Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].CN.[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:31][NH:32][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14]
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NC)ccc21
Yield: 48.4 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (75.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), methylamine (2.0 M solution in THF, 1.0 mL), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 421.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([N+:16]([O-])=O)[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:30]([C:32]3[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=3)=[O:31])[CH:27]=2)[CH:22]=[CH:21]1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]3[N:13]=[C:36]([C:35]4[CH:34]=[CH:33][C:32]([C:30]([NH:29][C:26]5[CH:27]=[C:28]6[C:23]([CH:22]=[CH:21][NH:20]6)=[CH:24][CH:25]=5)=[O:31])=[CH:39][CH:38]=4)[NH:16][C:9]=3[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3cc[nH]c3c2)cc1
Reactant: Cc1noc(C)c1-c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: Cc1noc(C)c1-c1ccc2nc(-c3ccc(C(=O)Nc4ccc5cc[nH]c5c4)cc3)[nH]c2c1

Procedure:
Compound 651 was prepared according to the procedure similar to that described in Scheme III from 1-(3,5-dimethylisoxazol-4-yl)-3,4-dinitrobenzene and 4-(6-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C27H21N5O2: 448.17; found: 447.97.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([O:30][CH2:31][CH2:32][CH3:33])[C:9]([N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:12]C(OCC1C=CC=CC=1)=O)=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]([O:30][CH2:31][CH2:32][CH3:33])[C:9]([N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH2:12])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCON(C(=N)N(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCON(C(=N)N(N)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A mixture of [N,N′-di(tert-butoxycarbonyl)] 3-(benzyloxycarbonylamino)-1-propoxyguanidine (760 mg, 1.7 mmol), as prepared in the preceding step, and 10% Pd/C (80 mg) in ethanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenated under hydrogen (balloon) for 30 min. The catalyst was removed by filtration through Celite, the filtrate was concentrated in vacuo, and the residue was purified by Waters Sep-Pak (10 g, 95:5 methylene chloride:methanol saturated with ammonia) to give the title compound as a colorless oil (160 mg, 28%). 1H-NMR (300 MHz, CDCl3) δ4.12 (t, J=6.1 Hz, 2H), 2.85 (t, J=6.7 Hz, 2H), 1.84 (pentet, J=6.2 Hz, 2H), 1.50 (s, 9H), 1.48 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(Cl)cc3)cc21

Procedure:
Prepared according to Procedure A from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 4-chlorophenyl boronic acid. White solid: mp 255-257° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.7 (d, 2H, J=8.52 Hz), 7.55 (m, 2H), 7.5 (d, 2H, J=8.52 Hz), 6.96 (d, 1H, J=8.52 Hz), 1.7 (s, 6H); MS (ESI) m/z 288 ([M+H]+, 70%); Anal. Calc. For C16H14ClNO2: C, 66.79, H, 4.90, N, 4.87. Found: C, 66.34, H, 4.76, N, 4.75
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][C:5]([CH3:13])([CH3:12])[C:6]2[CH:7]=[C:8]([S:16]([Cl:15])(=[O:18])=[O:17])[CH:9]=[CH:10][C:11]1=2
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=S(=O)(O)Cl
Product: CC1(C)CCC(C)(C)c2cc(S(=O)(=O)Cl)ccc21
Temperature: 60 °C

Procedure:
94.0 g (0.5 mol) of 1,2,3,4-tetrahydro-1,1,4,4tetramethylnaphthalene were stirred into 100 ml of chlorosulfonic acid at 20° C. within 30 min. The reaction solution was maintained at 60° C. for 1 hour, cooled to room temperature and then poured into 1.5 1 of ice and extracted with ether. The organic phase was washed to neutrality with brine and water, dried over magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from methanol yielded 55.0 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-sulfonyl chloride of melting point 71°-74° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:10]([CH2:13][C:14](OCC)=[O:15])([O-:12])=[O:11].N1CCCCC1>C1(C)C(C)=CC=CC=1>[N+:10]([C:13]1[C:14](=[O:15])[NH:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)([O-:12])=[O:11]
Reactant: Nc1ccccc1C=O
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2ccccc2cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 50.8 %

