Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:5]([C:7]([O:9]CC)=O)[N:6]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22].Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CO.O>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:5]([C:7](=[O:9])[NH:22][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])[N:6]=1
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1nc(N)sc1-c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: CN(C)CCNC(=O)c1nc(N)sc1-c1ccccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a solution of ethyl 2-amino-5-(2-pyridyl)-4-thiazolecarboxylate (2.49 g) in ethyleneglycol (10 ml) were added N,N-dimethylethylenediamine (1.76 g) and 36% hydrochloric acid (0.5 ml) and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was poured into water (50 ml), adjusted to pH 8 with aqueous potassium carbonate and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from acetonitrile to give 2-amino-4-[N-[2-(N,N-dimethylamino)ethyl]carbamoyl]-5-(2-pyridyl)thiazole (2.0 g).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[N:25]#[C:26]Br.O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][C:26]([NH2:25])=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH2:23][CH3:24]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(N)=NC2=N1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A partial solution of 4,5-diamino-2-(2-propoxyphenyl)-pyrimidin-6-one sulphate (1.1 g), cyanogen bromide (0.33 g), and sodium acetate trihydrate (0.42 g) in 50% aqueous ethanol (44 ml) was stirred at room temperature for 2 hours then allowed to stand overnight. The stirred mixture was then heated in a water bath (temperature 65° C.) for 3 hours, extra cyanogen bromide (0.05 g) added, and the mixture heated for a further 2 hours. The suspension was subjected to partial evaporation under reduced pressure then ammonium hydroxide was added to pH 5. The crude product was collected by filtration and recrystallised from acetonitrile to give the pure title compound, 0.6 g, m.p. 322°-335° C. dec. (after melting ca. 200° C.).
Reaction SMILES: [Br:1]Br.[CH:3]1([O:9]/[N:10]=[C:11](/[C:17](=[O:19])[CH3:18])\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH2:15]([O:14][C:12](=[O:13])/[C:11](=[N:10]\[O:9][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)/[C:17](=[O:19])[CH2:18][Br:1])[CH3:16]
Reactant: BrBr
Reactant: CCOC(=O)/C(=N\OC1CCCCC1)C(C)=O
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)/C(=N\OC1CCCCC1)C(=O)CBr
Reaction time: 2 h

Procedure:
A solution of bromine (4.5 ml) in carbon tetrachloride (50 ml) was added dropwise to a mixture of ethyl (Z)-2-(cyclohexyloxyimino)-3-oxobutyrate (20.0 g), hydrogen bromide in acetic acid (45%, 1.0 ml) and carbon tetrachloride (150 ml) over 1.5 h, at room temperature. The mixture was stirred for 2 h, then the solvent removed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Clc1ccncc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ncccc1NCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccc(Cl)cn1)c1ncccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A pressure tube (Aldrich) was charged with N-(5-chloropyridin-2-yl)-3-[(piperidin-4-ylmethyl)amino]pyridine-2-carboxamide (500 mg, 1.45 mmol), 4-chloropyridine hydrochloride (435 mg, 2.90 mmol), triethylamine (293 mg, 2.90 mmol) and EtOH (5 mL), sealed, and placed in a 110° C. bath. After 16 h, the mixture was cooled, concentrated, and the residue purified by column chromatography (SiO2: 5 to 7.5% methanol:methylene chloride) yielding 100 mg (16%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[I-].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33]CN(C)C)=[CH:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:33][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:23]([CH3:22])[CH:24]=2)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: Cc1cccc2c1c(CCN(C)C)cn2C
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Yield: 68 %

Procedure:
To a solution of (S)-3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (700 mg, 2.5 mmol) in DMF (50 mL) were added (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-amine iodide salt (1.3 g, 3.8 mmol) and K2CO3 (700 mg, 5.1 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 4 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product (S)-3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid ethyl ester (737 mg, 67%) as a yellow foam.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([CH2:19][NH2:20])[S:17][CH:18]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]N)=[CH:26][CH:25]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([CH2:19][NH:20][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=3)[S:17][CH:18]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NCCc1cccc(Cl)c1)c1csc(CNCc2ccc(OC(F)(F)F)cc2)n1

