Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]2[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[O:21])[CH:14]=3)=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[CH:4][C:3]=1[Cl:28].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:6]2[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:23][CH2:24][N:25]([S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])[CH2:26][CH2:27]4)=[O:21])[CH:14]=3)=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[CH:4][C:3]=1[Cl:28]
Reactant: CCS(=O)(=O)Cl
Reactant: O=C(c1cc(Cc2c[nH]c(=O)c3cc(Cl)c(Cl)n23)ccc1F)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1CCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 16, P1 in DMF (0.3 M), was added ethanesulfonyl chloride (1 eq) and DIPEA (1 eq). The resulting mixture was stirred for 1 hour at RT. The product was isolated by purification at preparative-HPLC. 1H NMR (400 MHz, DMSO-d6) δ: 10.91 (1H, m, J=5.6 Hz), 7.38-7.18 (3H, m), 7.14 (1H, s), 6.57 (1H, m, J=5.8 Hz), 4.37 (2H, m), 3.87-3.54 (4H, m), 3.31-3.18 (4H, m), 3.05 (2H, q, J=7.41 Hz), 1.21 (3H, t, J=7.20 Hz). MS (ES) C21H21Cl2FN4O4S requires: 514/516, found: 515/517 (M+H)+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1B(O)O.[Br:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=2)[CH:19]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:2]1[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=1)[CH:22]=[CH:21]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccc2oc3ccccc3c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Brc1ccc2cc(-c3ccc4oc5ccccc5c4c3)ccc2c1
Temperature: 85 °C
Reaction time: 7 h
Yield: 40.5 %

Procedure:
In argon atmosphere, a mixture of 18.53 g (87.4 mmol) of 2-dibenzofuranboronic acid, 25.00 g (87.4 mmol) of 2,6-dibromonaphthalene, 5.05 g (4.40 mmol) of tetrakis(triphenylphosphine)palladium (0), 300 ml of dimethoxyethane, and 132 g of a 2 M sodium carbonate aqueous solution was stirred at a bath temperature of 85° C. for 7 h. The reaction mixture was added with water and extracted with toluene. After washing with water, the organic phase was dried over magnesium sulfate. Then, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography to obtain 13.20 g (yield: 38%) of 2-(6-bromonaphthalene-2-yl)dibenzofuran.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.I[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>N.[Cu]I>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:7]2[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=[CH:5][C:6]2=[O:9])=[CH:14][CH:15]=1
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(-n2cc(C(F)(F)F)ccc2=O)cc1
Temperature: 135 °C
Yield: 39.1 %

