Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14](O)=[O:15])[C:11]3[C:17]([CH:24]=[O:25])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[S:19][C:10]=3[C:9]=2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:4][CH:3]=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.[CH:65]([N:68]1[CH2:72][CH2:71][CH:70]([NH:73][CH3:74])[CH2:69]1)([CH3:67])[CH3:66]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:73]([CH:70]3[CH2:71][CH2:72][N:68]([CH:65]([CH3:67])[CH3:66])[CH2:69]3)[CH3:74])=[O:15])[C:11]3[C:17]([CH:24]=[O:25])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[S:19][C:10]=3[C:9]=2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:6][CH:7]=1
Reactant: CNC1CCN(C(C)C)C1
Reactant: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)n(CC(=O)O)c2c1C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)n(CC(=O)N(C)C3CCN(C(C)C)C3)c2c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution (0.13 M) of [5-(4-chlorophenyl)-6-cyclohexyl-3-formyl-2-(methoxycarbonyl)-4H-thieno[3,2-b]pyrrol-4-yl]acetic acid in DMF was treated with DIEA (3 eq.), HATU (1.5 eq.) and a solution (0.5 M) of 1-isopropyl-N-methylpyrrolidin-3-amine (1.5 eq.) in DMF. The reaction mixture was stirred at RT for 3 h. The reaction was quenched with aqueous NaHCO3 (saturated solution) and extracted with AcOEt. The combined organic phase was washed with brine and dried. Evaporation under reduced pressure gave a residue that was purified by flash chromatography on silica gel (1:49 Et3N/AcOEt) to afford the title compound (62%) as a solid.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][CH:21]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCC(O)CC1
Product: CCCCN1C(=O)C(NC2CCC(O)CC2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-aminocyclohexanol in a similar manner as described for e.g. Example 6 and 7 affording a mixture of cis and trans isomeres. 1H NMR (500 MHz, CD3CN): δ 0.61-0.72 (m, 2H), 0.95-0.99 (m, 6H), 1.02-1.10 (m, 2H), 1.17-1.27 (m, 2H), 1.38-1.60 (m, 12H), 1.64-1.80 (m, 8H), 2.46 (d, 1H), 2.55 (d, 1H), 2.86-3.05 (m, 2H), 3.29-3.38 (m, 1H), 3.60-3.69 (m, 5H), 5.55-5.66 (m, 2H), 7.47-7.57 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:18](=[O:20])[CH3:19])[C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].[NH2:21]/[C:22](/[CH3:31])=[CH:23]\[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C(O)CCC>[C:18]([C:10]1[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([CH3:31])[NH:21][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16])(=[O:20])[CH3:19]
Reactant: C/C(N)=C/C(=O)OC(C)(C)C
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)CCCCCl
Solvent: CCCCO
Product: CC(=O)C1=C(CCCCCl)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1Cl

Procedure:
25 g (70 mmol) 6-(2,3-dichlorophenyl-methylene)-1-chloro-5,7-octanedione and 22 g (0.14 mol) tert-butyl β-amino-crotonate are boiled under reflux in 200 ml 1-butanol for 6 h. The mixture is concentrated and the residue is prepurified by chromatography with toluene/acetone=8/2. The product thus obtained is chromatographed again over silica gel with toluene/acetone=99/1. The title compound is obtained as a yellow oil. Yield: 5.8 g (18%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=O)=[N:14][CH:15]=1>C(O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[N:14][CH:15]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: Nc1ccccc1S
Solvent: CCO
Product: Brc1ccc(-c2nc3ccccc3s2)nc1
Temperature: 100 °C
Yield: 48.3 %

