Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15]>CC(C)=O>[CH2:12]([NH:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH2:11])=[CH:4][CH:3]=1)=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN=C=O
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CC(C)=O
Product: CCCCNC(=O)Nc1ccc(S(N)(=O)=O)cc1

Procedure:
A mixture of 4-aminobenzenesulphonamide (172 g, 1 mole), butylisocyanate (99 g, 1 mole) and acetone (150 ml) was refluxed for 7 hours. The urea, crystallizing after cooling, was collected and washed with acetone. Yield : 188 g. Melting point : 193° C. A second crop (48 g) was obtained by concentrating the filtrate to 0.5 l. The NMR spectrum was wholly consistent with the formula of N-butyl-N'-(4-sulphamoylphenyl) urea.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:3][CH:2]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:4]2[C:5]3[CH2:10][CH2:9][N:8]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(c2ccccc2)C3)cc1
Reaction time: 6 h
Yield: 6.4 %

Procedure:
The (5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-(4-trifluoromethylphenyl)amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added phenylboronic acid (83 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under the vacuum. The residue was purified using a gradient of ethyl acetate: hexane (0-100%) to give the desired compound as reddish powder (8.0 mg, 6.0%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8](Cl)[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][C@H:25]([CH3:29])[CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1>>[Br:1][C:2]1[C:10]2[NH:9][C:8]([N:26]3[CH2:27][CH2:28][N:23]([C:18]4[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:24][C@H:25]3[CH3:29])=[N:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1

Procedure:
4-Bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (1.2 g, 4 mmol, Example 6b) reacted with (3R)-1-(3-chloropyridin-2-yl)-3-methylpiperazine (0.95 g, 4.5 mmol, Example 74a) under the conditions of Example 3c to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 474 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH:16]2OCC[O:17]2)[CH:13]=[CH:14][CH:15]=1>CC(C)=O>[F:6][C:7]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH:16]=[O:17]
Reactant: Fc1ccc(Oc2cccc(C3OCCO3)c2)c(F)c1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=Cc1cccc(Oc2ccc(F)cc2F)c1
Temperature: 55 °C

Procedure:
Concentrated sulphuric acid (0.18 g) was added to a solution of 2-(3-(2,4-difluorophenoxy)phenyl)-1,3-dioxolane in acetone (200 cm3). The stirred mixture was heated at 55° C. for 5 hours. After cooling, the solvent was evaporated under reduced pressure, and the residue neutralised by addition of an aqueous solution of sodium hydrogen carbonate. This aqueous mixture was partitioned between diethyl ether and water. The ether layer was separated, dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure to give 3-(2,4-difluorophenoxy)benzaldehyde as an oil (6.4 g). The product was shown to be 85% pure by gas liquid chromatography, and was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19])=[C:4]([O:14]C)[C:5]2[C:10]([C:11]=1[O:12]C)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+]([O-])(O)=O>C(OCC)(=O)C.CC(O)=O.[Ag]=O>[Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[C:3]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19]
Reactant: COc1c(Br)c(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Agent: O=[Ag]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: C/C(=C\C1=C(Br)C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Following a modified procedure of Shinkawa et al. and Flader et al.,16,22 the acid 99e (0.291 g, 0.829 mmol) was dissolved in ethyl acetate (10.0 mL) at room temperature, then HNO3 (1.0 mL) and AcOH (6 drops) are added at room temperature. Silver (II) oxide (0.379 g, 3.05 mmol) was then added and the reaction was stirred vigorously at room temperature for 1 hour before being filtered through a pasture pipette and cotton plug, washing the solid with ethyl acetate, and then washing the organic layer with brine. The organic layer was dried over MgSO4, filtered, and condensed. The yellow oil was then purified by either flash column:chromatography (1:1 Et2O:hexanes 0.5% AcOH) or recrystallization from Et2O/hexanes to afford 39a (0.122 g 0.380 mmol, 46%) as a yellow solid.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:3][N:4]=3)[CH:7]=2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(-c2ccc3ncc(I)n3c2)cc1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Yield: 88.3 %

