Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH2:2].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:1]([C:6]1[CH:7]=[CH:8][C:3]([CH3:9])=[CH:4][CH:5]=1)[CH3:2]
Reactant: Cc1ccccc1
Reactant: C=C
Product: CCc1ccc(C)cc1

Procedure:
The catalyst samples as described in Examples 4 and 5 were also tested for activity and selectivity in the vapor phase alkylation of toluene with ethylene to produce p-ethyl toluene. At a WHSV of 1.0-1.2g toluene/gm catalyst/hr and a toluene:ethylene molar ratio of 2.5-2.8:1.0 the liquid product was collected over an 8-16 hour period for each of the reaction temperatures 400° C. and
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH2:7][CH2:8][N:9]=[N+]=[N-])([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH2:7][CH2:8][NH2:9])([O-:3])=[O:2]
Reactant: [N-]=[N+]=NCCc1cccc([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: NCCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
A mixture of 3-nitrophenethyl azide (0.9 g, 4.69 mmol), triphenyl phosphine (1.22 g, 4.66 mmol) and CH2Cl2 (80 mL) was stirred at room temperature for 3 days. Solvent was removed and the residue was taken up in EtOH (20 mL). The solution was heated to 70° C., added 2M NaOH aqueous solution (10 mL) and stirred at room temperature for 2 hrs. A 10% HCl aqueous solution (20 mL) was then added and refluxed for 2 hrs. After the mixture cool to room temperature, it was washed with benzene, basified with 5N NaOH to pH˜12, extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give the product (0.63 g) as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH2:12]1[CH2:13][O:14][C:2]2([CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]2)[O:1]1
Reactant: OCCO
Reactant: COC(=O)C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCCC2(C1)OCCO2
Temperature: 95 °C

Procedure:
A solution composed of 30 g (192 mmol) of crude methyl 3-oxocyclohexanecarboxylate and 430 cm3 of toluene is introduced into a one-liter three-necked flask equipped with a Dean and Stark apparatus, and 14.3 g (230 mmol) of ethylene glycol are then added with 814 mg (4.3 mmol) of para-toluenesulfonic acid monohydrate. The mixture is heated to reflux, the toluene-water azeotrope forms instantaneously and, after 40 min, no further refluxing of azeotrope (95° C.) takes place. The mixture is maintained for 6 h under reflux of the toluene (110° C.). After cooling, sodium hydrogen carbonate solution is added and the solution is then washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration, 39 g of a yellow oil are obtained, which product is either distilled or chromatographed on a column of 215 g of silica (eluant: cyclo-hexane/ether, 98:2).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:13]([O:15]C)=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].P(=O)(O)(O)O>C(O)C.O>[C:1]1([C:7]2[C:8]([C:13]([OH:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ncccc1-c1ccccc1
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncccc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of methyl 3-phenylpyridine-2-carboxylate (61.0 g, 286 mmol) in absolute ethanol was added potassium hydroxide (32.0 g, 572 mmol). After stirring at 50° C. for 2 h, the reaction mixture was cooled and adjusted to pH ˜7.5 with 1M phosphoric acid. The mixture was diluted with water (1 L) and extracted with EtOAc (2×600 ml). The organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 3-phenylpyridine-2-carboxylic acid as a solid (54.7 g).
Reaction SMILES: [Cl-].[CH3:2][CH:3]1[NH2+:7][C:6]2[CH:8]=[C:9]([S:12][CH3:13])[CH:10]=[CH:11][C:5]=2[Te:4]1.C(=O)(O)[O-].[Na+]>O>[CH3:2][C:3]1[Te:4][C:5]2[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1ccc2c(c1)[NH2+]C(C)[Te]2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CSc1ccc2[te]c(C)nc2c1

Procedure:
2-Methyl-5-methylthiobenzotellurazolium chloride (Example 16) (11.5 g=0.035 mole) was suspended in water and sodium bicarbonate in excess of that stoichiometrically required was added. The free base was extracted into dichloromethane. The organic solution was washed with saturated aqueous sodium sulfate, dried, and evaporated in vacuum to a yellow oil (9.06 g). Upon addition of isopropanol (40 ml) the oil crystallized spontaneously to almost white needles to give 8.18 g, 79.8% of theory, m.p. 64°-67° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2O)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][CH:7]=[CH:8]2
Reactant: Cc1ccc2c(c1)C(O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)C=CC2
Reaction time: 0.33 h

