Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH:4]=[C:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH3:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCO.CCOC(C)=O.C(Cl)Cl.[Pd]>[CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH3:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)CC(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Reaction time: 20 h

Procedure:
To a solution of N-methyl-3-(3-methyl-1H-indol-5-yl)-3-phenyl-acrylamide LXXII (386 mg, 1.33 mmol) in EtOH/EtOAc/DCM (2/1.5/1, 55 ml) was added Degoussa-type catalyst (Pd/C 10%, 40 mg), and the mixture was hydrogenated in a Parr apparatus at 50 psi of H2 for 20 hours. The reaction mixture was filtered through celite, and the filter cake was washed with MeOH, EtOAc and DCM. The filtrate was concentrated to afford N-Methyl-3-(3-methyl-1H-indol-5-yl)-3-phenyl-propionamide LXXIII as a white foamy solid (341 mg, 89% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C)=[CH:11][CH:10]=1)[N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.[NH4+].[OH-]>Cl>[CH3:1][CH:2]([CH3:19])[CH:3]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[N:4]1[CH:8]=[N:7][CH:6]=[N:5]1
Reactant: CC(=O)Nc1ccc(C(C(C)C)n2cncn2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)C(c1ccc(N)cc1)n1cncn1
Temperature: 60 °C
Yield: 75.4 %

Procedure:
A mixture of (±)—N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]acetamide (0.095 mol) in HCl (3N) (250 ml) was stirred and heated at 60° C. for 5 hours. The mixture was cooled, poured into ice, basified with concentrated NH4OH and extracted with CH2Cl2. The organic layer was dried, filtered off and evaporated. The residue was crystallized from 2-propanone/(C2H5)2O and filtered off, yielding 15.5 g (75%) of (±)-4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-benzenamine (interm. 2; mp. 117.8° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]([CH3:26])[N:19]=[C:20]([CH3:25])[C:21]=3[N+:22]([O-])=O)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.O.[Sn](Cl)Cl.O.O.O.C([O-])(=O)C.[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]([CH3:26])[N:19]=[C:20]([CH3:25])[C:21]=3[NH2:22])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C)c(N2CCN(C/C=C/c3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(C)c(N2CCN(C/C=C/c3ccc(Cl)cc3)CC2)c1N
Temperature: 25 °C
Reaction time: 34 h
Yield: 69.3 %

Procedure:
To a solution of the product obtained in Step B (800 mg) in tetrahydrofuran (8 ml) and methanol (8 ml) at room temperature under nitrogen was added tin(II) chloride monohydrate (2.9 g) and sodium acetate trihydrate (3.5 g). The resulting mixture was stirred at room temperature for 34 hours. The reaction mixture was partitioned between 1M sodium hydroxide and ethyl acetate, stirred for 10 min, the organic layer was separated, dried over sodium sulfate and concentrated. 1-[(E)-3-(4-Chlorophenyl)-allyl]-4-(2,5-dimethyl-4-amino-2H-pyrazol-3-yl)-piperazine (510 mg) was obtained as a red solid. 1H NMR (400 MHz, CDCl3) 2.3 (s, 3H), 2.8 (m, 4H), 3.3 (m, 4H), 3.4 (d, J=9 Hz, 2H), 3.8 (s, 3H), 6.4 (dt, J=18, 9 Hz, 1H), 6.7 (d, J=18 Hz, 1H), 7.3-7.4 (m, 4H); MS (ES+) 151/153 (cinnamyl), 196(M-cinnamyl), 346/348 (M+H+).
Reaction SMILES: [OH-:1].[K+].[C:3]1([C:9]2([O:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC=CC=1.[C:23](Cl)(=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30]>O>[C:23]([O:33][O:16][O:15][C:9]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:1])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)CCCCCC(=O)Cl
Reactant: [OH-]
Reactant: OOC1(c2ccccc2)CCCCC1
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)CCCCCC(=O)OOOC1(c2ccccc2)CCCCC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
In a four-necked flask of 200 ml provided with a stirrer was charged 33.7 g of an aqueous solution of 30% potassium hydroxide, to which was added a mixture of 22.1 g of 95% 1-phenylcyclohexyl hydroperoxide and 30 g of benzene while the liquid temperature was maintained at 10° C. with stirring. Furthermore, 19.1 g of neodecanoyl chloride was added dropwise over 7 minutes while the liquid temperature was maintained at 15° C. with stirring. After the liquid temperature was raised to 25° C. and the stirring was continued for 2 hours, 40 g of cold water was added and further the stirring was made for 5 minutes. The water phase was separated and washed with an aqueous solution of 40 g of 5% sodium hydroxide and further with water three times. The solution was dried on magnesium sulfate anhydride and benzene was removed off under vacuum to obtain 24.0 g of a desired compound as a light yellow liquid. This compound had an active oxygen amount of 4.20%, a purity of 91% through calculation and a yield of 63 mol %.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][OH:11])[C:3]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1.N.C(O)(=[O:37])C>Cl.O.CO>[OH:11][CH2:10][C@@H:9]([NH:8][C:4]1[N:5]=[CH:6][NH:7][C:2](=[O:37])[C:3]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)O
Reactant: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3N[C@H](CO)Cc3ccccc3)nc12
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)nc[nH]c3=O)nc12
Temperature: 100 °C
Yield: 37 %