Procedure:
A mixture of 5-(trifloromethyl)-2(1H)-pyridone (815.5 mg, 5 mmol), 4-iodoanisole (2.34 g, 10 mmol), CuI (952 mg, 5 mmol), K2CO3 (691 mg, 5 mmol) and DMF (5 ml) was heated at 135° C. overnight. The reaction mixture was diluted with 10% ammonia (15 ml) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride, dried over magnesium sulfate and evaporated. Column chromatography purification (30% ethyl acetate-hexane) afforded 526 mg (39.2%) of 1-(4-methoxyphenyl)-5-(trifloromethyl)-2-pyridone. This compound (268.2 mg, 1 mmol) was treated with 1M BBr3 solution in dichloromethane (DCM, 2 ml) in DCM (5 ml) for 2 hours at 0° C. Reaction mixture was diluted with DCM and washed 3 times with water. Organic phase was dried over sodium sulfate and evaporated. The residue was separated by column chromatography (20% ethyl acetate-DCM) to afford the title compound as an off-white solid, 226 mg (89%). The 1H NMR spectra was consistent with the structure of Compound 10.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].C(N(CC)CC)C>C(Cl)Cl>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:9](=[S:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:3][CH:4]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Reactant: O=C(Cl)CCCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
Thiourea 4 (6 g, 18.3 mmol, 1 equiv.) was stirred in CH2Cl2 (110 mL) under N2 atmosphere. 5-Bromovaleryl chloride (3.65 g, 18.3 mmol, 1 equiv.) was added, followed by triethylamine (2.51 mL, 18.3 mmol, 1 equiv.). The beige suspension was stirred at rt for 4 h and diluted with CH2Cl2 (50 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×50 mL), 10% aqueous sodium hydroxide (1×50 mL), and saturated brine (1×50 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting brown foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 5-bromo-pentanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide (intermediate JH140) (6.76 g, 77%) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]([Mg]Br)[CH3:12].B(F)(F)F>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2([NH2:7])[CH2:12][CH2:11]2)=[C:4]([F:10])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Product: NC1(c2ccc(Br)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled solution of 4-bromo-2-fluorobenzonitrile (432 mg, 2.16 mmol) in THF (10 mL) at −78° C., was added titanium (IV) isopropoxide (0.7 mL, 2.4 mmol). After stirring for 10 minutes, ethylmagnesium bromide (1M, 4.75 mL, 4.75 mmol) was added and the reaction mixture warmed to 0° C. and then to rt. BF3.OEt (0.53 mL, 4.32 mmol) was then added and the reaction mixture stirred for an additional 1 h at rt. The reaction was quenched with saturated NH4Cl and NaOH (1N). Extraction with EtOAc, and drying over MgSO4 yielded crude product which was taken forward as crude in the next step. HPLC-MS tR=0.34 min (UV254 nm); mass calculated for formula C9H9BrFN 228.99, observed LCMS m/z 230.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27])(=[O:22])=[O:21]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:24]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(S(C)(=O)=O)c3)CC2)ccc1Cl
Yield: 49 %

Procedure:
The title compound (22 mg, 49%) was prepared analogously to example 1 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 3-methylsulfonyl benzoic acid. MS: 451.4 (MH+)
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([N:16]([CH2:19][CH2:20]Cl)[CH2:17][CH3:18])[CH3:15].C(N(CC)CC)C>CC(C)=O>[CH2:14]([N:16]([CH2:19][CH3:20])[CH:17]([N:8]1[CH2:9][CH2:10][NH:11][C:12](=[O:13])[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18])[CH3:15]
Reactant: O=C1NCCNC1c1ccccc1
Reactant: CCN(CC)CCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Yield: 64 %

Procedure:
144 g. of 2-phenyl-3-keto piperazine are boiled under reflux with 121 g. of diethylamino ethylchloride, 340 cc. of triethylamine, and 1600 cc. of acetone for 24 hours. The cooled solution is filtered to remove triethylamine hydrochloride and the filtrate is evaporated to dryness. The residue is dissolved in water, 40 % sodium hydroxide solution is added thereto, and the oil which forms as upper layer, is extracted with benzene. The benzene solution is dried over anhydrous potassium carbonate, the benzene is removed by distillation, and the residue is distilled in a vacuum. A light yellow, viscous oil of the boiling point 175° C./0.05 mm. Hg is obtained. The oil is twice recrystallized from n-heptane. 145 g. of the above mentioned compound melting at 53°-56° C. are obtained. The yield is 64 % of the theoretical yield.
Reaction SMILES: [SH:1][C:2]1[C:7]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]2([CH3:18])[CH3:17])=[CH:6][N:5]=[CH:4][N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br.C(=O)([O-])[O-].[NH4+].[NH4+]>C(#N)C>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][S:1][C:2]1[C:7]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]2([CH3:18])[CH3:17])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CC1(C)Cc2ccccc2C1c1cncnc1S
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Product: CC1(C)Cc2ccccc2C1c1cncnc1SCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.57 g (0.002 mol) of 4-mercapto-5-(2,2-dimethylindan-1-yl)pyrimidine, 0.57 g (0.003 mol) of 3-fluorobenzyl bromide, and 0.41 g (0.003 mol) in 10 mL of acetonitrile was stirred at ambient temperature for 2 hr. Saturated aqueous ammonium carbonate (5 mL) was added and the mixture obtained was extracted with ethyl acetate. The extract solution was washed with water and with concentrated aqueous sodium chloride and then was dried over sodium sulfate and concentrated by evaporation under reduced pressure. The resulting oil was low pressure liquid chromatographed on silica gel eluting first with hexane and then with a 20:80 by volume mixture of ethyl acetate and hexane. The eluent fractions containing the major component were concentrated by evaporation under reduced pressure to obtain the title compound as a white solid melting at 60°-62° C.
Reaction SMILES: [OH:1][N:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([NH:5][C:6]1[S:10][N:9]=[N:8][CH:7]=1)=[O:4].[H-].[Na+].[CH3:19]I>C(OC(C)C)(C)C>[CH3:19][O:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:3]([NH:5][C:6]1[S:10][N:9]=[N:8][CH:7]=1)=[O:4]
Reactant: CI
Reactant: O=C(Nc1cnns1)N(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Product: CON(C(=O)Nc1cnns1)c1ccccc1
Temperature: 60 °C

