Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]#[N:13])=[CH:7][C:6]=2[Br:14]>C1COCC1>[F:16][C:2]([F:1])([F:15])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][C:6]=2[Br:14]
Reactant: N#Cc1cc(Br)c2[nH]c(C(F)(F)F)cc2c1
Solvent: C1CCOC1
Product: NCc1cc(Br)c2[nH]c(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 113.4 %

Procedure:
A solution of 2-(trifluoromethyl)-5-cyano-7-bromo-1H-indole (Intermediate 4, 200 mg) in THF (10 mL) cooled in an ice-water bath was treated with borane tetrahydrofuran complex (1.52 mL) dropwise via a syringe and stirred under argon for 18 hrs while allowing to warm to room temp. The reaction mixture was then quenched with methanol (5 mL) and stirred at room temperature for 10 min. The reaction mixture was then evaporated to dryness to give the title compound as a white foam (230 mg), which was used in the next step without further purification;
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.[C:15](=[O:18])(O)[O-:16].[Na+].O>O1CCOCC1.O>[C:4]([O:16][C:15]([N:2]1[CH2:5][CH:4]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:3]1)=[O:18])([CH3:6])([CH3:5])[CH3:3]
Reactant: O=C(c1ccc(Cl)cc1)C1CNC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(C(=O)c2ccc(Cl)cc2)C1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
A solution of azetidin-3-yl-(4-chloro-phenyl)-methanone hydrochloride (50 g, 210 mmol) in dioxan:water 1:1 (800 ml) is added powdered sodium bicarbonate (61.7 g, 730 mmol) and the reaction mixture cooled to 10° C. Di-tbutyl-dicarbonate (52.6 g, 240 mmol) is added portion wise and the reaction mixture allowed to warm to room temperature with stirring for 1.5 hours. The reaction mixture is poured into water (1500 ml) and the resulting white precipitate filtered off and dried under vacuum to afford 3-(4-Chloro-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR 400 MHz, CDCl3, δ 1.45 (9H), 4.10 (1H), 4.20 (4H), 7.47 (2H), 7.80 (2H)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:6]2[CH:14]=[CH:13][C:9]([CH3:10])=[CH:8][CH:7]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 148 %

Procedure:
Into a toluene suspension (200 ml) of aluminum chloride (26 g), a toluene solution (50 ml) of p-fluorobenzoyl chloride (16 g) was dropwise added at a room temperature. Subsequently, the mixture was stirred for 20 hours at a room temperature, and then carefully poured into ice-water. Toluene (200 ml) was added thereto, and then the organic layer was separated, and washed successively with aqueous 2N hydrochloric acid solution, water and aqueous saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4-fluoro-4'-methylbenzophenone (16 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:41]=[CH:40][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:37]([OH:39])=O)[CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.C(OC([NH:50][CH2:51][CH2:52][CH2:53][CH2:54][C@H:55]([C:57]([O:59]C(C)(C)C)=[O:58])[NH2:56])=O)(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.C(OC(NCCCC[C@H](C(O)=O)N)=O)(C)(C)C.OS([O-])(=O)=O.[K+].[BH4-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:37]([NH:56][C@@H:55]([C:57]([OH:59])=[O:58])[CH2:54][CH2:53][CH2:52][CH2:51][NH2:50])=[O:39])[CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:40][CH:41]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)[C@@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: CC(C)(C)OC(=O)NCCCC[C@@H](N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)N[C@H](CCCCN)C(=O)O
Reaction time: 0.08 h

