Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8].CCOCC>ClCCl>[C:1]([O:6][CH2:8][CH2:7][O:9][CH2:10][CH3:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C=COCC
Solvent: CCOCC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of 20 g methacrylic acid in 50 ml dichloromethane was added 19 g ethyl vinyl ether in 30 ml dichloromethane. The mixture was stirred overnight at room temperature and poured into ether and washed with a saturated aqueous solution of sodium bicarbonate until the solution ceased effervescing. The organic layer was dried with MgO/MgSO4 and concentrated in vacuo. The residue was distilled at 25° C./0.1 torr to give 7.1 g (19% yield) of ethoxyethyl methacrylate. A mixture of 7.0 g ethoxyethyl methacrylate and 0.076 g AIBN in 7 ml MEK was heated to 60° C. for 24 hr and 7 ml MEK was added. This solution (solution E) was used for further evaluation.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Cl[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[O:18][N:17]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[O:18][N:17]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole:
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([CH:23]=C)=[CH:17][CH:16]=4)[C:6]=1[C:25]([F:28])([F:27])[F:26])[CH:2]([CH3:4])[CH3:3].[O:29]=[O+][O-].C(N(CC)CC)C>ClCCl>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([CH:23]=[O:29])=[CH:17][CH:16]=4)[C:6]=1[C:25]([F:27])([F:26])[F:28])[CH:2]([CH3:3])[CH3:4]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(CC(C)C)c1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cc1onc(-c2onc3c2CCc2cc(C=O)ccc2-3)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of 3-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 5D, 0.045 g, 0.116 mmol) in dichloromethane (10 mL) at −78° C. was passed ozone from an ozone generator until the solution turned deep blue. The reaction mixture then was purged with oxygen until the blue color disappeared and then with nitrogen for 5 min. The reaction mixture was allowed to warm to room temperature, and triethylamine (0.016 mL, 0.116 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. and then concentrated under pressure to give 3-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.045 g, 85% yield) as a tan solid. The product had an HPLC ret. time=4.02 min. (condition B); LC/MS M+1=391.09.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:26])[C:14]([C:15]3[S:19][C:18]([C:20]4[N:21]([CH3:25])[N:22]=[CH:23][N:24]=4)=[N:17][CH:16]=3)=[C:10]2[N:9]=[C:8]([CH3:27])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[Cl:28]N1C(=O)CCC1=O>ClCCl.C(#N)C>[Cl:28][C:16]1[N:17]=[C:18]([C:20]2[N:21]([CH3:25])[N:22]=[CH:23][N:24]=2)[S:19][C:15]=1[C:14]1[C:13]([CH3:26])=[N:12][N:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]([CH3:27])=[N:9][C:10]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(CC)c1cc(C)nc2c(-c3cnc(-c4ncnn4C)s3)c(C)nn12
Solvent: CC#N
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nc2c(-c3sc(-c4ncnn4C)nc3Cl)c(C)nn12
Yield: 74 %

Procedure:
Stir a mixture of 7-(1-ethyl-propyl)-2,5-dimethyl-3-[2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl)-pyrazolo[1,5-a]pyrimidine (20 mg, 0.052 mmol) and N-chlorosuccinimide (7.6 mg, 0.0569 mmol) in dichloromethane (0.5 mL) and acetonitrile (0.5 mL) at room temperature overnight in a vial. Concentrate to a residue. Purify by flash chromatography, eluting with hexanes and then with hexanes/ethyl acetate (10/1.5) to give the title compound (16 mg). ES/MS m/z (35Cl) 416.0 (M+1)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[Cl:17][C:18]([Cl:28])=[CH:19][CH:20]1[C:22]([CH3:24])([CH3:23])[CH:21]1[C:25]([OH:27])=[O:26]>>[Cl:17][C:18]([Cl:28])=[CH:19][CH:20]1[C:22]([CH3:24])([CH3:23])[CH:21]1[C:25]([O:27][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[O:26]
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Agent: [Na]
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
In a similar manner, 3-phenoxybenzylchloride is reacted with the sodium salt of 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylic acid, prepared by the process of this invention, to yield 3-phenoxybenzyl 2-(2,2-dichlorovinyl)3,3-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[CH2:2].[OH-].[Na+].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.[Cl-].[Na+]>>[CH2:11]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][O:3][CH:1]=[CH2:2])[CH:13]1[O:15][CH2:14]1
Reactant: ClCC1CO1
Reactant: C=COCCCCO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: C=COCCCCOCC1CO1
Temperature: 40 °C
Yield: 94 %

