Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=NC(C)(C)C.CN(C)CCN(C)C.C([Li])CCC.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[O:41]1CCCC1>>[C:35]1([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH:1]=[O:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCCCCCCCc1ccccc1
Reactant: C1CCOC1
Reactant: Cc1ccccc1C=NC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Product: O=Cc1ccccc1CCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
) To a solution of N-[(2-methylphenyl)methylene]-1,1-dimethylethanamine (5.0 g, 0.03 mol) and N,N,N',N'-tetramethylethylene diamine (3.31 g, 0.03 mol) in tetrahydrofuran (40 mL), n-butyl lithium (2.5M, 11.4 mL, 0.03 mol) at 0° C. was slowly added. The solution was stirred for an additional 30 min followed by the quick addition of 1-bromo-7-phenylheptane (7.28 g, 0.03 mol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to room temperature and stirring was continued for 15 h. The reaction mixture was quenched with 10% aqueous hydrochloric acid (50 mL) and stirred for 30 min. The layers were separated, methylene chloride (50 mL) was added to the organic layer and the organics were washed with saturated brine solution (50 mL). The organics were then dried (magnesium sulfate), and concentrated to an oil to yield 2-(8-phenyloctyl)benzaldehyde (3.8 g, 45%): IR (neat film) 2920, 2880, 1695, 1600, 1455 cm-1 ; 1H NMR (CDCl3, 400 MHz) δ 10.25 (s, 1 H), 7.80 (dd, 1 H, J=1.2 and 7.7 Hz), 7.45 (m, 1 H), 7.33-7.13 (m, 7 H), 2.98 (t, 2 H, J=7.7 Hz), 2.58 (t, 2 H, J=7.7 Hz), 1.58 (m, 4 H), 1.30 (m, 8 H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][N:17]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]([CH2:20][C@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=[CH:18]1>>[C:23]([C@H:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]([CH3:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: Cn1cc(C[C@@H](N)C(=O)O)c2ccccc21
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: Cn1cc(C[C@@H](Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)c2ccccc21
Yield: 87 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 1-methyl-D-tryptophan to provide the title compound in 87% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[C:8]([O:22][CH2:23][CH3:24])[CH:7]=2.[NH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>C(#N)C>[CH2:23]([O:22][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([CH2:2][N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH2:37][CH2:36]3)[C:4]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=3)=[N:5]2)=[CH:10][C:9]=1[S:17]([CH2:20][CH3:21])(=[O:18])=[O:19])[CH3:24]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CBr)c(C(=O)OC)c2cc1S(=O)(=O)CC
Solvent: CC#N
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)OC)c2cc1S(=O)(=O)CC
Reaction time: 3 h
Yield: 51 %

Procedure:
A suspension of methyl 3-(bromomethyl)-7-(ethyloxy)-6-(ethylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.54 g, 6.31 mmol) and 4-(4-piperidinyl)morpholine (1.397 g, 8.20 mmol) in acetonitrile (30 mL) was stirred for 3 h. The solvent was removed under reduced pressure, and the residue was diluted with NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DMF and purified via HPLC (Biotage RP, 0-50% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford methyl 7-(ethyloxy)-6-(ethylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.09 g, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ8.37 (s, 1H), 7.97 (s, 1H), 7.90 (t, J=8.53 Hz, 2H), 7.76-7.81 (m, 2H), 4.39 (q, J=6.94 Hz, 2H), 4.01 (s, 3H), 3.50-3.64 (m, 9H), 2.63 (d, J=11.29 Hz, 2H), 2.38 (br. s., 4H), 1.95-2.05 (m, 1H), 1.81 (t, J=11.17 Hz, 2H), 1.61 (d, J=11.54 Hz, 2H), 1.45 (t, J=7.03 Hz, 3H), 1.19-1.30 (m, 2H), 1.15 (t, J=7.40 Hz, 3H); MS (m/z) 650.2 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13].C(=O)([O-])[O-].[Ca+2]>C(C(C)=O)C>[Cl:1][CH2:2][C:3]([N:17]1[CH2:18][CH2:19][N:14]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=2[CH3:13])[CH2:15][CH2:16]1)=[O:4]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCC(C)=O
Product: Cc1cccc(N2CCN(C(=O)CCl)CC2)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (1.47 ml, 18.5 mmol) is added dropwise to a solution of 1-(2,3-xylyl)piperazine (3.2 g, 16.8 mmol) and calcium carbonate (5 g, 50 mmol) in methyl ethyl ketone (40 ml) cooled to 0° C. The reaction mixture is stirred at this temperature for 1 h 30 and it is then filtered through Celite. The Celite is rinsed several times with ethyl acetate and 3M sodium hydroxide solution. The two phases of the filtrate are then separated and the organic phase is dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[CH:10]=[CH:11]/[C:12]([O:14]C(C)(C)C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)O)CSc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of Example 480A (5 g, 13.2 mmol) and Wilkinson's catalyst (1 g) in tolune (125 mL) was stirred under H2at 60° C. for 18 hours, cooled, filtered through silica gel, and concentrated. The concentrate was dissolved in 3:1:1 THF/water/MeOH (150 mL), treated with with a 10-fold excess of LiOH, and stirred for 24 hrs. The mixture was poured into saturated NaH2PO4 (200 mL) and extracted three times with ethyl acetate (200 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 324, 326 (M−H)−, (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([Cl:16])[CH:9]=2)=[O:5])[CH3:2].[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:23]1[CH2:24][CH2:25][N:20]([CH:17]([CH3:19])[CH3:18])[CH2:21][CH2:22]1)=[C:10]([Cl:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)c(Cl)cc2[nH]1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.7 %