Procedure:
Sodium borohydride (1.3 g) was added to a solution of 6-methyl-indane-1-one (5.0 g) in methanol (50 ml) at 0° C., and the mixture was stirred for one hour. The reaction mixture was poured into ice-cooled water, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 6-methylindane-1-ol (5.5 g). To a solution of 6-methylindane-1-ol in toluene (50 ml) was added p-toluene sulfonic acid monohydrate (0.2 g), and the mixture was stirred for 20 minutes. The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was washed with water, 5% sodium hydrogencarbonate aqueous solution, and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 5-methyl-1H-indene (5.5 g).
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)=O.N>CN(C=O)C>[OH:10][CH2:9][CH2:8][O:7][CH2:6][N:5]1[C:4]2[N:11]=[C:12]3[N:13]([CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=4)[NH:16]3)[C:14](=[O:15])[C:3]=2[N:2]=[CH:1]1
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ncn(COCCO)c2nc2[nH]c(-c3ccc(Br)cc3)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
A solution of 2.7 g acyclovir, 70 mL DMF, and 800 mg sodium hydride (80%) was stirred at room temperature for 15 min, then 4 g 2,4′-dibromo-acetophenone was added into the solution. The solution was stirred at room temperature for 3 hr, added 15 mL ammonia, and was continuously stirred overnight. The solvent was removed to obtain a residue, which was washed with 50 mL of water and acetone to produce a product, 3-(2-hydroxy-ethoxymethyl)-6-(4-bromophenyl)-3,5-dihydro-1,3,4,5,7a-pentaaza-s-indacen-8-one, 2.55 g (yellow, yield 53%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].OC(C(F)(F)F)=O.[CH:34]1([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][C:40]2=[O:45])[CH2:38][CH2:37][CH2:36][CH2:35]1>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:42]4[CH2:43][CH2:44][N:39]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:40](=[O:45])[CH2:41]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: O=C1CNCCN1C1CCCC1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C4CCCC4)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.450 mmol), 1-cyclopentylpiperazin-2-one TFA salt (129 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 5 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 1.1 min (conditions 4), MH+=477)
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:66])[C@H:41]([CH2:43][C:44]([NH:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[NH2:42])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:68]([O:70][CH3:71])=[O:69].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([C@H:8]([NH:39][C:40](=[O:66])[C@H:41]([CH2:43][C:44]([NH:46][C:47]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:45])[NH:42][C:68]([O:70][CH3:71])=[O:69])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:34])([CH3:35])[CH3:36])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Yield: 108.3 %

Procedure:
A solution of Example 168B (24 mg, 0.027 mmol) in dioxane (0.25 mL) was treated with methyl chloroformate (3.2 μL, 0.041 mmol) and triethylamine (7.5 μL, 0.054 mmol) at 25° C. for 0.5 h. The solvents were evaporated to give the crude title compound (27.7 mg, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([CH3:9])[CH2:3]1.[H-].[Na+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[CH2:15]>CN(C=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14](=[CH2:15])[CH2:13][C:4]2([CH3:9])[C:5](=[O:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]2)=[CH:17][CH:18]=1
Reactant: C=C(CBr)c1ccc(F)cc1
Reactant: CC1CN(C)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(CC1(C)CN(C)CCC1=O)c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 52.1 %

Procedure:
To a stirred solution of 1,3-dimethylpiperidin-4-one (2.8 g, 22.04 mmol) in DMF (10 mL) was added sodium hydride (970 mg, 24.25 mmol) at 0° C. After stiffing for 5 min, 1-(1-bromomethyl-vinyl)-4-fluoro-benzene (4.74 g, 22.04 mmol) was added dropwise and stirring was continued for 30 min. The reaction mass was quenched with ice water and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (4×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using silica (100:200) and 10% EtOAc-Hex as eluent to yield 3 g of 3-[2-(4-fluoro-phenyl)-allyl]-1,3-dimethyl-piperidin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:14](Cl)[CH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(O)C>[OH:16][CH2:15][CH2:14][N:11]1[CH2:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: OCCCl
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: OCCN1CC=C(c2ccc(F)cc2)CC1

