Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[OH:16][N:17]1[C:26](=[O:27])[C:25]2[CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=[C:23]3[C:24]=2[C:19](=[CH:20][CH:21]=[CH:22]3)[C:18]1=[O:34]>C(Cl)(Cl)Cl>[Si:8]([O:16][N:17]1[C:26](=[O:27])[C:25]2[CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=[C:23]3[C:24]=2[C:19](=[CH:20][CH:21]=[CH:22]3)[C:18]1=[O:34])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2cccc3cc([N+](=O)[O-])cc(c23)C(=O)N1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)ON1C(=O)c2cccc3cc([N+](=O)[O-])cc(c23)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
Triethyl amine (0.4 g, 4.0 mmol) and tert-butyldimethylsilyl chloride (0.6 g, 4.0 mmol) were added to a solution of 2-hydroxy-5-nitro-benzo[de]isoquinoline-1,3-dione (1.0 g, 3.9 mmol, from Example 1) in chloroform (10 mL). The mixture was stirred at room temperature for 3 hours and concentrated in vacuo to give a dark residue. Column chromatography (silica gel 2% methanol in chloroform) gave 1.1 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH:15]1[C:23]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1)=[O:24]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: Cc1ccc(-c2cc(N)n[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
3-Amino-5-(4-methylphenyl)pyrazole (35 mg) and indan-2-carboxylic acid (33 mg) were dissolved in pyridine (2 ml) to which was subsequently added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (30 ml), washed with water (30 ml), saturated aqueous sodium bicarbonate (30 ml) and saturated brine (30 ml) and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled away. The resulting crystalline residue was washed with ethyl ether to obtain the title compound (34 mg) as white crystals (melting point: 220-225° C.).
Reaction SMILES: C1(CNC(C2NC=C(C([C:15]3[C:16]([C:21]4[CH:26]=CC(F)=CC=4)=[N:17][O:18][C:19]=3C)=O)C=2)=O)CC1.[F:28][C:29]1[CH:30]=[C:31]([C:36]2[C:40]([C:41]([C:43]3[CH:44]=[C:45]([C:48](=[O:53])C(Cl)(Cl)Cl)[NH:46][CH:47]=3)=[O:42])=[C:39]([CH3:54])[O:38][N:37]=2)[CH:32]=[CH:33][C:34]=1[F:35]>>[O:18]1[CH2:26][CH2:21][CH:16]([NH:17][C:48]([C:45]2[NH:46][CH:47]=[C:43]([C:41]([C:40]3[C:36]([C:31]4[CH:32]=[CH:33][C:34]([F:35])=[C:29]([F:28])[CH:30]=4)=[N:37][O:38][C:39]=3[CH3:54])=[O:42])[CH:44]=2)=[O:53])[CH2:15][CH2:19]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c(C(=O)NCC2CC2)c1
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)NC2CCOCC2)c1

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-1H-pyrrole (intermediate 19) and tetrahydro-pyran-4-yl amine(commercially available) in 41.5 yield. (m/e): 416.1 (MH+; 100%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[S:37][CH3:38]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[S:37][CH3:38])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CSc1cc(C(C)=O)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.88 g, 8.5 mmol), K2CO3 (1.8 g) and 1-[4-(3-bromopropoxy)-3-methylmercaptophenyl]ethanone (2.3 g, 7.6 mmol) in acetonitrile (100 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was concentrated, then diluted with dichloromethane (250 ml). The insolubles were filtered off. The dichloromethane solution was concentrated to dryness as an oil. Purification was effected by flash a chromatography on a silica gel column (SiO2, 54 g, eluted with dichloromethane, 500 ml; 1% methanol-dichloromethane, 1.1 l). The purest fractions were combined to give a colorless oil which solidified to an off-white solid (2.4 g). Recrystallization from ethanol (100 ml) yielded 1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl]-1-piperidinyl]propoxy]-3-methylmercaptophenyl]ethanone as off-white needle crystals, 2.15 g, m.p.=150-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][C:6]=1[Br:7].[C:11]1([CH3:17])[CH:16]=CC=C[CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][C:11]([CH3:17])([CH3:16])[CH3:12])=[O:9])[O:5][C:6]=1[Br:7]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Product: CC(C)(C)OC(=O)c1cc(Br)c(Br)o1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture composed of 4,5-dibromo-2-furancarboxylic acid (20.00 g), DMF di-tert-butylacetal (71.08 ml) and toluene (100 ml) was stirred for 2 hours at 90° C. The reaction solution was diluted with toluene and washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/20), thereby giving 20.10 g of tert-butyl 4,5-dibromo-2-furancarboxylate.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:34]=[CH:33][C:23]2[N:24]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:26][C:22]=2[CH:21]=1>O1CCCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:30]1[CH2:31][CH2:32][N:27]([C:25]2[S:26][C:22]3[CH:21]=[C:20]([O:19][CH3:18])[CH:34]=[CH:33][C:23]=3[N:24]=2)[CH2:28][CH2:29]1)=[O:9])([CH3:2])[CH3:3]
Reactant: COc1ccc2nc(N3CCNCC3)sc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Solvent: C1CCOC1
Product: COc1ccc2nc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)sc2c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-Isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 6-Methoxy-2-piperazin-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white foam.