Procedure:
7.1 g (0.03 mole) 1-hydroxy-1-phenyl-3-(1,2,3-thiadiazole-5-yl)-urea were dissolved in 75 ml tetrahydrafuran and reacted with 1.44 g (0.03 mole) of a 50% dispersion of sodium hydride in oil. After an hour had elapsed at room temperature all of the gas evolvement had been completed and then 1.9 ml (0.03 mole) methyliodide were introduced and the reaction mixture over a period of 30 minutes heated to 60° C. Thereafter the reaction mixture was concentrated in vacuum and reacted with 100 ml of ice water. The resulting greasy crystals were digested with 50 ml diisopropylether and dried to a constant weight at 40° C. in vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].NC1C=CC([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:28]([NH2:30])=[O:29])=CC=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[NH:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[CH:19]=[C:20]([C:28]([NH2:30])=[O:29])[NH:21]2
Reactant: NC(=O)c1[nH]c2ccccc2c1-c1ccc(N)cc1
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccccc2-c2cccc3[nH]c(C(N)=O)cc23)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 226.9 %

Procedure:
0.115 cm3 (0.876 mmol) of 2-fluoro-5-methylphenyl isocyanate is added, at a temperature in the region of 20° C., under an argon atmosphere, to 0.2 g (0.796 mmol) of 3-(4-aminophenyl)-1H-indole-2-carboxamide in solution in 10 cm3 of tetrahydrofuran. After stirring for 18 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), to give 400 mg of a residue which is purified by flash chromatography [eluent: ethyl acetate/cyclohexane (7/3 by volume)]. After concentration under reduced pressure of the fractions containing the expected product, 250 mg of a yellow residue are obtained, which residue is stirred in 10 cm3 of dichloromethane and then filtered and dried under reduced pressure (2.7 kPa), to give 180 mg of 3-{4-[3-(2-fluoro-5-methylphenyl)ureido]phenyl}-1H-indole-2-carboxamide, in the form of a beige solid that melts at 220° C.;
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:11][CH:10]=1.Br[CH2:40][CH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(#N)C>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:23][CH2:24][N:25]([CH2:40][CH2:41][OH:42])[CH2:26][CH2:27]2)=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(N2CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccccc1-c1cc(N2CCN(CCO)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 70 h
Yield: 78.7 %

Procedure:
A mixture of 100 mg (0.186 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide (Example 53), 0.030 ml (0.42 mmol) 2-bromo-ethanol and 46 mg (0.33 mmol) potassium carbonate in 2 ml acetonitrile was stirred at 45° C. for 70 h. After cooling to room temperature 10 ml 1 N sodium hydroxide solution were added. Extraction with 3 15-ml portions of ethyl acetate, drying with sodium sulfate and concentration gave 138 mg of the crude product. Flash column chromatography afforded 85 mg (78.6%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([N:13]([CH3:12])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:6]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(F)c1
Reaction time: 8 h

