Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].[CH2:23]1COC[CH2:24]1>>[CH2:1]([O:8][CH2:9][C:10]([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:20])[CH:23]=[CH2:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COCc1ccccc1)COCc1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CC(O)(COCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7.4 g (27.4 mmol) of 1,3-bis(benzyloxy)-propan-2-one (Araki Y. et al., J. Chem. Soc., Perkin Trans. 1, 1981, 19) in 25 ml of THF was added dropwise at 10° C. and the mixture was stirred at ambient temperature for 2 h. Then 8 ml of a 20% aqueous NH4Cl solution was added, and the organic phase was evaporated, dissolved in ether, dried with MgSO4, and evaporated in vacuum to give 7.90 g of 1-benzyloxy-2-benzyloxymethylbut-3-en-2-ol as a crude oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.C1(N[S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1>[O:23]1[C:16]2([CH2:17][CH2:18][C:19]([O:22][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=[CH:20][CH2:21]2)[O:15][CH2:14][CH2:13]1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (7.6 mL, 54.3 mmol) in 200 mL THF cooled to −78° C. was added n-butyllithium (21.8 mL 2.5 M in hexane, 54.3 mmol) under argon.The solution was stirred for 10 minutes, then a solution of 1,4-cyclohexanedione monoethylene ketal (8.5 g, 54.3 mmol) in 75 mL THF was added slowly. The solution was stirred for 10 min, then a solution of N-phenyltrifluoromethane sulfonamide (19.5 g, 54.3 mmol) in 150 mL THF was added slowly. The reaction solution was warmed to r.t., poured onto saturated sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude material was passed through silica (3% methanol, dichloromethane) to give the product as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:13][CH:10]1[CH2:11][CH2:12][CH:8]([CH3:7])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:20][N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[N:27]=2)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: CC1CCC(C)N1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(N3C(C)CCC3C)c([N+](=O)[O-])c2)n1

Procedure:
Oxalyl chloride (152 mg; 1.2 mmol; 3 eq.), Intermediate 25 (106 mg; 0.4 mmol; 1 eq.), Intermediate 1 (66 mg; 0.4 mmol, 1 eq.) and DIEA (155 mg; 1.2 mmol; 3 eq.) were reacted according to general procedure 2. Purification by precipitation from Et2O/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: C([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:19])=[C:10]([CH2:17]Br)[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=O)C.[CH3:20][OH:21]>>[CH3:19][C:9]1[C:8]2[C:13](=[C:14]([CH3:15])[C:5]([OH:4])=[CH:6][CH:7]=2)[O:12][C:11](=[O:16])[C:10]=1[CH2:17][O:21][CH3:20]
Reactant: CC(=O)Oc1ccc2c(C)c(CBr)c(=O)oc2c1C
Reactant: CO
Product: COCc1c(C)c2ccc(O)c(C)c2oc1=O
Temperature: 25 °C

Procedure:
7-acetoxy-3-bromomethyl-4,8-dimethylcoumarin (2.50 g, 8.90 mmol) was refluxed in methanol (300 mL) overnight, cooled to room temperature and concentrated under vacuum to give crude 4,8-dimethyl-7-hydroxy-3-methoxymethylcoumarin. 1H NMR (CD3OD): δ7.52 (d, J=8.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 4.50 (s, 2H), 3.41 (s, 3H), 2.49 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]1([CH3:18])[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][Si:11]([CH3:17])([CH3:16])[O:12][SiH:13]([CH3:15])[CH3:14].[CH:19]([Si:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23])=[CH2:20]>>[CH3:18][Si:2]1([CH3:1])[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][Si:11]([CH3:16])([CH3:17])[O:12][Si:13]([CH2:20][CH2:19][Si:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23])([CH3:14])[CH3:15]
Reactant: C=C[Si](OC)(OC)OC
Reactant: CC1CN(CCC[Si](C)(C)O[SiH](C)C)[Si](C)(C)C1
Product: CO[Si](CC[Si](C)(C)O[Si](C)(C)CCCN1CC(C)C[Si]1(C)C)(OC)OC
Temperature: 120 °C

