Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:3]([CH:4]([OH:7])C#N)[CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].C(N(CC)CC)C>CO>[N+:8]([CH2:11][CH:4]([CH:3]1[CH2:1][CH2:2]1)[OH:7])([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: N#CC(O)C1CC1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])CC(O)C1CC1

Procedure:
Example 319 A) To cyclopropyl carboxaldehyde in MeOH is added nitromethane and triethylamine. After stirring, the solvent is removed in vacuo and the residue is dissolved in CH2Cl2. The 2-nitro-1-cyclopropylethanol is isolated from the methylene chloride solution and added to a mixture of sodium acetate and acetic anhydride under N2After stirring, the mixture is diluted with water and extracted with EtOAc. The combined extracts are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. The 2-nitroethenylcyclopropane is used without further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:34][C:35]1[CH:63]=[CH:62][C:38]([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47]OS(C)(=O)=O)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)=[CH:37][CH:36]=1.CN1CCNCC1>>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)=[CH:62][CH:63]=1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Yield: 39.5 %

Procedure:
Following the procedure of Example 1 (10), 2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as pale brown prisms (yield: 39.5%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].COC1C=CC2CC([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)C3C=C(C)C=CC=3OC=2C=1.[CH2:31](Br)[C:32]#[CH:33]>C(O)CCC>[C:31]([CH:21]1[CH2:20][NH:19][CH2:24][CH2:23][NH:22]1)#[C:32][CH3:33]
Reactant: C#CCBr
Reactant: COc1ccc2c(c1)Oc1ccc(C)cc1C(N1CCNCC1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CC#CC1CNCCN1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.8 G. of sodium carbonate are added to a solution of 10 g. of 1-[10,11 -dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-piperazine in 55 ml. of butanol and then a solution of 2.5 ml. of propargyl bromide in 20 ml. of butanol is added dropwise. Then, the mixture is stirred for 20 hours at room temperature and the solvent is removed by distillation under reduced pressure. After working-up in an analogous manner to that described in Example 13, there is isolated crude 1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[ b,f]oxepin-10-yl]-4-(2-propynylpiperazine in the form of an oil. The dihydrochloride, prepared in ethanol and recrystallized from methanol/ether, melts at 210°-212° C. (with decomposition).
Reaction SMILES: C([NH:8][C:9]1[CH:26]=[C:25]2[C:12]([S:13](=[O:29])(=[O:28])[NH:14][C:15]3[C:24]2=[CH:23][C:22]([Cl:27])=[C:21]2[C:16]=3[N:17]=[CH:18][CH:19]=[CH:20]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>Br>[Cl:27][C:22]1[CH:23]=[C:24]2[C:15](=[C:16]3[C:21]=1[CH:20]=[CH:19][CH:18]=[N:17]3)[NH:14][S:13](=[O:28])(=[O:29])[C:12]1[C:25]2=[CH:26][C:9]([NH2:8])=[CH:10][CH:11]=1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(NCc3ccccc3)ccc21
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 29 %

Procedure:
A solution of benzyl-(12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysen-9-yl)-amine 513 (218 mg, 0.52 mmol) in 48% aq. HBr (5 ml) was heated at 100° C. in a sealed tube for 3 h. After cooling, the mixture was neutralized with sat. NaHCO3 solution and the aqueous phase was extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM as the eluent to give the title compound (50 mg, 77%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Cu](C#N)[C:11]#[N:12].N1C=CC=CC=1.N>O.CN(C=O)C>[Br:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[C:11]#[N:12]
Reactant: Cc1cc(Br)cc(Br)c1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(C#N)c1
Temperature: 190 °C
Yield: 147.9 %