Procedure:
Prepared from 3-iodo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24 step 2) (2.3 g, 6 mmol) and trimethylsilylacetylene (1.64 mL, 12 mmol) as described in example C.20 step 4. Obtained the title compound as a yellow solid (1.9 g, 89%). MS (ISP) 359.1 [(M+H)+].
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][C:11]=3[CH:10]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O)(=O)=O.[CH2:27]([SH:30])[CH2:28][SH:29].[OH-].[Na+].CC(C)=O.[ClH:37]>O>[ClH:37].[CH:10]1[C:11]2[CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[CH:21][C:9]=1[C:7]1([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[S:30][CH2:27][CH2:28][S:29]1
Reactant: SCCS
Reactant: O=C(Cn1ccnc1)c1ccc2c(c1)Cc1ccccc1-2
Agent: CS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc2c(c1)Cc1cc(C3(Cn4ccnc4)SCCS3)ccc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10.0 g. of 2-(1H-imidazol-1-yl)-1-(9H-fluoren-2-yl)ethanone in 25 ml. of methanesulfonic acid were added 12.2 ml. of 1,2-ethanedithiol. After stirring overnight at room temperature, the reaction mixture was poured into water and the solution was made basic with sodium hydroxide. The resulting solid was recovered by filtration and crystallized from acetone/3 equivalents of hydrochloric acid to provide 10.16 g. of the title product, m.p. 248° C.
Reaction SMILES: C([NH:20][C@@H:21]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:22]([CH3:24])[CH3:23])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>CCOCC>[CH3:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][C@@H:21]([CH:22]([CH3:24])[CH3:23])[NH2:20]
Reactant: COCCOCCOC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Agent: Cl
Solvent: CCOCC
Product: COCCOCCOC[C@H](N)C(C)C

Procedure:
A solution of N-Trityl-O-[2-(2-methoxyethoxy)-1-ethyl]-(D)-valinol (1.0 g, 2.28 mmol) in dry ether saturated with HCl gaz (20 ml) was kept for 2.5 hours at room temperature. After concentration in vacuo, the resulting solid (1.16 g) was purified by flash chromatography (silica gel, dichloromethane first to elute trityl alcohol and then dichloromethane/diethylamine: 95/5, Rf.: 0.20) to give the title free amine as a colorless oil (0.46 g, quantitative).
Reaction SMILES: C[O-].[Na+].Br[CH2:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].[O:19]1CCOC[CH2:20]1.Cl>CO>[CH3:20][O:19][CH2:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cccc(CBr)c1[N+](=O)[O-]
Reactant: C1COCCO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cccc(C(=O)OC)c1[N+](=O)[O-]

Procedure:
Methanol solution (4.7 mL) of sodium methoxide (197 mg) was added dropwise into the mixture of methyl 3-bromomethyl-2-nitrobenzoate (1 g) and methanol (7 mL) under heating and refluxing. Two minutes later, the mixture was cooled down with ice and 1.82 mL of 4M hydrogen chloride dioxane solution was added dropwise thereto. After removing the solvent, diethylether and water were added and the organic layer thereof was dried over sodium sulfate. After removing the solvent, the obtained residue was purified with silica gel column chromatography to obtain 621 mg of methyl 3-methoxymethyl-2-nitrobenzoate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[C:17](=[O:26])[N:16]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[C:15]=3[CH3:37])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH2:38]([N:40]=[C:41]=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CNC.S([O-])(O)(=O)=O.[K+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23]([N:40]([CH3:41])[CH3:38])=[O:24])[C:17](=[O:26])[N:16]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=4)[C:15]=3[CH3:37])=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CCC(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CNC
Agent: O=S(=O)([O-])O
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CCC(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 11.1 %

