Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.Cl.[CH3:6][CH:7]1[CH:12]=[C:11]([C:13]([O:15]CC(Cl)(Cl)Cl)=[O:14])[N:10]2[C:21](=[O:24])[CH:22]([NH2:23])[C@H:9]2[S:8]1>CN(C)C=O.[Zn]>[CH3:6][CH:7]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]2[C:21](=[O:24])[CH:22]([NH2:23])[C@H:9]2[S:8]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Reaction time: 1 h
Yield: 44.3 %

Procedure:
Acetic acid (1 ml) and zinc powder (2.0 g) were added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (1.53 g) in dimethylformamide (10 ml) and the mixture was stirred for 1 hour at -5° to 0° C., after which the reaction mixture was filtered. The filtered zinc powder was washed with dimethylformamide and the filtrate and the washings were combined, after which a few mls. of water was added to the solution. The precipitated crystals were collected by filtration and dissolved in a small amount of a sodium bicarbonate aqueous solution and then the insoluble material was filtered off. The filtrate was adjusted to pH4 with 10% hydrochloric acid and the precipitated crystals were collected by filtration, washed with water and acetone and dried to give 2-methyl-7-amino-3-cephem-4-carboxylic acid (0.38 g), mp 222° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[CH3:16][P:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([O:27][CH3:28])[CH:21]=1)([CH3:19])=[O:18].Cl>CN(C=O)C.C(O)C>[CH3:19][P:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:3]=[C:4]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=[C:6]([CH3:8])[N:7]=2)=[C:22]([O:27][CH3:28])[CH:21]=1)([CH3:16])=[O:18]
Reactant: COc1cc(P(C)(C)=O)ccc1N
Reactant: Cc1nc(Cl)cc(Nc2ccccc2)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc(P(C)(C)=O)ccc1Nc1cc(Nc2ccccc2)nc(C)n1

Procedure:
To a solution of 6-chloro-2-methyl-N-phenylpyrimidin-4-amine (0.35 mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline (60 mg, 0.30 mmol) in 1 mL of DMF, is added 0.36 mL of 2.5M HCl in Ethanol. The reaction mixture can be heated in a sealed tube at 140 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: I[C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:23][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(C(=O)O)c1I
Product: CC(C)(C)c1ccc(Nc2c(C(=O)O)cccc2C(=O)O)cc1
Yield: 93 %

Procedure:
Similar reaction of 2-iodoisophthalic acid and 4-tert-butylaniline gave 2-[(4-tert-butyl)phenylamino]isophthalic acid (93%), mp (EtOAc/petroleum ether) 221-222° C. 1H NMR [(CD3)2SO] δ 1.24 (s, 9 H, 3×CH3), 6.84 (d, J=8.7 Hz, 2 H, H-2' and H-6' or H-3' and H-5'), 6.99 (t, J=7.7 Hz, 1 H, H-5), 7.21 (d, J=8.6 Hz, 2 H, H-3' and H-5' or H-2' and H-6'), 7.93 (d, J=7.8 Hz, 2 H, H-4 and H-6), 9.65 (br s, 1 H, NH) and 12.99 (br s, 2 H, 2×COOH Anal. (C18H13NO2) C, H, N.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][N:37]=[CH:38][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:20][N:21]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][N:37]=[CH:38][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Yield: 98.5 %

Procedure:
A solution of compound 6 (3.28 g, 6.37 mmol) in TFA/DCM (60, 1:1) was stirred at room temperature for 30 min. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel eluting with CH2Cl2/methanol/NH4OH (200:10:1) to give the title compound (7) as an off-white solid (2.60 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ 9.86 (1H, s), 9.28 (1H, s), 9.01 (1H, s), 8.68 (1H, br s), 8.45 (1H, d, J=4 Hz), 8.23 (1 H, d, J=8 Hz), 8.10 (1H, d, J=4 Hz), 8.04 (1H, d, J=8 Hz), 7.54 (1H, dd, J=8 Hz, J=4 Hz), 5.43 (1H, p, J=8 Hz), 3.35 (4H, m), 3.26 (4H, m), 2.40 (2H, m), 2.03-2.10 (4H, m), 1.78 (2H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 415.1, Calculated 415.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]CC2C=CC=CC=2)[C:5]([CH3:16])=[N:4][C:3]=1[C@@H:17]1[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]1[OH:19]>CO>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH3:16])=[N:4][C:3]=1[C@@H:17]1[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]1[OH:19]
Reactant: Cc1nc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(N)nc1OCc1ccccc1
Solvent: CO
Product: Cc1nc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(N)[nH]c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 116.6 %

