Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16]C(C)(C)[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][S:23]([NH2:26])(=[O:25])=[O:24])[O:12]1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>CCO>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[C@@H:11]2[O:12][C@H:13]([CH2:21][NH:22][S:23]([NH2:26])(=[O:24])=[O:25])[C@@H:14]([OH:18])[C@H:15]2[OH:16])=[CH:30][CH:29]=1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)NC[C@H]1O[C@@H](n2cnc3c(NCc4ccc(F)cc4)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 0.17 h
Yield: 23.2 %

Procedure:
A solution of N-{[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl}sulfamide (25.0 mg, 0.0618 mmol), 4-fluorobenzylamine (14.1 μL, 0.124 mmol), and DIPEA (10.8 μL, 0.0618 mmol) in EtOH (0.4 mL) was heated at 100° C. for 10 minutes using microwave irradiation. Upon cooling, the mixture was concentrated and the residue dissolved in TFA/water (1 mL, 9:1). The solution was stirred for 10 minutes, concentrated, taken up in MeOH, then concentrated. The residue was purified by reverse phase HPLC to yield 6.5 mg (23%) of final compound.
Reaction SMILES: FS([O-])(=O)=O.Cl[C:7]1[C:11]([Cl:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][N+:8]=1[CH3:18].[C:19](#[N:23])[CH2:20][C:21]#[N:22]>C(O)(C)C>[Cl:12][C:11]1[C:7](=[C:20]([C:19]#[N:23])[C:21]#[N:22])[N:8]([CH3:18])[S:9][C:10]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: N#CCC#N
Reactant: CCOC(=O)c1s[n+](C)c(Cl)c1Cl
Agent: O=S(=O)([O-])F
Solvent: CC(C)O
Product: CCOC(=O)C1=C(Cl)C(=C(C#N)C#N)N(C)S1
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
3,4-Dichloro-5-ethoxycarbonyl-2-methylisothiazolium fluorosulfonate (7.5 g, 0.022 mole) was dissolved in 75 ml of isopropanol. Malononitrile (1.5 g, 0.023 mol) was added the mixture stirred for 30 min. The yellow solid was collected and washed with isopropanol to yield 2.6 g (44%) of product, mp 134-136. Analysis--Calculated for C10H8ClN3O2SO2 : C 44.51; H, 3.00; Cl, 13.16; N, 15.57; S, 11.90. Found: C, 44.34; H, 2.82; Cl, 12.60; N, 14.82; S, 11.42.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:29][C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: Cn1ccc(N)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (93 mg, 0.27 mmol), 1-methyl-1H-pyrazol-3-ylamine (29 μL, 0.30 mmol) and N,N-diisopropylethylamine (141 μL, 0.81 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (79 mg, 69%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C18H21ClN4O4S [M+] 424.10, found 425 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.64 (m, 4 H, 2×CH2), 1.86 (m, 4 H, 2×CH2), 3.29 (s, 3 H, SO2CH3), 3.85 (s, 3 H, NCH3), 4.88 (p, J=4.1 Hz, 1 H, OCH), 6.69 (d, J=2.3 Hz, 1 H, Ar), 7.28 (d, J=2.3 Hz, 1 H, Ar), 7.55 (dd, Jo=8.2, Jm=1.3 Hz, 1 H, Ar), 7.66 (d, Jm=1.3 Hz, 1 H, Ar), 8.18 (d, Jo=8.2 Hz, 1 H, Ar), 9.16 (s, 1 H, NH).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[C:8]2[CH:15]=[CH:14][NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.CC1C=CC=C(C)C=1[Mg]Br.CON(C)[C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36].[Cl-].[NH4+]>O1CCCC1>[N:10]1[C:9]2[NH:13][CH:14]=[CH:15][C:8]=2[C:7]([C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])=[O:37])=[N:12][CH:11]=1
Reactant: Ic1ncnc2[nH]ccc12
Reactant: CON(C)C(=O)c1ccccc1C
Agent: CC(C)[Mg]Cl
Agent: Cc1cccc(C)c1[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1ncnc2[nH]ccc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
Isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 1.05 mL, 2.10 mmol) was gradually added dropwise to 4-iodo-7H-pyrrolo[2,3-d]pyrimidine (245 mg, 1.00 mmol) obtained in Reference Synthetic Examplea 1 in tetrahydrofuran (5 mL) cooled to −78° C., and the resulting reaction mixture was stirred at −78° C. for 15 minutes. The reaction mixture was warmed to room temperature and stirred with (2,6-dimethylphenyl)magnesium bromide (1.0 M solution in tetrahydrofuran, 1.1 mL, 1.1 mmol) and N-methoxy-N,2-dimethylbenzamide (180 mg, 1.00 mmol) in tetrahydrofuran (4 mL) at room temperature for one day. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1→1/1 (v/v)) to give the title compound as a pale yellow solid (162 mg, yield 68%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:46])([F:45])[C:17]1[CH:18]=[C:19]([C@H:27]([O:29][C@@H:30]2[C@@H:35]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C@H:34]([CH:43]=O)[CH2:33][CH2:32][O:31]2)[CH3:28])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.FC(F)(F)C(O)=O.[CH2:54]1[C:58]2([CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[C@@H:57]([O:64][C:65]([C@@:67]23[C:73]([CH3:75])([CH3:74])[C@@:70]([CH3:76])([CH2:71][CH2:72]2)[C:69](=[O:77])[O:68]3)=[O:66])[CH2:56][O:55]1.C(N(CC)CC)C>ClCCl>[F:46][C:16]([F:15])([F:45])[C:17]1[CH:18]=[C:19]([C@H:27]([O:29][C@@H:30]2[C@@H:35]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[C@H:34]([CH2:43][N:61]3[CH2:62][CH2:63][C:58]4([CH2:54][O:55][CH2:56][C@@H:57]4[O:64][C:65]([C@@:67]45[C:73]([CH3:74])([CH3:75])[C@@:70]([CH3:76])([CH2:71][CH2:72]4)[C:69](=[O:77])[O:68]5)=[O:66])[CH2:59][CH2:60]3)[CH2:33][CH2:32][O:31]2)[CH3:28])[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)O[C@H]1COCC13CCNCC3)OC2=O
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COC[C@@H]3OC(=O)[C@@]23CC[C@@](C)(C(=O)O2)C3(C)C)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 44.2 %

