Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:33]3[CH:32]=[CH:31][C:30]([CH2:29][N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:35][CH:34]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(CN4CCN(C)CC4)cc3)c3cc(Br)cnc32)cc1

Procedure:
5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.419 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine (160 mg, 0.503 mmol) and dichlorobis(triphenylphosphine)palladium (II) (30 mg, 0.042 mmol) were combined in CH3CN (5 ml) and 1 M Na2CO3 (5 ml) and stirred at 60° C. for 2 hrs. EtOAc was added and the organic phase was washed with water, dried and evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:4][CH:3]=1.[OH:25]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[O:25])=[CH:4][CH:3]=1
Reactant: O=c1ccc2cc(OCCCCSc3ccc(Br)cc3)ccc2[nH]1
Reactant: OO
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc(Br)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-bromophenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][CH:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C[C@@H]1C[C@H](C)CC[C@@H]1C1C=CC=CN=1>N1C=CC=CC=1>[CH3:1][C@@H:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C@H:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC1=CC(C)C(c2ccccn2)CC1
Agent: C[C@@H]1CC[C@H](c2ccccn2)[C@H](C)C1
Solvent: c1ccncc1
Product: CC1=C[C@@H](C)[C@H](c2ccccn2)CC1

Procedure:
The relative amounts of each individual isomer is dependent on the precise conditions used for their formation and whether the hydrogenation reaction is carried out on the mixture of isomers of 2-(2,4-dimethylcyclohex-3-en-1-yl)pyridine or an individual isomer thereof. For example, it has been found that when the hydrogenation reaction is performed on 2-[(1R,2S)-2,4-dimethylcyclohex-3-en-1-yl]pyridine, the major product formed in the resulting mixture of isomers of the pyridine of the invention is 2-[(1S,2R,4R)-2,4-dimethylcyclohexyl]pyridine. By contrast, hydrogenation of 2-[(1R,2R)-2,4-dimethylcyclohex-3-en-1-yl]pyridine conveniently gives a mixture of the 2-[(1R,2R,4R)-2,4-dimethylcyclohexyl]pyridine and 2-[(1R,2R,4S)-2,4-dimethylcyclohexyl]pyridine isomers as the major reaction product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:31][CH3:32].CCOC(C)=O>CN1CCCC1=O.[Cl-].[Na+].O>[CH2:31]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:14](=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]1=[O:22])[CH3:32]
Reactant: CCI
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
Combine 2-(2-(5-hydroxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione (900 mg, 2.9 mmol), cesium carbonate (960 mg, 2.9 mmol) and 1-iodoethane (920 mg, 5.9 mmol) in N-methylpyrrolidinone (5 mL) and stir at ambient temperature for 4 hours, pour into brine and extract twice with EtOAc. Wash the combined extracts three times with brine, dry over MgSO4, and concentrate under vacuum to give an oil. Chromatograph the oil on silica gel eluting with 20% EtOAc in hexanes to give the title compound as a white solid: ISMS 335 (M+1); Analysis for C20H18N2O3: calcd: C, 71.84; H, 5.43; N, 8.38; found: C, 71.97; H, 5.47; N, 8.36.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([CH3:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:21]I>CN(C=O)C.O>[CH3:21][N:6]([CH2:5][C:4]([CH3:3])([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)N1CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(C)(C)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 120 h
Yield: 119.5 %

Procedure:
To a suspension of 60% NaH in mineral oil (238 mg, 5.96 mmol) in dry DMF (5 mL) was added dropwise a solution of tert-butyl 2-methyl-2-morpholinopropylcarbamate (770 mg, 2.98 mmol) in dry DMF (5 mL). After 30 min MeI (0.928 mL, 14.9 mmol) was added dropwise. The mixture was stirred at room temperature for 5 d, poured in H2O and extracted with Et2O (30 mL). The organic layer was dried (Na2SO4) and concentrated to yield the desired crude product (970 mg,) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Si:19]([O:26][CH2:27][CH2:28]Br)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:28][CH2:27][O:26][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[C:6]([Cl:11])[CH:5]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCO[Si](C)(C)C(C)(C)C)c(Cl)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 2.50 g of 3-chloro-4-hydroxybenzoic acid methyl ester in 25 ml of DMF, 2.78 g of potassium carbonate and 4.31 ml of 2-(tert-butyldimethylsilyloxy)ethylbromide were added, and the mixture was stirred at 50° C. for 15 hours. The solvent was evaporated, EtOAc was added to the residue, and the organic layer was washed with water and brine and dried over sodium sulfate. After the evaporation of the solvent, the obtained residue was purified by silica gel column chromatography (eluent: hexane-EtOAc=10:1˜5:1) to obtain 4.88 g of 4-[2-(tert-butyldimethylsilyloxy)ethoxy]-3-chlorobenzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.P(Cl)(Cl)([Cl:19])=O>>[NH2:1][C:2]1[N:3]=[C:4]([Cl:19])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Temperature: 70 °C
Yield: 43.7 %