Procedure:
2-Aminobenzaldehyde (1.75 g, 14.5 mmol) was dissolved in xylene (87.5 mL). To this, ethyl 2-nitroacetate (6.43 mL, 58.0 mmol) and piperidine (1.58 mL, 16.0 mmol) were added and the mixture was stirred with heat at 150° C. for 1.5 hours and successively stirred with cooling in an ice bath for 0.5 hour. The precipitate was collected by filtration and dried under reduced pressure. Thus, 3-nitroquinolin-2(1H)-one (1.40 g, yield: 51%) was obtained.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][NH:5]1)#[N:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[C:47](Cl)(=[O:49])[CH3:48]>>[C:47]([N:5]1[CH2:6][CH2:7][C:8]2[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])=[N:12][C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[N:10][C:9]=2[CH:4]1[CH2:3][C:1]#[N:2])(=[O:49])[CH3:48]
Reactant: CC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3CC#N)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)=O)C3CC#N)cc1
Reaction time: 4 h

Procedure:
1-(4-(8-(Cyanomethyl)-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (0.100 g, 0.230 mmol) in dry N,N-Dimethylformamide (1.00 mL, 12.9 mmol) was added N,N-Diisopropylethylamine (0.120 mL, 0.689 mmol) followed by Acetyl chloride (0.0246 mL, 0.346 mmol). The reaction mixture was stirred for 4 hours. The reaction mixture was concentrated and chromatographed through silica gel (12 g, 0-5% MeOH in dichloromethane). LC/MS-m/z+478.5 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:5](Br)=[C:6](Br)[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].[Br-:14].C([N+](CC)(CC)CCCCC)C>C(Cl)Cl>[Br:1][C:2]([Br:14])=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCCc1cccc(Br)c1Br
Reactant: [Br-]
Agent: CCCCC[N+](CC)(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: BrC(Br)=Cc1ccccc1

Procedure:
A solution of 147.90 g. (0.431 mole) of 2-bromoethyl-dibromobenzene in 250 ml. of methylene chloride was stirred for 7 ks (2 hours) at 5 Hz (300 rpm) at 313 K. (40° C.) with 150 g (2.25 mole) of 60 percent sodium hydroxide solution and 3.12 g. (0.0124 mole) of triethylpentyl ammonium bromide. The product was washed with three 500-ml portions of water, dried over calcium sulfate (Drierite), and stripped of solvent in a rotary evaporator at a bath temperature of 323 K. (50° C.). The yield of product was 106.97 g. (77.2 percent of theory). GC analysis showed 27.1 percent of the desired ar-dibromostyrene, the remainder being largely unreacted starting material.
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1.[CH2:41]([NH2:43])[CH3:42]>O1CCOCC1.C(Cl)(Cl)Cl>[CH2:41]([NH:43][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1)[CH3:42]
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCBr)C(=O)c1cc2c(cc1-3)OCO2
Reactant: CCN
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CCNCCCOc1cc2c3c(n(CCCN4CCOCC4)c(=O)c2cc1OC)-c1cc2c(cc1C3=O)OCO2
Yield: 48.2 %