Procedure:
To a cold (0° C.) mixture of 6-chloro-5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (625 mg, 1.0 eq.), 1-Isopropyl-piperidin-4-ol (448 mg, 1.2 eq.) and triphenylphosphine (846 mg, 1.2 eq.) in tetrahydrofuran (8 mL) was added dropwise a solution of di-tert-butylazodicarboxylate (725 mg, 1.2 eq.) in tetrahydrofuran (7 mL). The reaction mixture was stirred for 20 h at room temperature. The volatile components were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with a gradient of dichloromethane/methanol/ammonia from 98:2:0 to 90:9:1 as eluant to afford 635 mg (67%) of the tide compound as a light-yellow foam.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:14](=[S:16])=[S:15].Br[CH2:18][C:19]#[N:20]>C1COCC1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[C:14]([S:16][CH2:18][C:19]#[N:20])=[S:15]
Reactant: N#CCBr
Reactant: CNc1ccncc1
Reactant: S=C=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C(=S)SCC#N)c1ccncc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a cold (−10° C.) solution of 4-(methylamino)pyridine (9 g, 0.0841 mol) in anhydrous THF (200 mL) was added n-butyl lithium (2.5M, 44 mL, 0.11 mol) dropwise such that the temperature remained below −7° C. The resulting pale yellow suspension was allowed to stir for about one hour at −10° C. To this mixture was added carbon disulfide (10.2 mL, 12.936 g, 0.168 mol) over one hour at 0° C. and the mixture was left to stir overnight at room temperature. The resultant mixture was cooled to 0° C. and bromoacetonitrile (8.8 mL, 15.14 g, 0.126 mol) was added dropwise. The resultant mixture was stirred at room temperature for two hours. The reaction mixture was extracted with diethyl ether (400 mL) and washed with saturated NaHCO3 and brine. The organic layers were combined and dried (Na2SO4) and reduced to a dark brown oil. The crude was dissolved in ethyl acetate and purified by column chromatography (silica gel 60, 70-230 mesh, 30% ethyl acetate in n-hexane as eluent), gave the title compound as off-white cubes (11.05 g, 59% yield). 1H nmr (CDCl3) δ (ppm) 3.78 (s, 3H, N—CH3); 4.05 (s, 2H, SCH2CN); 7.25 (m, 2H, m-ArH); 8.75 (m, 2H, o-ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:28](=[O:29])[N:27]([CH3:31])[CH3:26]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 399.9 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and N,N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M−H]−); IR (thin film) 3350, 1705, 1114, 808 cm−1.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:13](#[N:17])[CH2:14][C:15]#[N:16]>N1CCCCC1.C(O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[OH:12])[CH:7]=[C:14]([C:13]#[N:17])[C:15]#[N:16]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=C(C#N)C#N)cc(I)c1O