Procedure:
Following the method of Hull (J. Chem. Soc. 1957, 4845), a stirred suspension of 25.2 g (119 mmol) 2-amino-6-oxo-4-phenyl-1,6-dihydro-pyrimidine-5-carbonitrile in 27.1 ml (297 mmol) phosphorus oxychloride was heated at reflux for 2 h. The reaction mixture was then cooled to about 70° C. and poured cautiously onto rapidly stirred ice-water such that the temperature remained around 10° C. The resulting crystals were collected by filtration to afford 12.0 g (44%) 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile as a light beige crystalline solid. This material was pure enough to be used in subsequent steps, however analytically pure material was obtained by chromatography (ethyl acetate/hexane 1/1) which afforded 5.9 g (22%) 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 232 (M{37Cl}+, 26), 230 (M{35Cl}+, 80), 190 ([M—Cl]+, 100), 153 (38).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:27])[N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:27][C:4]1[N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[C:9]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[N:8]=2)[CH:6]=[C:2]([C:32]2[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=2)[N:3]=1
Reactant: Cc1nc(Br)cn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1nc(-c2ccc(N)nc2)cn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 2-(4-bromo-2-methyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.60) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a yellow solid (0.11 g, 47%). MS (ISP) 465.3 [(M+H)+]; mp 285° C.
Reaction SMILES: S(Cl)([O:4][CH2:5][Cl:6])(=O)=O.[N+:8]([C:11]1[CH:34]=[CH:33][C:14]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])=[O:22])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)(O)[O-].[Na+].O>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[N+:8]([C:11]1[CH:34]=[CH:33][C:14]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([O:4][CH2:5][Cl:6])=[O:27])=[O:22])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)Nc1ccccc1C(=O)O
Reactant: O=S(=O)(Cl)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)Nc1ccccc1C(=O)OCCl

