Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[C:49]1([SH:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[C:49]1([S:55][C:2]2[CH:3]=[C:4]([CH:8]([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Sc1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Sc5ccccc5)c4)c3)ncnc21
Yield: 80.1 %

Procedure:
To the 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.130 g, 0.000248 mol) from Example 429 Step 2, in dry 1,4-dioxane (1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). The solution was degassed with nitrogen, followed by addition of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.007 g, 0.00001 mol), bis(dibenzylideneacetone)palladium(0) (0.0036 g, 0.0000062 mol), and benzenethiol (0.025 mL, 0.00025 mol). Again the solution was purged with nitrogen. The reaction mixture in a sealed tube was heated to reflux for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The crude product was triturated with hexane-ethyl acetate 9:1 to yield 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (110 mg, 80%). LC/MS (M+H)+: m/z=554.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(OCC)C>[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH:18]1[CH2:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9]
Reactant: CN1CCNCC1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Solvent: CCOCC
Product: CN1CCNCC1CCCc1cccc2c1C(=O)NC2=O

Procedure:
3-Bromopropylphthalimide (536 mg; 2.0 mmoles) and N-methylpiperazine (0.44 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([C:23]#N)=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[PH2]([O-])=[O:28].[Na+].C(O)(=O)C>[Ni].N1C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]=[O:28])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C#N)cc(OC)c21
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C=O)cc(OC)c21
Temperature: 60 °C
Reaction time: 6 h
Yield: 68.3 %

Procedure:
A mixture of 480 mg (1.37 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonitrile (example 32), 15 mg Raney-Nickel (in water), 967 mg (11.0 mmol) sodium hypophosphite (in 10 ml water), 10 ml acetic acid and 20 ml pyridine is stirred for 6 h at 60° C. The catalyst is filtered off and the filtrate is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 330 mg of the title compound as a white crystalline solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br-].[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=O>O1CCCC1.BrCCBr>[Br:25][C:21]1[CH:20]=[C:19]([C:17]([C:3]2[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)=[CH2:16])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: COc1ccc(Br)cc1C(F)(F)F
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=C(c1cccc(Br)c1)c1ccc(OC)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of magnesium turnings (565 mg, 23.5 mmol, 1.2 eq) in 5 mL of dry tetrahydrofuran, 0.1 mL of 1,2-dibromoethane were added followed by 5 mL of a tetrahydrofuran solution of 5-bromo-2-methoxy-benzotrifluoride (5.0 g, 19.6 mmol, 1.0 eq in 30 mL tetrahydrofuran). The resulting mixture was gently heated to initiate the reaction. The remaining solution of bromide was added dropwise at such a rate that the reaction could reflux without external heating. After the addition the reaction mixture was heated at reflux for further 2 hours. The mixture was cooled to 0° C. and a solution of 3-bromoacetophenone (3.9 g, 19.6 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added dropwise. After 2 hours LC-MS showed complete conversion to the desired product. 50 mL of water were added followed by 25 mL of 1 M aqueous HCl. The organic fraction was washed with brine, dried over sodium sulfate and concentrated to give a yellow oil. The oil was dissolved in toluene (50 mL) and a few crystals of p-toluenesulfonic acid were added. The solution was heated to reflux for 2 hours in a flask equipped with a Dean-Stark apparatus. After this time, the mixture was cooled to room temperature, concentrated and the crude purified by flash chromatography eluting with cyclohexane/ethyl acetate (100:0 to 95:5). 5.1 g of clean product was obtained as colorless liquid (yield: 73%).
Reaction SMILES: NC1C=CC2N([CH:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=[O:25])C(=O)N(CC3C4C(=CC=CC=4C)N(C)C=3)C=2C=1.[Si](N=C=O)(C)(C)C.C(=O)(O)[O-].[Na+].[CH2:44]1COC[CH2:45]1>>[CH2:44]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:27][CH2:28][CH3:29])[CH3:45]
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(N)ccc21
Reactant: C1CCOC1
Agent: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-[5-Amino-3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]hexanoic acid: ethyl ester (50 mg, 0.111 mmol) in THF (30 ml) was added TMS isocynate (1.73 mg, 15 mmol). The solution was stirred at RT for 3 hours. The reaction was checked by LCMS. To the reaction mixture an aqeous solution of Sodium bicarbonate (60 ml) was added. The resulting mixture, stirred for another 30 minutes, was then extracted with Ethyl Acetate. The organic layer, dried over MgSO4, was filtered and evaporated to dryness to give a dark residue. The residue was purified by prep TLC, eluded with 10% methanol in Dichloromethane to give 10 mg (18%) of 3-[3-1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-5-ureido-2,3-dihydro-benzoimidazol-1-yl]hexanoic acid ethyl ester. LCMS (ESMS): m/z 491.58 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Br:10][C:11]([OH:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:14][C:11]([Br:10])([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(O)Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Br)OC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nicotinic acid chloride (2.56 g, 20 mmol) and 30 mg of DMAP were added to a mixture of 2-bromo-2-propanol (2.8 g, 20 mmol), triethylamine (5.6 mL, 20 mmol) in dichloromethane at 0° C. The resulting mixture was stirred at room temperature overnight. The product was partitioned between ethyl acetate and water. The organic phase was separated, dried over MgSO4, and concentrated to yield 1-Bromoisopropyl nicotinate, which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:7]([NH:17][C@H:18]([C:21](O)=[O:22])[CH2:19][OH:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C=O>[C:11]1([CH2:10][O:9][C:7](=[O:8])[NH:17][C@@H:18]([CH2:21][OH:22])[C:19](=[O:20])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: Nn1cccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N[C@@H](CO)C(=O)Nn1cccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of 1-aminopyrrole (3.28 g) and carbobenzyloxy-L-serine (9.57 g) in 100 ml of dry DCM and 10 ml of dry dimethylformamide was added DCC (10.0 g) at 0° C. After 10 minutes the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The precipitate was filtered and stirred in boiling ethyl acetate. The mixture was filtered and the filtrate was combined with the filtrate of the reaction mixture and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, DCM/methanol 20:1). The appropriate fractions were concentrated and the residue recrystallized from ethyl acetate to afford 7.48 g of the product as crystals, m.p. 163°-164° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[C@@H:23]([CH3:24])[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[CH2:20][C@@H:19]1[CH3:33])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH:19]([CH3:33])[CH:20]=[C:21]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:22][CH:23]1[CH3:24])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Nc1ccc(B(O)O)cc1
Reactant: C[C@H]1C=C(OS(=O)(=O)C(F)(F)F)C[C@H](C)N1C(=O)OC(C)(C)C
Product: CC1C=C(c2ccc(N)cc2)CC(C)N1C(=O)OC(C)(C)C
Yield: 56.9 %