Procedure:
1,000 g (8.61 mol) of 4-hydroxybutyl vinyl ether (HBVE manufactured by Maruzen Petrochemical) and 448 g (11.2 mol) of sodium hydroxide were charged in a 3 L cylindrical flask equipped with a stirrer, a thermometer and a dropping funnel. The temperature was raised to 40° C. under stirring, 1,243 g (13.4 mol) of epichlorohydrin was then gradually added, and a reaction was conducted under controlling to 40° C. to 60° C. At after 8 hours of the reaction, the sodium chloride generated by the reaction was removed by filtration, 1,000 g of hexane was put therein, and the mixture was washed with 400 g of a 3% aqueous solution of sodium hydrogen sulfate and further washed with 800 g of 17% brine. The organic layer was concentrated by using a rotary evaporator to thereby distill the hexane off, and filtration was conducted to give the objective vinyloxybutyl glycidyl ether with a purity of 94% and a yield of 94%. At this time, the 4-hydroxybutyl vinyl ether contained in the obtained substance was 0.5%.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[NH:12]([C:19]1[N:20]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:21]2[C:26]([C:27](=[O:29])[CH:28]=1)=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=[C:23](Cl)[N:22]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[NH:12]([C:19]1[N:20]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:21]2[C:26]([C:27](=[O:29])[CH:28]=1)=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=[C:23]([O:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[N:22]=2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)cc(C(F)(F)F)c12
Reactant: O=C1CCCN1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1CCOc1cc(C(F)(F)F)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
NaH (60% dispersion, 20.0 mg, 0.514 mmol) was added to a cooled (0° C.) and stirred solution of 1-(2-hydroxyethyl)-2-pyrrolidinone (0.06 mL, 0.514 mmol) in DMF. After 0.5 h, 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (178 mg, 0.428 mmol) was added as a solid in a single portion and the mixture was heated to 130° C. for 48 h. After cooling to room temperature the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (0.047 g, 64%): LCMS RT: 2.40 min, MH+: 509.2. This transformation can be accomplished by using other aprotic solvents such as DMSO, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([CH3:13])([CH3:12])[CH2:6]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C(O[CH2:26][N:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:28][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([O:4][CH:5]1[CH2:6][C:7]([CH3:13])([CH3:12])[CH:8]2[CH:9]([CH2:26][N:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:28]2)[C:10]1=[O:11])(=[O:3])[CH3:2]
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)OC1CC(C)(C)C=CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC1CC(C)(C)C2CN(Cc3ccccc3)CC2C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 23.2 g of 6-acetoxy-4,4-dimethylcyclohex-2-enone and 0.8 cm3 of trifluoroacetic acid in 770 cm3 of dichloromethane are added, at room temperature, 43 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine. The reaction mixture is stirred at room temperature for 15 hours then 5 g of potassium carbonate are added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 8 cm, height 53 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of ethyl acetate and cyclohexane (20/80 by volume) and collecting 250 cm3 fractions. Fractions 18 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 6.6 g of (3aRS,5RS,7aRS)-5 -acetoxy-2-benzyl-7,7-dimethyl-4-perhydroisoindolone are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH3:17])=[CH:12][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][C:11]([CH3:17])=[CH:12][C:13]=1[C:14](=[O:16])[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([Cl:18])[CH:20]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cc(C(=O)O)c(NC(=O)OC(C)(C)C)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)Nc2cccc(Cl)c2)c(NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.3 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-5-methyl-thiophene-3-carboxylic acid (1.16 g, 4.49 mmol) in dimethylformamide (50.00 ml) was treated with 3-chloro aniline (0.86 g, 6.73 mmol), DIPEA (1.74 g, 13.47 mmol) and TBTU (2.16 g, 6.73 mmol) and stirred at room temperature for 48 h. The volatiles were evaporated and the residue purified by flash chromatography (heptane/ethyl acetate), to yield [3-(3-chloro-phenylcarbamoyl)-5-methyl-thiophen-2-yl]-carbamic acid tert-butyl ester (0.45 g, 27%) as a yellow solid, MS (ISP): m/e=368.6 (M+H+)
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][NH:6][C@@H:5]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[O:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[CH2:4]1.C([O-])([O-])=O.[K+].[K+].F[C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[N:32][CH:33]=1.O>CN(C=O)C>[F:2][C@@H:3]1[CH2:7][N:6]([C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[N:32][CH:33]=2)[C@@H:5]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[O:15][C@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[CH2:4]1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Reactant: Fc1ccc(OC2CCOC2)c([C@H]2C[C@H](F)CN2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2C[C@@H](F)C[C@@H]2c2cc(F)ccc2O[C@H]2CCOC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To a solution of (2R,4S)-4-fluoro-2-(5-fluoro-2-((tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidine hydrochloride (4.74 g, 15.49 mmol) in dry DMF (20 ml), was added K2CO3 (4.85 g, 35.2 mmol) and stirred for 5 min at room temperature, then added 5-fluoro-2-nitropyridine (2.0 g, 14.08 mmol) under N2 atmosphere and stirred for 16 h at 80° C. After completion of reaction, poured the reaction mixture in ice cooled water and stirred for 10 min, solid precipitated was collected by filtration. Solid was dried under high vacuum to afford 5-((2R,4S)-4-fluoro-2-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)-2-nitropyridine as yellow solid (5.1 g, yield: 93%) MS (ESI): 392.1 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC(C)(C)[C:17]#[N:18].C([O-])([O-])=O.[K+].[K+]>C(O)C.C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:17]#[N:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: N#CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
To a solution of 2 g (10.6 mmoles) of 1-benzyl-piperidin-4-one in 14 ml of ethanol are added 6.8 ml (74.5 mmoles) of 2-hydroxy-2-methyl-propionitrile and 0.41 g (3 mmoles) of K2CO3 at 0° C. The mixture is stirred at 0° C. for 5 hours and diluted with diethyl ether. The organic layer is washed with water, dried over Na2SO4 and concentrated. Chromatography on silica gel (CH2Cl2:MeOH=9:1) gives 1.94 g of desired 1-benzyl-4-hydroxy-piperidine-4-carbonitrile in 85% yield.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[C:18]([NH:20][C:21]([NH:23][C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:22])[CH:17]=[C:16]([F:31])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:16]1[CH:17]=[C:18]([NH:20][C:21]([NH:23][C:24]2[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:22])[CH:19]=[C:14]([O:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:15]=1
Reactant: Cc1ccc(NC(=O)Nc2cc(F)cc(OC3CCN(C(=O)OC(C)(C)C)C3)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)Nc2cc(F)cc(OC3CCNC3)c2)cn1
Reaction time: 2 h

