Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]>[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:21]=[CH:22][C:5]([C:2]([CH3:3])([CH3:1])[CH3:4])=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(N)cc2)cc1
Reaction time: 0.5 h

Procedure:
4.5 g. (0.015 mol) 4-(1,1-Dimethylethyl)-N-(4-nitrophenyl)-benzamide (Example 15 ) are hydrogenated at normal pressure and ambient temperature in the presence of 0.5 g. 10% palladium on charcoal. After 30 minutes, the reaction mixture is filtered and the filtrate is evaporated in a vacuum. The residue is digested with ligroin and filtered off with suction. There are obtained 3.4 g. (85% of theory) of the title compound; m.p. 111°-113° C.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]2[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[C:16]([C:18]3[N:19]=[C:20]([NH2:23])[S:21][CH:22]=3)=[O:17])[C@H:5]2[S:4]1.[OH-].[Na+].[BH4-].[Na+].Cl>CO>[ClH:1].[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]2[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[CH:16]([OH:17])[C:18]3[N:19]=[C:20]([NH2:23])[S:21][CH:22]=3)[C@H:5]2[S:4]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2S1
Agent: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(=N)[nH]3)[C@H]2S1
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3csc(N)n3)[C@H]2S1

Procedure:
To a suspension of 2-methyl-7-[2-(2-aminothiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride, which can be represented as 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride, (3.80 g.) in methanol (70 ml.) was added 1 N sodium hydroxide aqueous solution (18.8 ml.) under ice-cooling and stirring. To the mixture was added sodium borohydride (0.13 g.) over 20 minutes under ice-cooling and stirring and the mixture was stirred for 30 minutes at the same temperature. After the reaction, methanol was distilled off from the reaction mixture. To the residue was added cold water (60 ml.), and the mixture was washed with ethyl acetate, adjusted to pH 2 with 10% hydrochloric acid and then filtered. The filtrate was subjected to column chromatography (non-ionic adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries) and the column was washed with water and then eluted with 10% aqueous isopropyl alcohol solution. The eluates containing the object compound were collected and then lyophilized to produce pale yellow powder. (1.80 g.). To the powder were added methanol (10 ml.) and 35% hydrochloric acid (0.5 g.) in turn, and thus obtained solution was subjected to column chromatography using activated carbon (2.0 g.) and then the column was eluted with methanol. The eluates containing the object compound were collected and then the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate and then dried to give 2-methyl-7-[2-hydroxy-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride, which can be represented as 2-methyl-7-[2-hydroxy-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride, (1.10 g.), mp >250° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17].C(N1CCC(CNC(C2C3C(=CC=CC=3)NC=2)=O)CC1)CCC>>[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[Cl:1])=[O:13])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]
Reactant: O=C(O)c1c(Cl)[nH]c2ccccc12
Reactant: CCCCN1CCC(CN)CC1
Agent: CCCCN1CCC(CNC(=O)c2c[nH]c3ccccc23)CC1
Product: CCCCN1CCC(CNC(=O)c2c(Cl)[nH]c3ccccc23)CC1

Procedure:
2-Chloroindole-3-carboxylic acid (L. Marchetti and A Andreani, Ann. Chim. (Rome), 1973, 63, 681) was converted to its acid chloride and reacted with N-(1-n butyl-4-piperidyl)methylamine (D 1) using the procedure of Description 1b to afford N-[(1-n butyl-4-piperidyl)methyl] 2-chloroindole-3-carboxamide.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[N:8]2[C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][CH2:13][C:7]2=[N:6][N:5]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCOCC1>[C:25]1(=[O:35])[N:29]([CH2:2][CH2:3][C:4]2[N:8]3[C:9]4[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=4[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:20])=[N:12][CH2:13][C:7]3=[N:6][N:5]=2)[C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12
Reactant: OCCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, 1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dioxane is treated with phthalimide, triphenylphosphine and subsequently with diethyl azodicarboxylate to give 1-(2-phthalimidoethyl)-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1.[CH3:19][C:20]1[CH:29]=[C:28]([CH3:30])[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.I[C:61]1[NH:65][C:64]([C:66]2([CH3:70])[CH2:69][O:68][CH2:67]2)=[N:63][C:62]=1[C:71]#[N:72].IC1NC(C)=NC=1C>>[C:71]([C:62]1[N:63]=[C:64]([C:66]2([CH3:70])[CH2:67][O:68][CH2:69]2)[NH:65][C:61]=1[C:27]1[C:28]([CH3:30])=[CH:29][C:20]([CH3:19])=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23])#[N:72]
Reactant: CC1(c2nc(C#N)c(I)[nH]2)COC1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1cc(-c2[nH]c(C3(C)COC3)nc2C#N)c(C)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) and 5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile (compound 202.3) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 326 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35]1(=O)[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][CH:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][N:21]([C:35]4[CH2:39][CH2:38][C:37](=[O:40])[CH:36]=4)[CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C1CCC(=O)C1
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Product: Cc1cc(F)ccc1[C@@H]1C(O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]21