Procedure:
2-Aminomethyl-thiazole-4-carboxylic acid [2-(3-chlorophenyl)ethyl]amide hydrochloride (0.10 g, 0.3 mmol) and 4-(trifluoromethoxy)benzyl amine (0.06 g, 0.3 mmol) were mixed with sodium cyanoborohydride (1 M in THF, 0.6 mL), ethanol (5 mL), and a catalytic amount of acetic acid (2 drops). The mixture was heated at reflux for 24 hours. The mixture was concentrated in vacuo, diluted with water and extracted with methylene chloride. The combined organic layers were washed with sodium carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude amine was purified by flash chromatography (EtOAc/hexane), treated with HCl in dioxane, and concentrated in vacuo to afford the title compound: 1H NMR (400 MHz, d6-DMSO): 9.83 (br s, 2H), 8.43 (t, 1H), 8.32 (s, 1H), 7.66 (d, 2H), 7.44 (d, 2H), 7.25 (m, 4H), 4.58 (s, 2H), 4.37 (s, 2H), 3.53 (m, 2H), 2.86 (t, 2H); MS (ESI-LCMS) for C21H20ClF3N3O2S: 470 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[Si:14]([O:1][CH:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CC[C@@H](c2ccc(F)cc2)O1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CC[C@@H](c2ccc(F)cc2)O1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
(5S)-2-Hydroxy-5-(4-fluorophenyl) tetrahydrofuran (211, 620 mg, 3.5 mmol), t-butyldimethylsilyl chloride (700 mg, 5.25 mmol) and imidazole (595 mg, 8.75 mmol) were dissolved in 2 mL of dry DMF. The resulting solution was stirred under dry argon overnight, poured into 200 mL of water, and extracted with a 2:1-mixture of ethyl acetate and hexane (3×100 mL). The combined organic extracts were washed with water (4×200 mL) and brine (100 mL), dried over sodium sulfate and the solvent was removed in vacuo to yield 1 g (96%) of (5S)-2-(t-Butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (212, mixture of cis and trains isomers) as a colorless oil, which did not need further purification. 1H-NMR (CDCl3) δ 7.40-7.50(2H, m, minor isomer), 7.25-7.35 (2H, m, major isomer), 7.00-7.10 (2H, m, both major and minor isomers), 5.71-5.75 (1H, m, major isomer), 5.59-5.62 (1H, m, minor isomer), 5.12-5.20 (1H, m, major isomer), 4.90-4.98 (1H, m, minor isomer), 2.40-2.55 (1H, m, both major and minor isomers), 2.05-2.17 (1H, m, both major and minor isomers), 1.87-2.00 (1H, m, both major and minor isomers), 1.67-1.70 (1H, m, both major and minor isomers), 0.92 (s, 9H, both major and minor isomers), 0.16 (s, 6H, both major and minor isomers).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:26]=[CH:25][C:19]3[O:20][C:21]([F:24])([F:23])[O:22][C:18]=3[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.FC1(F)OC2C=CC(NCC3CCCCC3)=CC=2O1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:26]=[CH:25][C:19]3[O:20][C:21]([F:23])([F:24])[O:22][C:18]=3[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc3c(c2)OC(F)(F)O3)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: FC1(F)Oc2ccc(NCC3CCCCC3)cc2O1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc3c(c2)OC(F)(F)O3)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,2-difluorobenzo[1,3]dioxol-5-yl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)ureido]-thiazol-4-yl}-acetic acid, using 2,2-difluoro-benzo[1,3]dioxol-5-yl-cyclohexylmethylamine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=2[CH3:33])=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:30]2[NH:31][C:32]([CH3:33])=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:36])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.5 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (38 mg, 28%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([Cl:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:20]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[Cl:19])[CH2:23][CH2:22][CH2:21]1
Reactant: C1CNC1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(OCc2ccccc2)cc1Cl)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(benzyloxy)-2-chlorophenyl]acetic acid (0.52 g, 1.88 mmol) was dissolved in DMF (1 ml) and azetidine (0.161 g, 2.82 mmol), DIEA (0.99 ml, 5.64 mmol), and HATU (1.43 g, 3.76 mmol) added. The mixture was stirred at RT for 1 hr. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 316 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16](OCC)=[O:17])=[CH:10][CH:9]=2)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>C(OCC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH2:16][OH:17])=[CH:12][CH:13]=2)[CH:2]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC/C=C/c1ccc(Cc2cccnc2)cc1
Reaction time: 1 h
Yield: 52 %