Procedure:
To a solution of (S)-2-[6-chloro-5-(6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl)-pyrimidin-4-ylamino]-3-phenyl-propan-1-ol in 4 N HCl (0.5 mL) and acetic acid (0.5 mL) was added two drops of water. The reaction mixture was heated to 100° C. for 8 h, cooled to room temperature, and neutralized with ammonia in methanol. After concentration, the residue was purified by prep. HPLC to yield the title compound (26 mg, 37% for two steps). 1H NMR (400 MHz, CD3OD) δ 9.41 (1H, narrow t, J=1.5 Hz), 8.06 (1H, narrow dd, J=1.6, 1.9 Hz), 7.93 91H, s), 7.77 (1H, narrow dd, J=1.6, 1.8 Hz), 7.73 (1H, narrow d, J=1.9 Hz), 7.11–7.21 (6H, m), 4.70–4.74 (1H, m), 3.74 (2H, d, J=4.7 Hz), 3.11 (1H, dd, J=6.1, 13.5 Hz), 3.00 (1H, dd, J=7.8, 13.5 Hz), 2.70 (3H, s). LCMS (M+H)+ m/z 442 (t=2.17 min.).
Reaction SMILES: CN(C1C=[CH:18][C:19]([C:22](N[C@H](C(O)=O)CCC(O)=O)=[O:23])=CC=1)CC1C=NC2N=C(N)N=C(N)C=2N=1.Cl.[NH2:35][C:36]1[N:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[C:37]=1[NH2:44].OC(O)C(=O)C>O>[NH2:42][C:40]1[N:41]=[C:36]([NH2:35])[C:37]2[C:38](=[N:43][C:19]([CH3:18])=[C:22]([OH:23])[N:44]=2)[N:39]=1
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reactant: Nc1nc(N)c(N)c(N)n1
Agent: CC(=O)C(O)O
Agent: Cl
Solvent: O
Product: Cc1nc2nc(N)nc(N)c2nc1O

Procedure:
The well-known Ellard process is exemplified by U.S. Pat. No. 4,080,325 Ellard and claim 1 of the patent sets out the steps for preparing methotrexate as follows: (a) reacting tetraaminopyrimidinehydrochloride with dihydroxyacetone in the presence of air and water and at a pH in the range of 5.5±0.2 to give 2,4-diamino-6-hydroxy-methylpteridine; (b) converting the 2,4-diamino-6-hydroxy-methylpteridine to the hydrobromide salt, namely, 2,4-diamino-6-hydroxymethylpteridine hydrobromide salt; (c) reacting the 2,4-diamino-6-hydroxymethylpteridine hydrobromide salt with triphenyldibromophosphorane to give 2,4-bis(triphenylphosphazine)-6-bromomethylpteridine hydrobromide; (d) reacting the 2,4-bis(triphenylphosphazino)-6-bromomethylpteridine hydrobromide with ethyl N-(p-methylamino)benzylglutamate to give the phosphazino derivative of methotrexate ester; (e) hydrolyzing the phosphazino derivative of methotrexate ester to give triphenylphosphine oxide and methotrexate ester; and (f) hydrolyzing the methotrexate ester to give methotrexate.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C@@H:26]([OH:39])[CH2:27][O:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH:43]([O:45][CH2:46][CH3:47])=[CH2:44].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[CH2:1]([N:8]([CH2:25][C@@H:26]([O:39][CH:43]([O:45][CH2:46][CH3:47])[CH3:44])[CH2:27][O:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)(=[O:31])=[O:30])[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)C[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CN(Cc1ccccc1)[C@@H](CC(=O)OC)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl 4-methyl (2S)-2-[benzyl((2R)-2-hydroxy-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate (43.0 g, 0.0774 mol) in methylene chloride (500.0 mL, 7.800 mol) was added ethyl vinyl ether (15.0 mL, 0.157 mol) followed by pyridinium p-toluenesulfonate (4.0 g, 0.016 mol). The mixture was stirred at rt for 3 g. After concentrated to dry, the residue was purified by silical gel column (eluting with 0 to 20% EtOAc in hexane) to provide the ether compound (38.1 g, 78.4%). MS (ESI): (M+H)+=628.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A mixture of [4-(methylsulfonyl)phenyl]boronic acid (540 mg, 2.7 mmol), 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (1 g, 2.7 mmol), Pd(PPh3)2Cl2 (190 mg, 0.27 mmol), DME (10 mL) and 2M Na2CO3 (5 mL) was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, charged with water, and extracted with Et2O. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The aqueous phase was further extracted with CH2Cl2. The CH2Cl2 extracts were combined with the Et2O extracts, dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 1.5% MeOH/CH2Cl2, followed by recrystallization from MeOH. The recrystallized material and the mother liquor were combined, then concentrated to give 705 mg (58%) of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as an off-white solid. This material contained a minor impurity which was carried on to the next step. 1H NMR (400 MHz, CDCl3): δ 8.41 (d, 1H, J=2.7 Hz), 8.14 (d, 2H, J=8.4 Hz), 8.01 (d, 2H, J=8.4 Hz), 7.75 (d, 1H, J=8.7 Hz), 7.34 (d, 1H, J=8.2 Hz), 4.26-4.10 (m, 2H), 3.92 (d, 2H, J=6.3 Hz), 3.07 (s, 3H), 2.83-2.66 (m, 2H), 2.10-1.94 (m, 1H), 1.84 (d, 2H, J=12.82 Hz), 1.46 (s, 9H), 1.38-1.21 (m, 2H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: OC1CCCNC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1CCCN(c2ccc(Br)cc2)C1