Procedure:
The title compound was prepared from (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-2-methylphenyl)octahydropyrano[3,4-c]pyrrole and cyclopentane-1,3-dione according to the procedures used for example 3. MS: (MH)+572.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:21])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15](Cl)[N:14]=1.[OH2:22]>CC1OCCNC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:21])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15]([N:6]2[CH2:7][CH2:8][O:22][CH:4]([CH3:3])[CH2:5]2)[N:14]=1
Reactant: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
Reactant: O
Agent: CC1CNCCO1
Product: CC1CN(c2cc(=O)[nH]c(CC(=O)N3CCc4c(F)cccc43)n2)CCO1

Procedure:
A solution of 200 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one in 2 ml of 2-methylmorpholine is heated at 100° C. for 15 minutes. The reaction medium is taken up with 10 ml of water. The solid formed is filtered off and washed with water and then dried so as to give 216 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methylmorpholin-4-yl)-3H-pyrimidin-4-one in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21](OC)OC.[OH:26][CH:27]([CH:29]([OH:31])[CH3:30])[CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21]1[O:31][CH:29]([CH3:30])[CH:27]([CH3:28])[O:26]1
Reactant: COC(OC)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reactant: CC(O)C(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1OC(c2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc2Cl)OC1C

Procedure:
30 g of 3-(4-chloro-3-dimethoxymethylphenyl)-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, 2.1 g of 2,3-dihydroxybutane and 0.3 g of p-toluenesulfonic acid were dissolved in 100 ml of anhydrous toluene, and the stirred solution was refluxed for 7 hours in the absence of water. For working up, the solution was washed in succession with water and 10% strength NaHCO3 solution, dried over Na2SO4 and evaporated down.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=4)[C:7]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.B(Br)(Br)Br.COC1C=CC2NC3CC(C(OCC4C=CC=CC=4)=O)C4C(=O)NC(=O)C4C=3C=2C=1>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[C:7]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)cc1
Agent: BrB(Br)Br
Agent: COc1ccc2[nH]c3c(c2c1)C1C(=O)NC(=O)C1C(C(=O)OCc1ccccc1)C3
Product: O=C1NC(=O)c2c1c(-c1ccc(O)cc1)cc1[nH]c3ccc(O)cc3c21
Yield: 92 %

Procedure:
The reaction of 9-hydroxy-4-(4-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione prepared as decribed in example 34 with BBr3 using the procedure described in example 80 of Scheme 2 gave 9-Hydroxy-4-(4-hydroxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (24) (I, Ar=4-hydroxyphenyl) in a 92% yield; mp 230° C. (dec). 1H NMR δ [(CD3)2SO] 11.67 (s, 1H), 10.96 (s, 1H), 9.59 (s, 1H), 9.22 (s, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.41 (d, J=8.6 Hz, 2H), 7.04 (dd, J=8.7, 2.4 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H). FABMS found [M+H]+: 345.0875. C20H13N2O4 requires 345.0875.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C1C=CC=CC=1>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]=[CH:1][C:3]2[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(C)Oc1ccc(C=Nc2ccc(Cl)cc2)cc1
Reaction time: 6 h
Yield: 94.8 %