Procedure:
A mixture of 2-aminothiophenol (5.01 g, 40.0 mmol), 5-bromo-2-formylpyridine (7.44 g, 40.0 mmol) and ethanol (40 mL) was heated to reflux (100° C.) while open to the atmosphere for 3 days. Upon confirming consumption of the starting materials by TLC (SiO2, 29:1 hexanes-acetone), the reaction was cooled to RT, the resulting mixture filtered and the filtrant washed copiously with ethanol to afford 9 (5.62 g, 48% yield) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][NH2:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:16]1(C)[CH:21]=CC(S(O)(=O)=O)=C[CH:17]=1>CC(C)=O>[OH:1][C:2]1[C:3]([C:12]([NH:14][N:15]=[C:16]([CH3:21])[CH3:17])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNC(=O)c1cc2ccccc2cc1O
Solvent: CC(C)=O
Product: CC(C)=NNC(=O)c1cc2ccccc2cc1O
Temperature: 20 °C

Procedure:
A four neck flask (3 liters) equipped with a thermometer, a reflux condenser and a stirrer was charged with 121.2 g (0.6 mol) of 3-hydroxy-2-naphthohydrazide, 1.14 g (0.006 mol) of p-toluenesulfonic acid and 2 liters of acetone and then heated under reflux for 5 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby the intended compound (slightly yellow crystal) was obtained.
Reaction SMILES: [C@@H:1]1(N2C=CC(=O)NC2=O)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C(C=O)=O.[NH:21]1[C:30](=[O:31])[C:29]2[NH:28][CH:27]=[N:26][C:25]=2[N:24]=[C:22]1[NH2:23].P([O-])([O-])([O-])=O.B(O)(O)O.C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.[Na+].[Na+]>>[CH:3]([CH:5]=[O:8])=[O:4].[C@@H:1]1([N:26]2[C:25]3[N:24]=[C:22]([NH2:23])[NH:21][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: O=CC=O
Agent: O=P([O-])([O-])[O-]
Product: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
Glyoxal-2′-deoxyguanosine was synthesized from 2′-deoxyuridine and glyoxal-guanine under the following conditions, by using any one of the aforementioned three sets of enzyme solutions and the Bacillus stearothermophilus JTS 859 enzyme solution obtained in Production Example 2. Specifically, 5 mM phosphate buffer (pH 7) containing 30 mM 2′-deoxyuridine, 30 mM glyoxal-guanine, 100 mM boric acid, and 4 mM disodium ethylenediaminetetraacetate was first prepared.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(O)(O)C1C=CC=C(F)C=1>>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]([CH:18]4[CH2:22][CH2:21][NH:20][CH2:19]4)=[N:16][CH:17]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)C1
Agent: OB(O)c1cccc(F)c1
Product: c1ccc(-c2ncc(-c3cnc(C4CCNC4)[nH]3)cn2)cc1

Procedure:
The title compound was prepared according to the method described in Example 22, except that (±)-tert-butyl 3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (Example 28) was used instead of (±)-tert-butyl 3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate. MS (ESI+) m/z 292 (M+1); H-PGDS FPBA IC50: 2 μM.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH2:20]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:8][CH:9]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1ccc(Nc2ccc(C(N)=O)cn2)cc1
Solvent: CO
Product: NC(=O)c1ccc(Nc2ccc(CCNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.9 %

Procedure:
Combine 6-[4-(2-amino-ethyl)-phenylamino]-nicotinamide (200 mg, 0.78 mmol) (step 2, Example 16), benzaldehyde (83 mg, 0.78 mmol), 3 Å molecular sieves (0.2 g), and methanol (10 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (0.4 mg) to the reaction and stirred at room temperature for 4 hours. Add water (20 mL) then extract with dicholormethane (3×50 mL). Dry the dichloromethane extracts with sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 0.2 g of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with 10% conc. ammonium hydroxide in ethanol and chloroform to yield 6-[4-(2-Benzylamino-ethyl)-phenylamino]-nicotinamide (24 mg): 1H NMR (MeOD, 300.00 MHz): 8.66 (d, 1H, J=1.8 Hz), 8.00 (dd, 1H, J=9.0, 2.4 Hz), 7.55-7.15 (m, 10H), 6.81 (d, 1H, J=8.8 Hz), 3.80 (s, 2H), 3.38 (m, 1H), 2.84 (m, 5H); m/z=347.01(M+1); HPLC=95% @ 5.54 minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][C:21](=[CH:23][C:24]#[N:25])[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1.N12CCCN=C1CCCCC2>C(#N)C>[OH:18][CH:19]1[CH2:20][C:21]([CH2:23][C:24]#[N:25])([N:26]2[CH:30]=[C:29]([C:31]3[N:36]=[CH:35][NH:34][C:33]4=[N:37][CH:38]=[CH:39][C:32]=34)[CH:28]=[N:27]2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: N#CCC1(n2cc(-c3nc[nH]c4nccc3-4)cn2)CC(O)C1
Temperature: 50 °C