Procedure:
Sodium iodide (0.060 g, 0.408 mmol) and compound 19 (0.020 g, 0.034 mmol) were diluted with dioxane (8 mL), and ethylamine (0.020 mL, 0.408 mmol, 70 wt. % solution in water) was added dropwise. The mixture was stirred at reflux for 26 h. The mixture was diluted to a volume of 200 mL with CHCl3, washed with H2O (2×50 mL) and saturated aq NaCl (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography (SiO2, ˜40 g), eluting with a gradient of 0.5% MeOH in CHCl3, to yield the product 24 as a solid (0.009 g, 46%): mp 187-188° C. (dec). IR (film) 1648, 1553, 1392, 1254, 1116, 1033, 785 cm−1; 1H NMR (CDCl3) δ 7.53 (s, 1H), 7.24 (s, 1H), 6.90 (s, 1H), 6.60 (s, 1H), 5.89 (s, 2H), 4.06 (s, 2H), 3.85 (s, 6H), 3.72 (s, 3H), 3.49-3.38 (m, 4H), 3.19-3.12 (m, 9H), 2.25-2.19 (m, 4H); ESIMS m/z 550 (MH+); HRESIMS m/z 550.2553 (MH+), calcd for C30H36N3O7 550.2553; HPLC purity: 98.36% (C-18 reverse phase, MeOH—H2O, 80:20).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.C([O:10][C:11](=[O:17])[CH2:12][C:13](=O)[CH2:14]Br)C>CO>[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:13]([CH2:12][C:11]([OH:17])=[O:10])=[CH:14][N:4]2[N:3]=1
Reactant: Cc1nnc(N)s1
Reactant: CCOC(=O)CC(=O)CBr
Solvent: CO
Product: Cc1nn2cc(CC(=O)O)nc2s1
Temperature: 80 °C

Procedure:
A mixture of 5-methyl-[1,3,4]thiadiazol-2-ylamine (300 mg, 2.6 mmol), 4-bromo-3-oxo-butyric acid ethyl ester (908 mg, 2.6 mmol) and 5 mL of MeOH was combined in a sealed tube and was heated to 80° C. for 3 hours. The reaction was cooled and the MeOH was removed in vacuo. The residue was dissolved in dichloromethane and the organic solution was washed with saturated aqueous NaHCO3 solution (2×). The organic solution was dried over sodium sulfate, filtered and concentrated. The crude product was purified by Combiflash (Teledyne ISCO, Lincoln, Nebr.) chromatography using 0-100% EtOAc/heptanes. Both the desired product and (2-methyl-imidazo[2,1-b][1,3,4]thiadiazol-6-ylyacetic acid methyl ester (formed by trans esterification with solvent MeOH) were obtained with a total mass of 333 mg (54%). The crude mixture was used directly in the next step
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[CH:15]1([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:21][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CC1CCCCC1
Product: CC(C)(C)OC(=O)NC1CCN(CC2CCCCC2)CC1

Procedure:
The title compound was prepared (1.83 g, 83%) from tert-butyl piperidin-4-ylcarbamate (1.50 g, 7.48 mmol) and cyclohexanecarbaldehyde (0.84 g, 7.48 mmol) by following the general procedure described for Preparation 3. 1H NMR (400 MHz, CDCl3) δ 4.80 (bs, 1H), 3.71 (m, 1H), 3.63 (m, 2H), 2.53 (m, 2H), 2.43 (m, 2H), 2.00-1.61 (m, 9H), 1.44 (s, 9H), 1.23 (m, 4H), 0.95 (m, 2H); MS (ESI) m/z: Calculated for C17H33N2O2, 297.25; Observed: 297.1 (M++1).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:21][CH2:22][CH:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:14]1([O:13][C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][C:4]4[CH:3]=[CH:2][N:21]([CH2:22][CH:23]([OH:25])[CH3:24])[C:5]=43)=[CH:10][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=CCC1Cc2ccc(OC3CCCC3)cc2C1=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)Cn1ccc2c1-c1cc(OC3CCCC3)ccc1C2
Reaction time: 0.75 h
Yield: 48.5 %

Procedure:
A solution of 2.58 g of (RS)-2-(2-oxoethyl)-6-cyclopentoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.44 g (48%) of (RS)-1-(7-cyclopentoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+].[Cl-].[Na+]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: O=C(N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1)c1ccc(Cl)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To the aqueous solution of (R)-1-(p-chlorobenzoyl)-3-amino piperidine obtained in Example 14 (amount: 3 g), p-chlorobenzoyl chloride (0.15 g) was added. The pH of the mixture was kept from pH 8.0 to 9.0 using sodium hydroxide. The mixture was stirred at 15° C. for 3 hours, and chlorobenzene (3 ml) and sodium chloride (0.5 g) were added. The mixture was stirred at 90° C. for 10 minutes. The water layer was removed, and the solvent was evaporated under reduced pressure to obtain the title compound as yellow crystal (0.16 g, yield: 36%).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[F:17])=[N+]=[N-]>[Pd].C1COCC1.CCO>[NH2:1][C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][C@H:5]1[F:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N=[N+]=[N-])[C@H](F)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Reaction time: 2 h
Yield: 35.7 %

