Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](Cl)=[O:21].[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.CN1CCOCC1>ClCCl>[O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:32])([F:23])[F:33])=[CH:30][N:29]=1)=[O:21]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(Cl)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)Nc1ccc(C(F)(F)F)cn1
Reaction time: 18 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetyl chloride (Example 246A, 0.157 g, 0.5 mmol) dissolved in dichloromethane (5 mL) was added 5-(trifluoromethyl)pyridin-2-amine (0.081 g, 0.5 mmol) and N-methylmorpholine (0.085 mL, 0.75 mmol) under nitrogen. After stirring for 18 hours, the reaction mixture was concentrated, loaded onto silica gel column (Analogix®, Burlington, Wis.) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes (Flow=30 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.70 (s, 1H), 8.53 (s, 1H), 8.24 (d, J=8.7, 1H), 7.90 (dd, J=2.3, 8.8, 1H), 7.44-7.18 (m, 10H), 4.21 (s, 2H), 3.55 (t, J=6.5, 2H), 2.88 (t, J=6.5, 2H); MS (DCI) m/z 440.1 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[NH:4][C@@H:5]1[C@@H:12]([OH:13])[C@H:11]([OH:14])[C@@H:10]([CH3:15])[O:9][C@H:6]1[O:7][CH3:8].[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C.O>[CH3:1][N:2]([N:17]=[O:18])[C:3](=[O:16])[NH:4][C@@H:5]1[C@@H:12]([OH:13])[C@H:11]([OH:14])[C@@H:10]([CH3:15])[O:9][C@H:6]1[O:7][CH3:8]
Reactant: O=N[O-]
Reactant: CNC(=O)N[C@H]1[C@H](OC)O[C@H](C)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CO[C@@H]1O[C@H](C)[C@@H](O)[C@H](O)[C@H]1NC(=O)N(C)N=O
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Methyl 2,6-dideoxy-2-(N'-methyl-ureido)-β-D-glucopyranoside (124 mg) of the formula: ##STR35## was dissolved in a mixture of 0.5 ml of glacial acetic acid and 2.5 ml of water, and the resulting solution was admixed with 55 mg of sodium nitrite at ambient temperature and under agitation to effect the nitrosation. The reaction mixture so obtained was then allowed to stand overnight in a refrigerator, so that a crystalline product was deposited. This crystalline product was collected by filtration and then washed with ethanol, affording 80 mg of methyl 2,6-dideoxy-2-(N'-methyl-N'-nitroso-ureido)-β-D-glucopyranoside as the desired product. The mother liquor was then treated with Amberlite IR-120 (H+ form) to remove the sodium ion, and the mother liquor so treated was concentrated by distilling off the solvent under reduced pressure. Crystallization of the residue from ethanol gave 45 mg of the desired product as a second crop. Yield 125 mg (90%). [α]D28 -14° (c 0.52, H2O).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][C:18](B(O)O)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[NH:13][CH:14]=[CH:15]4)[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nccc2ccc(-c3ccc4[nH]ccc4c3)cc12
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A mixture of 7-bromo-1-chloroisoquinoline (0.50 g, 2.1 mmol), 5-indoleboronic acid (0.40 g, 2.5 mmol), tetrakis(triphenylphosphene)palladium (0.035 g, 0.08 mmol), potassium carbonate (2.1 mL, 2 M, 4.1 mmol), N,N-dimethylformamide (11 mL) was stirred while purging the headspace with argon for 30 min. The mixture was then brought to reflux for 16 h before being allowed to cool to RT. The mixture was filtered through a bed of silica gel, diluted with water (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was separated and washed with NaOH (2×20 mL, 10% aq.), water (5×30 mL, until refractive changes were no longer seen at the organic-aqueous interface), and ammonium chloride (20 mL, sat.). The organic layer was then adsorbed onto silica gel and flash-chromatographed (ethyl acetate/hexanes) to afford 0.14 g (25%) of a yellow solid. MS (ESI): calculated for C17H11ClN2, 278.1. found 301.0 [M+Na]+. 1H NMR (300 MHz, DMSO-d6) δ 6.56-6.58 (m, 1H), 7.44 (t, J=2.77 Hz, 1H), 7.57-7.59 (m, 2H), 7.93 (m, 1H), 8.04 (s, 1H), 8.13-8.20 (m, 1H), 8.27-8.31 (m, 2H), 8.43 (m, 1H), 11.25 (brs, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:17])=[O:16])[C:10]=2[F:18])[CH2:5][CH2:4]1)[CH3:2].C(O)=O>[Pd].C(O)(C)C>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:17])=[O:16])[C:10]=2[F:18])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(S(C)=O)c2F)CC1
Agent: [Pd]
Solvent: O=CO
Solvent: CC(C)O
Product: CCN1CCC(c2cccc(S(C)=O)c2F)CC1

