Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@H:20]4[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]4)[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:31]([O:33][P:34](Cl)([O:36][CH2:37][CH3:38])=[O:35])[CH3:32]>N1C=CC=CC=1>[CH2:31]([O:33][P:34](=[O:35])([O:36][CH2:37][CH3:38])[O:30][CH2:29][C@@H:22]1[C@@H:23]([OH:28])[C@H:24]([OH:27])[C@@H:25]([OH:26])[C@H:20]([C:14]2[CH:15]=[CH:16][C:17]([CH2:18][CH3:19])=[C:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:13]=2)[O:21]1)[CH3:32]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)OC[C@H]1O[C@@H](c2ccc(CC)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 500 mg, 1.2 mmol) in pyridine (5 ml) was added diethylchlorophosphate (0.27 ml, 1.9 mmol) at −40° C. After stirring for 1 h at same temperature, reaction was quenched with the addition of 1N HCl and extracted with ethyl acetate (2×10 ml). Combined organic layers were washed with brine (10 ml), dried over sodium sulfate, concentrated and purified by preparative HPLC to give 220 mg of phosphoric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester diethyl ester as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[OH:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3ncc(C(O)c4c(F)cc5ncccc5c4F)n3n2)cn1
Temperature: 150 °C

Procedure:
(rac)-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(5,7-difluoro-quinolin-6-yl)-methanol (Stage 171.3, 1.8 g, 5.19 mmol) was introduced in a microwave reactor together with 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.08 g, 5.19 mmol), tetrakis(triphenylphosphine)-palladium (300 mg, 0.26 mmol), 2 M Na2CO3 (9.34 mL) and DME (20 mL). The mixture was heated at 150° C. under microwave irradiation for 50 min. The RM was taken up with EtOAc and washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with Et2O and the precipitate was filtered off to give the title compound as a black solid (tR 0.8 min (conditions 2), MH+=393)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH:10]1[C:19]2[C:14](=[C:15]([CH:20]([CH3:24])[C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:21](=[O:22])[CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH:13]=[CH:12][N:11]=[CH:10]3)[CH3:24])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)cc1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(Br)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-bromobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 371, 369 (M+H)+; MS (ESI−) m/z 369, 367 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.57 (d, J 7.1, 3H), 4.23 (d, J 6.1, 2H), 4.63 (q, J 7.1, 1H), 7.14 (m, 2H), 7.47 (m, 2H), 7.76 (m, 1H), 7.98 (t, J 7.5, 1H), 8.17 (d, J 7.1, 1H), 8.43 (d, J 7.8, 1H), 8.69 (br s, 1H), 8.74 (d, J 6.8, 1H), 8.92 (t, J 5.8, 1H), 9.88 (s, 1H); Anal. Calcd for C19H17BrN2O+1.4 HCl: C, 54.30; H, 4.41; N, 6.66. Found: C, 54.49; H, 4.28; N, 6.75.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1.[Al+3].[Cl-:15].[Cl-].[Cl-]>>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[Cl:15]
Reactant: Cc1ccc(C)cc1
Reactant: [Cl-]
Agent: CS(=O)(=O)Cl
Agent: [Al+3]
Product: Cc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 2.3 g (0.02 mole) of methanesulfonyl chloride, 20 ml (0.16 mole) of p-xylene, and 3.1 g (0.023 mole) of AlCl3 was stirred for one hour at 25° C. The product was worked up as described above in Example 1. 2,5-dimethylchlorobenzene was obtained in a 70% yield. NMR and VPC analysis of the crude product showed the presence of less than 1% of 2,5-dimethylphenyl methyl sulfone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([C:15](=[O:23])[CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH2:7][CH2:6]2.O.O.[Sn](Cl)Cl.Cl>C(O)C.CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([C:15](=[O:23])[CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN1CCOCC1)CC2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: COc1cc2c(cc1N)N(C(=O)CN1CCOCC1)CC2
Reaction time: 8 h