Procedure:
N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-valine (14.7, 0.025 mmol), tert-butyl N6-(tert-butoxycarbonyl)-D-lysinate hydrochloride (10.3, 0.03 mmol) and N-methylmorpholine (10 μl, 91 μmol) were dissolved in DCM (1.5 ml). After 5 min, TBTU (9.8 mg, 0.03 mmol) was added and the reaction mixture was stirred overnight. Additional N6-(tert-butoxycarbonyl)-D-lysinate hydrochloride (3.4 mg, 0.01 mmol), N-methylmorpholine (5 μl, 45/μmol) and TBTU (3.3 mg, 0.01 mmol) were added and the mixture was stirred for 2 h. Aqueous KHSO4 (3 ml) was added and the mixture (pH of 3) was extracted with DCM (3×5 ml). The combined organic phases were washed with water (2×5 ml) and dried over Na2SO4. The solvent was removed under reduced pressure. The crude residue (17.1 mg) was dissolved in DCM (1.5 ml) and TFA (1 ml). The solution was stirred for 1.5 h. The solvent was removed under reduced pressure. Toluene was added and evaporated to assist the removal of TFA. The residue was dissolved in methanol (2 ml) and sodium borohydride (11.5 mg, 0.30 mmol) was added. The mixture was for ca 15 minutes. After removal of the solvent under reduced pressure, the residue was purified with preparative HPLC on a C8 column. A gradient from 20% to 50% MeCN in 0.1M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid. (7.8 mg, 43%). 1H-NMR (400 MHz, DMSO-d6): 0.75 (d, 3H), 0.79 (d, 3H), 1.17-1.63 (m, 4H), 1.96-2.06 (m, 1H), 2.61-2.69 (m, 2H), 2.85-2.93 (m, 2H), 3.72-3.80 (m, 1H), 4.12 (t, 1H), 4.27 (s, 0.5H), 4.30 (s, 0.5H), 4.53-5.64 (m, 2H), 4.67-4.76 (m, 1H), 5.01-5.05 (m, 1H), 6.94 (d, 2H), 7.03-7.16 (m, 4H), 7.29-7.39 (m, 4H), 7.50-7.57 (brs, 1H), 8.05 (d, 1H). M/z: 713.1.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:24]([C:25]2[NH:29][CH:28]=[C:27]([CH2:30][N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:26]=2)=[CH:23][CH:22]=[CH:21][N:20]=1.[S:40]1[CH:44]=[CH:43][N:42]=[C:41]1[S:45](Cl)(=[O:47])=[O:46]>O1CCCC1.O>[F:18][C:19]1[C:24]([C:25]2[N:29]([S:45]([C:41]3[S:40][CH:44]=[CH:43][N:42]=3)(=[O:47])=[O:46])[CH:28]=[C:27]([CH2:30][N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH:26]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2nccs2)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a suspension of sodium hydride (60% in oil, 31 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.16 mL), a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (183 mg) in tetrahydrofuran (1 mL) and 1,3-thiazole-2-sulfonyl chloride (160 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→ethyl acetate) to give the title compound as a pale-yellow oil (yield 168 mg, 62%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3ccccc3Cl)c2n1
Product: Clc1ccccc1CSc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2-chlorobenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 178°-180° C.) and piperazine.
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[C:8]([F:24])[CH:7]=1)[NH2:2].[OH:26]/[CH:27]=[C:28](/[CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=1)\[C:29](OC)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:29]=[C:28]([CH2:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=4)[C:27](=[O:26])[N:25]=3)=[CH:7][C:8]=2[F:24])=[CH:14][C:15]=1[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)/C(=C\O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(F)c3)nc2=O)cn1
Temperature: 160 °C
Yield: 14.5 %

Procedure:
A mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorophenyl)ethyl imidocarbamate (200 mg, 0.380 mmol), methyl (2Z)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (170 mg, 0.759 mmol) and K2CO3 (115 mg, 0.835 mmol) in NMP (5 mL) was heated with a microwave condition at 160° C. for 1.5 h. Purification via reverse phase flash chromatography afforded the title compound (32 mg, 0.055 mmol, 14.54% yield). LCMS: rt=3.53 min, [M+H]=551
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]2OCCO2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl-].[OH:23][NH3+:24].O>ClC(Cl)(Cl)Cl.C1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:14]=[N:24][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH3+]O
Reactant: c1ccc(Oc2cccc(C3OCCO3)c2)cc1
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: ON=Cc1cccc(Oc2ccccc2)c1
Yield: 94 %

Procedure:
To a solution of 24.2 g. of 2-(3-phenoxyphenyl)-1,3-dioxolane in 150 ml. of ethyl alcohol a solution of 14 g. of hydroxylammonium chloride in 150 ml. of water is added, and the mixture is boiled until no traces of starting compound can be detected by thin layer chromatography (silica gel, 1:1 mixture of benzene and tetrachloromethane, development: by UV light). Alcohol is distilled off and the aqueous residue is cooled in ice water. The precipitated crystals are filtered off. 20 g. (94%) of 3-phenoxybenzaldehyde oxime are obtained, melting at 45° to 46° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(N(CC)CC)C.ClC(OCC)=O.Cl.[C:24](=S)=[S:25]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[C:24]=[S:25])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: S=C=S
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Fc1ccc(N=C=S)cc1F
Temperature: 25 °C
Yield: 70.2 %

