.64 (dd, J=8.4, 1.1 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.89 (br s, 1H), 8.19 (s, 1H. LC-MS retention time: 4.32 min; 488 m/z (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:18])=[CH:6][C:7]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=2.[CH2:19]([Sn](CCCC)(CCCC)C=C)[CH2:20]CC.[Li+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:5]1[N:4]=[N:3][C:2]([CH:19]=[CH2:20])=[C:7]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[CH:6]=1
Reactant: Fc1cccc2[nH]c(-c3cc(Cl)nnc3Cl)cc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1nnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 80 °C
Reaction time: 12 h
Yield: 30.1 %

Procedure:
To a degassed solution of 2-(3,6-dichloropyridazin-4-yl)-4-fluoro-1H-indole (500 mg, 1.7 mmol), tributyl(vinyl)stannane (560 mg, 1.7 mmol) and LiCl (375 mg, 8.9 mmol) in DMF (5 mL) was added Pd(PPh3)2Cl2 (30 mg) under N2, and the mixture was stirred at 80° C. for 12 h. After the solvent was removed, the residue was purified by prep-TLC (PE:EtOAc=2:1) to give the product of 2-(6-chloro-3-vinylpyridazin-4-yl)-4-fluoro-1H-indole (140 mg, yield: 29%). 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 7.61 (s, 1H), 7.16 (dd, J=10.8, 16.8 Hz, 2H), 7.03 (s, 1H), 6.87 (d, J=6.8 Hz, 2H), 6.68 (s, 1H), 5.79 (s, 1H). MS (M+H)+: 274/276.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Br:11]Br.C(O)C.[O-]CC.[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([Br:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc[nH]1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Br)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1H-Pyrrole-2-carboxylic acid ethyl ester (10 g) was dissolved in carbon tetrachloride (50 ml). A carbon tetrachloride solution (50 ml) of bromine was added dropwise thereto on ice over 30 minutes. The reaction mixture was stirred at 25° C. for one hour. The suspension of reaction mixture was added dropwise to an ethanol solution (100 ml) of 10% sodium ethoxide on ice over 20 minutes. The solvent was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (40 ml) and water (20 ml). The organic layer was washed with an aqueous solution saturated with sodium chloride (10 ml), and then concentrated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate). Thus, a brown solid was obtained (10 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([CH3:24])[N:9]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)[C:10](=[O:12])[CH:11]=1.[OH-].[Na+].C(O)(=O)C>O1CCOCC1.O>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([CH3:24])[N:9]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[C:10](=[O:12])[CH:11]=1
Reactant: COC(=O)c1ccc(Cn2c(C)nc(OCc3ccc(F)cc3F)cc2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(OCc2ccc(F)cc2F)cc(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.7 %

Procedure:
A mixture of methyl 4-{[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]methyl}benzoate (0.20 g, 0.0005 mol, from step 3) and 2N NaOH (0.4 mL, 0.0008 mol) in dioxane (0.25 mL) is stirred at room temperature for 45 min. The resulting clear solution is diluted with water (5.0 mL), acidified with acetic acid and extracted with dichloromethane (2×10 mL). The combined organic extracts are washed with water (2×10 mL), dried (Na2SO4), filtered and concentrated to dryness to afford the title compound (0.15 g, 78%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 7.99 (d, 2H, J=8.0 Hz), 7.54 (m, 1H,), 7.27 (d, 2H, J=8.0 Hz), 6.00 (m, 2H), 5.78 (s, 1H), 5.39 (s, 2H), 5.32 (s, 2H), 2.45 (s, 3H), and 2.13 (s, 3H); ES-HRMS m/z 387.1134 (M+H calcd for C20H17N2O4F2 requires 387.1151). 19F NMR(CD3OD/400 MHz) −111.79 (m) and −116.08 (m)
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1)[C:2]([CH3:4])=O.[CH2:12]([NH2:15])[CH2:13][CH3:14]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([NH:15][C:2]([CH3:4])=[CH:1][C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1)[CH2:13][CH3:14]
Reactant: CCCN
Reactant: CC(=O)Cc1nc(CCl)no1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCNC(C)=Cc1nc(CCl)no1
Reaction time: 1 h