Procedure:
To 6.5 g of 3-{3-fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-carboxylic acid tert-butyl ester was added 20 mL of a 1:1 mixture of trifluoroacetic acid and dichloromethane at room temperature and the resultant reaction mixture was stirred for 2 hours. The reaction mixture was concentrated. To the residue was added 5 mL of saturated brine solution and 1 N NaOH was added until a pH of 10 was observed. The mixture was extracted with ethyl acetate. The organics were dried with sodium sulfate, filtered, and concentrated to 1-[3-fluoro-5-(pyrrolidin-3-yloxy)-phenyl]-3-(6-methyl-pyridin-3-yl)-urea, a compound of Formula I, as an oil that was used directly in the subsequent reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[O:33][CH:34]=[CH:35][CH:36]=1)CCC>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Product: c1ccc(COc2ccc(Nc3ncnc4cnc(-c5ccco5)cc34)cc2)cc1

Procedure:
Prepared according to Procedure B from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and 2-(tri-n-butylstannyl)furan (Aldrich); δH [2H6]-DMSO 9.08 (1H,s), 8.70 (1H,s), 8.55 (1H,s), 7.90 (1H,d), 7.69 (2H, d), 7.40 (5H,m), 7.10 (1H,d), 7.03 (2H,d), 6.69 (1H,m), 5.10 (2H,s); m/z (M+1)+395.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.CCN(C(C)C)C(C)C.[Cl-].[CH:28]1([O:34][C:35]([C:37]2[N:38]=[C:39]([CH:42]3[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]3)[S:40][CH:41]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:5]([CH2:12][C:13]([N:45]2[CH2:44][CH2:43][CH:42]([C:39]3[S:40][CH:41]=[C:37]([C:35]([O:34][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:36])[N:38]=3)[CH2:47][CH2:46]2)=[O:15])[N:4]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(OC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C(F)(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (288 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred at room temperature for 30 min. 4-{4-[(Cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-1, 330 mg) is added, and the mixture is stirred for a further 5 min before bromo-tris-pyrrolidinophosphonium hexafluorophosphate (559 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-(1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (348 mg, 65%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([NH:7][C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:6])[CH3:3].Cl.Cl[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>C(O)C>[Cl:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:21]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:8]3([NH:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:13][CH2:12][N:11]([C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)[CH2:10][CH2:9]3)[C:16](=[O:35])[CH2:17]1)(=[O:22])=[O:23])[CH:33]=[CH:32]2
Reactant: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1
Yield: 41.6 %