Procedure:
Preparation according to Example 2. 1-ethyl-4-[2-fluoro-3-(methylsulfinyl)phenyl]-1,2,3,6-tetrahydropyridine (150 mg, 0.56 mmol), formic acid (0.1 ml, 2.8 mmol), palladium on carbon (0.1 g), isopropanol (20 ml). MS m/z (relative intensity, 70 eV) 269 (M+, 11), 254 (bp), 239 (84), 84 (13), 57 (11).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:13][S:22]([CH3:21])(=[O:24])=[O:23])(=[O:24])=[O:23]
Reactant: OCCOCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOCCOCCOS(C)(=O)=O
Reaction time: 1 h
Yield: 99.8 %

Procedure:
15 g of tetraethyleneglycol and 23.4 g of triethylamine were dissolved in 200 mL of dichloromethane, to which 22.1 g of methanesulfonylchloride was added dropwise at 0° C., and then the solution was stirred for 1 hour. The reaction solution was filtrated to remove insolubles, and then the filtrate was concentrated under reduced pressure. The residue was separated with ethyl acetate-water, and the organic layer was concentrated under reduced pressure after washing with water. The residue was purified with silica gel column chromatography to obtain 27 g of the objective compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[NH:10][CH:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH3:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][CH:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH3:12])[C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC(C)c2cccs2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(NC(C)c2cccs2)c2cccc(N)c2)cc1
Yield: 85.6 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[1-(2-thienyl)ethyl]amine (2.11 g) [prepared as described in step (a) above] in ethanol (40 ml), nickel chloride hexahydrate (2.71 g) and sodium borohydride (863 mg) were reacted, to afford the title compound (1.66 g) as a dark brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([C:9]2[C:13]([CH3:14])=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[N:11]([CH3:19])[N:10]=2)=[N+:6]([O-])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:24]>CN(C)C=O>[Cl:1][C:2]1[C:7](=[O:24])[NH:6][C:5]([C:9]2[C:13]([CH3:14])=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[N:11]([CH3:19])[N:10]=2)=[C:4]([F:20])[CH:3]=1
Reactant: Cc1c(-c2c(F)cc(Cl)c[n+]2[O-])nn(C)c1S(C)(=O)=O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1c(-c2[nH]c(=O)c(Cl)cc2F)nn(C)c1S(C)(=O)=O
Temperature: 22 °C
Reaction time: 8 h

Procedure:
2.6 go 5-chloro-3-fluoro-2-(5-methanesulfonyl-1,4-dimethyl-[1H]-pyrazol-3-yl)-pyridine-1-oxide (Example P40) are introduced into 35 ml of dry dimethylformamide. At a temperature of 10° C., 16.8 g of trifluoroacetic anhydride are added dropwise and the mixture is then stirred overnight at 22° C., subsequently poured into 2 liters of ice-water and extracted with tert-butyl methyl ether. After drying over magnesium sulfate, filtering and concentrating to dryness by evaporation in vacuo, 1.8 g of the desired compound are obtained as crude product, which can be used directly in the next step.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13](Br)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:19]#[N:20]>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:19]#[N:20])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)sc1C(=O)NCc1ccccc1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: Cc1cc(C#N)sc1C(=O)NCc1ccccc1
Temperature: 150 °C
Reaction time: 7 h
Yield: 37.6 %

Procedure:
A mixture of N-benzyl-5-bromo-3-methylthiophene-2-carboxamide (1.00 g, 3.22 mmol) and copper cyanide (0.72 g, 8.06 mmol) in anhydrous N,N-dimethylformamide (15 mL) was stirred under nitrogen atmosphere at 150° C. for 7 h. The mixture was allowed to cool to ambient temperature, and partitioned between ethyl acetate (150 mL) and 14% aqueous ammonium hydroxide (100 mL). The organic layer was washed with 14% aqueous ammonium hydroxide (75 mL), water (75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0-25% ethyl acetate in hexanes) to afford the title compound as a colorless solid (0.31 g, 37%): 1H NMR (300 MHz, CDCl3) δ 7.41-7.29 (m, 6H), 6.13 (br s, 1H), 4.61 (d, J=5.7 Hz, 2H), 2.50 (s, 3H); MS (ES+) m/z 257.2 (M+1), 279.2 (M+23).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.B>C(COC)OC.O1CCCC1>[CH2:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(I)cc1
Agent: B
Solvent: C1CCOC1
Solvent: COCCOC
Product: Ic1ccc(NCc2ccccc2)cc1