Procedure:
Solid sodium triacetoxyborohydride (107 mg, 0.504 mmol) was added to a stirred mixture of 2-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde (Description 11; 121 mg, 0.36 mmol), (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4R)-2-oxa-8-aza-spiro[4.5]dec-4-yl ester trifluoroacetate (Description 10; 130 mg), triethylamine (0.1 ml, 0.72 mmol) and dichloromethane (3 ml) at room temperature. The mixture was stirred for 45 minutes, quenched with saturated aqueous NaHCO3 and extracted into dichloromethane. The organic extract was dried (Na2SO4) and concentrated. The residue was purified by preparative TLC (dichloromethane:methanol) to give the title compound (100 mg). The HCl salt was prepared and recrystallised from ethyl acetate:methanol.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:11])[CH:4]=1)=[O:2].[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Cl)[CH3:13].CC[O-].[Na+].O>C1C=CC=CC=1.C(O)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[O:2][CH:16]2[C:15]([O:14][CH2:12][CH3:13])=[O:18])=[CH:4][C:5]=1[CH3:11])#[N:8]
Reactant: Cc1cc(C=O)ccc1C#N
Reactant: CCOC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1OC1c1ccc(C#N)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-formyl-2-methylbenzonitrile (1.5 g, 10.3 mmol) and chloroacetic acid ethyl ester (1.2 g, 10 mmol) were dissolved in 60 mL of dry benzene. Freshly prepared EtONa (12.4 mmol) in 5 mL of ethanol was added, and the mixture was stirred at room temperature for 2 hours. The mixture was added water, then extracted with EtOAc. The organic layers were dried over Na2SO4 and concentrated to afford ethyl 3-(4-cyano-3-methylphenyl)oxirane-2-carboxylate. MS m/z: 232 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].CC(C)([O-])C.[K+].Cl[C:32]([O:34][CH:35]1[CH:40]([C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH3:43])[CH3:42])[CH2:39][CH2:38][CH:37]([CH3:50])[CH2:36]1)=[O:33].C1(C(C)(C)C2CCC(C)CC2O)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][C:13]=3[N:12]([C:32]([O:34][C@@H:35]3[CH2:36][C@H:37]([CH3:50])[CH2:38][CH2:39][C@H:40]3[C:41]([CH3:42])([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:43])=[O:33])[C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCS1(=O)=O)N2
Reactant: CC1CCC(C(C)(C)c2ccccc2)C(OC(=O)Cl)C1
Agent: CC(C)(C)[O-]
Agent: CC1CCC(C(C)(C)c2ccccc2)C(O)C1
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@H](OC(=O)N2C3=C(C(=O)COC3)C(c3ccc(F)c(Br)c3)C3=C2CCS3(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of the product from Example 11D (1.58 g, 3.7 mmol) in THF (40 mL) at 0° C. under a nitrogen atmosphere was added a 1M solution of potassium tert-butoxide in THF (4.1 mL) dropwise over 5 minutes. The mixture was stirred at ambient temperature for 30 minutes, cooled to 0° C., treated with a solution of 8-phenylmenthol chloroformate prepared from (−)-8-phenylmenthol as described in (Yamamoto, Y., J. Amer. Chem. Soc. (1992), 114, 121-125) (1.31 g, 4.4 mmol) in THF (20 mL) over 5 minutes, stirred at ambient temperature for 16 hours, diluted with methylene chloride (150 mL) and washed with aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography over silica gel (3:2:1 chloroform/hexanes/diethyl ether) to provide 0.98 g of the less polar diasteriomer.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].CN.[C:16](=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][N:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH:6][CH3:16])=[S:5]
Reactant: CN(C)C(C(N)=S)c1ccccn1
Reactant: O=C([O-])[O-]
Agent: CN
Agent: [Na+]
Product: CNC(=S)C(c1ccccn1)N(C)C