Procedure:
A solution of 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid (prepared in Example 73) (26.4 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (13.8 mg), 1-hydroxy-7-azabenzotriazole (15.9 mg) and N,N-diisopropylethylamine (0.1 ml) in tetrahydrofuran (0.5 ml) was cooled under ice-cooling and thereto was added dimethylamine (0.05 ml: 2M tetrahydrofuran solution) and the resulting mixture was stirred at room temperature for five hours. To the reaction mixture was 1M aqueous potassium hydrogen sulfate solution (20 ml) and the resulting mixture was then extracted with ethyl acetate (20 ml×2). The organic layer was washed with water (10 ml) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3-[5-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]-N,N-dimethylpropaneamide (3.1 mg).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1(=[O:20])[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.N1C=CC=CC=1>CCOCC>[C:10]([OH:15])(=[O:20])[C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13]([OH:9])=[O:14].[CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1OC(=O)c2ccccc21
Agent: C#CCC(O)CCCC
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(O)c1ccccc1C(=O)O

Procedure:
A mixture consisting of 6.3 parts of 1-octyn-4(RS)-ol, 7.4 parts of phthalic anhydride and 10 parts by volume of pyridine is heated at the reflux temperature for about 3 hours, then allowed to cool for about 16 hours. At the end of that time the mixture is diluted with ether, then is washed with dilute hydrochloric acid. Extraction with dilute sodium hydroxide, followed by acidification of the alkaline extract affords an aqueous solution which is then extracted with ether. The ether extract is dried over anhydrous sodium sulfate, decolorized with activated carbon and stripped of solvent to afford 1-octyn-4(RS)-ol phthalate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:8][C:9]3([O:21][C:5]=2[CH:4]=1)[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:11][CH2:10]3.[OH-].[Li+].[ClH:32]>C(O)C>[ClH:32].[C:16]([CH2:15][N:12]1[CH2:13][CH2:14][C:9]2([CH:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[CH:28]=[CH:29][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:21]2)[CH2:10][CH2:11]1)([OH:18])=[O:17]
Reactant: CCOC(=O)CN1CCC2(C=C(c3ccccc3)c3ccc(OC)cc3O2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)OC1(C=C2c2ccccc2)CCN(CC(=O)O)CC1
Temperature: 4 °C

Procedure:
A mixture of ethyl 7-methoxy-4-phenylspiro[2H-1-benzopyran-2,4′-piperidine]-1′-acetate (3.38 g, 8.60 mmol), ethyl alcohol (250 cm3) and aqueous lithium hydroxide solution (2 N, 6.44 cm3, 12.88 mmol) was heated to reflux for 3.5 h. Upon cooling, the mixture was treated with hydrochloric acid (5 N, 70 cm3) and some of the ethyl alcohol was removed until precipitation began. The mixture was then cooled to 4° C. until crystallisation was complete. The solid was removed by vacuum filtration to afford the title product as a white solid, m.p. 195-230° C., positive ion ESI (M+H)+366.4.
Reaction SMILES: C([O:5][C:6](=[O:40])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N:16]=[C:17]2[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20](=[O:29])[C:19](=[C:30]3[N:34]([CH3:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[S:31]3)[S:18]2)[CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:22]([N:21]1[C:20](=[O:29])[C:19](=[C:30]2[N:34]([CH3:35])[C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[S:31]2)[S:18][C:17]1=[N:16][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH3:15])[C:6]([OH:40])=[O:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCNc1ccc(C(=O)OC(C)(C)C)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNc1ccc(C(=O)O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The product of Example 90 was treated with 55% TFA/DCM for 1 h, concentrated under reduced pressure, diluted with DCM, concentrated once again, diluted with DCM, allowed to stand over solid NaHCO3, filtered and concentrated to afford the title product. MS(ESI): 517 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+].Cl>CO>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:16][N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C=C[N+](=O)[O-])cc1
Temperature: 3 °C
Reaction time: 2 h