Procedure:
6-Amino-2-benzyloxy-3-methyl-5-β-D-ribofuranosylpyrazine (21 mg, 0.060 mmol) was dissolved in MeOH (3 mL) at RT and the solution cooled to 0° C. PdOH--C was added and the suspension stirred under H2 (g) for 1 h at 0° C. The catalyst was quickly removed by filtration and the product containing solution recovered in a precooled flask. The resulting colorless solution was cooled in N2 (1). Evaporation of the solvent at low temperature under high vacuum yielded 6-amino-3-methyl-5-(β-D-ribofuranosyl)-pyrazin-2-one (18 mg, quant.) as amorphous white solid. Dissolution of the crude product at RT in H2O followed by addition of CH3CN and cooling yielded a few mg of crystalline material. The rest of the material was recovered as amorphous solid after evaporation of the solvent. M.p. 165° C. (dec.); FAB-MS (glycerin): 258 (M+ +1); IR (KBr): 3420 (br.), 3930, 1625 (br.), 1540, 1475, 1375, 1160 (sh), 1075 (br.), 960, 795; 1H-NMR (DMSO): 2.07 (s, 3H, Me-C(3)), 3.40-3.58 (m, 2H, Ha-C(5') and Hb-C(5')), 3.75-3.78 (quadruplettoide m, 1H, H--C(4')), 3.95 (s, very br., 1H, H--C(3')), 4.16-4.17 (quadruplettoide m, 1H, H--C(2')), 4.60 (d, J=6.7, 1H, H--C(1')), 4.75-4.79 (m, 2H, HO--C(2') and HO--C(3')), 5.11-5.13 (triplettoide m, br., 1H, HO--C(5')), 5.79 (s, br. 2H, NH2), 11.1 (s, very br., 1H, NH); 1H-NMR (D2O): 2.19 (s, 3H, Me-C(3)), 3.79 (dd, J=3.4, 12.5, 1H, Ha-C(5')), 3.84 (dd, J=3.0, 12.5, 1H, Hb-C(5')), 4.07 (ddd, J=3.0, 3.4, 3.7, 1H, H--C(4')), 4.25 (dd, J=3.7, 5.8, 1H, H--C(3')), 4.37 (dd, J=5.8, 7.7, 1H, H--C(2')), 4.79 (d, J=7.7, 1H, H--C(1')); 13C-NMR (D2O): 19.91 (q, Me-C(3)), 64.06 (t, C(5')), 73.59, 75.42, 82.94 and 87.69 (d, C(1'), C(2'), C(3') and C(4')), 116.97, 141.05, 145.86 and 160.09 (s, C(2), C(3), C(5) and C(6)); Anal. calc. for C10H15N3O5 (257.25): C 46.69, H 5.88, N 16.33; found: C 46.31, H 5.82, N 15.82.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH2:36]([N:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][NH2:42])[CH3:37]>C1COCC1>[CH2:36]([N:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][NH:42][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:35])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH3:37]
Reactant: CCN(CC)CCCN
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)C)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 75.1 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (18 mg, 0.04 mmol) in THF (3 mL) was added N,N-diethyl-1,3-propanediamine (0.028 mL, 0.18 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (17 mg, 83%). LC-MS m/z 566 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 6H), 1.27 (d, 6H), 1.55 (m, 2H), 2.30 (s, 3H), 2.40 (m, 2H), 2.52 (m, 4H), 3.07 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[O:13])=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1.Br[C:35]1[C:40]([Cl:41])=[CH:39][C:38]([Cl:42])=[CH:37][N:36]=1>C1(C)C=CC=CC=1.CCO.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[O:13])=[CH:10][C:9]=1[C:35]1[C:40]([Cl:41])=[CH:39][C:38]([Cl:42])=[CH:37][N:36]=1
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: COc1ccccc1NC(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccccc1NC(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Temperature: 100 °C
Yield: 67.1 %

Procedure:
A solution of 2N Na2CO3 (5.85 mL) and Pd(PPh3)4 (340 mg, 0.29 mmol) was added to a degassed mixture of 4-chloro-N-(2-methoxy-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (2.2 g, 5.85 mmol) and 2-bromo-3,5-dichloro-pyridine (1.47 g, 6.44 mmol) in toluene (30 mL) and EtOH (6 mL). The mixture was heated at 100° C. for 12 hrs. Upon cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water and brine, and was dried over Na2SO4. After filtration and concentration the mixture was taken up in EtOAc, filtered, washed with EtOAc (3×), MeOH and ether to yield 1.6 g of 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide. MS [M+H]+: 406.9; tR=3.03 min. (method 1)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:26](O)[C:27]#[C:28][CH3:29]>>[CH2:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)[C:27]#[C:28][CH3:29]
Reactant: CC#CCO
Reactant: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(-c2cccs2)cc1
Product: CC#CCOc1ccc(SC(C(=O)OCC)c2ccc(-c3cccs3)cc2)cc1
Yield: 74 %