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (30 ml) and ethanol (6 ml) were added to 1-[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (5.21 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the precipitated crystals were filtered off, washed with ethyl acetate-ethanol, and dried to obtain 1-[4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.71 g). A solution of 1-[4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.40 g), 4-chloropyridine hydrochloride (1.12 g) and triethylamine (3.48 ml) in ethanol (100 ml) was reacted at 150° C. for 9 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with a 5% aqueous sodium carbonate solution and water, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:10% aqueous ammonia-containing methanol=95:5→80:20), and the precipitated crystals were washed with ethanol-ether to obtain the colorless crystalline title compound (1.52 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.O1CCCC1.[CH3:17][NH2:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:18][CH3:17])=[N:6][CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-bromo-2-chloro-3-nitropyridine (456 mg, 1920 μmol) was dissolved in MeOH (6.0 ml) and methylamine, 2.0 M solution in tetrahydrofuran (2.5 ml, 5.0 mmol) was added. The reaction was stirred at room temperature for 6 hours, allowed to stand at room temperature overnight, and then concentrated. material was taken directly to the next step.
Reaction SMILES: [CH2:1]([O:4][C:5](OCCC)=[N:6][NH:7][C:8]([O:10]C)=O)[CH2:2][CH3:3].[CH3:16][NH2:17]>CO.C(O)C>[CH2:1]([O:4][C:5]1[N:17]([CH3:16])[C:8](=[O:10])[NH:7][N:6]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=NNC(=O)OC)OCCC
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CCCOc1n[nH]c(=O)n1C
Temperature: 100 °C

Procedure:
693.6 g (94.4%) of methyl N′-dipropoxymethylenehydrazinecarboxylate (3 mol) were dissolved in 1752 g of methanol and admixed with 564.7 g (6 mol) of methylamine, dissolved in ethanol, and the mixture was heated in an autoclave at 100° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, the residue was taken up in water (880 ml) the mixture was extracted with methylene chloride and the extract was concentrated under reduced pressure. The crystals which precipitated out on cooling were filtered off and dried. This gave 383 g (71.2%, content 87.6%) of 5-propoxy-4-methyl-2,4-dihydro-1,2,4-triazol-3-one in the form of a solid. Melting point: 72.5-73.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH2:13][CH2:14][CH3:15])[C:10](O)=[O:11].S(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH2:13][CH2:14][CH3:15])[C:10]([Cl:18])=[O:11]
Reactant: CCCC(Cc1ccccc1Br)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCC(Cc1ccccc1Br)C(=O)Cl

Procedure:
A 500-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a thermometer and a NaOH trap was charged with 277 mmol of 3-(2-bromophenyl)-2-propylpropionic acid and 200 ml of thionyl chloride, and the mixture was heated under reflux for 2 hours. Then, the excess thionyl chloride was removed by a single distillation, and the distillation of the residue under reduced pressure gave 77.4 g of a crude product having a boiling point of 130° to 135° C./1 mmHg as a pale brown transparent liquid. This acid chloride was used in the next reaction without further purification
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:19]=1[CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:6][CH2:7][N:2]([C:26]([C:23]3[CH:22]=[C:21]([CH2:20][C:19]4[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:18]=4[F:17])[O:25][N:24]=3)=[O:27])[CH2:3][CH2:4]2)=[CH:9]1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2cc(F)ccc2F)on1)N1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.7 %

Procedure:
The mixture of 3-(piperidin-4-yl)-1H-indole hydrochloride (0.060 g; 0.253 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.061 g; 0.253 mmol), HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.096 g: 0.253 mmol) and N,N-diisopropylethylamine (0.110 mL; 0.634 mmol) in DMF (3 mL) was stirred for 72 hours at room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 0 to 10% of ethyl acetate in dichloromethane) to give 0.069 g (65%) of (4-(1H-indol-3-yl)piperidin-1-yl)(5-(2,5-difluorobenzyl)isoxazol-3-yl)methanone as a white solid.