Procedure:
(a) In 100 ml of dried benzene are dissolved 17.0 g of ethyl 2-(4-formylphenoxy)propionate and 9.73 g of 4-chloroaniline, and the mixture is refluxed under heating and with stirring for 6 hours. Concentration of the reaction mixture gives 24.0 g of ethyl 2-[4-{N-(4-chlorophenyl)formimidoyl}phenoxy]propionate as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>C1COCC1>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C@@H:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[N:8]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(Br)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(Br)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of the compound of Example 49B (2.25 g, 6.14 mmol) in dry THF (25 mL) was treated with sodium hydride (295 mg of 60% in oil, 177 mg, 7.37 mmol) followed by stirring at room temperature for 1 h. The solution was then treated with SEM-Chloride (1.20 mL, 1.13 g, 6.76 mmol) followed by stirring at room temperature for 18 h. The mixture was quenched by addition of water and the mixture was diluted with ethyl acetate. The mixture was extracted with water and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge, eluting with 20-75% ethyl acetate in hexanes. These procedures afforded the product (2.24 g, 73%) as a heavy oil, which solidified after setting for several days. This mixture of both regioisomeric SEM derivatives was not separated for use in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=O)[CH2:6][C:7](=O)[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:2].[NH2:22][NH2:23]>CCO>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[NH:23][N:22]=1)=[O:21])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCCO[Si](C)(C)C(C)(C)C
Solvent: CCO
Product: CCOC(=O)c1cc(CCCO[Si](C)(C)C(C)(C)C)[nH]n1
Yield: 2.1 %

Procedure:
A solution of 7-(tert-butyl-dimethyl-silanyloxy)-2,4-dioxo-heptanoic acid ethyl ester (1.627 g, 51.4 mmol) and hydrazine (17 mL, 55 mmol) in EtOH was heated at reflux for 6 h. The reaction was concentrated in vacuo. Purification by flash chromatography (6:4 hexanes:EtOAc) provided the title compound (333 mg). 1H NMR (400 MHz, CDCl3) δ 6.64 (s, 1H), 4.37 (q, 2H), 3.67 (t, 2H), 2.85 (t, 2H), 1.88 (m, 2H), 1.38 (t, 3H), 0.88 (s, 9H), 0.05 (s, 6H); MS 313 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:12][C:13]([F:16])([F:15])[F:14])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: NCCCCO
Product: O=S(=O)(NCCCCO)c1ccc(Br)cc1OC(F)(F)F

Procedure:
Using a method analogous to that described in Example 1, 4-bromo-2-trifluoromethoxyphenyl sulphonyl chloride was reacted with 4-aminobutanol, and the title compound obtained as a white solid after recrystallisation from ether/petrol. δC (CDCl3, 62.9 MHz): 26.5, 29.4, 43.3, 62.1, 127.3, 131.7, 131.7, 133.1, 135.4 and 137.9.
Reaction SMILES: CC(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2([CH:24]([CH3:26])[CH3:25])[CH2:21][C:20]([OH:22])=[CH:19][C:18](=[O:23])[O:17]2)=[CH:10][CH:9]=1)(C)C.C([O-])([O-])=O.[K+].[K+].[C:34]([C:38]1[CH:43]=[C:42]([CH2:44][OH:45])[C:41]([CH3:46])=[CH:40][C:39]=1[S:47]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:37])([CH3:36])[CH3:35].O>C(Cl)Cl.CC(O)=O.CCOC(C)=O>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]2([CH:24]([CH3:25])[CH3:26])[O:17][C:18](=[O:23])[C:19]([S:47][C:39]3[CH:40]=[C:41]([CH3:46])[C:42]([CH2:44][OH:45])=[CH:43][C:38]=3[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:20]([OH:22])[CH2:21]2)=[CH:12][CH:13]=1
Reactant: CC(C)C1(CCc2ccc(NC(=O)OC(C)(C)C)cc2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(N)cc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of {4-[2-(4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-phenyl}-carbamic acid 1,1-dimethylethyl ester (0.26 g, 0.69 mmol; prepared in Example QQQQQ) in CH2Cl2 was cooled to 5° C. and treated with a steady stream of gaseous HCI for 5 minutes. The solution was concentrated, and the residue was triturated with ether. The crude material was dissolved in DMF (5 mL) and treated with 1.0 g (7.0 mmol) of K2CO3 and 0.25 g (0.69 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF). The reaction mixture was stirred overnight at room temperature. Water (30 mL) and EtOAc (50 mL) were added; the mixture was cooled in an ice bath and acidified to pH 5.5 with AcOH. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated. The product was chromatographed on silica gel, eluting with CHCl3 :MeOH (90:10) to give the title compound, m.p. 139-141° C. 1H NMR (DMSO-d6) δ 0.88 (m, 6 H), 1.42 (s, 9 H), 1.87 (m, 5 H), 2.14 (m, 1 H), 2.40 (m, partially obscured by DMSO, 2 H), 2.66 (d of ABXq, 1 H), 2.88 (d, of ABXq, 1 H), 4.30 (s, 2 H), 4.90 (br s, 1 H), 6.43 (d, 2 H), 6.64 (s, 1 H), 6.77 (d, 2 H), 7.20 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]=[O:22]>CN(C)C=O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][NH:20][C:21]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[CH:10][C:11]([S:14](=[O:15])(=[O:16])[N:17]([CH3:18])[CH3:19])=[CH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1)=[O:22])[CH3:28]
Reactant: CCOC(=O)CN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(S(=O)(=O)N(C)C)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N(C)C)cc2)s1