Procedure:
A mixture of 1,3-dibromo-5-methylbenzene (1.0 g, 4.0 mmol), copper cyanide (0.179 g, 2.00 mmol), pyridine (0.323 mL, 4.00 mmol), and DMF (15 mL) were heated at 190° C. for 10 h in microwave reactor. The reaction mixture was allowed to cool to r.t., and then poured into a solution of H2O (20 mL) and aq. NH3 solution (25-35% NH3, 10 mL) and the water phase was extracted with EtOAc. The combined organic extracts were dried (Mg2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatograpy (hexane/EtOAc gradient elution) to afford the title compound (0.58 g, 74% yield): 1H NMR (500 MHz, CDCl3) δ ppm 2.39 (s, 3 H) 7.41 (s, 1 H) 7.58 (s, 1 H) 7.60 (s, 1 H); MS (EI) m/z 195 M+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 97 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 97%). 1H NMR (300 MHz, CDCl3): δ 3.27-3.30 (m, 4H), 3.74-3.77 (m, 4H), 4.15 (s, 3H), 6.75-6.78 (m, 3H), 7.11-7.45 (m, 3H), 7.74-7.76 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][OH:12].C(=O)(O)[O-].[Na+]>>[Cl:8][C:7]1[C:2]([NH:9][CH2:10][CH2:11][OH:12])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Product: OCCNc1ncccc1Cl

Procedure:
After 11.46 g of 2,3-dichloropyridine and 9.8 mL 2-aminoethanol were heated at 100° C. for 24 hours, an aqueous saturated sodium bicarbonate solution was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane) to give 2.1 g of the title compound (yellow oil).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[C:13]([F:20])[CH:12]=3)=[CH:8][C:7](=[O:21])[C:6]=2[C:22]=1[NH:23][C:24](=O)[C:25](C)([CH3:27])C.[H-].[Na+].I[CH2:34][CH2:35][CH2:36]CCC.[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[C:13]([F:20])[CH:12]=3)=[CH:8][C:7](=[O:21])[C:6]=2[C:22]=1[NH:23][CH2:24][CH2:25][CH2:27][CH2:34][CH2:35][CH3:36]
Reactant: CN(C)c1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)cc(F)c3o2)cc1F
Reactant: CCCCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
500 mg (1.50 mmol) of Compound 38 obtained in Example 38 was dissolved in 5 ml of dimethylformamide under argon atmosphere, 120 mg of sodium hydride (60% oil disperison) and 0.441 ml of 1-iodohexane were added under ice-cooling and the mixture was stirred at room temperature for 3 hours. An aqueous saturated solution of ammonium chloride was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) and recrystallized from n-hexane/ethyl acetate to give Compound 58 which was converted into hydrochloride according to the same manner as that in Example 16 to give 494 mg (79%).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[CH3:21][N:22]1[C:27]2[CH:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:32][C:29]3[CH:30]=[CH:31][C:26]4[O:25][CH2:24][CH2:23][N:22]([CH3:21])[C:27]=4[CH:28]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: CN1CCOc2ccc(N)cc21
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)N(C)CCO4)nn12

Procedure:
The titled compound was prepared in analogous fashion as Example 113 using 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine and 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamine to give 645 [7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-amine as a brown lyophilate. LCMS (E/I+) 388 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.88 (d, 1H, J=7.5 Hz), 7.27 (t, 1H, J=8 Hz), 7.04 (m, 3H), 6.95 (d, 1H, J=3.6 Hz), 6.81 (d, 1H, J=3.8 Hz), 6.72 (d, 1H, J=8.5 Hz), 6.65 (m, 2H), 4.24 (s, 2H), 3.81 (s, 3H), 3.20 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][NH2:23])=[O:21])=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[Cl:24][CH2:25][C:26](OCC)(OCC)OCC>>[Cl:24][CH2:25][C:26]1[O:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:9]3[C:10]([CH3:13])=[CH:11][CH:12]=[C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])[CH:8]=3)=[CH:15][CH:16]=2)=[N:22][N:23]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NN)cc1
Reactant: CCOC(CCl)(OCC)OCC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1

Procedure:
N-Cyclopropyl-4′-(hydrazinocarbonyl)-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 40) (150 mg) in 2-chloro-1,1,1-triethoxyethane (5 ml) was heated at 150° C. for 18 hours. The reaction was applied to a biotage cartridge (silica, 90 g) and eluted with an ethyl acetate/cyclohexane gradient. The product fractions were reduced to dryness under vacuum to give 4′-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[CH3:18][C:19]1([CH3:30])[CH2:23][C:22](=O)[CH:21]([C:25](OCC)=[O:26])[CH2:20]1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[OH:10][C:9]1[C:8]2[C:22]3[CH2:23][C:19]([CH3:30])([CH3:18])[CH2:20][C:21]=3[C:25](=[O:26])[O:12][C:7]=2[CH:6]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:11]=1
Reactant: CCOC(=O)C1CC(C)(C)CC1=O
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CC(C)(C)C3