Procedure:
3,4-Difluoroaniline (600 g) and 1410 g of triethylamine were mixed and, with ice cooling and stirring, 389 g of carbon disulfide was dropped in during 2.5 hours. The mixture was stirred at the same temperature for 2 hours more whereupon crystals gradually appeared. The mixture was gradually warmed up to the room temperature, stirred for 2 hours, and kept in a refrigerator for two nights. Chloroform (2 liters) was added to the reaction mixture in which crystals were solidified, the mixture was stirred to make it suspended, and ethyl chloroformate was dropped in at 10° C. (inner temperature) during 2 hours. The mixture was stirred 3.5 hours more at room temperature. After the reaction, the reaction solution was poured over into ice water, the mixture was made weakly acidic with concentrated hydrochloric acid, and the chloroform layer was collected. This was washed with water, dried and concentrated and the residue was purified by a column chromatography (n-hexane/silica gel) to give 558.6 g of 3,4-difluorophenyl isothiocyanate in colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[Li]CCCC.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19].[Cl-].[NH4+]>C1COCC1>[CH3:17][Sn:18]([CH3:20])([CH3:19])[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound from Step A (0.92 g, 4 mmol) in THF (25 mL) was added n-BuLi (2.5 M solution in hexane, 3.48 mL) dropwise at −78° C. After the addition, the reaction mixture was stirred at −78° C. for an additional 30 min. To this solution was added trimethyltin chloride (0.88 g, 4.4 mmol) in THF (8 mL) dropwise for a period of 10 min. The reaction mixture was brought to room temperature slowly and stirred at room temperature overnight. Saturated aqueous ammonium chloride (60 mL) was added and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified over silica gel to give the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=2[CH3:24])[CH:6]=[CH:7][CH:8]=1.[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[NH:31][CH2:30][C:29]=12>>[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[N:31]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([C:10]4[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)=[C:16]([CH3:24])[CH:17]=3)=[O:20])[CH2:30][C:29]=12
Reactant: COc1cccc(C2=C(c3ccc(C(=O)O)cc3C)CCCC2)c1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: COc1cccc(C2=C(c3ccc(C(=O)N4Cc5cccn5Cc5ccccc54)cc3C)CCCC2)c1
Yield: 62.9 %

Procedure:
4-[2-(3-Methoxy-phenyl)-cyclohex-1-en-1-yl]-3-methyl-benzoic acid of Step B (0.066 g, 0.205 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.041 g, 0.223 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether/diethyl ether afforded the title compound (0.063 g) as white crystals, m.p. 91–94° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18](O)[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].P(Cl)(Cl)(Cl)(Cl)[Cl:23].P(Cl)(Cl)(Cl)=O>O>[Cl:23][C:18]1[C:17]([F:21])=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:19]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(F)c(Cl)nc1Nc1ccc(F)cc1F
Yield: 34.7 %