Procedure:
Ethyl {[4-(2-butynyloxy)phenyl]sulfanyl}[4-(2-thienyl)phenyl]acetate was prepared according to the general method as outlined in example 83 (step 2), starting from ethyl [(4-hydroxyphenyl)sulfanyl][4-(2-thienyl)phenyl]acetate (1.6 g, 4.3 mmol) and 2-butyn-1-ol (0.33 ml, 4.32 mmol); 1.34 g yellow oil. Yield 74%; MS(EI): 421.71 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][O:13][C:12]3=[O:22])=[N:7][C:6]=12.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[N:47]=[CH:46][N:45]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[N:44]=3)=[CH:39][CH:38]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:16]1([C@H:15]2[CH2:14][O:13][C:12](=[O:22])[N:11]2[C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[CH:3][C:2]([C:37]4[CH:38]=[CH:39][C:40]([C:43]5[N:47]=[CH:46][N:45]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[N:44]=5)=[CH:41][CH:42]=4)=[C:6]3[N:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2ccc(-c3ncn(COCC[Si](C)(C)C)n3)cc2)OC1(C)C
Reactant: O=C1OC[C@H](c2ccccc2)N1c1ccn2ncc(Br)c2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccccc5)nc34)cc2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution of (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one (0.7 g, 1.9 mmol) in dioxane bubbled with nitrogen was added sodium carbonate (2.0 M, 4.9 mL, 9.7 mmol) and 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (1.0 g, 2.5 mmol), and the reaction was degassed with nitrogen for 30 minutes. XPHOS (0.093 g, 0.19 mmol) and Pd2 dba3 (0.089 g, 0.097 mmol) were added to the mixture and the reaction was stirred for 2 hours at 80° C. The reaction was poured into water and the aqueous layer extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material purified by normal phase chromatography using 25% EtOAc/DCM as the eluent to yield (S)-4-phenyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.80 g, 1.4 mmol, 74% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]=[N+]=[N-])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@H](C(NN)=O)CC1N=CNC=1)=O)C1C=CC=CC=1.[C:46]1([NH:52][C:53]([C@@H:55]2[CH2:59][CH2:58][CH2:57]N2)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]1[CH2:57][CH2:58][CH2:59][C@H:55]1[C:53]([NH:52][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:54])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reactant: O=C(Nc1ccccc1)[C@@H]1CCCN1
Agent: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1)OCc1ccccc1

Procedure:
To 45 ml of an ethyl acetate solution of Nα -benzyloxycarbonyl-L-histidine azide (4) prepared from 3.03 g of Nα -benzyloxycarbonyl-L-histidine hydrazide (3) by a known method was added 1.52 g of compound (94) under ice-cooling and the reaction was maintained overnight in a refrigerator. The reaction mixture was concentrated and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with chloroform-methanol (95:5), 2.49 g of Nα -benzyloxycarbonyl-L-histidyl-N-phenyl-L-prolinamide (95) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Br[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[CH:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2
Reactant: Brc1ccc2ccccc2c1
Reactant: Nc1cccc2cccnc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1cc2c(c(Nc3ccc4ccccc4c3)c1)NCCC2
Temperature: 25 °C
Yield: 52 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added 8-aminoquinoline (6.81 grams, 47.2 mmoles), 2-bromonapthalene (9.58 grams, 46.3 mmoles), tris(dibenzylideneacetone)dipalladium (0) (0.84 grams, 0.92 mmoles), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.6 grams, 0.92 mmoles), sodium tert-butoxide (8.86 grams, 92.2 mmoles) and anhydrous toluene (90 mL). The contents of the flask were refluxed for sixteen hours; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (135 mL). The combined organic layers were concentrated in vacuo to yield a yellow solid. The solid was chromatographed on silica gel, eluting with a hexane/ethyl acetate gradient to afford 6.6 grams of the desired product as a yellow solid. 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.4 (bs, 1H), 8.05 (d, 1H), 7.6-7.9 (m, 5H), 7.25-7.5 (m,5H), 7.2 (d, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].F[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:35]1([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[C:10]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:9]=3)[CH2:4][CH2:3]2)[C:36]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: OC1CCN(c2nc(-c3ccccc3)nc3ccccc23)CC1
Reactant: Fc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(N3CCC(Oc4cccc5ccccc45)CC3)c3ccccc3n2)cc1