Procedure:
A mixture of 7.5 g. of 2-dimethylamino-2-(2-pyridyl)thioacetamide and 15 ml. of 30% aqueous methylamine is heated for 30 minutes, then cooled and 25 ml. of 5% aqueous sodium carbonate solution is added. The solution is extracted with chloroform, the organic solution is dried and concentrated and the residue is recrystallized to give 2-dimethylamino-N-methyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][S:15][C:16](SC)=[N:17][C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:18]([N:17]=[C:16]([S:15][CH3:14])[NH:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])#[N:19]
Reactant: CSC(=NC#N)SC
Reactant: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSC(=NC#N)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A mixture of 2.02 g (10.0 mmol) of 2-nitrobenzene-sulfonamide, 1.46 g (10.0 mmol) of dimethyl N-cyanodithioiminocarbonate and 1.38 g (10.0 mmol) of powdered, anhydrous K2CO3 in 16 ml of acetone was heated at reflux for 20 hours. The reaction mixture was filtered and the solid collected was washed several times with acetone. The filtrate was evaporated and the orange oily residue was triturated with ether to afford a solid. The solid was collected by filtration, washed with ether and suspended in 10 ml of 1N HCl. After stirring for 1 hour the solid was collected by filtration, washed with water and dried to yield 1.65 g (55 percent) of the desired product as a cream colored solid, mp 122° C. (decomposition). IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][C@@H:26]([O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:25][C:24]4=[O:47])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:48])[O:11]1)[Si](C(C)(C)C)(C)C.B(Cl)(Cl)Cl.ClCCl>C1COCC1>[O:29]([C@@H:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:21]=[CH:22][C:14]3[N:13]4[C:12](=[O:48])[O:11][C@@H:10]([CH2:9][OH:1])[C@@H:18]4[CH2:17][O:16][C:15]=3[CH:19]=2)[C:24](=[O:47])[CH2:25]1)[Si:30]([C:43]([CH3:45])([CH3:44])[CH3:46])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OC(=O)N2c3ccc(N4CC[C@@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC4=O)cc3OC[C@@H]12
Agent: ClB(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@@H]1CCN(c2ccc3c(c2)OC[C@H]2[C@H](CO)OC(=O)N32)C(=O)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.1 %

Procedure:
Compound (3R,3 aS)-3-((t-butyldimethylsiloxy)methyl)-7-((R)-4-(t-butyldiphenylsiloxy)-2-oxopiperidin-1-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (0.78 g, 1.135 mmol) was dissolved in THF. A solution of BCl3 in dichloromethane (1M, 6.81 ml, 6.81 mmol) was added, stirred at room temperature for 24 h, and dried by spinning. Column chromatography afforded pale yellow solid 0.56 g, yield 86.0%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]=2)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:25]2[CH:26]=[CH:21][CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[N:28]=3)[CH:24]=2)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(B(O)O)ccc1OCc1ccccc1
Reactant: FC(F)(F)c1cccc(-c2cccc(Br)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-benzyloxy-3-methoxyphenylboronic acid (1.0 g, 3.87 mmol) and 2-(3-bromophenyl)-6-(trifluoromethyl)pyridine (1.063 g, 3.52 mmol) in toluene (10 mL) and ethanol (1 mL) at room temperature under argon was added 2 N aqueous sodium carbonate solution (5.41 mL, 10.82 mmol) followed by tetrakis(triphenylphosphine)palladium (0.22 g, 0.19 mmol). The resulting mixture was stirred at 90° C. for two hours and then allowed to cool to room temperature. The phases were separated and the aqueous phase was extracted with toluene (5 mL). The combined organic phases were washed with water and brine, then dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent left a brown oil that was chromatographed over silica gel (petroleum ether/ethyl acetate, 9:1) to give 2-(4′-(benzyloxy)-3′-methoxybiphenyl-3-yl)-6-(trifluoromethyl)pyridine as a clear oil, 1.072 g (70%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH2:23]1[O:33][C:32]2[C:25](=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH:27]=O)[O:24]1.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:27][C:26]4[CH:29]=[CH:30][CH:31]=[C:32]5[O:33][CH2:23][O:24][C:25]=45)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc2c1OCO2
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(NCc4cccc5c4OCO5)c23)c1