Procedure:
To a solution of 5-(methyloxy)-1-(4-morpholinylacetyl)-6-nitro-2,3-dihydro-1H-indole (0.56 g, 1.74 mmol) in absolute ethanol (100 mL) and DMA (20 mL) was added tin(II)chloride dihydrate (2.36 g, 10.45 mmol) and 1M HCl (1.0 mL). After overnight stirring, reaction was quenched with excess saturated NaHCO3 solution, stirred for one hr, filtered through celite which was and rinsed with methanol. After organic solvent removal, the aqueous layers were extracted with dichloromethane (2×200 mL), the combined organic layers were adsorbed to silica gel and purified by column chromatography (DCM to 5% MeOH/DCM+0.1% NH4OH) to afford 5-(methyloxy)-1-(4-morpholinylacetyl)-2,3-dihydro-1H-indol-6-amine. ESIMS (M+H)+=292.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][C:17]([F:38])([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:37])([O:28]COCC[Si](C)(C)C)[CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[C:10]([CH3:39])[C:9]=1[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:15][CH2:16][C:17]([F:38])([C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:28])([CH3:37])[CH3:27])=[CH:22][N:21]=3)[CH2:18][CH2:19]2)=[C:10]([CH3:39])[C:9]=1[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(F)(c3ccc(C(C)(C)OCOCC[Si](C)(C)C)cn3)CC2)c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(F)(c3ccc(C(C)(C)O)cn3)CC2)c1C

Procedure:
This example is prepared from compound 36 and TFA following a procedure described for example 63.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:30]=[CH:31]/[C:32]([O:34]C)=[O:33])[CH:7]=[C:8]([F:29])[C:9]=1[C@@H:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C@@H:12]([CH3:23])[N:11]1[CH2:24][C@H:25]([CH3:28])[CH2:26][F:27])=[CH:21][CH:20]=[CH:19][CH:18]=3.CO.Cl>C1COCC1.O.CCOC(C)=O>[F:29][C:8]1[CH:7]=[C:6](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[CH:5]=[C:4]([F:3])[C:9]=1[C@@H:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C@@H:12]([CH3:23])[N:11]1[CH2:24][C@H:25]([CH3:28])[CH2:26][F:27])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2C[C@H](C)CF)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](CF)CN1[C@H](c2c(F)cc(/C=C/C(=O)O)cc2F)c2[nH]c3ccccc3c2C[C@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
2M Sodium hydroxide (3.0 ml, 6.00 mmol) was added to a solution of (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-((S)-3-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (275 mg, 0.60 mmol) in THF (1.5 ml)/methanol (1.5 ml). The reaction was stirred at room temperature for 3 h. EtOAc (1.5 ml) and water (15 ml) were added, then the pH of the aqueous was adjusted to ˜7 by addition of 2N HCl. The layers were separated and the aqueous was extracted with EtOAc (15 ml). The combined organics were dried over Na2SO4 and concentrated. The crude product was purified by flash silica chromatography, elation gradient 0 to 10% methanol in DCM. Pure fractions were evaporated to dryness to afford the title product (250 mg, 94%) as a pale yellow solid. 1H NMR (400 MHz, DMSO, 30° C.)δ 0.77 (3H, d), 1.06 (3H, d), 1.93 (1H, n), 2.18 (1H, dd), 2.58 (1H, dd), 2.65 (1H, dd), 2.84 (1H, dd), 3.35 (1H, dd), 4.32 (1H, d), 4.44 (1H, d), 5.16 (1H, s), 6.67 (1H, d) 6.93-7.04 (2H m), 7.21 (1H d), 7.42 (1H, d), 7.46 (2H m), 7.54 (1H, d), 10.57 (1H, s), 12.51 (1H, s). m/z: ES+ [MH]+ 443.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH2:15][OH:16])=[O:5]>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]([F:17])([F:18])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH:15]=[O:16])=[O:5]
Reactant: COc1ccc(NC(=O)CC(F)(F)F)c(CO)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc(NC(=O)CC(F)(F)F)c(C=O)c1
Yield: 84.9 %

Procedure:
To a solution of 3,3,3-trifluoro-N-(2-(hydroxymethyl)-4-methoxyphenyl)propanamide (6.30 g, 23.9 mmol) in anhydrous CH2Cl2 (200 mL) was added MnO2 (20.0 g, 229 mmol). The mixture was refluxed for 16 hours. The mixture was filtered off and the filtrate was concentrated to give the product (5.30 g, yield 84%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][NH2:5].Br[CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[O:21])=[C:17]([CH3:19])[N:18]=2)[C:10]1=[O:31]>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20]([C:16]2[S:15][C:14]([N:11]3[CH2:12][CH2:13][CH:9]([NH:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])[C:10]3=[O:31])=[N:18][C:17]=2[CH3:19])=[O:21])=[CH:25][CH:26]=1
Reactant: NCCC(F)(F)F
Reactant: Cc1nc(N2CCC(Br)C2=O)sc1C(=O)NCc1ccc(F)cc1
Product: Cc1nc(N2CCC(NCCC(F)(F)F)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 19 %