Procedure:
A mixture of 4-methylsulphonylbenzaldehyde (22.08 g, 120 mmol) and nitromethane (12.5 ml, 14.2 g, 233 mmol) in MeOH (1 l) is cooled to 3° C. in an ice bath; sodium hydroxide solution (32%, 420 ml, 567 g, 135 g of NaOH, 3.36 mol) is then added dropwise, a clear solution being formed after addition of 30 ml (time needed 1 h). The mixture is stirred at 10° C. for 2 h and then added dropwise at 10° C. to initially introduce HCl (20%, 1080 ml, 216 g of HCl, 5.9 mol) (time needed 40 min). The HCl-acidic mixture is stirred until formation of the precipitate is complete (30 min). The nitrostyrene crystallizate is filtered off with suction, washed with ice water until the wash phase gives a neutral reaction and dried over P2O5 in an evacuated desiccator. The yield of crystallizate is 16.03 g after drying.
Reaction SMILES: [Cl:1][O-].[Ca+2].Cl[O-].[F:6][CH:7]([F:20])[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][C:14]2=[O:19]>O.C(O)(=O)C.C(#N)C.O>[Cl:1][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([O:8][CH:7]([F:6])[F:20])[CH:10]=1)[O:17][CH2:16][CH2:15][C:14]2=[O:19]
Reactant: [O-]Cl
Reactant: O=C1CCOc2c(OC(F)F)cccc21
Agent: [Ca+2]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCOc2c(OC(F)F)cc(Cl)cc21
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of calcium hypochlorite (29.4 g, 137.8 mmol) in water:acetic acid (125:9.5) was added a solution of 8-difluoromethoxychroman-4-one (7.4 g, 34.6 mmol, see step (iv) above) in acetonitrile (20 mL), whereafter the reaction mixture was stirred overnight. The mixture was diluted with water and extracted with ether (3×) and with EtOAc (1×). The combined organic layers were washed with water (3×), dried (Na2SO4) and evaporated, yielding 8.0 g (93%) of the sub-title compound.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.C(N(CC)CC)C.[P:26](=[O:44])(Cl)([S:38][CH2:39][CH2:40][CH2:41][CH3:42])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:26](=[O:44])([S:38][CH2:39][CH2:40][CH2:41][CH3:42])([O:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1)[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=1
Reactant: CCCCSP(=O)(Cl)Oc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(O)c2cc3ccccc3nc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCSP(=O)(Oc1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])c2nc3ccccc3cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Hydroxy-4-nitroacridine (0.01 mole), triethylamine (0.01 mole) tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-(4-trifluoromethylphenyl) S-butyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-(4-trifluoromethylphenyl) O-(4-nitroacridin-1-yl) S-butyl phosphorothioate.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[CH:14]([C:16]([CH3:18])=O)=[CH2:15]>O1CCOCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:11]([C:16]([CH3:18])=[CH:14][CH:15]=[N:10]2)=[CH:12][CH:13]=1
Reactant: Nc1cccc(Br)c1
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccnc2cc(Br)ccc12
Reaction time: 1 h

Procedure:
H2SO4 (14.4 mL, 270 mmol) is added to a solution of 3-bromoaniline (Aldrich, 30.0 g, 174 mmol) in 1,4-dioxane (1 L) at RT. The mixture is heated to reflux and treated with methyl vinyl ketone (Aldrich, 19.5 mL, 270 mmol) in 1,4-dioxane (50 mL) dropwise over 3 h. Heating is continued for 1 h after the addition, followed by removal of the solvent in vacuo. The residue is dissolved in water (100 mL), neutralized with Na2CO3 and extracted with CH2Cl2. The combined organic extracts are washed with water and brine, dried (Na2SO4) and filtered. The filtrate is concentrated, and the residue chromatographed on silica gel (Biotage, eluting with 20% EtOAc/Hexanes) to give the title compound, 15.0 g (43%), as a brownish solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][S:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[F:16][C:2]([F:1])([F:15])[CH2:3][S:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(SCC(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(SCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
To a solution of methyl 6-[(2,2,2-trifluoroethyl)sulfanyl]pyridine-3-carboxylate (Intermediate 210, 345 mg, 1.37 mmol) in MeOH (10 mL) was added a 2M sodium hydroxide aq. solution (1.37 mL, 2.74 mmol). The resulting reaction mixture was stirred at room temperature for 4 h and then evaporated to dryness. The remaining residue was dissolved in water (20 mL), acidified to pH 4.5 with a 1M aq. HCl solution and extracted with DCM (3×25 mL). Combined organics were dried over magnesium sulfate and evaporated to dryness to afford the title compound as a white solid (300 mg, 93%). Method C HPLC-MS: MH+ requires m/z=238. Found: m/z=238, Rt=1.35 min (98%).
Reaction SMILES: [Cl:1]C1C=CC=C(O)C=1C=O.F[C:12]1[CH:23]=[CH:22][C:15]2[O:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:14]=2[CH:13]=1.ClC1C=CC2C=C(C(O)=O)OC=2C=1>>[Cl:1][C:12]1[CH:23]=[CH:22][C:15]2[O:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:14]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(F)ccc2o1
Reactant: O=Cc1c(O)cccc1Cl
Agent: O=C(O)c1cc2ccc(Cl)cc2o1
Product: O=C(O)c1cc2cc(Cl)ccc2o1