Procedure:
A mixture of the 20.67 g (68.1 mmol) of 1-(3-(2,2,4-trimethyl-1-aza-2-silacyclopentyl)propyl-1,1,3,3-tetramethyldisiloxane, 10.6 g (71.5 mmol) of vinyltrimethoxysilane which had been distilled from sodium, and 0.03 g of a chloroplatinic acid-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex having about 0.7 weight percent platinum was heated for one hour at 120° C. The resulting product was distilled and the distillate was collected at 152° C. and 0.1 mm Hg. The amount of distillate collected was 28.2 g of 1-(3-(2,2,4-trimethyl-1-aza-2-silacyclopentyl)propyl)-3-(2-trimethoxysilylethyl)-1,1,3,3-tetramethyldisiloxane which was identified by 13C and 29Si NMR (nuclear magnetic resonance) and GC-MS.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]#[N:11])[CH2:4][CH2:3]1
Reactant: Oc1ccncc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 4-hydroxypyridine (4.04 g, 40 mmol), chloroacetonitrile (2.78 mL, 44 mmol) and potassium carbonate (22 g, 160 mmol) in acetonitrile (50 mL) was stirred at rt for overnight. The insolubles were filtered off, the filtrate was concentrated to give 5.6 g of (4-hydroxy-piperidin-1-yl)-acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[NH:5][C:6]=1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[H][H]>[Pd].O1CCCC1.CO>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[NH:5][C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1nc(-c2ccccc2[N+](=O)[O-])[nH]c1-c1cccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2N)[nH]c1-c1cccnc1
Yield: 94.7 %

Procedure:
A mixture of 4-methyl-2-(2-nitrophenyl)-5-(3-pyridyl)imidazole (4.99 g) and 10% palladium on carbon (1.0 g) in a mixture of tetrahydrofuran (150 ml) and methanol (150 ml) was hydrogenated at ambient temperature under atmospheric pressure of hydrogen gas. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 2-(2-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (4.22 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:22]([NH2:24])[CH3:23]>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4]([NH:24][CH2:22][CH3:23])[N:3]=1
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(Cl)nc(N)nc32)O[C@@H]1CO
Reactant: CCN
Solvent: CC#N
Product: CCNc1nc(N)nc2c1ncn2[C@H]1C[C@H](N=[N+]=[N-])[C@@H](CO)O1
Temperature: 70 °C
Yield: 59 %

Procedure:
2-Amino-9-(3-azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-6-chloro-9H-purine (0.23 g, 0.74 mmol) was dissolved in 20 mL anhydrous acetonitrile in a sealed tube. The solution was cooled to 0° C., saturated with ethylamine (Aldrich, lot #00115JV) and sealed. After heating at 70° C. for 16 hours, the reaction mixture was filtered and the filtrate evaporated to dryness. The residue was preloaded onto silica gel and eluted from a silica column using CHCl3 /MeOH (95:5, v/v). Combination and evaporation of appropriate fractions yielded 0.140 g (0.44 mmol, 59%) of product. mp=199°-201° C.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[F:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=1>C(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][NH:15][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[N:12][CH:13]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)NNc1ccc(F)cn1
Yield: 93 %