Procedure:
Following the procedure as described in Example 5, making variation as required to use 3,3,3-trifluoropropan-1-amine in place of 2-cyclopropylethanamine to react with 2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 19% yield: mp 142-143° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.35 (m, 2H), 7.07-6.93 (m, 2H), 6.00 (br s, 1H), 4.51 (d, J=5.4 Hz, 2H), 4.29-4.16 (m, 1H), 3.65-3.81 (m, 1H), 3.76-3.64 (m, 1H), 3.15-3.02 (m, 1H), 2.98-2.85 (m, 1H), 2.61 (s, 3H), 2.60-2.48 (m, 1H), 2.43-2.22 (m, 2H), 2.08-1.89 (m, 1H), 1.79 (br s, 1H); MS (ES+) m/z 445.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11]>N1C=CC=CC=1>[Cl:11][CH2:10][CH:12]([OH:14])[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: ClCC1CO1
Reactant: O=Cc1cccc(O)c1
Solvent: c1ccncc1
Product: O=Cc1cccc(OCC(O)CCl)c1

Procedure:
A mixture of 3-hydroxybenzaldehyde (24.4 g, 0.2 mol), epichlorohydrin (47 ml) and pyridine (0.4 ml) is heated 5 hours on a steam bath. The crude mixture is partitioned between methylenechloride-water and the CH2Cl2 extract washed with dilute aqueous NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo to give the crude title product. Distillation gives a colorless oil bp 160° (0.2 mm); 21.2 g.
Reaction SMILES: [OH:1]CCCNC(=O)[C@H](C(CO)(C)C)O.[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>C(OC)(=O)C>[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:1])=[O:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCCO
Solvent: c1ccncc1
Solvent: COC(C)=O
Product: COc1ccc(C=CC(=O)O)cc1
Yield: 86 %

Procedure:
17.4 g of D-panthenol )0.085 mol) are placed in 300 ml of methyl acetate while gassing with argon in a 750 ml 4-necked sulphonation flask provided with a thermometer, a 100 ml dropping funnel, a magnetic stirrer and a reflux condenser. A solution of 75.5 g of 4-methoxycinnamic acid chloride (0.38 mol) in 150 ml of methyl acetate is then added dropwise within about 20 minutes. A solution of 33.6 g of pyridine (0.425 mol) is added dropwise within about 40 minutes. The reaction mixture is finally heated to reflux temperature for 4 hours. After cooling the precipitate is filtered off under suction. The filtrate is washed with 2× 150 ml of 5% HCl and then with 2× 100 ml of water. After drying over Na2SO4 the organic phase is concentrated on a rotary evaporator. The yellow, viscous residue (74.2 g) is chromatographed (toluene/ethyl acetate, 7:1) on 1 kg of silica gel (0.040-0.063 mm) under 0.5 bar pressure. There are obtained 50.1 g of yellow <R>-panthenol triester of p-methoxycinnamic acid (yield 86%).
Reaction SMILES: [CH2:1]([NH:17][CH2:18][CH2:19][NH2:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:21](OCC)(=[O:26])[CH2:22][C:23]([CH3:25])=O>>[CH2:1]([N:17]1[C:21](=[O:26])[CH2:22][C:23]([CH3:25])=[N:20][CH2:19][CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCCCCCNCCN
Product: CCCCCCCCCCCCCCCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 284.1 g (1 mole) of N-hexadecylethylenediamine and 130.1 g (1 mole) of ethyl acetoacetate. At 160° to 170° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-hexadecyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [CH:1]([CH:3]([CH2:8][CH2:9][O:10][CH3:11])[CH2:4][CH2:5][O:6][CH3:7])=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[CH3:7][O:6][CH2:5][CH2:4][CH:3]([CH2:8][CH2:9][O:10][CH3:11])[CH:1]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COCCC(C=O)CCOC
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=CC(CCOC)CCOC
Yield: 82.7 %