Procedure:
A solution of chloromethyl chlorosulphate (275 mg) in dichloromethane (1 ml) was added, dropwise over 1/2 minute, to a stirred mixture of 2-[N-(4-nitrobenzyloxycarbonyl)glycylamino]benzoic acid (500 mg), sodium bicarbonate (450 mg), tetrabutylammonium hydrogensulphate (70 mg), dichloromethane (10 ml), and water (10 ml). After stirring at room temperature for 1h the solid which had precipitated was redissolved by addition of dichloromethane (50 ml). The organic layer was separated and was washed with dilute brine (2×10 ml), dried (MgSO4), and evaporated to give the crude product, chloromethyl 2-[N-(4-nitrobenzyloxycarbonyl)glycylamino]benzoate, as a solid. Without further purification, the crude chloromethyl ester was dissolved in dry acetone (50 ml) and was treated with sodium iodide (2.11 g). After stirring at room temperature for 24 h the mixture was evaporated. The residue was dissolved in ethyl acetate (50 ml) and was washed with water (3×10 ml), dried (MgSO4), and evaporated to give the crude product, iodomethyl 2 -[N-(4-nitrobenzyloxycarbonyl)glycylamino]benzoate, as a solid. Without futher purification, the crude iodomethyl ester was dissolved in dry dimethylformamide (10 ml) and treated with sodium 6β-[2-(2-aminothiazol-4-yl)-(Z)-2-(cyclohexyloxyimino)a cetamido]penicillanate (688 mg). After stirring at room temperature for 1 h the mixture was diluted with ethyl acetate (50 ml) and was washed with 5% citric acid (10 ml), brine (10 ml), saturated NaHCO3 (10 ml), and brine (3×10 ml). The dried (MgSO4) organic layer was evaporated and the residue chromatographed on silica gel eluting with methyl acetate/hexane mixtures to give the title compound as an amorphous solid (550 mg), νmax (CHCl3) 3600-3100, 1790, 1730 sh., and 1695 cm-1 ; δH [(CD3)2CO] 1.20-2.00 (16H, m), 4.03 (2H, d, J 6.3 Hz, collapses to s on exch. D2O), 4.05-4.25 (1H, m), 4.50 (1H, s), 5.36 (2H, s), 5.68 (1H, d, J 4.2 Hz), 5.7.9 (1H, dd, J 8.3 and 4.2 Hz, collapses to d, J 4.2 Hz on exch. D2O), 6.12 and 6.17 (2H, AB q, J 6.0 Hz), 6.55 (2H, s, exch. D2O), 6.83 (1H, s), 7.18-7.40 (2H, m, IH exch. D2O), 7.65-7.72 (1H, m), 7.76 (2H, d, J 8.4 Hz), 8.07 (1H, d, J 8.0 Hz), 8.12 (1H, d, J 8.3 Hz, exch. D2O), 8.27 (2H, d, J 8.4 Hz), 8.76 (1H, d, J 8.4 Hz), and 11.27 (1H, s, exch. D2O).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[C:41]([O:49][CH3:50])=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:39][C:40]1[C:41]([O:49][CH3:50])=[C:42]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[CH:44][CH:45]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1c(F)cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1c(F)cccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 72.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (3-fluoro-2-methoxyphenyl)boronic acid (69 mg, 0.4 mmol), sodium carbonate (43 mg, 0.4 mmols) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane-ethyl acetate) to give 79 mg (73% yield) of the title compound. Purity 100%.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[C:23]([CH3:24])=[N:22][N:21]=[C:20]2[CH2:25]O)=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10])([O-:3])=[O:2].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[C:23]([CH3:24])=[N:22][N:21]=[C:20]2[CH2:25][N:31]2[C:30](=[O:32])[C:29]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]3[C:27]2=[O:37])=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10])([O-:3])=[O:2]
Reactant: Cc1nnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, a mixture of 5-nitro-2'-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran was treated with diethyl azodicarboxylate to give 5-nitro-2'-chloro-2-[3-(phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][C:39]#[N:40].[F-].[Cs+]>CS(C)=O.O>[C:37]([CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:14])([CH3:15])[CH3:16])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=3[F:33])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1)#[N:36]
Reactant: N#CCCN
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NCCC#N)n2)s1
Yield: 13.2 %

Procedure:
A 5 mL microwave tube was charged with N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (250 mg, 0.464 mmol) and 3-aminopropionitrile (163 mg, 2.319 mmol) and CsF (70.5 mg, 0.464 mmol) in dimethyl sulfoxide (3.00 mL) to give a yellow solution at rt under nitrogen. The sealed reaction mixture was microwaved at 90° C. for 30 min. For second time, the sealed reaction mixture was microwaved at 100° C. for 1 h. The reaction was diluted with water and a white solid formed. The reaction was filtered and washed with water. The crude product was chromatographed on silica gel column and eluted with CH2Cl2 with chloroform/methanol/ammonium hydroxide (90:9:1) (5% to 100%) and collected fractions. Water and DCM were added to solid and take to a pH=6 and extracted with DCM (3×). The CH2Cl2 layers were dried over Na2SO4, filtered, and concentrated to obtain N-{3-[5-{2-[(2-cyanoethyl)amino]-4-pyrimidinyl}-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (35 mg, 12%). MS (ESI): 573 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21]COC)=[C:5]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][CH2:14]3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>CO>[OH:21][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[NH:15][CH2:14]2
Reactant: COCOc1c(-c2ccc3c(c2)CNC3=O)ccc(OC)c1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2ccc3c(c2)CNC3=O)c(O)c1OC
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 5-(3,4-dimethoxy-2-(methoxymethoxy)phenyl)isoindolin-1-one (600 g, 1.81 mmol) in methanol (20 mL) at 0° C., was added concentrated hydrochloride acid (1 mL) and the resultant reaction mixture was stirred at 50° C. for 15 min. The reaction mixture was concentrated under reduced pressure and basified with aq sodium bicarbonate solution extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the resulting residue by washings with ether afforded the title compound as a solid.
Reaction SMILES: Cl.N[C:3]1[C:4]2[C:5](=[N:15][N:16]([CH3:18])[CH:17]=2)[NH:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[N:9]=1.C(=O)([O-])[O-:20].[K+].[K+]>C(O)C.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:7]2[NH:6][C:5]3=[N:15][N:16]([CH3:18])[CH:17]=[C:4]3[C:3](=[O:20])[NH:9][C:8]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc2c(n1)Nc1ccc(Cl)cc1N=C2N
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cn1cc2c(n1)Nc1ccc(Cl)cc1NC2=O