Procedure:
2.19 Grams of p-iodoaniline and 1.06 g of benzaldehyde were dissolved in 50 ml of glyme and the resulting solution heated to 60° for two hours. The temperature was maintained for an additional hour after the addition of 30 ml of a 1 M solution of borane in tetrahydrofuran. The excess boron hydride was then destroyed by the addition of about 10 ml of methanol. To this mixture was added 100 ml of a 0.3 M solution of sodium hydroxide and the resulting solution extracted with 100 ml of ether to yield N-benzyl-p-iodoaniline, Rf =0.70.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:12][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH:7]=[CH:6][C:5]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: Nc1cc(Br)ccc1S(N)(=O)=O
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccc(S(N)(=O)=O)c(N)c1
Yield: 99.4 %

Procedure:
A mixture of 4-bromo-2-aminobenzenesulfonamide (140 mg, 0.56 mmol), 2-methoxyphenylboronic acid (106 mg, 0.70 mmol), Pd(PPh3)2Cl2 (20 mg, 5 mol %) in 1,2-dimethoxyethane (30 ml) and Na2CO3 (2M, 3 ml, 6 mmol) was refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO3 (20 ml) and extracted with EtOAc (2×40 ml). The organic layer was washed with brine (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 155 mg (100%) of 2-amino-4-(2-methoxyphenyl)-benzenesulfonamide as colorless powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 219–221° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]#[N:15].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[C:14]([C:3]1[S:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)=[CH:6][C:2]=1[NH:1][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[O:17][CH3:16])#[N:15]
Reactant: COc1ccccc1C(=O)Cl
Reactant: N#Cc1sc(-c2ccc(F)cc2)cc1N
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)Nc1cc(-c2ccc(F)cc2)sc1C#N
Reaction time: 16 h
Yield: 74 %

Procedure:
A solution of 3-amino-5-(4-fluorophenyl)thiophene-2-carbonitrile (2.0 g, 9.2 mmol) in pyridine (40 mL) was cooled in an ice bath, and 2-methoxybenzoyl chloride (1.2 mL, 9.2 mmol) was added dropwise. The cooling bath was removed, and the reaction was stirred for 16 h. The reaction was poured into water, and the resulting suspension was acidified with 1 M hydrochloric acid. The solid was filtered, washed with water, and dried under vacuum to give N-(2-cyano-5-(4-fluorophenyl)thiophen-3-yl)-2-methoxybenzamide (2.4 g, 74% yield).
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:16][C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:17]([Cl:16])=[O:19]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cccc(Nc2ccccc2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N(c1ccccc1)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
2,3-Difluoro-N-phenylaniline (100 mg, 0.487 mmol) and triphosgene (159 mg, 0.536 mmol) were dissolved in CH2Cl2 (1 mL). The solution was cooled in an ice bath, and pyridine (79 μL, 0.975 mmol) was added slowly. Upon complete addition, the reaction was warmed to room temperature and stirred for 1 h. Then, it was cooled in an ice bath and quenched by the slow addition of H2O (1 mL). The reaction mixture was extracted with H2O (5 mL) and CH2Cl2 (5 mL). The aqueous layer was extracted again with CH2Cl2 (5 mL). The organic layers were combined and washed once with H2O (10 mL), dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to yield the title compound as a light brown oil (114.7 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[N:19]([CH3:20])[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)[C:8]=1[CH3:25].ClC1C=CC=C(C(OO)=[O:34])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[N:19]([CH3:20])[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)=[O:34])[C:8]=1[CH3:25]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3n2C)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2C)c1C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
0.25 g of 2-{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthio-1-methylbenzimidazole was dissolved in 20 ml of dichloromethane to obtain a solution. 0.18 g of 80% m-chloroperbenzoic acid was added to the solution at -50° C. The obtained mixture was stirred for one hour, followed by the addition of 0.14 g of triethylamine and 20 ml of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was stirred at a room temperature for one hour. The dichloromethane layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate twice, dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was purified by silica gel column chromatography to obtain 0.12 g of the title compound as a pale yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>C(O)(=O)C>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
196 mg (0.6 mmol) of (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone are dissolved in 5 ml of glacial acetic acid and after the addition of 0.1 g (1 mmol) of acetic anhydride stirred for 3 hours at ambient temperature. Then 15 ml of water are added, the product precipitated is suction filtered, washed with water and dried.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[CH:7]=[CH:8][NH:9][C:10](=[O:24])[C:11]=2[CH:12]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:25](I)([CH3:27])[CH3:26]>CN(C)C=O>[CH:25]([O:24][C:10]1[N:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:3])[NH:5]2)([CH3:27])[CH3:26]
Reactant: CC(C)I
Reactant: CCOC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2ccnc(OC(C)C)c2C1c1cccs1
Temperature: 25 °C