Procedure:
3,5-Difluorobenzoyl chloride (50 mg, 0.28 mmol, CAS RN 129714-97-2) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (45 mg, 0.23 mmol, example 1, intermediate a) and DIPEA (79 μL, 0.45 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired compound as a waxy solid (26 mg, 34%). MS (ESI): m/z=339.1 [M+H]+.
Reaction SMILES: [Sn](Cl)Cl.Cl.[Cl:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:13]=2[C:14]#[N:15])=[CH:8][C:7]=1[CH3:25].[OH-].[K+]>>[NH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]([CH2:11][O:10][C:9]2[CH:23]=[CH:24][C:6]([Cl:5])=[C:7]([CH3:25])[CH:8]=2)[C:13]=1[C:14]#[N:15]
Reactant: Cc1cc(OCc2cccc([N+](=O)[O-])c2C#N)ccc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Product: Cc1cc(OCc2cccc(N)c2C#N)ccc1Cl
Temperature: 15 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a cooled (15° C.) and stirred solution of tin (II) chloride (0.37 g, 1.65 mmol) and con. hydrochloric acid (2.0 mL) was added a solution of 2-(4-chloro-3-methylphenoxymethyl)-6-nitrobenzonitrile (100.0 mg, 0.33 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was poured on to crushed-ice and potassium hydroxide solution, stirred, extracted with dichloromethane, filtered and dried to yield 80 mg of 2-amino-6-(4-chloro-3-methylphenoxymethyl)benzonitrile.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH2:14])[CH:8]=1>CO>[Cl:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:13][C:1](=[O:5])[CH:2]=[N:14]2
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=CC(=O)O
Solvent: CO
Product: O=c1cnc2cc(Cl)ccc2[nH]1
Reaction time: 24 h

Procedure:
Following the procedure of J. Med. Chem., 24, 93 (1981), glyoxylic acid (29.4 ml) is added to a solution of 4-chloro-1,2-phenylenediamine (38.0 g) and methanol (1.87 L) at 15°. The solution is stirred for 24 hr at 20°-25° and is concentrated. The residue is washed with water (4×608 ml), isopropanol (145 ml), and dried under reduced pressure to give a solid. Two successive recrystallizations from hot (ca 90°) 2-methoxyethanol (1.49 l and 0.927 l) gives the title compound, NMR (DMSO-d6) 12.55, 8.22, 7.86, 7.62 and 7.32 δ.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[CH2:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH:21][C:22]1[C:27](I)=[CH:26][CH:25]=[CH:24][C:23]=1[C:29](=[O:31])[CH3:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16](/[CH:17]=[CH:18]/[C:27]3[C:22]([OH:21])=[C:23]([C:29](=[O:31])[CH3:30])[CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(I)c1O
Reactant: C=Cc1ccc(OCCCCc2ccc(F)cc2)cc1
Product: CC(=O)c1cccc(/C=C/c2ccc(OCCCCc3ccc(F)cc3)cc2)c1O
Yield: 70 %