Procedure:
to 13.5 g. of 5-(3-methyl-2-octyl)-resorcinol and 10.5 g. of 4,4-dimethyl-2-carboethoxycyclopentanone [Canadian J. of Chem. 47, 1982-1988 (1969)] in 59 ml. of benzene was added 4.3 ml. of phosphorus oxychloride with stirring and refluxing for 6 hours. The red solution was let stand at room temperature for 8 hours, poured into ice and sodium carbonate solution. The colorless mixture was extracted with ether, dried over magnesium sulfate and concentrated. The mixture was extracted with cold pentane and the pentane was discarded. The residue [9-hydroxy-7-(3-methyl-2-octyl)-2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran] was obtained as a gummy solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[CH:14]([C:20]([OH:22])=[O:21])[CH:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CS(C)=O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[CH:14]([C:20]([OH:22])=[O:21])[C:15](=[CH:18][O:19][C:25](=[O:27])[CH3:26])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(CO)CS[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O

Procedure:
7-(2-Phenylacetamido)-3-hydroxymethylcepham-4-carboxylic acid (4 g.), dimethylsulfoxide (20 ml) and acetic anhydride (20 ml.) were treated in a similar manner to that of Example 4 (2) to give 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylic acid (2 g.).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])C)[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]1(S(CC2C(C(O)=O)=C(O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.C(OC(NC(C)CO)=O)(C)(C)C>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH2:22][CH:23]([NH:24][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH3:38])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCN(C)C(=O)OC(C)(C)C
Reactant: O=C(O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: CC(CO)NC(=O)OC(C)(C)C
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCC(C)NC(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 125, starting from methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 114) and 2-(N-t-butoxycarbonylamino)-1-propanol as a white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)([F:7])[F:6])=[N+]=[N-]>CCOC(C)=O.[Pd]>[F:7][C:5]([F:6])([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)[CH2:4][NH2:1]
Reactant: Cc1ccc(C(F)(F)CN=[N+]=[N-])nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(F)(F)CN)nc1
Reaction time: 24 h
Yield: 0.1 %

Procedure:
A solution of 2-(2-Azido-1,1-difluoro-ethyl)-5-methyl-pyridine (2.46 g, 12.42 mol), as prepared in the previous step, in EtOAc (150 mL) was treated with 2.46 g, 10 wt. % Pd—C under a H2 atmosphere. After 24 h, the reaction was filtered through Celite and the filtrate concentrated to afford the product as a clear yellow oil (1.85 g, 10.76 mmol, 86% crude yield). 1H NMR (300 Hz, CDCl3) δ 8.48 (s, 1H), 7.61 (m, 2H), 3.42 (t, J=14.2 Hz), 2.39 (s, 3H); LC/MS (m/z) [M+1]+ 173.0 (calculated for C8H11F2N2, 173.2).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]([N:15]=[C:16]=S)([CH3:14])[CH3:13].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1.N1C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[N:11]=[C:16]([NH:15][CH:12]([CH3:14])[CH3:13])[NH:10][C:4]=2[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CC(C)N=C=S
Reactant: Nc1cc(Cl)c(Cl)c(Br)c1N
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)Nc1nc2c(Br)c(Cl)c(Cl)cc2[nH]1
Yield: 608.4 %

Procedure:
3-Bromo-4,5dichloro-1,2-phenylenediamine (25.0 g, 97.7 mmol), isopropyl isothiocyanate (11.2 g, 110.5 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (56.8 g, 134.1 mmol) and pyridine (500 mL) were used according to general procedure I. The product was isolated by silica gel chromatography using 7:3 hexane/ethyl acetate to afford 192 g (62%) of a tan solid; m p. 247-249° C. Anal. Calcd for C10H10BrCl2N3-(0.08 C6H14): C, 38.15; H, 3.40; N, 12.74. Found: C, 38.15; H, 3.39; N, 12.77.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].C1([Se]Cl)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C1C(=O)CC(C)CC1C
Agent: Cl[Se]c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)CC(C)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.4 %