Procedure:
To a stirred solution of 350 mg of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole in 10 ml of dry benzene-ether (3:1) was added dropwise with ice-cooling a solution of 190 mg of titanium tetrachloride in 1 ml of dry benzene. After the mixture was stirred for 1 hour, there was added dropwise 360 mg of n-propylamine with ice-cooling. The stirring was continued for 3 hours and then at room temperature for additional 3 hours. After the filtration of the reaction mixture, the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using benzene-acetonitrile (10:1) as eluent to give 5-[2-(n-propylamino)-1-propenyl]-3-chloromethyl-1,2,4-oxadiazole as an oil.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH:5]1[C:10]2[C:11]3[C:22](=O)[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[O:13][C:14](=[O:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:22]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12](=[O:13])[C:11]=3[C:10]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:14]2=[O:15])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2-c2c1c1ccccc1c(=O)n2C1CC1
Yield: 91 %

Procedure:
Cyclopropylamine (10 mL) was added to a stirred solution of benz[d]indeno[1,2-b]pyran-5,11-dione (2) (0.28 g, 1.1 mmol) in CHCl3 (10 mL). The red solution stirred overnight before CHCl3 (50 mL) was added and the mixture washed with H2O (3×20 mL) and brine (1×20 mL), dried (MgSO4), and concentrated under reduced pressure to give a red solid (0.3 g, 91%): mp 206-208° C.; IR (thin film) 3751, 1665, 1500, 1420, 1311, 1083, 950 cm−1; 1H NMR (CDCl3, 300 MHz) δ8.62 (d, 1H, J=7.7 Hz), 8.29 (d, 1H, J=8.4 Hz), 7.88 (d, 1H, J=7.0 Hz), 7.69 (td, 1H, J=6.9, 1.2 Hz), 7.59 (dd, 1H, J=6.1, 1.3 Hz), 7.40 (m, 3H), 3.37 (m, 1H), 1.45 (q, 2H, J=6.8 Hz), 0.99 (m, 2H); CIMS m/z (relative intensity) 288 (MH−, 100). Anal. Calcd for C19H13NO2: C, H, N.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:21][C:22]([CH3:42])([CH2:27][C:28](=O)[CH2:29][S:30][C:31]1[S:32][C:33]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:34]=2[N:35]=1)[C:23]([O:25]C)=[O:24]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)[C:29]([S:30][C:31]3[S:32][C:33]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:34]=4[N:35]=3)=[C:28]2[CH2:27][C:22]([CH3:42])([CH3:21])[C:23]([OH:25])=[O:24])=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: COC(=O)C(C)(C)CC(=O)CSc1nc2cc(Cl)ccc2s1
Agent: Cl
Product: CC(C)c1ccc2c(c1)c(Sc1nc3cc(Cl)ccc3s1)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 104, but 1-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]-hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-5-(5-chlorobenzothiazol-2-ylthio)pentanoate as starting materials followed by hydrolysis at reflux gave the title compound, m.p 154°-156°.
Reaction SMILES: [Cl:1][C:2]([C:4]([Cl:6])=[CH2:5])=[CH2:3].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1>C1(C)C=CC=CC=1>[Cl:1][CH:2]1[C:4]([Cl:6])=[CH:5][CH:9]2[C:10]([O:12][C:7](=[O:13])[CH:8]2[CH2:3]1)=[O:11]
Reactant: O=C1C=CC(=O)O1
Reactant: C=C(Cl)C(=C)Cl
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2CC(Cl)C(Cl)=CC12
Yield: 61.7 %

Procedure:
A 500 mL reaction flask was charged with 34.5 g of 2,3-dichlorobutadiene and 27.5 g of maleic anhydride. 200 mL of toluene was added, along with a small amount of BHT (0.5 g). The solution was heated to reflux until the reaction was complete. The toluene was removed and the product recrystallized from ethyl acetate/hexanes to give 38.25 g (61.8%) of 4,5-dichlorotetrahydrophthalic anhydride.