Procedure:
(3-[tert-Butyl(diphenyl)silyl]oxycyclobutylidene)acetonitrile (0.15 g, 0.00043 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.14 g, 0.00043 mol) in acetonitrile (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.064 mL, 0.00043 mol) was added under nitrogen. The mixture was heated to 50° C. over night. LCMS showed a peak with m/z of 425.4, indicating a de-silyl reaction occurred simultaneously during the Micheal addition. The reaction was concentrated and purified on combiflash (silica gel, 0-100% EtOAc/Hex) to yield the desired produt. LCMS (M+H) 425.4.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:4]=2[O:3]1.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[N:23]=[C:11]([C:8]3[CH:9]=[CH:10][C:4]4[O:3][C:2](=[O:1])[NH:6][C:5]=4[CH:7]=3)[O:13][N:15]=2)[CH:18]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2oc(=O)[nH]c2c1
Agent: N
Product: O=c1[nH]c2cc(-c3nc(-c4cccnc4)no3)ccc2o1

Procedure:
The title compound was prepared according to Method C using 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxylic acid (Matrix) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, CD3OD) δ 7.40 (d, J=8.5 Hz, 1H), 7.64 (ddd, J=8.0, 5.0, 0.9 Hz, 1H), 7.90 (d, J=1.7 Hz, 1H), 8.01 (dd, J=8.3, 1.9 Hz, 1H), 8.55 (dt, J=7.8, 1.9 Hz, 1H), 8.74 (dd, J=4.8, 1.7 Hz, 1H), 9.29 (dd, J=2.2, 0.9 Hz, 1H). ppm; MS (DCI/NH3) m/z 281 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.O[CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][O:31][CH2:32][C:33]5[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=5)[C:36]([O:38][CH3:39])=[O:37])=[CH:24][CH:25]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: COC(=O)c1cccc(COCCO)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(O)cc4)C(=O)O3)ccc2O1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)c1
Reaction time: 0.25 h

Procedure:
(5R)-5(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-hydroxyphenyl)ethyl]-1,3-oxazolidin-2-one{Example 28 v)} (300 mg), methyl 3-[(2-hydroxyethoxy)methyl]benzoate (340 mg) and triphenylphosphine (642 mg) were dissolved in DCM (10 ml) and stirred for 15 min. To this was added 1,1′-(azodicarbonyl)dipiperidine (612 mg) and the solution was stirred for 16 h. The solution was then diluted in DCM, washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, 90 g) eluting with CH2Cl2-MeOH (250:1) to give the title compound (450 mg). LCMS RT=3.62 min.
Reaction SMILES: [NH2:1][C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:6][F:7])[C:3](O)=[O:4].B.O1CCCC1.Cl>C1COCC1>[NH2:1][C:2]([CH2:6][F:7])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][OH:4]
Reactant: NC(CF)(Cc1ccccc1)C(=O)O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NC(CO)(CF)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-amino-2-benzyl-3-fluoropropanoic acid (50 mg, 0.25 mmol) (for synthesis see EP 0 040 150 A1) in 2.5 mL THF, cooled to 0° C., was added borane-tetrahydrofuran complex (1M in THF, 0.75 mL, 0.75 mmol) dropwise. The reaction was stirred at rt overnight, quenched with MeOH and concentrated. Hydrochloric acid (1M, 7.5 mL, 7.5 mmol) was added, the mixture was heated to 45° C. for 1 h and concentrated. The reaction was made basic with saturated NaHCO3 and exacted with CHCl3. Drying and solvent evaporation gave 2-amino-2-(fluoromethyl)-3-phenylpropan-1-ol. 1H NMR (400 MHz, CDCl3) δ 7.35-7.21 (m, 5H), 4.30-4.11 (two q, ABX system, J=47.4 Hz, J=20.8 Hz, J=9.0 Hz, 2H), 3.49 (m, 2H), 2.76 (m, 2H).
Reaction SMILES: [S-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[NH:19][C:20]1[C:29]2[C:24](=[CH:25][C:26](F)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][C:21]=1[C:33]#[N:34].CN1CCCC1=O.C1(S)C=CC=CC=1.[Na]>O1CCCC1>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[NH:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([S:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][C:21]=1[C:33]#[N:34]
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: [S-]c1ccccc1
Agent: Sc1ccccc1
Agent: [Na+]
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(Sc4ccccc4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 120 °C
Yield: 27.6 %