Procedure:
Equimolar quantities of 4-(4-hydroxypiperidinyl)-2-phenylquinazoline, sodium hydride and 1-fluoronaphthalene are heated in dimethylformamide to prepare the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[NH:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=2[F:20])[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=2[F:20])[CH3:11])[C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CC(NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1ccc(F)c(F)c1F
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(NC(c1ccc(Cl)cc1)c1cccc(N)c1)c1ccc(F)c(F)c1F

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 3.96 g of N-[(4-chlorophenyl)-(3-nitrophenyl)methyl]-N-[1-(2,3,4-trifluorophenyl)ethyl]amine [prepared as described in step (a) above], 4.47 g of nickel chloride hexahydrate and 1.42g of sodium borohydride were reacted, to obtain 1.05 g of isomer A and 720 mg, of isomer B of the title compound, each as a pale yellow oil.
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[C:23]([NH:33][C:34](=[O:56])[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]3[N:44]=[C:45]([C:49]4[O:50][CH:51]=[CH:52][CH:53]=4)[O:46][C:47]=3[CH3:48])=[C:37]([O:54][CH3:55])[CH:36]=2)=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=O.O>CN(C)C=O>[O:50]1[CH:51]=[CH:52][CH:53]=[C:49]1[C:45]1[O:46][C:47]([CH3:48])=[C:43]([CH2:42][O:41][C:38]2[CH:39]=[CH:40][C:35]([C:34]([NH:33][C:23]3[C:22](/[CH:20]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:26][N:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:24]=3)=[O:56])=[CH:36][C:37]=2[O:54][CH3:55])[N:44]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(C(=O)Nc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
To a solution of tetraethyl methylenediphosphonate (277 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 38 mg), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added a solution of N-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzamide (400 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 1:0, v/v), then methanol-ethyl acetate (0:1 to 0.5:9.5, v/v) to give diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzoyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless amorphous form (380 mg, yield 75%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:16][CH2:17][CH:18]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20]>>[CH2:31]([O:30][C:28]([NH:27][CH:18]([C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:17][NH:16][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: NCC(NC(=O)OCc1ccccc1)C(=O)N1CCCCC1
Product: O=C(NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1)OCc1ccccc1
Yield: 44 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-[3-amino-2-(benzyloxycarbonylamino)propionyl]piperidine to give N-[2-(benzyloxycarbonylamino)-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)piperidine-4-carboxamide in 44% yield;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[N:15]12[CH2:22][CH2:21][CH2:20][C:19]1([CH2:23][NH2:24])[CH2:18][CH2:17][CH2:16]2>>[N:15]12[CH2:22][CH2:21][CH2:20][C:19]1([CH2:23][NH:24][C:2]1[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:18][CH2:17][CH2:16]2
Reactant: NCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1ccc2ccccc2c1Cl
Product: O=[N+]([O-])c1ccc2ccccc2c1NCC12CCCN1CCC2
Yield: 84.1 %

Procedure:
1-Chloro-2-nitronaphthalene and (1-azabicyclo[3.3.0]octan-5-yl)methylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 84.1%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:12].N1C=CC=CC=1.C([O:22][C:23]1[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:25](Cl)=[O:26])(=O)C.Cl>CC(C)=O.CO.[OH-].[Na+]>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:12])[NH:11][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[OH:22]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Nc1cc(Br)c(O)c(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: CO
Product: O=C(Nc1cc(Br)c(O)c(C(=O)O)c1)c1ccccc1O
Yield: 95.8 %

Procedure:
3-Bromo-5-aminosalicylic acid (0.73 g.) was dissolved in acetone (30 ml.) and pyridine (0.4 ml.) to which an acetone (14 ml.) solution containing acetyl-salicyloyl chloride (prepared from 0.53 g. of acetyl-salicylic acid) was added dropwise with stirring. After reaction the solution was evaporated to dryness under reduced and the residue was dissolved in ethyl acetate. After washing the solution with water and 1 N hydrochloric acid successively, the ethyl acetate was evaporated off under reduced pressure, yielding a residue which was redissolved in a mixture of methanol and 2 N sodium hydroxide (14 ml. each). After stirring the solution for several hours and then acidifying with 2 N hydrochloric acid solution, a precipitate was formed, collected and crystallized from aqueous methanol to give light brown crystals (0.90 g.) of 3'-bromo5'-carboxy-2,4'-dihydroxybenzanilide,