Procedure:
4-(2-Amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide (Example 24a) (0.083 g, 0.28 mmol) and ethyl isocyanatoacetate (0.05 ml, 0.34 mmol) are stirred in dimethylformamide at 100° C. for 3 hours. The mixture is then partitioned between 1M aqueous hydrochloric acid and ethyl acetate. The organic extract is washed with brine, dried over MgSO4 and the solvent removed in vacuo. Purification by preparative HPLC affords the title compound. MH+ (TOF, MS, ES+): 441.4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.Cl[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: ClCc1cccnc1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCc1cccnc1
Yield: 18 %

Procedure:
Using an analogous procedure to that described in Example 32, 4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxyquinazoline was reacted with 3-chloromethylpyridine, hydrochloride salt to give 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-pyridylmethoxy)-quinazoline in 18% yield;
Reaction SMILES: [S:1](=[O:13])(=[O:12])([O:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11])[NH2:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([C:39](O)=[O:40])[N:32]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([C:39]([NH:2][S:1](=[O:13])(=[O:12])[O:3][C:4]2[C:5]([Cl:11])=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:10])=[O:40])[N:32]=1
Reactant: COc1cc(OC)nc(C(=O)O)n1
Reactant: NS(=O)(=O)Oc1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(OC)nc(C(=O)NS(=O)(=O)Oc2c(Cl)cccc2Cl)n1
Reaction time: 3 h

Procedure:
2.4 g of 2,6-dichlorophenyl sulfamate are added in portions at 0° C. to 2° C. to a mixture of 2.3 g of dicyclohexylcarbodiimide, 120 mg of 4-dimethylaminopyridine and 2.2 g of 4,6-dimethoxypyrimidine-2-carboxylic acid in 80 ml of absolute dichloromethane, and stirring is continued for 0.5 hour at 0° C. and 3 hours at room temperature. The mixture is filtered off with suction, the organic phase is washed with 100 ml of 1 N hydrochloric acid and then with water and dried over sodium sulfate. The solvent is distilled off, and the residue is recrystallized from diisopropyl ether. This gives 3.2 g of 2,6-dichlorophenyl N-[(4,6-dimethoxypyrimidin-2-yl)carbonyl]sulfamate of melting point 136°-139° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[C:4]([CH2:11][CH3:12])[CH:3]=1.C[CH2:14][N:15](CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:15][CH3:14])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: CCc1cc(Br)ccc1CCO
Solvent: ClCCl
Product: CCc1cc(Br)ccc1CCNC
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.7 %

Procedure:
Mesyl anhydride (430 mg, 2.46 mmol) was added portionwise to a solution of 36B (470 mg, 2.05 mmol) in CH2Cl2 (10 mL) and Et3N (0.57 mL, 4.1 mmol) at 0° C. After stirring for 15 h at ambient temperature, the mixture was diluted with CH2Cl2 (80 mL), washed with 1.0 M HCl, NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo. The crude mesylate was dissolved in EtOAc (20 mL) and methyl amine (33%, 5 mL) and heated in a pressure tube for 2 h. The reaction mixture was concentrated in vacuo to afford 36C (500 mg, 99%) as a yellow oil. MS (ESI) m/z 242.0/244.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:22]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:22])[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrBr
Reactant: CCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
6-Amino-9-benzyl-2-propylaminopurine (87 mg, 0.31 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (95 mg, yield 85%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.N1C=CC=CC=1.[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[N:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:26])[N:7]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1-n1nc(Br)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
0.5 g (2.43 mmol) of intermediate 2a are placed in the presence of 0.4 mL (4.85 mmol) of pyridine, 0.66 g (4.85 mmol) of o-tolyl boronic acid, 0.66 g (3.64 mmol) of copper acetate in 50 mL of CH2Cl2. The reaction medium is stirred for 24 h at room temperature and then filtered on celite. The filtrate is washed with water, and then with 0.01N hydrochloric acid. After drying on MgSO4, the organic phase is dry concentrated. After washing the obtained residue with diethyl ether, 0.54 g of a white solid corresponding to the compound 41 are isolated (yield 75%)