Procedure:
The title compound was then prepared according to the Suzuki coupling procedure of Example 35, step (b) using 4-aminophenylboronic acid (219 mg, 1.00 mmol) and cis/trans-2,6-dimethyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared above, 321 mg, 1.00 mmol). Silica gel chromatography (10-20% EtOAc/hexanes) afforded 4-(4-amino-phenyl)-2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (172 mg, 57%): Mass spectrum (ESI, m/z): Calcd. for C18H26N2O2, 303.2 (M+H) found 303.1.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][NH2:11]>O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([NH:10][NH2:11])[N:3]=1
Reactant: NN
Reactant: Nc1nc(Cl)cc(=O)[nH]1
Solvent: O
Product: NNc1cc(=O)[nH]c(N)n1
Yield: 45.4 %

Procedure:
A stirred suspension of 15.0 g (103 mmol) of 1 in 250 mL water was added 12 g (375 mmol) of anhydrous hydrazine, and the mixture was heated at reflux for 3 h. The resulting clear solution was cooled, and the precipitate which separated was collected by filtration, washed with water followed by ethanol and dried to give 6.6 g (46%) of white solid. mp decomposes at 313° C. (Literature mp 314-315° C., see Taylor, E. C.; Cocuzza, J. A. Synthesis and Properties of 7-Azaxanthopterin. J. Org. Chem. 1979, 44, 1125-1128).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13][CH3:14])[CH:3]=1.[I:15]Cl.CC(O)=O>C(O)(=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:12]([I:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13][CH3:14])[CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1SC
Reactant: ClI
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(I)c(N)cc1SC
Temperature: 60 °C
Yield: 62.4 %