Procedure:
4-Amino-7-chloro-2,10-dihydro-2-methylpyrazolo[3,4-b][1,5]benzodiazepine hydrochloride (11.3 g) and potassium carbonate (16.8 g) were heated under reflux in a mixture of ethanol (200 ml) and water (20 ml) for 48 hours. Water (300 ml) was added and the solution cooled. The precipitate was crystallised from acetic acid to give the title compound m.p.>260° C.
Reaction SMILES: [CH2:1]([CH:8]([CH2:19][CH2:20][C:21]#[N:22])[CH2:9][C:10]([CH2:17][CH3:18])([C:14]([O-:16])=[O:15])[C:11]([O-:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:23]>CCO.[OH-].[OH-].[Pd+2]>[ClH:23].[CH2:1]([CH:8]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:9][C:10]([CH2:17][CH3:18])([C:11]([OH:13])=[O:12])[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC(CCC#N)Cc1ccccc1)(C(=O)[O-])C(=O)[O-]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CCC(CC(CCCN)Cc1ccccc1)(C(=O)O)C(=O)O
Reaction time: 22 h
Yield: 70 %

Procedure:
The crude benzyl-(2-cyanoethyl)-diethylmalonate from above was dissolved in EtOH (1750 mL) and 5M aqueous HCl (250 mL, 1.25 mol). Pearlman's catalyst containing 20% palladium hydroxide (40 g) was added, and the mixture was hydrogenated in a 1 gallon Hastalloy vessel on a Parr shaker at 50° C. under 40 psi H2 for 22 h. The slurry was filtered through a pad of solkafloc (100 g), and the pad was washed with EtOH (2000 mL). The filtrates were evaporated (25" Hg, bath at 100° C.), and the oily residue was dissolved in water (3500 mL). The aqueous solution was washed with 2:1 by vol hexane-MTBE (1000 mL), and the organic phase was extracted with water (500 mL). The combined aqueous phases were extracted with CH2Cl2 (3×500 mL). The organic extracts were dried over Na2SO4 and evaporated (100° C. at 10 Torr) to an oily residue which crystallized upon cooling to afford benzyl-(3-aminopropyl)-diethylmalonate HCl salt (240.0 g, 70%). 1H NMR (250 MHz, CD3OD) δ 7.97 (br s, 1 H), 7.28-7.10 (m, 5 H), 4.19 (q,J=5.2 Hz, 4 H), 3.23 (s, 2 H), 3.01 (br s, 2 H), 1.90-1.73 (br m, 4 H), 1.23 (t,J=5.2 Hz, 4 H).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:23])[C:19]([O:21][CH3:22])=[O:20].C(O)(C)C>CC(C)=O.O>[Br:14][CH2:15][CH2:16][CH2:17][C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(O)CCCBr
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C(=O)CCCBr
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
Jones' reagent (CrO3 :9.58 g, H2SO4 : 8.47 ml, H2O:36.8 ml) was added to a magnetically stirred solution of Part (3) compound (12.53 g, 59.3 mmole) in acetone (150 ml) at room temperature. The addition was controlled to maintain the temperature below 35° C. After the completion of the addition, the reaction was stirred at room temperature for 45 minutes. Isopropyl alcohol (30 ml) was added dropwise and stirred for 30 minutes. The reaction was then diluted with H2O (500 ml) and the products were extracted with CH2Cl2 (1 1.). The CH2Cl2 layer was washed with brine (100 ml×3) and dried over MgSO4. Filtration and evaporation of solvents gave the title compound (11.4 g, 54.5 mmole, 92%) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Cl>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([Cl:26])[CH:28]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: ClCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCc2cccc(Cl)c2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.2 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 3-chlorobenzyl chloride (0.09 ml, 0.7 mmol) in order. The mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (92 mg, yield 47%).