Procedure:
Palladium on carbon (10%, 0.876 g, 0.823 mmol) was added to a solution of (cis)-tert-butyl 4-azido-3-fluoropiperidine-1-carboxylate (2.01 g, 8.23 mmol) dissolved in THF and EtOH (1:1, 82 mL). The reaction was placed under a hydrogen atmosphere (balloon pressure) and stirred for 2 hours. The mixture was filtered through GF/F paper and concentrated in vacuo. The amine was purified on a Varian Bond Elut SCX column, eluting with methylene chloride followed by a solution of MeOH containing 6% aqueous NH4OH. The second eluant was concentrated in vacuo to provide the desired product (642 mg). MS ESI (+) m/z 218.8 (M+1) detected.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C@@H:47]([CH3:50])[CH2:48][OH:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:42])[NH:46][C@@H:47]([CH3:50])[CH2:48][OH:49])=[CH:35][CH:36]=3)=[C:28]([CH:43]([CH3:44])[CH3:45])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: C[C@H](N)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)N[C@@H](C)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and (S)-2-amino-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[CH:24][C:25]([C:27]([OH:29])=O)=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:31]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:36][CH2:37][NH:38][C:27]([C:25]2[CH:24]=[CH:23][C:18]3[NH:19][C:20](=[O:22])[CH2:21][C:15]4[CH:14]=[N:13][C:12]([NH:11][C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:30][C:16]=4[C:17]=3[CH:26]=2)=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NCCN1CCCC1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)O)ccc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)NCCN4CCCC4)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic acid (I-43) and 2-(pyrrolidin-1-yl)ethanamine were converted to I-75 (6%) after purification by C-18 RP LC-MS chromatography. HRMS Calcd. for C27H30N61O4: 503.2406, Found 503.2399.
Reaction SMILES: OCC(N[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][C:16]2[CH:17]=[C:18]([C@H:23]3[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]3)[CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:13][CH:12]=1)(C)C.[NH2:36][C:37]([CH2:42][OH:43])([CH2:40][OH:41])[CH2:38][OH:39]>>[OH:39][CH2:38][C:37]([NH:36][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[CH:17]=[C:18]([C@H:23]3[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]3)[CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:34][CH:35]=1)([CH2:42][OH:43])[CH2:40][OH:41]
Reactant: NC(CO)(CO)CO
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCNC(C)(C)CO)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCNC(CO)(CO)CO)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The same procedure was employed as for amine 24, using 2-amino-2-(hydroxyl-methyl)propane-1,3-diol, to provide the product 25 as the bisformate salt. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.53 (s, 2 H), 6.98-7.23 (m, 7 H), 4.39 (d, J=9.3 Hz, 1 H), 4.13 (d, J=9.1 Hz, 1H), 3.94-4.03 (m, 2 H), 3.69 (s, 6 H), 3.34-3.50 (m, 3 H), 3.03-3.13 (m, 2 H), 2.58-2.69 (m, 2 H), 2.20 (s, 3 H), 2.12-2.18 (m, 3 H), 1.70 (m, 4 H). [M+H]+=537.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(OC)C=CC=CC=1.CCS.[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>[CH2:11]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:7]=[CH:8]1
Reactant: COc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: S=C=S
Product: C1=Cc2ccccc2C1