Procedure:
A mixture of sodium thiophenoxide (181 mg, 1.37 mmol) and 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (100 mg, 0.27 mmol) in 3 mL of tetrahydrofuran is heated at reflux overnight. N-methylpyrrolidone (2 mL) is added and the reaction mixture is heated at 120° C. for 1 hour then at 140° C. for for 45 min. An additional 100 mg of sodium thiophenol is added and the reaction mixture is heated at 140° C. for 3 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a 1:4 ethyl acetate:hexane to provide 36 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-phenylsulfanyl-3-quinolinecarbonitrile, mp 220-222° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=S(Cl)Cl.[NH2:20][C:21]1[S:22][C:23]([CH:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[NH:28][S@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[C:24]([CH3:26])[N:25]=1.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:20][C:21]4[S:22][C:23]([CH:27]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[Cl:41])[NH:28][S@@:29]([C:31]([CH3:34])([CH3:32])[CH3:33])=[O:30])=[C:24]([CH3:26])[N:25]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1nc(N)sc1C(N[S@](=O)C(C)(C)C)c1ccccc1Cl
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(N[S@](=O)C(C)(C)C)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (864 mg, 4.2 mmol) was slowly added SOCl2 (916 μL, 12.6 mmol) followed by DMF (3 drops). The reaction mixture was heated at 60° C. for 0.5 h. The excess SOCl2 was removed under vacuum. The acid chloride was then dissolved in anhydrous CH2Cl2 (6 mL) and was slowly added to a solution of (R)-N-((2-amino-4-methylthiazol-5-yl)(2-chlorophenyl)methyl)-2-methylpropane-2-sulfinamide (Isomer A) (1.35 g, 3.8 mmol) and Et3N (2.92 mL, 21.0 mmol) in anhydrous CH2Cl2 (18 mL). The reaction mixture was stirred at room temperature for 18 h, diluted with CH2Cl2 and washed with 1N HCl solution, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4 and concentrated to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((2-chlorophenyl)((R)-1,1-dimethylethylsulfinamido)methyl)-4-methylthiazol-2-yl)cyclopropanecarboxamide (Isomer A) as an orange solid (1.54 g, 75%) that was used without further purification. HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; ESI-MS 546.5 m/z (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][CH:24]=[CH:25][C:18]=34)=[C:12]([F:26])[CH:11]=2)[CH:3]=1.C(N(C(C)C)C(C)C)C.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(O)CCC>[F:26][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:3]=[C:2]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[N:7]=[C:6]([NH2:8])[N:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[CH:25][C:18]=12
Reactant: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(N2CCNCC2)n1

Procedure:
75 mg (0.20 mmol) of 6-chloro-N4-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]pyrimidine-2,4-diamine (from example 60) are dissolved in 3 ml of 1-butanol. 0.35 ml of N-ethyldiisopropylamine and 70 mg (0.81 mmol) of piperazine are added, and the mixture is heated at reflux for 5 hours. The solvent is then removed under reduced pressure and the residue is purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([OH:25])[C:19](=[CH:23][CH:24]=3)[C:20]([OH:22])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+:28].O>C1COCC1>[Na+:28].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([OH:25])[C:19](=[CH:23][CH:24]=3)[C:20]([O-:22])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1O