Procedure:
A solution of 23 (1.10 g, 6.88 mmol) and (carbethoxymethylene)triphenylphosphorane (2.63 g, 7.56 mmol, 1.1 equiv) was refluxed in CH2Cl2 (8.2 mL) for 24 h. The solvent was removed at reduced pressure. The oily residue was chromatographed [silica, hexanes/diethyl ether (1:1)] to yield a pale yellow oil (1.31 g, 88%): 1H NMR δ 1.50-1.62 (m, 2H), 1.69-1.85 (m, 2H), 2.45-2.51 (m, 1H), 3.23-3.33 (m, 10H), 5.79 (d, J=16.1 Hz, 1H), 6.71 (dd, J=9.5 Hz, J2=16.1 Hz, 1H); 13C NMR δ 14.46, 34.42, 36.40, 58.79, 60.48, 70.42, 122.03, 152.01, 166.73; FAB-MS obsd 231.1596, calcd 231.1598 [(M+H)+, M=C12H22O4].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10]([O:12]C)=[O:11].[OH-].[Na+]>C1COCC1.O.O>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)O
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Methyl 1-methyl-4-nitro-1H-pyrrole-2-carboxylate (5.0 g, 27.17 mmol) in 120 ml of 1:1 THF/H2O was added 8 g of NaOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 3˜4 with 20% H3PO4 and extracted with EtAc (4×60 ml). The organic solutions were combined, dried over MgSO4, filtered, evaporated and crystallized with ethanol/EtAc/Hexane to afford 4.06 g (88%) of the title product. 1H NMR (DMSO) 13.12 (s, 1H), 8.21 (s, 1H), 7.25 (s, 1H), 3.91 (s, 3H); 13C NMR 160.97, 134.01, 129.16, 123.81, 111.38, 37.47; MS m/z−169.1 (M−H).
Reaction SMILES: Br[C:2]#[N:3].N1C=CN=C1.[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:21][NH2:22])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1>C(Cl)Cl.C1COCC1>[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[O:20][C:2]([NH2:3])=[N:22][N:21]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: NNC(=O)c1ccc2cnccc2c1
Reactant: N#CBr
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1nnc(-c2ccc3cnccc3c2)o1
Yield: 95.1 %

Procedure:
A 3 M DCM solution of bromoformonitrile (0.2 mL, 0.6 mmol) (commercially available from Aldrich) was mixed with imidazole (0.157 g, 2.3 mmol) (commercially available from Aldrich) in 10 mL DCM. The mixture was heated and maintained to reflux for 30 minutes in a round bottom flask. After the DCM was removed under a reduced pressure, isoquinoline-6-carbohydrazide (0.1 g, 0.53 mmol) suspended in 50 mL THF was added into the flask. The mixture was heated and maintained at reflux for 3 hours. After removing the THF, the remaining residue was mixed with 10 mL water and filtered. After washing with water and air drying, a white solid was obtained as the desired product (0.107 g, 96%) LCMS (API-ES) m/z (%): 213.0 (100%, M++H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][Si:6]([CH3:21])([CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]1[CH2:14][O:13]1>C(O)C>[CH3:21][Si:6]([CH3:5])([CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([OH:13])[CH2:14][NH:4][CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: CC(C)NCC(O)COCCC[Si](C)(C)CC[Si](C)(C)C
Temperature: 60 °C

Procedure:
Isopropylamine (2.15 g, 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 60° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 60° C. for an additional 8 hours. Ethanol and isopropylamine were stripped off on the rotovap. The mixture was distilled under vacuum distillated to remove impurities.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:21][C:22]([C@@H:24]4[CH2:26][C@H:25]4[C:27]([O:29]CC)=[O:28])=[O:23])[CH:18]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:21][C:22]([C@@H:24]4[CH2:26][C@H:25]4[C:27]([OH:29])=[O:28])=[O:23])[CH:18]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)Nc1ccc2c(c1)CC(NC(=O)c1nc(Cl)c(CC)[nH]1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1[nH]c(C(=O)NC2Cc3ccc(NC(=O)[C@@H]4C[C@H]4C(=O)O)cc3C2)nc1Cl
Yield: 74.1 %