Procedure:
In 200 ml of anhydrous diethyl ether was dissolved 24.0 g of ethyl (E)-3-[4-(pyridin-3-ylmethyl)phenyl]acrylate, and thereto was added in small portions 2.4 g of lithium aluminum hydride with ice-cooling over one hour. The resulting mixture was subjected to reaction for one hour with ice-cooling and then for a further one hour at room temperature, after which 91 ml of hydrous tetrahyrofuran (water content: 10% by volume) was added in small portions. Insolubles were removed by filtration and the solvent was removed by distillation under reduced pressure. The resulting oily product was dissolved in 200 ml of chloroform, and 40 ml of water was added to the resulting solution, after which the pH thereof was adjusted to 7 with 2N hydrochloric acid. The organic layer was separated, washed successively with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (1:1 by volume)] to obtain 10.5 g (yield 52.0%) of colorless, oily (E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyl alcohol. This was crystallized from a mixed solvent of chloroform and diethyl ether to obtain colorless needle crystals having a melting point of 81°-82° C.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27]>CC(C)=O>[CH2:26]([N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:18]=[CH:17][C:11]=2[CH2:12][CH2:13]1)[CH3:27]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=[N+]([O-])O
Product: CCN1CCc2ccc([N+](=O)[O-])cc2CC1
Reaction time: 2 h

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitrate salt (1.03 g/4 mmol) was suspended in acetone (10 mL). Potassium carbonate and iodoethane were added sequentially and the suspension was heated to reflux with vigorous stirring for 2 hours. The mixture was then filtered through a pad of celite (rinsing with acetone) and the filtrate concentrated onto silica gel. 3-Ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine was isolated by column chromatography on silica gel (eluting with 0→10% methanol/methylene chloride) as a yellow/orange oil (600 mg/72%). 1H NMR (400 MHz, CDCl3) δ 7.98 (m, 2H), 7.28 (m, 1H), 3.15 (s, 4H), 2.91 (s, 4H), 2.79 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])=[O:9].C(N(CC)CC)C.[C:27](=[O:35])([O:32][CH2:33][CH3:34])[O:28][CH:29](Cl)[CH3:30].[I-].[Na+]>CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH:29]([O:28][C:27]([O:32][CH2:33][CH3:34])=[O:35])[CH3:30])=[O:14])=[O:9]
Reactant: O=C(C=Cc1cccs1)Nc1ccccc1C(=O)O
Reactant: CCOC(=O)OC(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)OC(C)OC(=O)c1ccccc1NC(=O)C=Cc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
A mixture of 2-[3-(2-thienyl)acrylamido]benzoic acid (273 mg, 1 mmol) and triethylamine (0.2 ml, 1.4 mmol) in dry acetone (10 ml) was stirred at room temperature for 30 minutes. To the solution, 1-chloroethyl ethyl carbonate (214 mg, 1.4 mmol) and sodium iodide (210 mg, 1.4 mmol) were added under ice cooling, and the mixture was heated under reflux for 19 hours. The reaction mixture was filtered by suction and the solvent was removed from the filtrate. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate, then with saturated aqueous sodium chloride, and dried over magnesium sulfate. After removing the solvent, the residue was purified by silica gel column chromatography (developing solvent:benzene:ether=49:1). The second eluate was collected. After removing the solvent, the resulted oily product was crystallized with isopropyl ether to give the desired compound (98 mg, yield, 25%). m.p., 154°-156° C. (white crystals, recrystallized from methanol/tetrahydrofuran/water).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CS(O[C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]1)(=O)=O>CN(C=O)C>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([C@H:35]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34]3)[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:18]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: Nc1ncnc2[nH]nc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc([N+](=O)[O-])cc3)c3c(N)ncnc32)C1
Reaction time: 6 h
Yield: 51.8 %