Procedure:
50 mg (0.13 mmol) of Compound 15 was suspended in approximately 1 ml of THF, then 126 μl of 1N sodium hydroxide aqueous solution was added dropwise. The solution was confirmed to have become uniform, then 30 ml of water was added and the mixture freeze-dried to quantitatively obtain the above-identified compound in an amorphous state in an amount of 52 mg. Properties: colorless amorphous, PMR (δ ppm, CD3OD): 7.11 (1H, s), 7.19 (1H, d), 7.58 (1H, d), 7.63 (1H, s), 7.92 (1H, d), 8.03 (1H, d).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C1(NC2CCCCC2)CCCCC1.C(#N)C>[Cu]I.CCOCC>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:15]#[C:14][CH2:13][CH2:12][OH:16]
Reactant: Brc1ccc2ccccc2n1
Reactant: C#CCCO
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOCC
Solvent: CC#N
Product: OCCC#Cc1ccc2ccccc2n1
Reaction time: 5 h

Procedure:
A mixture of 2-bromoquinoline (0.44 g), 3-butynol (0.2 ml), N,N-dicyclohexylamine (0.46 ml), BTPC (30 mg), copper (I) iodide (5 mg) and acetonitrile (10 ml) was stirred at 22° for 5 h. Ether (50 ml) was added, and the mixture filtered and evaporated in vacuo. The residue was purified by FCC eluting with ether followed by ether-methanol (19:1), to afford the title compound as a colourless solid (0.41 g). A small sample recrystallised from ethyl acetate-hexane had m.p. 89°-91°.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([F:12])[N:9]=[C:8]([F:13])[C:7]=1[F:14])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C[O:24]B(OC)OC.OO.[OH-].[Na+]>C1COCC1.C(O)(=O)C>[C:1]([O:5][C:6]1[C:11]([OH:24])=[C:10]([F:12])[N:9]=[C:8]([F:13])[C:7]=1[F:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: COB(OC)OC
Reactant: CC(C)(C)Oc1cc(F)nc(F)c1F
Agent: CC(C)[N-]C(C)C
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)Oc1c(O)c(F)nc(F)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 11.16 g (54.39 mmol) sample of 4-t-butoxy-2,3,6-trifluoropyridine, from Example 253 step b above, was dissolved in 50 mL of THF, and the solution was cooled to -78° C. To this solution was added LDA (65.6 mmol) with stirring for 30 min, during which a solid preciptated. To this mixture was added 7.5 mL of trimethoxyborane, with stirring for 25 min at -78° C. To this mixture was added 10 mL of acetic acid, and the mixture was stirred and allowed to warm to room temperature. Next was added 100 mL of 30% hydrogen peroxide and 100 mL of 2N sodium hydroxide while cooling in an ice bath. The mixture was then stirred at room temperature for 16 hours, and quenched with saturated NH4Cl solution. The mixture was extracted with ether, and the extract was washed with brine and dried over MgSO4. The solvent was removed under vacuum, and the residue was purified by flash chromatography on silica gel, eluting with 1:8 ethyl acetate:hexane. Removal of the solvent gave 9.769 g of the title product as a colorless liquid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14]([O-])(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Na+].CN(C=O)C.S(Cl)([Cl:28])=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14]([Cl:28])(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of sodium 5-(4-trifluoromethylphenyl)thiophene sulfonate (1.50 g) and DMF (498 mg) in thionyl chloride (7.5 ml) was stirred for 2 hours at 50° C. The mixture was concentrated and partitioned between AcOEt and 3% aqueous sodium bicarbonate. The organic layer was separated, washed with 3% aqueous NaHCO3 solution and brine, dried over sodium sulfate and evaporated in vacuo after filtration to give 1.39 g of 5-(4-trifluoromethylphenyl)thiophene-2-sulfonylchloride as a solid.