Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[N:13]=1.[CH2:19]([C@H:21]1[O:23][CH2:22]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:23]1[CH2:22][C@@H:21]1[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:13][C:12]=2[CH:14]=1
Reactant: ClC[C@@H]1CO1
Reactant: Oc1ccc2oc(-c3ccc(Cl)cc3Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(-c2nc3cc(OC[C@H]4CO4)ccc3o2)c(Cl)c1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of 2-(2,4-dichlorophenyl)benzoxazol-5-ol (6.0 g, 36 mmol), (S)-(+)-epichlorohydrin (3.3 g, 315 mmol) (20 ml, 182 mmol), and potassium carbonate (20 g, 144 mmol) in acetone (100 ml) was heated to reflux and allowed to stir overnight. The solution was allowed to cool and filtered through Celite 512. The filtrate was evaporated under reduced pressure to yield an oil, which was chromatographed on silica gel, eluting with 20% ethyl acetate/hexanes, to yield 5-[((2R)oxiran-2-yl)methoxy]-2-(2,4-dichlorophenyl)benzoxazole as white solid (6.2 g, 28 mmol).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClC(Cl)C>[NH:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9]1
Reactant: c1ccc(CN2CCCC3(Cc4ccccc4O3)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: c1ccc2c(c1)CC1(CCCNC1)O2
Yield: 94.2 %

Procedure:
A solution of 13 g (46 mmole) of 1'-benzyl-2,3-dihydrospiro(benzofuran-2,3'-piperidine) in 100 mL dichloroethane was treated with 7.31 g (5.2 mL, 51 mmoles) of 1-chloroethylchloroformate at room temperature for 1/2 hour. The reaction mixture was concentrated and the residue dissolved in CH3OH and heated to reflux for 1/2 hour. The methanol was evaporated at reduced pressure, and the residue partitioned between ethyl acetate and 1 N HCl. The ethyl acetate layer was discarded and the aqueous phase was basified to pH 9 and reextracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give 8.2 g product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(Cl)(Cl)[Cl:14].C(Cl)Cl.CO>C(O)C.O=[Pt]=O>[ClH:14].[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: ClC(Cl)Cl
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CC1CCCCN1
Product: Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(pyridin-2-yl)acetate (24.51 g, 148.4 mmol) was dissolved in ethanol (130 ml), and PtO2 (3.37 g, 14.84 mmol, 0.1 eq.) and chloroform (20 ml) were added. The suspension was stirred overnight under a H2 atmosphere (8 bar) at 40° C. According to TLC monitoring (silica gel, DCM/methanol 95:5), the reaction was incomplete, so that further chloroform (15 ml) was added and stirring was carried out for a further 2 d under a H2 atmosphere (8 bar) at 40° C. (TLC monitoring). After cooling, the catalyst was first removed by filtration over filtering earth and the filtrate was concentrated to dryness in vacuo. The ethyl 2-(piperidin-2-yl)acetate hydrochloride was used in the next stage without being purified further. Yield: 31.51 g, >100%
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11].[F:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1OC>CN(C=O)C>[Cl:24][C:22]1[CH:21]=[CH:20][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[O:11])=[C:8]([O:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=2[O:4][CH3:1])[CH:23]=1
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(Cl)cc1F
Reactant: O=C([O-])[O-]
Reactant: COc1cc(O)ccc1F
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1cc(Cl)ccc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
Cs2CO3 (651.6 mg, 2.0 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-chlorobenzamide (53.3 mg, 0.20 mmol) and 4-fluoro-3-methoxyphenol (284.3 mg, 2.0 mmol) in DMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (16) (22.1 mg, 28%). ESI-MS m/z calc. 388.06. found 389.15 (M+1)+; Retention time: 1.53 minutes (3 minutes run).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2].[CH2:18]([NH2:21])[CH2:19][CH3:20].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:21][CH2:18][CH2:19][CH3:20])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1nc(Cl)c(-c2ccccc2)nc1C#N
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCNc1nc(C#N)c(C#N)nc1-c1ccccc1
Yield: 91.9 %