Procedure:
To a solution of ethyl 4-amino-2-fluorobenzoate (12 g, 65.5 mmol) in DMF (100 mL) was added NaSMe (9.17 g, 131 mmol) and the mixture was stirred at 60° C. for 20 h. After cooling to rt, the reaction was diluted with H2O and extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford ethyl 4-amino-2-(methylthio)benzoate. To a pre-heated 60° C. solution of ethyl 4-amino-2-(methylthio)benzoate (65 mmol) in acetic acid (150 mL) was added ICl/AcOH solution (1M, 72 mL, 72 mmol) dropwise during 40 min and the temperature was maintained at 60° C. for 3 h. After cooling to rt the reaction was diluted with EtOAc (500 mL) and washed with 5% sodium thiosulfate solution (3×100 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-20% EtOAc/Hexanes) to afford ethyl 4-amino-5-iodo-2-(methylthio)benzoate (13.67 g, 53% yield). For ethyl 4-amino-2-(methylthio)benzoate: LC-MS m/z 212 [M+H]+. For ethyl 4-amino-5-iodo-2-(methylthio)benzoate: LC-MS m/z 338 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 6.47 (s, 1H), 4.49 (br s, 2H), 4.31 (q, J=7.2 Hz, 2H), 2.38 (s, 3H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>CN(C=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[N:13]=[CH:12][CH:20]=[CH:19][C:15]=2[C:16]([NH2:18])=[O:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2ncccc2C(N)=O)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
4-Hydroxyacetophenone (1 equiv), 6-chloronicotinamide (1 equiv) and K2CO3 (1.4 equiv) in anhydrous DMF (0.4 M) was heated at 150° C. under nitrogen during 2.5 days. After cooling down to room temperature, toluene was added and solvents were evaporated. The residue was partitioned in water/EtOAc. The aqueous layer was thoroughly extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum (toluene was added to aid DMF evaporation). The crude mixture was purified by flash chromatography using EtOAc/CH2Cl2/2 M NH3 in MeOH (12:7:1) as eluent in 20% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[N:8]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(Br)cc21
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl (6S)-5′-bromo-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (3.00 g, 7.73 mmol) in THF (30 mL) at 0° C. was added triethylamine (1.29 mL, 9.28 mmol). The resulting mixture was stirred for 10 min, then 2-(trimethylsilyl)ethoxymethyl chloride (1.64 mL, 9.27 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to ambient temperature and stirring was continued for 4 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=520.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]2[CH2:30][O:29]2)[N:11]=1.C1COCC1.[CH3:36][NH:37][CH3:38]>C(O)C>[CH3:36][N:37]([CH3:38])[CH2:30][CH:28]([OH:29])[CH2:27][CH2:26][N:12]1[C:13]2=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][CH:17]=[C:18]2[C:10]([NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])=[N:11]1
Reactant: Cc1cccc(C)c1Nc1nn(CCC2CO2)c2nc(Nc3ccccc3)ncc12
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc(C)c1Nc1nn(CCC(O)CN(C)C)c2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 60 mg (0.15 mmol) of N3-(2,6-dimethylphenyl)-1-(2-(oxiran-2-yl)ethyl)-N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine 42 (Example 9, Step A) in 4 mL of absolute ethanol was treated with 375 μl (2.0 M, 0.8 mmol) of a THF solution of dimethylamine. The resulting yellow solution was stirred at room temperature for 2.5 h and then heated to 40° C. for an additional 2 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 19:1 grading to CH2Cl2:MeOH, 9:1) to give the title compound 43. 1H-NMR (CD3OD) δ 1.75-1.84 (m, 1H), 1.95-2.05 (m, 1H), 2.19 (s, 6H), 2.26 (s, 6H), 2.27-2.43 (m, 2H), 3.63-3.70 (m, 1H), 4.17-4.31 (m, 2H), 7.00 (t, J=7.4 Hz, 1H), 7.09-7.16 (m, 3H), 7.30 (t, J=8.0 Hz, 2H), 7.75 (dd, J=8.7 Hz, 1.0 Hz, 2H), 8.10 (s, 1H). Mass Spectrum (ESI) m/e=446.2 (M+1).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[CH:7][N:6]=1.O>CN(C=O)C>[CH3:1][S:2][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[CH:7][N:6]=1
Reactant: Clc1cc(-c2ccccc2)ncn1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(-c2ccccc2)ncn1
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