Procedure:
Treatment of p-methoxydeoxybenzoic (32) (FIG. 4) with PCl5 in refluxing benzene provided p-methoxy-α'-chlorostilbene 33 (Nagano, 1955), which underwent Friedel-Crafts conditions with anisole to furnish the triarylethylene 34. The carbonyl group in deoxybenzoic 32 was converted to a gem-dichloride intermediate, using phosphorus pentachloride, and with the subsequent elimination of HCl, the vinyl chloride 33 was obtained. Compound 32 was prepared using Friedel-Crafts conditions involving phenylacetyl chloride and anisole in carbon disulfide and aluminum chloride (BUCK, J. S. and IDE, W. S. (1932), "The isomeric desoxybenzanisoins", Journal of the American Chemical Society, 54, 3012). Demethylation of 35 was accomplished with EtSH/AlCl3, and 36 was isolated by column chromatography. Drying of phenol 36 at a high temperature resulted in the formation of an indene, which was observed previously (MAGARIAN, R. A., MELTON, S. AND NATARELLI, G. (1972), "2-Chloro-1-phenylindene from 1,1-dichloro-trans-2,3-diphenylcyclopropane", Journal of Pharmaceutical Sciences, 61, 1216). Compound 36 was isolated as the diacetate (37) using column chromatography.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](O)=O)[CH3:2].[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1)[CH2:9][CH2:10][CH3:11]>C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[NH:19][C:14]2[CH:13]=[C:12]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:17]=[CH:16][C:15]=2[N:18]=1)[CH3:2]
Reactant: CCCCc1ccc(N)c(N)c1
Reactant: CCOCC(=O)O
Solvent: CCOC(C)=O
Product: CCCCc1ccc2nc(COCC)[nH]c2c1

Procedure:
20.8 g of ethoxyacetic acid are added to 23 g of crude 4-butyl-1,2-phenylene-diamine and the mixture is heated at 130° for 90 minutes. It is allowed to cool and is taken up in ethyl acetate, washed with sodium bicarbonate solution and then three times with water, dried over sodium sulphate and filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is chromatographed on 600 g of silica gel using chloroform as the solvent. After a small initial fraction, 2-ethoxymethyl-5-butyl-benzimidazole is obtained in the main fraction.
Reaction SMILES: [Br-].[NH2:2][C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2CC2C=CC=CC=2)=[CH:5][C:4]=1[C:21]([O:23]CC)=O.[CH3:26][N:27](C=O)C.C(O)=O>C(N)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[NH:7][C:3]2[N:2]=[CH:26][N:27]=[C:21]([OH:23])[C:4]=2[CH:5]=1
Reactant: CCOC(=O)c1cc(-c2cccc[n+]2Cc2ccccc2)[nH]c1N
Reactant: CN(C)C=O
Agent: [Br-]
Solvent: O=CO
Solvent: NC=O
Product: Oc1ncnc2[nH]c(-c3ccccn3)cc12

Procedure:
Under a protective gas, 27.07 g of 2-(5-amino-4-ethoxycarbonyl-1H-pyrrol-2-yl)-N-benzyl-pyridinium bromide in 195 ml of formamide are heated for 16 hours at 150° C. with 97.6 ml of DMF (dried over 4A molecular sieve) and 48.8 ml of formic acid. When the dark-brown reaction mixture is cooled in an ice-bath, the title compound crystallizes and can be filtered off and washed with isopropanol and diethyl ether; 1H-NMR (300 MHz, DMSO-d6): 12.5 and 11.9 (2s, 2H), 8.60 (d, J=7, 1H), 8.05-7.8 (m, 3H), 7.28 (dd, J1 =7, J2 =9, 1H), 7.20 (s, 1H); FAB-MS: (M+H)+ =213.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17](O)[CH3:18]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:16])[CH2:11][CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: CC(CCC(=O)O)c1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)CCC(C)c1ccc([N+](=O)[O-])cc1
Yield: 97 %

Procedure:
A mixture of 110 g of 4-(4-nitrophenyl)valeric acid, 600 ml of absolute ethanol and 10 ml of concentrated sulfuric was heated under reflux overnight. The ethanol was evaporated in vacuo and the residue was partitioned between ether and water. The ether extract was washed with 5% of sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered and evaporated to give 119 g (97%) of product, bp 127°-128° (1.5 mm).