Reaction SMILES: [F:1]/[C:2](=[C:5](\[CH3:16])/[CH:6]=[CH:7]/[C:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[S:10][C:9]=1[CH3:15])/[CH2:3][OH:4]>CCOCC.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1]/[C:2](=[C:5](\[CH3:16])/[CH:6]=[CH:7]/[C:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[S:10][C:9]=1[CH3:15])/[CH:3]=[O:4]
Reactant: CC(/C=C/c1c(C)sc(C)c1C)=C(\F)CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(/C=C/c1c(C)sc(C)c1C)=C(\F)C=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The solution of 2E,4E-2-fluoro-3-methyl-5-(2,4,5-trimethyl-3-thienyl)-2,4-pentadien-1-ol in ether and methylene chloride was added to a rapidly stirred suspension of 40 g. of activated manganese dioxide in methylene chloride. After 14 hours of stirring at 25° C., thin layer chromatography indicated that no starting alcohol remained. The manganese dioxide was removed by filtration through Celite. The filtrate containing 2E,4E-2-fluoro-3-methyl-5-(2,4,5-trimethyl-3-thienyl)-2,4-pentadien-1-al was concentrated and used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:33]3[CH:32]=[N:31][CH:30]=[C:29]([F:28])[CH:34]=3)[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncc(F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide (Stage 182.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=5.71 min, UPLC-MS (Condition 3) tR=1.11 min, m/z=481.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=6.84 Hz, 3H) 3.15 (m, J=7.00 Hz, 2H) 3.32-3.41 (m, 2H) 3.42-3.52 (m, 2H) 4.61 (t, J=5.08 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.83 (d, J=0.78 Hz, 2H) 7.95 (d, J=1.17 Hz, 1H) 8.06 (d, J=1.00 Hz, 1H) 8.52-8.66 (m, 2H) 8.75 (d, J=2.74 Hz, 1H) 10.25 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([CH:29]=[CH2:30])=[CH:28][C:23]4=[N:22][CH:21]=3)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1.[OH2:39].CC(C)=O.[OH2:44]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([CH:29]([OH:44])[CH2:30][OH:39])=[CH:28][C:23]4=[N:22][CH:21]=3)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(C(O)CO)ccn12
Temperature: 25 °C

Procedure:
To a solution of N-(1-benzyl-1H-indazol-4-yl)-7-vinylimidazo[1,2-a]pyridine-3-carboxamide (27 mg; 0.069 mmol) in acetone/water (3:2; 1 mL) were added osmium tetroxide (0.1 equivalents as a 2% solution in t-butanol) and N-methylmorpholine N-oxide (1.2 equivalents as a 50% solution on water). The mixture was stirred at ambient temperature for several days. Further aliquots of osmium tetroxide and N-methyl morpholine N-oxide were added at intervals until the reaction was complete by LC. The mixture added to water and extracted into ethyl acetate. Some insoluble material was isolated by filtration. The extracts were combined, concentrated under vacuum and combined with the solids isolated by filtration. The combined material was purified by preparative thin layer chromatography on silica, eluting with dichloromethane/ethanol/ammonium hydroxide (100:20:0.5) to give the desired product (2.6 mg). MS (APCI), m/z=428.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[C:11](Cl)(=[O:13])[CH3:12]>>[C:9]([CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][CH:5]=1)#[N:10]
Reactant: N#CCc1cccc(N)c1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
To a mixture of (3-amino-phenyl)-acetonitrile (500 mg, 3.79 mmol) and TEA (498 mg, 4.93 mmol) was added acetyl chloride (387 mg, 4.93 mmol) slowly at 0° C. The resulting mixture was stirred at room temperature for 10 min. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with DCM twice. The combined organic layers were washed with aqueous ammonia chloride and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound (558 mg, 3.20 mmol, 85% yield) as a pale-yellow solid. MS (ESI) m/z 175.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:57])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:56])[CH:48]([NH2:55])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[O:58]1[CH2:63][CH2:62][CH:61]([CH2:64][C:65](O)=[O:66])[CH2:60][CH2:59]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3](=[O:57])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:56])[CH:48]([C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)[NH:55][C:65](=[O:66])[CH2:64][CH:61]6[CH2:62][CH2:63][O:58][CH2:59][CH2:60]6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(N)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: O=C(O)CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)CC6CCOCC6)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