Procedure:
The same operation as in Example (91d) was performed using ethyl trans(±)-2-[(2-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-2,3-dihydro-1H-inden-5-yl)carbamoyl]cyclopropanecarboxylate obtained in Example (98b) (100 mg, 0.23 mmol), 2 N lithium hydroxide (3 mL, 6 mmol) and methanol (3 mL), to obtain 71 mg of the title compound as a colorless solid (76%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH2:18][C:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)C>C1(C)C=CC=CC=1>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH2:14][CH2:13][N:12]([CH2:18][C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: C1=C(/C=C/c2ccccc2)CCNC1
Solvent: Cc1ccccc1
Product: C1=C(/C=C/c2ccccc2)CCN(Cc2c[nH]c3ncccc23)C1
Yield: 56.5 %

Procedure:
A solution of (E)-4-(2-phenylethenyl)-1,2,3,6-tetrahydropyridine (204 mg, 1.1 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (192 mg, 1.1 mmol) [prepared by the method of M. M. Robison and B. L. Robison, J. Am. Chem. Soc.,1955, 77, 457] in toluene (15 ml) was stirred under reflux for 24 h. The hot solution was filtered and the filtrate allowed to cool, giving the title compound (196 mg, 55%) as a pale brown solid, m.p. 210°-212° C.; (Found: C, 80.43; H, 6.45; N, 13.18. C21 H21N3O. 0.1 PhMe requires: C, 80.31; H, 6.74; N, 12.95%); δH (CDCl3) 2.42 (2H, br s, 3'-CH2), 2.72-2.75 (2H, m, 2'-CH2), 3.20 (2H, br s, 6'-CH2), 3.83 (2H, s, CH2N), 5.82 (1H, br s, CH=CR), 6.44 (1H, d, J 16.1 Hz, CH=CHPh), 6.78 (1H, d, J 16.3 Hz, CH=CHPh), 7.07-7.10 (1H, m, 5-H), 7.17-7.21 (1H, m, ArH), 7.26-7.31 (3H, m, ArH), 7.38-7.40 (2H, m, ArH), 8.09 (1H, dd, J 7.9, 1.5 Hz, 4-H), 8.31 (1H, dd, J 4.8, 1.5 Hz, 4-H), and 9.31 (1H, br s, NH); m/z (CI+, NH3) 316 (M+1)+.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]([CH:9]1[C:13]2([CH2:15][CH2:14]2)[NH:12][C:11](=[O:16])[CH2:10]1)=C>CO.O.[Os](=O)(=O)(=O)=O>[O:16]=[C:11]1[CH2:10][CH:9]([CH:7]=[O:2])[C:13]2([CH2:15][CH2:14]2)[NH:12]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC1CC(=O)NC12CC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=CC1CC(=O)NC12CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Osmium tetroxide (55 mg, 0.22 mmol) and sodium periodate (1.4 g, 6.6 mmol) were added in portions to a solution of 7-ethenyl-4-azaspiro[2.4]heptan-5-one (0.50 g, 3.3 mmol) in methanol (8 mL) and water (12 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was dried under reduced pressure to afford 5-oxo-4-azaspiro[2.4]heptane-7-carbaldehyde. The material was used in the next step without purification. MS ESI calc'd. for C7H10NO2 [M+H]+ 140. found 140.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:36])[O:33][CH:32]([CH2:34]O)[CH2:31][O:30]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([O:27][CH2:34][CH:32]3[CH2:31][O:30][C:29]([CH3:36])([CH3:28])[O:33]3)=[O:26])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reactant: CC1(C)OCC(CO)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)OCC2COC(C)(C)O2)cn3C2CC2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
1-cyclopropyl-6-fluoro-4-oxo-7-(4-propylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (8.86 g, 23.70 mmol) was dissolved in anhydrous dichloromethane (370 ml) under argon. 2,2-dimethyl-1,3-dioxolane-4-methanol (4.71 g, 35.60 mmol), triethylamine (9.59 g, 94.80 mmol) and HBTU (9.90 g, 26.10 mmol) were added and the reaction mixture was stirred at room temperature for three days (exclusion of light). The reaction mixture was washed with saturated NaHCO3 solution (500 ml), aqueous (pH 5) hydrochloric acid (500 ml) and water (500 ml) successively. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure, yielding 10.28 g (89%) of a yellow solid.