Procedure:
By the same procedure, 5-fluorosalicyaldehyde and 6-chlorosalicylaldehyde are converted, respectively, to 5-fluorobenzo[b]furan-2-carboxylic acid and 6-chlorobenzo[b]furan-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH3:16])[N:10]=1.Cl.[OH-].[K+]>O>[C:2]1([NH:1][C:13]2[CH:12]=[C:11]([CH3:16])[N:10]=[C:9]([NH2:8])[N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Nc2ccccc2)nc(N)n1
Yield: 34.5 %

Procedure:
Compound No. 45. (CNI-4594) A mixture of aniline (0.93 g) and 2-amino-4-chloro-6-methylpyrimidine (1.44 g) in 36 mL water was treated with 0.84 mL conc HCl and heated at reflux for 1 hr. Addition of 20 mL 1N KOH gave a light buff solid, which was filtered out, dried, and recrystallized from ethyl acetate/2-methoxyethanol and ethyl acetate/hexane to give 0.69 g 4-phenylamino-2-amino-6-methylpyrimidine, mp 179°-180° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]([CH2:13][O:14][S:15]([CH3:18])(=[O:17])=[O:16])([CH2:9][N:10]=[N+]=[N-])[CH2:7][N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5]1.[H][H]>C(OCC)(=O)C.[Ni]>[CH3:1][O:2][N:3]=[C:4]1[C:8]([CH2:13][O:14][S:15]([CH3:18])(=[O:16])=[O:17])([CH2:9][NH2:10])[CH2:7][N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5]1
Reactant: CON=C1CN(Cc2ccccc2)CC1(CN=[N+]=[N-])COS(C)(=O)=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CON=C1CN(Cc2ccccc2)CC1(CN)COS(C)(=O)=O
Yield: 86 %

Procedure:
1-benzyl-4-methanesulfonyloxymethyl-4-azidomethyl-pyrrolidine-3-one-O-methyloxime was dissolved in 100 ml of ethyl acetate and thereto 5 ml of 50% Raney nickel slurry was added and the resulting mixture was stirred for 3 hours under the pressure of hydrogen. The reaction mixture was filtered and concentrated under the reduced pressure to give 8.0 g of 1-benzyl-4-methanesulfonyloxymethyl-4-aminomethyl-pyrrolidine-3-one-O-methyloxime (yield: 86%). The obtained compound was dissolved in 200 ml of acetonitrile and thereto 3.9 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene was dropped, and the resulting mixture was stirred for 8 hours, concentrated under the reduce pressure, and dissolved in 150 ml of dichloromethane, washed with 100 ml of water and with 100 ml of saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure to give 4.0 g of 6-benzyl-2,6-diazaspiro[3,4]octane-8-one-O-methyloxime (yield: 69.3%). The obtained compound and 2.5 ml of triethylamine were dissolved in 50 ml of dichloromethane and thereto 3.9 g of di-t-butyldicarbonate. The resulting mixture was stirred for 4 hours, washed with 50 ml of water, dried with magnesium sulfate, filtered and concentrated under the reduced pressure. The concentrated residue was purified by silicagel column chromatography(ethylacetate:normal hexane:dichloromethane=3:5:1) to give 4.6 g of the titled compound (yield: 80.9%).