[1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.085 g, 0.097 mmol), (Tetrahydro-pyran-4-yl)-acetic acid (0.017 g, 0.117 mmol), and N-methylmorpholine (0.032 mL, 0.292 mmol) were suspended in DMF (0.972 mL) at room temperature. Solid HATU (0.055 g, 0.146 mmol) was added and the suspension was allowed to stir at room temperature overnight. Upon completion, the reaction was quenched with a small amount of formic acid and purified by reverse phase HPLC (10-45% acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving {2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester (0.062 g, 62%) as a white solid. LCMS-ESI+: calc'd for C52H58N8O6: 890.45 (M+); Found: 892.4 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH2:13][C:14](=[O:16])[CH2:15][C:11]=2[C:10]([C:17]([OH:19])=[O:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27].C(Cl)CCl>C(Cl)Cl>[O:27]=[C:22]1[CH2:23][CH2:24][C:25](=[O:26])[N:21]1[O:18][C:17]([C:10]1[C:11]2[CH2:15][C:14](=[O:16])[CH2:13][C:12]=2[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]=1)=[O:19]
Reactant: O=C1Cc2c(C(=O)O)nn(Cc3ccccc3)c2C1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1Cc2c(C(=O)ON3C(=O)CCC3=O)nn(Cc3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step C (1.34 g, 5.25 mmol) in CH2Cl2 (50 mL) was added N-hydroxy succinimide (1.21 g, 10.5 mmol) followed by EDC (2.01 g, 10.5 mmol). After stirring at room temperature for 18 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL), washed with saturated NaHCO3, solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. A yellow solid was obtained.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:6][C:7]=1[CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH3:2].[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH2:1]([C:3]1[O:4][C:5]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=2)=[CH:6][C:7]=1[CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:15])=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)c1ccccc1
Reactant: CCOC(=O)CCNC
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1ccccc1
Yield: 84.6 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-[{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}(phenyl)methoxy]benzoic acid (117 mg) as well as ethyl 3-(methylamino)propanoate (39 mg) to give the title compound (117 mg, 98%) as an amorphous compound.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](Cl)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][CH:5]([C:3]([N:2]([CH3:28])[CH3:1])=[O:4])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:33][N:32]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: CN(C)C(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(C(=O)N(C)C)CC4)cc3n2)c(OC)n1

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid dimethylamide was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine in General Procedure A. Purification on silica yielded 125. NMR (CDCl3): 1.74 (m, 2H, CH2), 2.02 (m, 2H, CH2), 2.17 (m, 2H, CH2), 2.55 (m, H, CH), 2.97 (s, 3H, CH3), 3.04-3.07 (m+s, 5H, CH2+CH3), 3.84 (s, 2H, CH2), 3.88-3.90 (m, 4H, 2×CH2), 4.03-4.05 (m, 4H, 2×CH2), 4.08 (s, 3H, CH3), 4.11 (s, 3H, CH3), 7.30 (s, H, ArH), 8.93 (s, H, ArH). MS: (ESI+): MH+=528.45
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:13][C:12]([F:14])([F:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][NH2:1]
Reactant: O=[N+]([O-])C=Cc1ccccc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCCc1ccccc1C(F)(F)F

Procedure:
In close analogy to the procedure described above, 1-(2-Nitro-vinyl)-2-trifluoromethyl-benzene is reacted with lithium aluminium hydride to provide the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:11][CH3:12])=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1)[CH3:2].C(Cl)(Cl)Cl>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[C:4]([O:11][CH3:12])=[CH:5][C:6]([CH:9]=[O:10])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(CO)cc1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCc1cnc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.5 %

Procedure:
To a solution of 49 mg of (5-ethyl-4-methoxypyridin-2-yl)methanol in 1 mL of dichloromethane, 0.13 g of manganese dioxide was added. The mixture was stirred at room temperature for 1 hour 30 minutes, 0.13 g of manganese dioxide was then added thereto, and the mixture was stirred for 1 hour 30 minutes. Chloroform was added to the reaction mixture, the insoluble substance was filtered off, and the solvent was distilled off under reduced pressure to obtain 54 mg of 5-ethyl-4-methoxypyridine-2-carbaldehyde as a brown oily substance.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=O)[CH3:2].[C:8]([CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])#[N:9].C(O)(=O)C.N1CCCCC1>>[CH2:14]([O:13][C:11](=[O:12])[C:10]([C:8]#[N:9])=[CH:4][CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#CCC(=O)OCc1ccccc1
Reactant: CCC(C=O)CC
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCC(C=C(C#N)C(=O)OCc1ccccc1)CC
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a mixture of 2-ethylbutyraldehyde (2.0 mL, 16.2 mmol) and benzyl cyanoacetate (2.85 g, 16.2 mmol) at 0° C. was added acetic acid (0.1 mL, 1.62 mmol), then piperidine (0.16 mL, 1.62 mmol) dropwise. The ice bath was removed, and stirring continued for 10 minutes. Additional acetic acid (0.1 mL) and piperidine (0.16 mL) were added, followed by the additional of oven-dried 4A molecular sieves such that stirring was not impeded. The mixture was stirred 1.5 h, then partitioned between EtOAc and sat. NaHCO3 (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to provide 3.96 g (95%) of 2-cyano-4-ethyl-hex-2-enoic acid benzyl ester as a colorless oil. 1H NMR (CDCl3) δ 7.39 (m, 6H), 5.28 (s, 2H), 2.60 (m, 1H), 1.62 (m, 2H), 1.40 (m, 2H), 0.88 (t, J=7.6 Hz, 6H). 13C NMR δ 168.69, 161.40, 135.01, 128.90, 128.82, 128.50, 114.11, 109.94, 68.07, 46.35, 27.30, 11.95. IR (neat) 2233, 1729 cm−1. LRMS: m/z 256.1 (M−1). Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.75; H, 7.52; N, 5.50.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([OH:12])[CH2:6][C:5]1([CH3:14])[CH3:13].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:15]([O:1][CH2:2][CH2:3][N:4]1[C:5]([CH3:14])([CH3:13])[CH2:6][CH:7]([OH:12])[CH2:8][C:9]1([CH3:10])[CH3:11])(=[O:17])[CH3:16]
Reactant: CC1(C)CC(O)CC(C)(C)N1CCO
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCCN1C(C)(C)CC(O)CC1(C)C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Into a 250 ml flask equipped with a magnetic stirbar, thermometer, addition funnel and nitrogen atmosphere was placed 1-(2-hydroxyethyl)-2,2,6,6-tetramethyl-4-piperidinol (10.0 g, 0.499 mole) and 75 ml of methylene chloride. The resulting slurry was cooled to -20° C. and the addition funnel wash charged with acetic anhydride (5.1 g, 0.496 mole) and 15 ml of methylene chloride. The anhydride was added dropwise to the diol slurry with no apparent reaction. The mixture was warmed to 15° C. at which temperature the solids began to dissolve. The mixture was stirred at ambient temperature for 2 hours. The mixture was poured into 80 ml of 10% sodium carbonate (aqueous) and stirred for 15 minutes at ambient temperature. The mixture was transferred to a separatory funnel and extracted with 100 ml of methyl t-butyl ether. The ether solution was dried with anhydrous magnesium sulfate and the solvent removed using aspirator and high vacuum systems. The product was a white solid melting at 56°-58° C. This material was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1)(O)=[O:2].ClC(OCC)=O.[NH3:17]>O1CCOCC1.C(N(CCCC)CCCC)CCC>[C:1]([C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1)(=[O:2])[NH2:17]
Reactant: N
Reactant: Cc1cnc(C(=O)O)cn1
Agent: CCOC(=O)Cl
Solvent: C1COCCO1
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cnc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Carboxy-5-methylpyrazine (9.7 g) in dry dioxan (114 ml) and tributylamine (17.7 ml) was treated with ethyl chloroformate (7.5 ml), keeping the temperature at 0°-5° C. After ten minutes, dioxan (190 ml) saturated with ammonia was added. The mixture was stirred for 3 hours at room temperature, then dioxan was distilled off, and the residue was taken up in saturated aqueous sodium bicarbonate (20 ml). The mixture was filtered and the product washed with water to give 2-carbamoyl-5-methylpyrazine (9.2 g), m.p. 204°- 206° C. This amide (7 g) in glacial acetic acid (30 ml) and 35% hydrogen peroxide (20 ml.) was heated with stirring at 70° C for 7 hours. The reaction mixture was cooled, the product which separated was filtered and washed with water to give 2-carbamoyl-5-methylpyrazine 4-oxide (5.5 g), m.p. 206°- 208° C.