Procedure:
A mixture of 9.5 g of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate, 26.5 g of phosphorus pentachloride and 46.9 g of phosphorus oxychloride was subjected to reaction at 70°-80° C. for 4 hours. Subsequently, the reaction mixture was gradually added to 285 ml of water, and the crystals thus deposited were collected by filtration and then washed with 57 ml of water. The crystals thus obtained were purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene] to obtain 3.5 g (yield 34.7%) of methyl 6-chloro-2-(2,4-difluorophenylamino)-5fluoronicotinate having a melting point of 137°-139° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8](Cl)[C:7]([O:11][CH3:12])=[N:6][CH:5]=1>O1CCOCC1.C([O-])([O-])=O.[K+].[K+].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>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:3]=[C:4]([CH3:9])[CH3:5])[C:7]([O:11][CH3:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(OC)c(Cl)c1
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: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cnc(OC)c(C=C(C)C)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
To a solution of 5-chloro-6-methoxy-nicotinic acid methyl ester (880 mg, 4.37 mmol) and 2,4,6-tri-(2-methyl-propenyl)-cycloboroxane pyridine complex (1.42 g, 4.37 mmol, prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971) in dioxane (10 mL) and 2 M aq. K2CO3 solution (5 mL), Pd(PPh3)4 (101 mg, 87 μmol) is added after the mixture has been degassed and put under N2. The mixture is stirred at 80° C. for 18 h before it is cooled to rt, diluted with EA and washed with water. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 6-methoxy-5-(2-methyl-propenyl)-nicotinic acid methyl ester (300 mg) as a colourless oil; LC-MS: tR=1.01 min; [M+1]+=222.00; 1H NMR (CDCl3): δ 1.85 (d, J=1.3 Hz, 3H), 1.97 (d, J=1.0 Hz, 3H), 3.93 (s, 3H), 4.04 (s, 3H), 6.20 (s, 1H), 8.04 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:7]=1[CH3:17])O.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:7]=1[CH3:17])[CH2:3][CH:2]([CH3:18])[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)cc1C(O)CC(C)C
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butan-1-ol (1.5 g) in toluene (20 mL) was added thionyl chloride (0.9 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (1.6 g, 100%) as an oil.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1N.Cl.N([O-])=O.[Na+].[O:16]=[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]([O:25]CC)=[O:24].[OH-].[Na+]>O>[O:16]=[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: Cl
Agent: Nc1cc(Cl)c(Cl)cc1Cl
Agent: O=N[O-]
Solvent: O
Product: O=C(O)C1CCCCC1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,4,5-trichloroaniline (2.48 g, 12.6 mmol) in H2O (5 mL), cooled to 0° C., conc. HCl (7.5 mL) was added, and then stirred for 20 min. NaNO2 (0.87 g, 12.0 mmol) dissolved in water (5 mL), was added slowly and the reaction was continued at 0° C. for 1 h, filtered and the filtrate was used further. In another setup, ethyl 2-oxocyclohexanecarboxylate (2.0 g, 12.0 mmol) was added to 5N NaOH (0.56 g) and stirred for 16 h. The reaction mixture was cooled to 0° C., conc. HCl (1.2 mL) was added slowly, stirred for another 45 min. to obtain 2-oxocyclohexanecarboxylic acid which was added to the filtrate (prepared above) at 0° C. The resulting yellow solid precipitate was filtered, air dried to give the title compound (1.7 g, 44%) which was used in the next step without any spectroscopic analysis.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and ((S)—N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.O[C:15]1[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH2:28][CH3:29])[CH:16]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([O:13][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH2:28][CH3:29])[CH:16]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(O)cc1CC
Reactant: CCCCC(O)c1cccc(Br)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(CC)c1)c1cccc(Br)n1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
To a stirred solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (250 mg, 1.02 mmol) and ethyl (4-hydroxy-2-ethylphenoxy)acetate (230 mg, 1.02 mmol) in dry THF (21 mL) at 0° C. (ice/water bath) under nitrogen was added ADDP (517 mg, 2.04 mmol) followed by nBu3P (510 μL, 2.04 mmol) drop-wise. The mixture was stirred with slow warming to rt over 18 hours and then concentrated under vacuum, diluted with EtOAc (150 mL) and washed with water (3×75 mL), dried (MgSO4), filtered and reduced to give an oil. Purification by SPE (silica, 10 g Cartridge) eluting with cyclohexane:EtOAc (gradient 20:1 to 5:1) afforded the title compound (307 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[O:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>>[CH2:20]([NH:22][C:23]([N:16]1[C:17]([CH3:19])=[CH:18][C:14]([O:13][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][C:4]=2[Cl:12])=[N:15]1)=[O:24])[CH3:21]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Yield: 62.8 %

Procedure:
3-(2,6-Dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole was reacted with ethyl isocyanate in the same manner as in Example 17 to give a white solid of N-ethyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (5.37 g, yield: 62.8%). Melting point: 80˜82° C., 1H-NMR (Acetone-d6, Acetone, ppm): δ1.10 (t, J=7.2 Hz, 3H), 2.55 (d, J=0.8 Hz, 3H), 3.25 (dq, J=6.1 and 7.2 Hz, 2H), 5.71 (q, J=0.8 Hz, 1H), 7.37˜7.48 (brt, 1H, J=6.1 Hz), 7.67 (q, 2H, JHF=0.7 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]#[CH:20]>CC(CC)=O>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])[C:19]#[CH:18]
Reactant: C#CCBr
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1ccccc1S(N)(=O)=O

Procedure:
A mixture of 35 g of 2-hydroxyphenylsulfonamide, 55.2 g of potassium carbonate, 15.5 ml of propargyl bromide and 1000 ml of ethyl methyl ketone is refluxed for 1.5 hours; it is then cooled, filtered, and concentrated by evaporation. The yield after recrystallisation of the residue from ethyl acetate is 30 g of 2-propargyloxyphenylsulfonamide, m.p. 143°-145° C.