Procedure:
1.77 g of 4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine, 0.8 g. of ethylene chlorohydrin, 1.2 g. of sodium carbonate and a few crystals of sodium iodide are heated under reflux conditions in 10 ml. of ethanol for 24 hours and filtered hot and the filtrate is evaporated to dryness. The residual oil is purified by column chromatography on silica gel with acetic acid ethyl ester-ethanol (1:1) as eluting agent. The 1-(2-hydroxyethyl)-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine obtained from the eluate melts at 96°-98°C. after recrystallization from cyclohexane.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=O)=O.[CH3:30][CH:31]([CH3:48])[CH2:32][C:33]#[C:34][Sn](CCCC)(CCCC)CCCC>>[CH2:21]([O:20][C:18]([NH:17][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[C:34]#[C:33][CH2:32][CH:31]([CH3:48])[CH3:30])[C:13]([O:15][CH3:16])=[O:14])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCC[Sn](C#CCC(C)C)(CCCC)CCCC
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Product: COC(=O)c1ccc(C#CCC(C)C)c(NC(=O)OCc2ccccc2)c1
Yield: 88.9 %

Procedure:
Methyl 3-benzyloxycarbonylamino-4-(4-methyl-1-pentynyl)benzoate (2.25 g) was prepared from 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (3.0 g) and (4-methyl-1-pentynyl)(tributyl)stannane (2.7 g) in a similar manner to that of Preparation 1 (2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:9][CH2:10]1
Reactant: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 99.9 %

Procedure:
tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (3.6 g, 14 mmol) and 10% Pd/C moistered with water (0.8 g) was mixed in MeOH (75 mL) and stirred under H2 (1 atm) for 4 h. The mixture was filtered through Celite and concentrated to give the title compound (3.6 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCC#Cc1ccc(F)c(Cl)c1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: OCCCc1ccc(F)c(Cl)c1
Temperature: 65 °C
Reaction time: 10 h
Yield: 75.5 %

Procedure:
A suspension of Compound 61-1 (3.20 g) and chlorotris(triphenylphosphine)rhodium(I) (3.00 g) in toluene (70 ml) was stirred under a hydrogen atmosphere at 65° C. for 10 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-75:25) to give the object product (2.47 g) as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:10]([CH3:14])[C:11]=2[CH:12]=[O:13])=[CH:3][CH:2]=1.[BH4-].[Na+].P([O-])([O-])([O-])=O>CO>[OH:13][CH2:12][C:11]1[C:10]([CH3:14])=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[S:8][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1C=O
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.4 %