Procedure:
Isopropyl isocyanate (0.25 mL, 2.60 mmol) was added dropwise, over 2 min, to a solution of 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 0.30 g, 2.36 mmol) in dry DCM (10 mL) at RT and stirred for 3 h. The solvent was evaporated and the residue triturated (diethyl ether) and filtered to give the title compound as a colourless solid (464 mg, 93%). LCMS (Method 1): Rt 1.92 min, m/z 213 [MH+].
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:28][CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][C:21]([N:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:31][C:30]4=[O:43])=[CH:22][CH:23]=3)[N:18]([CH3:44])[C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][N:29]([C:21]2[CH:20]=[C:19]3[C:24]([C:25]4[CH2:26][CH2:27][CH2:28][NH:15][CH2:16][C:17]=4[N:18]3[CH3:44])=[CH:23][CH:22]=2)[C:30](=[O:43])[CH:31]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCCN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCCNC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl-8-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate (54 mg, 0.11 mmol) in CH2Cl2 (2.0 mL), and the resulting solution was stirred at ambient temperature for 30 min. The mixture was carefully quenched with saturated NaHCO3 solution until the solution was basic. The mixture was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 0:100 over 20 column volumes and held for 15 column volumes) provided the title compound (31 mg, 73%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J=8.5 Hz, 1H), 7.43-7.36 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.0, 1.5 Hz, 1H), 6.08 (d, J=2.5 Hz, 1H), 6.03 (dd, J=7.5, 3.0 Hz, 1H), 5.05 (s, 2H), 4.10 (s, 2H), 3.64 (s, 3H), 3.23 (t, J=5.5 Hz, 2H), 2.92 (t, J=6.0 Hz, 2H), 1.90-1.86 (s, 2H); ESI MS m/z 400 [M+H]+.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:36]1([CH:41]2[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:43]4[CH2:44][CH2:45][CH:41]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH2:42]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: C1CCN(C2CCNC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N5CCCC5)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-pyrrolidinyl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 472 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>CO>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:19])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2ccc(F)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
p-Anisidine (760 mg, 6.18 mmol) was added to a solution of 4-fluoro-3-nitrophenylsulfonyl chloride (740 mg, 3.09 mmol; Example A) in MeOH (10 ml) at ambient temperature. After stirring at room temperature for 15 min, the reaction mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate and filtered through a pad of silica gel. Concentration of the filtrate, followed by chromatography, provided 603 mg (60% yield) of the title compound. 1H-NMR (CDCl3): δ 8.42 (1H, dd, J=2.3, 6.8 Hz), 7.88 (1H, ddd, J=2.4, 4.0, 8.8 Hz), 7.33 (1H, dd, J=8.8, 9.9 Hz), 6.98 (2H, m), 6.81 (2H, m), 6.45 (1H, s), 3.77 (3H, s). MS (EI): 326 (11, M+), 122 (100). Anal. Calcd. for C13H11FN2O5S: C, 47.85; H, 3.40; N, 8.59; S, 9.83. Found: C, 47.68; H, 3.44; N, 8.54; S, 9.88.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[S:20][C:21]1[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[Br:27][CH2:28][CH2:29]Br>>[Br:27][CH2:28][CH2:29][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:5][C:4]1[CH:17]=[CH:18][C:19]([S:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:2]([F:1])[CH:3]=1
Reactant: Cn1ccnc1Sc1ccc(Nc2ncnc3ccc(O)cc23)cc1F
Reactant: BrCCBr
Product: Cn1ccnc1Sc1ccc(Nc2ncnc3ccc(OCCBr)cc23)cc1F
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 22, a mixture of 4-[3-fluoro-4-(1-methylimidazol-2-ylthio)anilino]-6-hydroxyquinazoline was reacted with 1,2-dibromoethane to give 6-(2-bromoethoxy)-4-[3-fluoro-4-(1-methylimidazol-2-ylthio)anilino]quinazoline in 45% yield;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:9]([CH:12]=[O:13])=[CH:10][N:11]=2)[C:7]=1[CH3:8].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:7]1[N:6]2[C:9]([CH:12]=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=[CH:3][C:2]=1[C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c(Br)ccc2ncc(C=O)n12
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccnc2)ccc2ncc(C=O)n12
Yield: 40 %