To a suspension of sodium methanethiolate (0.88 g) in dry DMF (15 ml) at 0° C. was added dropwise over 20 minutes a solution of 4-chloro-6-phenylpyrimidine (2.18 g) in dry DMF (25 ml). Ater stirring for a further 15 minutes, the temperature was allowed to rise to room temperature. After 2 hours the reaction mixture was poured into water and extracted with ether (×3). The combined ether extracts were washed with water (×2), dried, filtered and evaporated to give 4-methylthio-6-phenylpyrimidine (2.16 g, 87% pure by GC analysis) as a yellow liquid which was used directly in the next stage.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[C:23](F)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[C:23](=[O:24])[NH:7][CH2:8][CH2:9][SH:10])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCCS
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (134.3 mg, 1.6 mmol) in 7.8 mL water was added 2-aminoethanethiol hydrochloride (97.5 mg, 0.86 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25d (170.3 mg, 0.78 mmol) in 7.8 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 205.8 mg (96% from 24d) of clean 26d as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[N+:20]([O-])([OH:22])=[O:21]>>[Br:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([N+:20]([O-:22])=[O:21])=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:8])([F:9])[F:10]
Reactant: Cn1nc(-c2cc(F)ccc2F)c(Br)c1C(F)(F)F
Reactant: O=[N+]([O-])O
Product: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Br)c1C(F)(F)F
Temperature: 28 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
At 15° C., 9.5 g (0.03 mole) 4-bromo-3-(2,5-difluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole was slowly added to 100 mL of fuming nitric acid. The reaction warmed to 28° C. over a period of 20 minutes. The reaction mixture was stirred at 30° C. for 4 hours. The mixture was poured into 500 mL of ice. After stirring for 1 hour, the slurry was extracted 3 times with methylene chloride. The methylene chloride extracts were washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chromatographically using 10% ethyl acetate in hexane as the eluent to give 5.84 g (55%) of 4-bromo-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole as a white solid, mp 45.5° C.
Reaction SMILES: [Cl:1][C:2]([Cl:4])=[CH2:3].[CH2:5]([C:7]1(Cl)[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6].Cl>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>[Cl:1][C:2]([Cl:4])=[CH:3][C:7]1([CH2:5][CH3:6])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C=C(Cl)Cl
Reactant: CCC1(Cl)CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1(C=C(Cl)Cl)CCCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
10 g of anhydrous aluminum chloride were added to 291 g (3 mol) of 1,1-dichloroethene at -20° C., and thereafter 133 g (1 mol) of 1-ethyl-cyclopentyl chloride (Chem. Abstr. 42, 6,328 (1948)) were added dropwise at 0° to 10° C. The reaction solution was allowed to warm up to 20° C., a further 5 g of aluminum chloride were added, and stirring was continued for a further 2 hours at 20° C. The mixture was poured onto ice, and was worked up with methylene chloride and dilute hydrochloric acid. 158 g (82% of theory) of 1-(2,2-dichlorovinyl)-1-ethylcyclopentane of boiling point 45° to 50° C./0.1 mm Hg were obtained by fractional distillation of the organic phase after it had been dried over sodium sulphate. ##STR16##
Reaction SMILES: C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:25][CH:24]=1.CO>O1CCCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([OH:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:27][CH:28]=1
Reactant: COC(=O)CCCCCC(=O)c1ccc(F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCCCC[C@H](O)c1ccc(F)cc1
Reaction time: 0.42 h
Yield: 98.4 %

Procedure:
To a solution of (R)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (1.1 g) in tetrahydrofuran (20 ml) was added at 0° C. 1M tetrahydrofuran solution of boranetetrahydrofuran complex (4 ml). To this solution were added dropwise a solution of methyl 7-(4-fluorophenyl)-7-oxoheptanoate (10.0 g, 39.6 mmol) in tetrahydrofuran (20 ml) and 1M tetrahydrofuran solution of boranetetrahydrofuran complex (20 ml), simultaneously, taking 25 minutes. The mixture was stirred for 30 minutes at the same temperature range, to which was added methanol (20 ml), followed by stirring for 30 minutes at room temperature. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography to give methyl (S)-7-(4-fluorophenyl)-7-hydroxyheptanoate (9.91 g). Physico-chemical properties and spectral data of this product are shown in [Table 7]. Likewise, Compound 1-2 was prepared.