Procedure:
Ethyl 2,4-dimethyl-6-oxocyclohexanecarboxylate (from Step 2, 0.5 g) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 0.15 g, washed with hexane) in THF at 0° C. After addition was complete, the mixture was stirred at 0° C. for 10 min and then a solution of phenylselenium chloride (0.58 g) in THF was added dropwise. The resulting mixture was slowly warmed to rt where it stirred overnight. After this time, the mixture was treated with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic layers were concentrated under vacuum and the resulting residue was dissolved in dichloromethane. This solution was treated with 30% aqueous hydrogen peroxide (3×0.3 mL, added at 10 min intervals) and the mixture was stirred for an additional 30 min. At the conclusion of this period, the mixture was washed with water and concentrated under vacuum to yield a residue. This residue was purified by column chromatography on silica gel, eluting with 10% ethyl acetate/hexanes, to provide racemic ethyl 2,4-dimethyl-6-oxocyclohex-1-enecarboxylate as an oil (200 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20][N:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20][N:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2nsc3ccccc23)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(Cl)c(NC(=O)c2nsc3ccccc23)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
Methyl 4-amino-5-chloro-2-fluorophenylacetate (753 mg, 3.25 mmol), benzo(d)isothiazole-3-carboxylic acid (583 mg, 3.25 mmol), HOBt (834 mg, 6.18 mmol), EDC HCl (934 mg, 4.88 mmol) and DMAP (catalytic amount) were dissolved in DMF (16 ml). The resulting solution was stirred for 10 hours at 80° C. After cooling, the reaction mixture was poured in 1M HCl, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure, n-hexane/ethyl acetate 9:1, 15 ml/min, φ 50×300 mm) to give ethyl (5-chloro-2-fluoro-4-((3-benzo(d)isothiazolylcarbonyl)amino)phenyl)acetate. The resulting ester was dissolved in THF/methanol (4 ml, 3:1), and to the resulting solution was added 1M NaOH (1 ml). The mixture was stirred for 18 hours at room temperature. The solvent was distilled off under reduced pressure, and the residue was poured in 1M HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (5-chloro-2-fluoro-4-((3-benzo(d)isothiazolylcarbonyl)amino)phenyl)acetic acid (354 mg, 30%) as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O>Cl>[NH2:21][C:18]1[N:17]=[C:16]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[C:15]([C:12]2[CH:11]=[CH:10][C:9](=[O:8])[NH:14][CH:13]=2)=[CH:20][N:19]=1
Reactant: Nc1ncc(-c2ccc(OCc3ccccc3)nc2)c(-c2ccco2)n1
Agent: Cl
Solvent: O
Product: Nc1ncc(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A suspension of 5-[6-(benzyloxy)-3-pyridyl]-4-(2-furyl)-2-pyrimidinylamine (8.35 g, 24.2 mmol) in concentrated hydrochloric acid (40 ml)-water (40 ml) was stirred at 80° C. for 1 hour. After cooling as it was, the reaction mixture was washed with ethyl acetate twice. The aqueous layer was neutralized with an aqueous 5N sodium hydroxide solution. The resulting solid was collected by filtration, washed with water and dried at 50° C. for 14 hours, to give the title compound (5.54 g, 90%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([NH:9][C:10](=[O:12])[CH3:11])[CH:8]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([NH:9][C:10](=[O:12])[CH3:11])=[C:6]([CH3:13])[CH:5]=1
Reactant: BrBr
Reactant: COc1ccc(C)c(NC(C)=O)c1
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)c(C)cc1Br
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of N-(5-methoxy-2-methylphenyl)acetamide in acetic acid (40 mL) was added Br2 (3 g, 19 mmol) slowly. The mixture was capped and stirred at 50° C. for 5 hours. The reaction was cooled to room temperature, then quenched with sodium sulfite aqueous solution, and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over Na2SO4 and concentrated to give crude N-(4-bromo-5-methoxy-2-methylphenyl)acetamide as a brown oil, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Cl.[F:11][C:12]([F:39])([F:38])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>COCCOC>[F:11][C:12]([F:39])([F:38])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(C(C)=O)C(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 28.4 g. of 2,4-pentanedione and 20 ml. of 1,2-dimethoxyethane is added to a suspension of 13.6 g. of sodium hydride in 220 ml. of 1,2-dimethoxyethane under argon. A solution of 28.7 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is stirred at room temperature for 12 hours, cooled, poured on ice-and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue is then chromatographed over silica gel to yield the product as a white solid.