Procedure:
To a stirred solution of 2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde (0.145 g) in methanol (10 mL) was added sodium borohydride (0.11 g) at 0° C. The mixture was stirred at room temperature for 30 minutes. Phosphate buffer was added to the reaction mixture and MeOH was removed by evaporation. The residue was extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with ethyl acetate-CH2Cl2 --MeOH (1:1:0.04) to give the subtitle compound (0.170 g).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]([O:19][CH2:20][S:21][CH3:22])=[CH:17][C:16]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[C:15]([F:36])[CH:14]=1>[Cl-].C(Cl)Cl>[Cl:12][C:13]1[C:18]([O:19][CH2:20][S:21]([CH3:22])=[O:9])=[CH:17][C:16]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[C:15]([F:36])[CH:14]=1
Reactant: CSCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCS(C)=O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1.0 g of 3-chloro-perbenzoic acid in 15 ml of metyylene chloride is added dropwise while stirring at 0° C. during 1 hour to a solution of 2.3 g of 1-[4-chloro-2-fluoro-5 -(methylthio)methoxy-phenyl]-3-methyl-4-trifluoromethyl-2,6-(1H,3H)-pyrimidinedione in 30 ml of methylene chloride. The reaction mixture is subsequently stirred at room temperature for 15 hours, washed with dilute aqueous sodium bicarbonate solution and then with water and dried over anhydrous sodium sulphate. The organic phase is evaporated to dryness under reduced pressure and the residue is purified by chromatography on a silica gel column using diethyl ether/ethyl acetate and thereafter ethyl acetate alone as the eluent. There is obtained 1-[4-chloro-2-fluoro-5-(methylsulphinyl) methoxy-phenyl]-3-methyl-4-trifluoromethyl-2,6(1H,3H)pyrimidinedione, 1H-NMR (CDCl3, 400 MHz): 7.33 ppm (d.1H). 7.27 ppm (2d,1H), 6.34 ppm (2s,1H). 4.91-5.05 ppm (m,2H), 3.54 ppm (d,3H), 2.72 ppm (s,3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(C)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
A mixture of 2-chloro-6-methyl-nicotinic acid (2 g, 12 mmol), N,O-dimethylhydroxylamine hydrochloride (1.14 g, 12 mmol), EDCI (2.68 g, 14 mmol), HOBt (81 mg, 16 mmol) and DIPEA (1 mL) in DCM (100 mL) was stirred at RT overnight. The reaction mixture was then partitioned between water and DCM, the organic layer separated, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, gradient from 0 to 25% in 25 minutes) to afford 2.4 g of 2-chloro-N-methoxy-6,N-dimethyl-nicotinamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH:7]([C:19]([NH:21][S:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)(=[O:24])=[O:23])=[O:20])[C:8]([N:10]([CH2:17][CH3:18])[C:11]2[CH:16]=CC=C[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.C([NH:40][C:41]1C=NC=[CH:45][CH:46]=1)(C)C.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH:7]([C:19]([NH:21][S:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)(=[O:24])=[O:23])=[O:20])[C:8]([N:10]([CH:11]([CH3:12])[CH3:16])[C:17]2[CH:18]=[N:40][CH:41]=[CH:46][CH:45]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)Nc1cccnc1
Reactant: CCN(C(=O)C(Cc1ccc(Cl)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C)N(C(=O)C(Cc1ccc(Cl)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1cccnc1
Yield: 32.2 %

Procedure:
In the same manner as in Example 13, the object compound was obtained using the compound (418 mg) obtained in Example 267 (1) and 3-(isopropylamino)pyridine (163 mg). This was dissolved in ethanol, 1 mol/L hydrochloric acid was added, and the mixture was concentrated under reduced pressure to give the title compound (74 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:5]=1[Cl:12].[Br-:14].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5]([Cl:12])=[CH:6][C:7]([NH2:11])=[C:8]([Br:14])[C:9]=1[Cl:10]
Reactant: [Br-]
Reactant: COC(=O)c1c(Cl)cc(N)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COC(=O)c1c(Cl)cc(N)c(Br)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 139.4 %

Procedure:
To a solution of 2,6-dichloro-4-aminobenzoic acid methyl ester (2.80 g) in CH2Cl2 (20 mL) at −10° C. was added a solution of tetrabutylammonium tribromide (6.94 g) in CH2Cl2 (30 mL) dropwise at −10° C. After 2 h, the mixture was warmed to room temperature, washed with satd. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel; eluent: EtOAc/hexane 1:4) to yield 2,6-dichloro-3-bromo-4-aminobenzoic acid methyl ester (2.99 g). ESMS: m/z 298 (MH+).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]4[C:20]=3[CH2:21][CH2:22][CH2:23]4)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]2)[CH2:32][O:31]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]4[C:20]=3[CH2:21][CH2:22][CH2:23]4)[CH:13]=[N:12]2)[C:8]([NH:41][C:38]2[CH:39]=[CH:40][N:36]([CH2:35][C@@H:33]3[CH2:32][O:31][C:30]([CH3:42])([CH3:29])[O:34]3)[N:37]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: Cc1ccc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c2c1CCC2
Product: Cc1ccc(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)c2c1CCC2

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(7-methyl-indan-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 71) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(7-methyl-indan-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as an off-white solid as a mixture of diastereomers (1.09 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]1([CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH:7]=[CH:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(c1ccccc1)C=C2
Yield: 59.1 %

Procedure:
To 1.5 L of toluene was added 32 g (0.133 mol) of 6-methoxy-1-phenyl-indan-1-ol and 100 mg of p-toluenesulfonic acid and the mixture was placed on a Rotovap® and the solvent was distilled in vacuo (40 mm) until a brown oil residue was obtained. The brown oil was chromatographed (silica, 1:1 hexane/methylene chloride) to afford 17.47 g (60.2 %) of 1-phenyl-6-methoxy-indene as a pale yellow oil.