Procedure:
2,3-Dicyano-5-chloro-6-phenylpyrazine (12.03 g; 0.05 mole) was dissolved in 1,400 ml of toluene. The solution was cooled to 5° to 10° C., and with stirring, 3.25 g (0.055 mole) of n-propylamine was added dropwise over the period of 10 minutes. Subsequently, 55 ml of a 1 N aqueous solution of sodium hydroxide was added dropwise over the period of 10 minutes. The mixture was then stirred at 5° to 10° C. for 30 minutes. After the reaction, the reaction mixture was separated into two layers. The toluene layer was concentrated under reduced pressure to obtain a solid. The solid was washed twice with 200 ml of water, dried under reduced pressure, and recrystallized successively from toluene and ethanol to afford 12.1 g (yield 92%) of 2,3-dicyano-5-n-propylamino-6-phenylpyrazine.
Reaction SMILES: C(O[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][C:6]1[CH2:10][CH2:9][CH2:8][N:7]=1)C.F[B-](F)(F)F.[CH3:22][S:23]([OH:26])(=[O:25])=[O:24]>C(NCC)C>[CH2:6]([N:7]([CH2:8][CH3:9])[C:4]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[CH:5][C:6]1[CH2:10][CH2:9][CH2:8][N:7]=1)[CH3:5].[CH3:22][S:23]([O-:26])(=[O:25])=[O:24]
Reactant: CCOC(=CC1=NCCC1)c1ccccc1
Reactant: CS(=O)(=O)O
Agent: F[B-](F)(F)F
Solvent: CCNCC
Product: CCN(CC)C(=CC1=NCCC1)c1ccccc1
Product: CS(=O)(=O)[O-]

Procedure:
The solution of 9.1 g (0.03 mole) of 2-[2-ethoxy-2-phenyl-ethenyl]-1-pyrroline-tetrafluoroborate in 25 ml of diethylamine is refluxed for 12 hours; it is then processed analogously to Example 1 to yield crude 2-[2-(diethylamino)-2-phenyl-ethenyl]-1-pyrroline. By the addition of 2.8 g of methanesulphonic acid to the solution of the crude base in isopropanol, removal of the crystals by filtration and recrystallisation from isopropanol, there is obtained 2-[2-(diethylamino)-2-phenyl-ethenyl]-1-pyrroline-(1:1)-methanesulphonate, m.p. 143°-145° (decomposition).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O>[S:17]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
99.26 g of anthranilic acid was added to 830 g of water, the resulting mixture was heated at 75° C. and 165.3 g of p-toluenesulfonyl chloride was added thereto over 30 minutes with stirring. 495 g of 28% aqueous solution of sodium hydroxide was added dropwise and the mixture was stirred at 80° C. for one hour. The reaction mixture was added dropwise to a mixed solution of 360 g of 35% hydrochloric acid and 270 g of water at 70 to 80° C. and stirred for one hour. After cooling to 30° C., the mixture was filtered, the resulting crystals were washed with water, and the wet crystals were heated and solved in 750 g of 1-propanol to obtain a solution. After cooling to a room temperature, the solution was filtered, the resulting crystals were washed with 1-propanol, and dried under a reduced pressure to obtain 175 g of N-tosyl anthranilic acid.
Reaction SMILES: CS([C:4]1[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N+:21]3([O-])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[N:5]=1)=O.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.S([O-])(O)=O.[Na+].N>C(Cl)(Cl)Cl>[CH:28]1([NH:31][C:4]2[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)[N:5]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: CS(=O)c1nc(Nc2ccc(C[N+]3([O-])CCOCC3)cc2)ncc1C(N)=O
Agent: N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Nc2ccc(CN3CCOCC3)cc2)nc1NC1CC1
Temperature: 90 °C
Reaction time: 15 h
Yield: 23.6 %

Procedure:
A 1 ml portion of chloroform solution containing 11.7 mg of 4-methylsulfinyl-2-({4-[(N-oxidomorpholin-4-yl)methyl]phenyl}amino)pyrimidine-5-carboxamide was mixed with 5.1 mg of cyclopropylamine and 5.8 mg of diisopropylethylamine, followed by stirring at 90° C. for 15 hours. A 1 ml portion of aqueous solution containing 50 mg of sodium hydrogen sulfite was added to the reaction mixture, followed by stirring at room temperature for 4 hours. This was mixed with 0.1 ml of aqueous ammonia and extracted with 2 ml of chloroform. By evaporating the solvent under a reduced pressure and fractionating the residue by an HPLC (Wakosil-II 5C18AR, 0.1% HCOOH—H2O/MeOH=7/3−0/10), 2.6 mg of 4-cyclopropylamino-2-(4-morpholin -4-ylmethylphenylamino)-pyrimidine-5-carboxamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[F:34][C:25]([F:24])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH:32][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[O:28][N:27]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example AF) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 479.0355 (M−H)−.
Reaction SMILES: [CH2:1]([C:5](C)=[O:6])[CH:2](C)C.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1.C(Cl)(=O)C=C>C(N(CC)CC)C>[C:5]([O:14][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([OH:8])=[CH:10][CH:11]=1)(=[O:6])[CH:1]=[CH2:2]
Reactant: CC(=O)CC(C)C
Reactant: OCc1ccc(O)cc1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCc1ccc(O)cc1
Reaction time: 0.5 h
Yield: 26 %