Procedure:
6-bromo-5-methylimidazo[1,2-a]pyridine-3-carbaldehyde (125 mg, 0.523 mmol), Pyridine-3-boronic acid (77.5 mg, 0.603 mmol), dichlorobis(triphenylphosphine) palladium (II) (36.7 mg, 0.05 mmol) and 2M aqueous Na2CO3 (2 ml) were dissolved in DMF (3 ml) and refluxed for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was evaporated to obtain crude product, which was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to obtain the title compound. Yield: 40%; 1H NMR (DMSO-d6; 300 MHz): 69.90(s, 1H), 8.39 (s, 1H), 7.73 (d, 1H, J=9.6 Hz), 7.56 (d, 1H, J=9.3 Hz), 3.11 (s, 3H); MS: m/z 238 (M+1)+.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:6][CH2:5][N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:3]1>CCO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C@@H:7]2[CH2:6][CH2:5][N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:3][C@H:2]2[F:1])=[C:10]([C:18]([F:21])([F:19])[F:20])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)[C@H](F)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(N)cc2C(F)(F)F)[C@H](F)C1
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of tert-butyl (3R,4R)-3-fluoro-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (1.2 g, 1.0 eq, 2.9 mmol) and Pd—C (10%, 0.3 g) in EtOH (50 mL) was hydrogenated at 30 psi for 1 hour. The mixture was filtered through celite and the filter cake washed with EtOH (2×10 mL). The filtrate was concentrated under vacuum to give the desired product in 82% yield. This product was taken to next step with out further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3([OH:47])[CH2:46][CH2:45][CH2:44]3)=[C:39]([O:48]C)[N:38]=2)=[CH:19][CH:20]2[N:24](CC3C=CC(OC)=CC=3OC)[C:23](=[O:36])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>C1(OC)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:37]2[NH:38][C:39](=[O:48])[C:40]([C:43]3([OH:47])[CH2:44][CH2:45][CH2:46]3)=[CH:41][CH:42]=2)=[CH:19][C@H:20]2[CH2:21][CH2:22][C:23](=[O:36])[NH:24]2)=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1ccc(CN2C(=O)CCC2C=C(c2ccc(C(C)(C)C)cc2)c2ccc(C3(O)CCC3)c(OC)n2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(C(=C[C@H]2CCC(=O)N2)c2ccc(C3(O)CCC3)c(=O)[nH]2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 5-{2-(4-tert-butylphenyl)-2-[5-(1-hydroxycyclobutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (EZ mixture) (35 mg) in anisole (1 mL), and the mixture was stirred at 85° C. overnight. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:5). The resulting compound was dissolved in 1,4-dioxane (1 mL) and 48% hydrobromic acid (1 mL) was added, after which the mixture was stirred at 65° C. for one hour. Aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire 19×150 mm 5 μm, rate: 20 mL/min, eluent: A=acetonitrile, B=0.1% trifluoroacetic acid solution, gradient: 10 to 90%) to give one isomer (A) of the title compound (1 mg, 8%) and the other isomer (B) of the title compound (1.0 mg, 8%) as colorless powders.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH2:9]([C:16]1[S:20][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:21]([C:19]1[S:20][C:16]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:17][CH:18]=1)(=[O:22])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc(Cc2ccccc2)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(Cc3ccccc3)s2)c1Br
Yield: 22 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-5-benzylthiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-benzyl-2-thiophenesulfonyl chloride in 22% yield. The product was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid, m.p. 49-50° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2.[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][N:9]2[S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: ClCCOc1cccc2[nH]ncc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ncc2c(OCCCl)cccc21
Reaction time: 0.5 h

Procedure:
A stirred solution of 4-(2-chloroethoxy)-1H-indazole (1.1 g, 5.59 mmol) in tetrahydrofuran is treated with NaH (0.335 g, 60% in mineral oil, 8.39 mmol) under nitrogen at room temperature, stirred for 30 minutes, treated with benzenesulfonyl chloride (0.86 ml, 6.71 mmol), stirred at room temperature for 18 hr, quenched with water and diluted with ethyl acetate. The phases are separated and the organic phase is washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane: 3/7) to give the desired product as a white solid, 1.75 g (93%), mp 102-104° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[N:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[CH:24][CH:25]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: CN(C)CCO
Product: CN(C)CCn1ncc(-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)c1-c1ccc(Cl)cc1

Procedure:
The title compound is prepared as described in Example 54, starting from {4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine (Example 32) and 2-dimethylamino-ethanol (Fluka).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: NCC1CCCCN1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-aminomethylpiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.93 minutes; C23H25Cl2N5O2 (474.39); mass spectrum: (M−H)−=473/475/477 (chlorine isotope).