Procedure:
A preferred method of synthesis of (E)-1-cyano-3- (3-iodo-4,5-hydroxyphenyl)acrylonitrile (Compound 2) is as follows: The compound was prepared as described in Ohmichi et al., 1993, Biochemistry 32:4650 in two steps. First, 3-methoxy-4-hydroxy-5-iodobenzylidene malononitrile was prepared by adding 3 drops of piperidine to 1.4 g of 5-iodovanillin and 0.4 g of malononitrile in 25 ml of ethanol and refluxing the mixture for 4 hours. 0.8 g (49% yield) of a yellow solid resulted.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C(N(CC)CC)C.[O:15]=[CH:16][C:17]([Cl:20])([Cl:19])[Cl:18].C(O)(=O)C>C1C=CC=CC=1>[CH3:7][O:6][C:4]([C@H:3]1[C@H:16]([C:17]([Cl:20])([Cl:19])[Cl:18])[O:15][CH:2]=[N:1]1)=[O:5]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: [C-]#[N+]CC(=O)OC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1N=CO[C@H]1C(Cl)(Cl)Cl
Yield: 85.7 %

Procedure:
5.0 g of methyl α-isocyanoacetate and 5.0 g of triethylamine are dissolved in 40 ml of benzene. 7.4 g of chloral are added to the solution at 0° C under stirring. The mixture is stirred at room temperature for 4 hours. Then, the mixture is neutralized with acetic acid, and evaporated under reduced pressure to remove solvent. The residue is dissolved in 50 ml of ethyl acetate. The solution is washed with water, dried, and then evaporated under reduced pressure to remove ethyl acetate. The residue thus obtained is distilled under reduced pressure. 10.6 g of trans-4-methoxycarbonyl-5-trichloromethyl-2-oxazoline are obtained. Yield: 85% B.p. 95° C/1 mmHg
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:24]=[C:25]=[O:26])[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:24][C:25](=[O:26])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=NCc1ccco1
Product: O=C(NCc1ccco1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with furfurylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (15.3 mg, 28%) having the following characteristics.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([O:18]CC)=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)Cl.[H-].C([Al+]CC(C)C)C(C)C.C[OH:42].[C:43]1([CH3:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O>[CH2:49]([O:42][C:11]1[CH:10]=[CH:9][CH:14]=[CH:13][C:12]=1[CH:15]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:16]=[O:18])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CO
Reactant: CCOC(=O)C(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: O=CC(Cc1ccccc1)c1ccccc1OCc1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
9.5 g (0.026 mol) of ethyl 2-(4-benzyloxyphenyl)-3-phenylpropionate, 40 ml of toluene and 30 ml of methylene chloride are introduced into a three-necked flask. The mixture is cooled to -70° C. 44 ml of 1M diisobutylaluminium hydride in toluene are added over a period of 15 minutes. The mixture is stirred at that temperature for one hour. 30 ml of methanol and 60 ml of water are added at -70° C. The alumina is filtered off and the aqueous phase is extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated to dryness. There are obtained 8.2 g of 2-benzyloxyphenyl-3-phenylpropionaldehyde. Yield: 100%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
(R)-1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid (922.3 mg, 4.285 mmol) was dissolved in dichloromethane (42.8 mL, 0.1M) at room temperature under nitrogen and was treated with N,O-dimethylhydroxylamine hydrochloride (501.6 mg, 5.142 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea (1955 mg, 5.142 mmol), and N,N-diisopropylethylamine (1493 μL, 8.570 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was then diluted to 100 mL with dichloromethane and washed with water (100 mL). The water layer was back extracted with 4/1 dichloromethane/isopropanol (2×50 mL). The combined organics were washed with water (100 mL), were isolated, dried over sodium sulfate, filtered and concentrated to an oil. The crude product was loaded onto an SP1 samplet and purified by silica gel chromatography using a gradient from 10% to 70% acetone in hexanes. Product containing fractions (ninhydrin visualization) were pooled and concentrated to afford (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate as an oil (1.1 gram, 100% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH2:16])[CH:8]=2)[CH2:3][CH2:2]1.[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH:16][C:20]([CH:17]3[CH2:19][CH2:18]3)=[O:21])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(N2CCOCC2)n2nccc2n1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(N2CCOCC2)n2nccc2n1)C1CC1