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 2,3-methylenedioxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(2,3-methylenedioxybenzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 214-215° C.; HPLC: TRet (Grad5-40)=24.1.
Reaction SMILES: CS(C)=O.[NH:5]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>O>[NH:5]([C:12]1[S:13][CH:14]=[C:15]([CH:17]=[O:18])[N:16]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OCc1csc(Nc2ccccc2)n1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=Cc1csc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A dimethyl sulfoxide solution (120 ml) of 20 g of sulfur trioxide pyridine complex was added dropwise to a mixture comprising 8.3 g of 2-anilinothiazol-4-ylmethanol, 16.5 ml of triethylamine and 120 ml of dimethyl sulfoxide. The resulting mixture was stirred at room temperature for 10 minutes and then poured into water. followed by extraction with ethyl acetate. The extract was washed successively with aqueous acetic acid, aqueous sodium chloride solution and aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The residue afforded by evaporation of the solvent under reduced pressure was recrystallized from a mixture of benzene and acetone. The resulting product was a brown powder having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:11]=1[N+:22]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:11]=1[NH2:22]
Reactant: COCC(C)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: COCC(C)Nc1nccc(-c2ccc(OC)cc2Cl)c1N
Yield: 241.7 %

Procedure:
[4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine (0.10 g, 0.27 mmol) and Na2S2O4 (0.38 g, 2.21 mmol) were treated substantially as described in Part E of Example 9 to give 0.21 g (81%) 4-(2-chloro-4-methoxy-phenyl)-N2-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine: MS (AP) m/z 321.8 [(M+H)+, 100].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[O:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: FC(F)(F)c1cc(Br)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.6 %

Procedure:
A mixture of 4-bromo-2-trifluoromethyl-phenylamine (0.88 g, 3.66 mmol), tetrahydro-4H-pyran-4-one (0.5 ml, 5.49 mmol), oven dried molecular sieves 4 Å (1 g) and sodium triacetoxyborohydride (1.15 g, 5.49 mmol) in 1,2-dichloroethane (30 ml) was stirred at room temperature for 72 hours. The mixture was filtered through a diatomaceous earth pad. The diatomaceous earth pad was washed with dichloromethane. The combined filtrates were washed with NaHCO3 (aqueous saturated solution), dried over Na2SO4 and evaporated till dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/MeOH(NH3) up to 5%). The desired fractions were collected and evaporated in vacuo to yield intermediate 13 as a yellow oil (1.11 g, 99%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH3:21])([CH3:20])[CH2:18][F:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:21][C:17]([N:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)([CH3:20])[CH2:18][F:19]
Reactant: CC(C)(CF)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(CF)N1CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.8 %

Procedure:
4-(1,1-Dimethyl-2-fluoroethyl)piperazine-1-carboxylic acid benzyl ester (270 mg, 0.92 mmol) was dissolved in ethanol (20 mL), and 10% palladium hydroxide/carbon (100 mg) was added thereto. The mixture was stirred for two days at room temperature under a hydrogen stream at normal pressure. The catalyst was separated by filtration, and then the reaction liquor was concentrated under reduced pressure, and dried to obtain the title compound (97 mg, 66%) as an oily matter. This compound was used in the subsequent reaction without performing further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[O:22][C:23]=1[CH3:24]>>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[N:20][C:19]=1[CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1CCl
Reactant: Oc1ccc(CCCCn2cncn2)cc1
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCn2cncn2)cc1
Yield: 54 %

Procedure:
In substantially the same manner as in Working Example 37, 1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole was allowed to react with 4-chloromethyl-5-methyl-2-(2-naphthyl)oxazole to give 1-[4-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole. The yield was 54%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 134-135° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OC[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[S:50]1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][S:50][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: C1CSCN1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCSC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and thiazolidine and isolated as light-yellow gum (10.6 mg, 58%). MS (m/e): 389.4 (MH+).