Procedure:
2.1 g (70 mMole) sodium hydride (80% in oil) are suspended in 100 ml dry dimethylformamide and, while stirring at ambient temperature, 20 g (63 mMole) ethy (±)-1,4,5,6-tetrahydro-2-methyl-5-oxo-4-(2-thienyl)-1,6-naphthyridine-3-carboxylate are added thereto portionwise. After cessation of the gas evolution, the reaction mixture is further stirred for 30 minutes at ambient temperature. 16 g (94 mMole) isopropyl iodide in 30 ml diemthylformamide are then added thereto. The reaction mixture is stirred for two days at ambient temperature, the solvent is removed in a vacuum and the residue is taken up with water and ethyl acetate. After shaking up, the ethyl acetate phase is separated off and dried over anhydrous magnesium sulphate. After distilling off the solvent, the residue obtained is separated chromatographically on silica gel with toluene/ethyl acetate (3:1 v/v). The fraction with the Rf of 0.3 is isolated and recrystallized from n-hexane. There is obtained ethyl (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-thienyl)-1,6-naphthyridine-3 -carboxylate in the form of colorless crystals; mp 110°-111° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=O)=[C:4]([NH:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:16]=[C:15]([CH3:24])[CH:14]=2)[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:6]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=2)[N:12]=[C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:16]=[C:15]([CH3:24])[C:14]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Nc2cc(F)c(F)cc2C(=O)O)n(-c2ccccn2)n1
Product: Cc1nn(-c2ccccn2)c2nc3cc(F)c(F)cc3c(Cl)c12
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A solution of 4,5-difluoro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (8.14 g, 24.6 mmol) in phosphorous oxychloride (13 mL, 138 mmol) was heated under reflux for 1.5 hours. The solution was cooled to room temperature and concentrated under reduced pressure, and the residue was poured into iced water. The solution was neutralized by the addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give the title compound (4.42 g, 54% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][O:5][C:4]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:3]1=2.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23](Cl)=[O:24].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:4]3[O:5][CH2:6][C:2]([CH3:19])([CH3:1])[C:3]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: Cc1cc2c(cc1-c1ccc(N)nc1)C(C)(C)CO2
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1-c1ccc(NC(=O)c3c(F)cccc3F)nc1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (172) (25 mg, 0.1 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (25 μl, 2 eq) followed by addition of DIEA (87 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (200 μl) at r.t. for 1 h and before worked up with EA/brine. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(3,3,6-trimethyl(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (173) (20.1 mg, yield: 51%, purity>95%) as white solid.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[N:18]=[CH:19][N:20]3[C:26]4[CH:27]=[CH:28][S:29][C:25]=4[C:24](=[O:30])[N:23]4[CH2:31][CH2:32][C@H:22]4[C:21]=23)[N:13]=1>CN(C)C=O>[CH2:1]([N:5]([CH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[N:18]=[CH:19][N:20]3[C:26]4[CH:27]=[CH:28][S:29][C:25]=4[C:24](=[O:30])[N:23]4[CH2:31][CH2:32][C@H:22]4[C:21]=23)[N:13]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1c2sccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.9 %

Procedure:
0.6 ml (3.45 mmol) of dibutylamine was added to a suspension of 400 mg (1.15 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e]-[1,4]diazepin-8-one in 10 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 12 hours. The solution was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution was extracted with methylene chloride and the organic phases were dried with magnesium sulfate, filtered and evaporated. The residue was chromatographed (silica gel, methyl acetate/methanol 10:1). There were obtained 425 mg (84%) of (S)-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.31 (silica gel, methyl acetate/methanol 10:1).