Procedure:
1400 g of methyl isobutyl ketone, 50 g of 4-hydroxybenzyl alcohol and 40 g of triethylamine were charged into a separable flask having a capacity of 3 liters, provided with a stirrer and a nitrogen gas feed tube, and deaerated for 30 minutes, and then 33 g of acrylic acid chloride was dropwise added thereto at 3° C. over 50 minutes. Then, stirring wascontinued at room temperature for 3 hours. After completion of the reaction, the reaction mixture was recovered by filtration. The filtrate was washed with 0.5N hydrochloric acid and with water, dehydrated over anhydrous sodium sulfate, and then subjected to silica gel column chromatography (eluent: n-hexane/ethyl acetate =10/1 by volume) to obtain the desired fraction. By distilling off the methyl isobutyl ketone solventfrom the fraction under reduced pressure, 15 g of 4-hydroxybenzyl acrylate of the following chemical formula was obtained (yield: 26%): ##STR7##
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].BrCC#CC>>[CH3:10][O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:11][C:12]#[C:13][CH3:14]
Reactant: COC(=O)CC(C)=O
Reactant: [Li]CCCC
Agent: CC#CCBr
Agent: [H-]
Agent: [Na+]
Product: CC#CCCC(=O)CC(=O)OC

Procedure:
In accordance with the process of Reference 1, sodium hydride (550 mg; 23 m mol), methyl acetoacetate; (2.56 g; 22 m mol), n-butyl lithium (23 m mol) and 4-bromo-2-butyne were used to obtain 2.53 g of 3-oxo-6-octynoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23](I)=[CH:22][C:21]=3[O:27][CH2:28][CH3:29])=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33]>C(N(CC)CC)C.CN(C)C=O.[Cu]I.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:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])=[CH:22][C:21]=3[O:27][CH2:28][CH3:29])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(I)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C#CC(C)(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Temperature: 50 °C
Yield: 83.7 %

Procedure:
4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-iodophenyl)-4,5-dihydro-1H-imidazole (566 mg, 1.05 mmol, example 27), copper(I) iodide (9.5 mg, 0.11 mmol), dichlorobis(triphenylphosphine)-palladium(II) (148 mg, 0.211 mmol) and 3,3-dimethyl-1-butyne (0.182 mL, 1.48 mmol) were dissolved under nitrogen in a flame-dried Schlenk tube in a mixture of triethylamine (1.7 mL) and dimethylformamide (1.7 mL). The reaction mixture was warmed in a 50° C. oil bath for 20 h, allowed to cool to room temperature and then partitioned between 2% sodium carbonate solution (70 mL) and diethyl ether (2×100 mL). The combined organic phases were washed with water (2×50 mL) and brine (50 mL), then dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluting with 1% methanol in methylene chloride) to give 4,5-bis-(4-chlorophenyl)-2-[4-(3,3-dimethylbut-1-ynyl)-2-ethoxyphenyl]-4,5-dihydro-1H-imidazole as an off-white foam (0.432 g, 83%). LC-MS: 491.3 [(M+H)+].
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][CH2:31][C:32](O)=[O:33])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][CH2:31][C:32]([N:12]1[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]1)=[O:33])[CH2:27]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CCC1C2CC3CC(C2)CC1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CCC1C3CC4CC(C3)CC1C4)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 44.1 μl was added to a methylene chloride of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 50.0 mg and stirred at 0° C. for 30 min. 3-(2-adamantyl) propionic acid 60.4 mg and WSC 65.7 mg were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 13 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-[3-(2-adamantyl)propionyl]-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 5 ml solution of lithium aluminum hydride 12.0 mg and refluxed under heating for 3 hours. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of, silica gel column chromatography (Wako gel, C200, chloroform) to obtain the product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[CH:33][C:28]=2[CH2:27][CH2:26]1>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:34]3[NH:22][C:21]4[CH:20]=[CH:19][C:6]([NH:7][C:8](=[O:18])[C:9]5[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:33][C:28]=2[CH2:27][CH2:26]1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc2c(c1)CCO2
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc5c(c4)CCO5)nc3c2)cc1

Procedure:
Compound 183 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and 2,3-dihydrobenzofuran-5-carboxaldehyde. [M+H]+ calcd for C24H24N4O2: 399.18; found: 399.47.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]#[N:12].C(O/[C:25](/[CH3:32])=[CH:26]\[C:27]([O:29][CH2:30][CH3:31])=[O:28])C>C(O)C>[NH2:12][C:11]1[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:2]=2[N:1]=[C:25]([CH3:32])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: COc1ccc(Cn2c(N)c(C#N)c3c2CCCC3)cc1
Reactant: CCOC(=O)/C=C(/C)OCC
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(c1N)c1c(n2Cc2ccc(OC)cc2)CCCC1
Yield: 64 %