Procedure:
Following the process described in example 20 (point D), starting from 4-[4-(4-fluorophenyl)butoxy]-styrene and 2'-hydroxy-3'-iodoacetophenone, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:ethyl ether, 95:5 (70% yield).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][CH:4]([N:6]2[C:10]3[N:11]=[C:12]([S:22][CH3:23])[N:13]=[C:14]([C:15]4[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=4)[C:9]=3[CH2:8][CH2:7]2)[CH2:3]1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[F:24][C:2]1([F:1])[CH2:3][CH:4]([N:6]2[C:10]3[N:11]=[C:12]([S:22]([CH3:23])=[O:33])[N:13]=[C:14]([C:15]4[CH:20]=[N:19][C:18]([NH2:21])=[N:17][CH:16]=4)[C:9]=3[CH2:8][CH2:7]2)[CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2cnc(N)nc2)c2c(n1)N(C1CC(F)(F)C1)CC2
Solvent: ClCCl
Product: CS(=O)c1nc(-c2cnc(N)nc2)c2c(n1)N(C1CC(F)(F)C1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
To a suspension of crude 5-[7-(3,3-difluorocyclobutyl)-2-(methylsulfanyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine (˜80% purity) (768 mg, 2.63 mmol) in DCM (87 mL) at 0° C. was added m-chloroperbenzoic acid (844 mg, 3.42 mmol, 70% purity) in three portions over 1 min. The reaction mixture was stirred at 0° C. for 15 min, whereupon it was diluted with DCM and washed with saturated aqueous NaHCO3 and water. The organic layer was concentrated and purified via HPLC reversed phase column (0-50% of gradient A to B over 25 min; A: water with 0.1% acetic acid, B: acetonitrile with 0.1% acetic acid) to afford the title compound (251 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 2 H), 7.19 (s, 2 H), 4.61-4.48 (m, 1 H), 3.83 (t, J=8.4 Hz, 2 H), 3.38-3.31 (m, 2 H), 3.14-2.98 (m, 2 H), 2.97-2.85 (m, 2 H), 2.83 (s, 3 H). m/z (APCI+) for C15H16F2N6OS 367.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.[O:17]1[CH:19]2[CH2:20][C:21]3[C:26]([CH:18]12)=[CH:25][CH:24]=[CH:23][CH:22]=3>O1CCOCC1.O>[OH:17][C@@H:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:18]1[NH:1][C:2]1[C:3]2[N:4]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1
Reactant: COC(=O)c1cc(N)c2nc(C)c(C)n2c1
Reactant: c1ccc2c(c1)CC1OC21
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(N[C@@H]2c3ccccc3C[C@H]2O)c2nc(C)c(C)n2c1
Temperature: 100 °C
Reaction time: 60 h
Yield: 77.2 %

Procedure:
10.0 g (45.7 mmol) methyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate and 18.1 g (137 mmol) 1,2-epoxyindane are suspended in 300 ml dioxane and 100 ml water. The reaction mixture is stirred at 100° C. for 2.5 d. After cooling down in an ice bath, the precipitate is collected and washed with water. The product is suspended in a mixture of 2-propanol and acetone (1:1) and filtered by suction. After drying in vacuo at 50° C., 12.4 g (77%) of the title compound are isolated as a colourless solid (m.p. 261-262° C.).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].C(=O)C.C(O)(C)C.[P:14](=[O:18])([OH:17])([OH:16])[OH:15]>>[P:14]([O-:18])([OH:17])([OH:16])=[O:15].[C:2]([OH:6])(=[O:5])[CH:3]=[O:4]
Reactant: O=P(O)(O)O
Agent: CC=O
Agent: O=CC(=O)O
Solvent: CC(C)O
Solvent: O
Product: O=P([O-])(O)O
Temperature: 40 °C
Reaction time: 20 h

Procedure:
32.3 g (0.100 mole) of 4'-methoxy-4-diazodiphenylamine hydrogensulfate was dissolved in 70 ml of an 85% phosphoric acid solution. Then 6.64 g (0.0700 mole) of glyoxylic acid monohydrate (97%) was added to this solution and the mixture was stirred at 40° C. for 20 hours. Then 3.96 g (0.0900 mole) of acetaldehyde was added to the reaction mixture and the mixture was stirred at 40° C. for additional 20 hours. Thereafter, the reaction solution was poured into 800 ml of isopropyl alcohol while stirring, to give yellow precipitate. The yellow precipitate was obtained by filtering and washed with isopropyl alcohol, to give dihydrogenphosphate of of a condensate of 4'-methoxy-4-diazodiphenylamine with glyoxylic acid.acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:33]=[CH:32][C:26]2[O:27][C:28]([F:31])([F:30])[O:29][C:25]=2[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:33]3[CH:23]=[CH:24][C:25]4[O:29][C:28]([F:30])([F:31])[O:27][C:26]=4[CH:32]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Product: O=C1N(c2ccc3c(c2)OC(F)(F)O3)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 148 step E or example 179 step A for an alternative synthesis) and 5-bromo-2,2-difluoro-benzo[1,3]dioxole. Off-white solid. MS (ESI): 485.1 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].CC1C=C(C=CC=1)C[Zn+]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:31])[CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: Cc1cccc(C[Zn+])c1
Agent: [Cl-]
Product: Cc1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Yield: 66 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (3-methylbenzyl)zinc(II) chloride in 66% yield.