Procedure:
Synthesis of(S)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate. A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.62 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 6 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford (S)-tert-butyl 3-(4-amino-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.43 g, 52% yield). ESI-MS m/z [M+H]+ found 426.7, calculated 426.2.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:20]([N:39]1[CH:43]=[C:42]([CH2:44][CH2:45][CH2:46][C:47](O)=[O:48])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([NH:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:47](=[O:48])[CH2:46][CH2:45][CH2:44][C:42]2[N:41]=[CH:40][N:39]([C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:43]=2)=[CH:9][CH:8]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Reactant: O=C(O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C(=O)CCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6,95 g of N-tert-butyl-p-bromobenzamide is dissolved in 175 ml of tetrahydrofuran at -70° under nitrogen and 20.1 ml of n-butyllithium (2.7M) is added dropwise. After 30 min, a solution of 5.35 g of 4-(1-trityl-4-imidazolyl)-butanoic acid in 10 ml of tetrahydrofuran is added slowly. The reaction mixture is allowed to warm slowly to room temperature and 20 ml of an aqueous ammonium chloride solution is added. The organic layer is separated, dried over sodium sulfate and evaporated to yield 1-(p-N-tert-butylaminocarbonylphenyl)-4-(1-trityl-4-imidazolyl)-1-butanone
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/[C:25](C)=[O:26])=N\O.COC1C=CC(C=O)=CC=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:26][CH3:25])=[CH:16][CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: COc1ccc(C=O)cc1
Product: COc1ccc(-c2nc(CI)c(C)o2)cc1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 4-methoxybenzaldehyde gave 4-iodomethyl-2-(4-methoxyphenyl)-5-methyloxazole.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>O.C(O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[C:9]([C:10]2[S:4][C:3]([NH2:5])=[N:2][N:1]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: NNC(N)=S
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CCO
Product: Nc1nnc(-c2cccc(Br)c2)s1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
To a solution of thiosemicarbazide (0.493 g, 5.40 mmol, 1.0 equiv) in 6 mL of water at 70° C. is added a solution of 3-bromobenzaldehyde (0.633 ml, 5.40 mmol, 1.0 equiv) in 4.5 mL ethanol. After the precipitate is formed, iron(III) chloride hexahydrate (2.92 g, 10.81 mmol, 2.0 equiv) in 6 mL water is added and the mixture is stirred for 2.5 h at 85° C. Upon completion, the mixture is allowed to cool to room temperature and the resulting precipitate is collected by filtration and taken up in 12 mL pyridine. Ice water is then added to the pyridine slurry. The mixture is cooled then filtered to give 5-(3-bromophenyl)-1,3,4-thiadiazol-2-amine (553 mg, 39.9% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85-7.88 (m, 1H), 7.67 (d, J=8.22 Hz, 1H), 7.53-7.59 (m, 1H), 7.45 (s, 2H), 7.36 (t, J=8.02 Hz, 1H);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2].Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([O:11][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Product: CCOC(=O)c1cc(OCCc2ccccc2)cc(Oc2ccc(C#N)cc2)c1
Yield: 69.5 %

Procedure:
Using 1.0 g (3.53 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester and (2-bromo-ethyl)-benzene (0.65 g, 3.53 mmol) and following the procedure of Example 42(b) afforded 0.95 g of the required product. 1H NMR (CDCl3): δ 1.35 (3H, t), 3.1 (2H, t), 4.2 (2H, t), 4.35 (2H, q), 6.78 (1H, t), 7.0 (2H, s), 7.22 (1H, m) 7.32 (5H, m), 7.42 (1H, m), 7.62 (2H, s).