Procedure:
The title compound was prepared in 64% yield from 2-amino-3-cyano-1-(4-methoxyphenyl)methyl-4,5,6,7-tetrahydroindole (D5) and ethyl β-ethoxycrotonate in a procedure similar to Description 6. Product was obtained as beige crystals from ethanol.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][O:15][CH2:16][C:17]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:18]
Reactant: COCC(=O)Cl
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-6-nitrobenzothiazole (5.9 g) is dissolved in pyridine (100 ml) and thereto is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (5.1 g) having the following physical properties.
Reaction SMILES: CO[CH2:3][N:4]([CH2:12][Si](C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:17]([O:19][C:20](=[O:38])/[C:21](/[CH3:37])=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:24]=1)[CH3:18].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:21]1([CH3:37])[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:3][N:4]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:12]1)=[O:38])[CH3:18]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CC1c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a stirred solution of N-methoxymethyl-N-(phenylmethyl)trimethylsilylmethylamine (27 g, 113.7 mmol) and (E)-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-methyl-acrylic acid ethyl ester (19 g, 62.4 mmol) in CH2Cl2 (50 mL), cooled to 0° C., was added trifluoroacetic acid (1.0 M in CH2Cl2, 22.8 mL, 22.8 mmol). The reaction mixture was stirred at room temperature for 1 hour, then another molar equivalent of N-methoxymethyl-N-(phenylmethyl)tri-methylsilylmethylamine (14.8 g, 62.4 mmol) added over 10 minutes. Stirring was continued for 3 hours, then the CH2Cl2 was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1.0 N aqueous HCl (2×50 mL), water, 1.0 N aqueous NaOH solution, water, and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a pale yellow oil. Chromatography on silica gel (9:1, hexanes:ethyl acetate) provided the product as an amber oil (16.7 g, 61% yield). 1H NMR (300 MHz, CDCl3) δ (ppm); 7.39-7.23 (m, 5H, aromatic), 6.91 (s, 1H, aromatic), 6.78 (m, 2H, aromatic), 4.75 (m, 1H), 4.18 (q, 2H, OEt), 3.86 (m, 1H), 3.81 (s, 3H, OCH3), 3.75 (d, 1H, J=13.2 Hz), 3.62 (d, 1H, J=13.2 Hz), 3.20 (d, 1H, J=9.5 Hz), 3.01 (m, 1H), 2.91 (m, 1H), 2.51 (d, 1H, J=9.5 Hz), 1.93-1.58 (M, 8H, cyclopentyl), 1.28 (t, 3H, OEt), 0.9 (s, 3H, CH3).
Reaction SMILES: ClCCl.[NH2:4][C@H:5]([CH3:22])[C@:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])([OH:13])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C@@:6]([OH:13])([CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)[C@H:5]([NH:4][S:31]([CH3:30])(=[O:33])=[O:32])[CH3:22]
Reactant: C[C@@H](N)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[C@@H](NS(C)(=O)=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
To dichloromethane (10 ml) was added (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (0.54 g). To the mixture was added, under ice-cooling, triethylamine (0.28 ml), to which was added dropwise methanesulfonyl chloride (0.15 ml), followed by stirring for 15 minutes at room temperatures. To the mixture was added water (20 ml), which was subjected to extraction with dichloromethane (30 ml). The extract was washed with water (20 ml) and dried (MgSO4). Then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel chromatography (2.9×30 cm, eluent: ethyl acetate/methanol =25/1). The object fraction was concentrated to give N-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2, 4-triazol-1-yl)-2-butyl]methanesulfonamide (Compound 49, 0.52 g) as a colorless oily product. 1H-NMR(CDCl3) δ: 1.04(3H,d,J=6.6 Hz), 3.07(3H,s), 4.12-4.21(1H,m), 4.81(1H,d,J=14 Hz), 4.97(1H,d,J=14 Hz), 5.28(1H,d,J=10 Hz), 6.69-6.82(2H,m), 7.27-7.39(1H,m), 7.79(2H,s)
Reaction SMILES: [O:1]=[C:2]1[C:7](C(OCC)=O)=[CH:6][NH:5][N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12.[Cl-].[Na+].O>CS(C)=O>[NH:5]1[CH:6]=[CH:7][C:2](=[O:1])[C:3]2=[CH:15][CH:14]=[CH:13][N:4]12
Reactant: CCOC(=O)c1c[nH]n2cccc2c1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc[nH]n2cccc12

Procedure:
Ethyl 4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate (412 mg, 2.00 mmol), sodium chloride (200 mg), water (1 mL), and DMSO (1 mL) were heated at 150° C. for 3 hours. The solvent was concentrated in vacuo and the residue was purified using 0-50% EtOAc/Hexanes to provide pyrrolo[1,2-b]pyridazin-4(1H)-one. MS: Found M+H+=135.