Procedure:
7-Morpholinopyrazolo[1,5-a]pyrimidin-5-amine (9A, 0.10 mmol) in pyridine (0.4 ml), cyclopropanecarboxylic acid (0.15 mmol) in pyridine (0.4 ml), HATU (0.17 mmol) in pyridine (0.4 ml) and DIEA (0.34 mmol) are mixed together before microwave irradiation at 150° C. for 6 minutes. The crude product was then purified by preparatory HPLC to give the titled compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00-1.09 (m, 2H) 1.09-1.16 (m, 2H) 1.99-2.09 (m, 1H) 3.91-3.98 (m, 4H) 4.12-4.21 (m, 4H) 6.47 (d, J=2.26 Hz, 1H) 7.27 (s, 1H) 7.51 (s, 1H) 7.98 (d, J=2.07 Hz, 1H) 13.03 (br. s., 1H); ESI-MS: m/z 288 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[O:3]1.[OH-].[K+].[F:21][C:22]1[C:27]([CH:28]=[O:29])=[C:26]([F:30])[CH:25]=[CH:24][C:23]=1[NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33]>CO>[F:21][C:22]1[C:27]([CH:28]([OH:29])[C:17]2[C:11]3[C:12](=[N:13][CH:14]=[C:9]([B:4]4[O:3][C:2]([CH3:18])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]4)[CH:10]=3)[NH:15][CH:16]=2)=[C:26]([F:30])[CH:25]=[CH:24][C:23]=1[NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F

Procedure:
In a round bottom flask, 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (27, 0.400 g, 1.64 mmol) is combined with 10 mL of methanol and potassium hydroxide (0.256 g, 4.56 mmol). Propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (28, 0.400 g, 1.52 mmol) is added and the reaction is stirred at room temperature for 3 hours, with additional potassium hydroxide added up to 7 equivalents. The reaction is concentrated under vacuum, the solid added to water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of 10-100% ethyl acetate (with 2.5% acetic acid) in hexanes. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound. MS (ESI) [M+H+]+=508.37.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)[N:11]=[C:5]2[CH:4]=1)#[N:2].[C:21]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH2:29])([CH3:24])([CH3:23])[CH3:22].CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH:29][CH2:28][CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:30])=[O:18])=[CH:19][CH:20]=3)[N:11]=[C:5]2[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: N#Cc1ccn2cc(-c3ccc(C(=O)O)cc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2cn3ccc(C#N)cc3n2)cc1

Procedure:
6.6 g of 4-(7-cyanoimidazo[1,2-a]pyridin-2-yl)benzoic acid [obtainable as in Example 5]in 100 ml of dichloromethane and 25 ml of DMF are stirred with 4.5 g of β-alanine tert-butyl ester in the presence of 5.25 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide and 6 ml of N-methylmorpholine at room temperature for 20 h. This is followed by extraction 3-4 times with 30 ml of water each time, evaporation and the customary working-up. Tert-butyl 3-[4-(7-cyanoimidazo[1,2-a]pyridin-2-yl)benzamido]propionate is obtained, m.p. 212° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].C[Si]([N:20]=[C:21]=[S:22])(C)C.CN(C)C=O>CN(C)C(=O)C>[NH2:20][C:21]([NH:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])=[S:22]
Reactant: C[Si](C)(C)N=C=S
Reactant: NC(=O)c1cc(-c2ccccc2)sc1N
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)sc1NC(N)=S
Yield: 35.3 %

Procedure:
A solution of 2-amino-5-phenyl-3-thiophenecarboxamide (1.09 g, 5 mmol) and trimethylsilyl isothiocyanate (0.85 ml, 6 mmol) in N,N-dimethylacetamide was stirred at 75° C. for 7 days. N,N-Dimethylformamide was added until solution. The solvent was removed and the resulting slurry was chromatographed on silica gel eluting with isohexane followed by methylene chloride and diethyl ether to give the product as a yellow solid (0.49 g, 35%).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.Cl.C(O)C.O>O1CCCC1>[C:3]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)#[CH:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=C(Br)Br)cs2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of tert-butyl 4-[4-(2,2-dibromovinyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (1.26 g, 2.79 mmol) in anhydrous tetrahydrofuran (25 ml) was added dropwise at −78° C. a mixture of 1.6M-n-butyllithium-hexane solution (5.2 ml, 8.4 mmol) and anhydrous tetrahydrofuran (10 ml). After stirring at −78° C. for 2 hrs, 1.25M hydrogen chloride-ethanol solution (6.7 ml, 8.4 mmol) was added dropwise to the reaction mixture. The mixture was warmed to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was concentrated, and the concentrated residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9→1:4) to give tert-butyl 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (553 mg, yield 68%) as a yellow solid.