Procedure:
A solution of 1-bromo-4-iodobenzene (Aldrich, 4 g, 14.14 mmol), piperidin-3-ol (Aldrich, 1.14 g, 11.31 mmol), copper (I) iodide (0.269 g, 1.41 mmol) and K3PO4 (6.00 g, 28.3 mmol) in N,N-dimethylformamide (50 mL) under N2 were stirred at 100° C. for 48 h. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed successively with water and brine then dried over anhydrous Na2SO4, filtered through celite and concentrated under reduced pressure. The sample was purified on silica gel column chromatography using a cyclohexane to cyclohexane/ethyl acetate 70:30 as eluant. The appropriate fractions were combined and concentrated in vacuo and the residue was triturated with pentane. The resulting solid was filtered, washed with pentane and dried to give the title compound 1-(4-bromophenyl) piperidin-3-ol as a beige powder. LCMS: (M+H)+=256-258; Rt=2.90 min.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>CO>[CH3:4][C:3]1([CH3:5])[S:6][CH:10]([C:11]2[CH:18]=[CH:17][C:14]([CH3:15])=[CH:13][CH:12]=2)[NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: CO
Product: Cc1ccc(C2N[C@@H](C(=O)O)C(C)(C)S2)cc1
Reaction time: 1 h

Procedure:
A solution containing 1.50 g (10 mmoles) of D-penicillamine and 1.18 ml (10 mmoles) of 4-methylbenzaldehyde in 30 ml of 30% methanol is stirred for 1 hour. The precipitated crystals are filtered out and washed with 30% methanol to give the crude title acid in a yield of 2.25 g (89.5%) which can be recrystallized from methanol by adding water, m.p.: 89°-90° C., [α]D =+53.5 (c=0.784, dimethylsulphoxide).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)[N:16]=[CH:15][CH:14]=[C:13]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[C:38]([F:49])[CH:37]=1)#[N:9].O.C(=O)(O)O>C(OCC)(=O)C>[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[N:16]=[CH:15][CH:14]=[C:13]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[C:38]([F:49])[CH:37]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4)c3cc2C#N)CC1
Agent: O=C(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ccnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 113.9 %

Procedure:
After adding 5 ml of trifluoroacetic acid to 340 mg of tert-butyl 4-(((6-cyano-4-(4-(((cyclopropylamino)carbonyl)amino)-3-fluorophenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate, the mixture was stirred at room temperature for 7 minutes. Saturated bicarbonate water and ethyl acetate were added to the reaction solution for extraction. The ethyl acetate layer was washed with saline and dried over sodium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 320 mg of a light yellow solid.
Reaction SMILES: [N:1]([C@@H:4]([C:7]1[CH:8]=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH2:5][OH:6])=[N+]=[N-]>[Pd].CCOC(C)=O>[NH2:1][C@@H:4]([C:7]1[CH:8]=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH2:5][OH:6]
Reactant: COc1ccc([C@@H](CO)N=[N+]=[N-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc([C@H](N)CO)cn1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A mixture of (S)-2-azido-2-(6-methoxypyridin-3-yl)ethanol (0.90 g, 4.6 mmol), EtOAc (50 mL), and 10% Pd—C (100 mg) was stirred under H2 (1 atm) for 1 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to yield a thick oil (0.78 g, 100%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:36])=[O:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(OS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(OS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[(2-n-butyl-6-benzenesulphonyloxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:17]=1[F:36])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1.Cl.Cl.[CH2:42]([O:49][C:50]([C:52]1[CH:53]=[N:54][NH:55][C:56]=1[NH:57][NH2:58])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.COC(=O)N=C(SC)C(C1C=C(OC)C=C(OCCCO[Si](C(C)(C)C)(C)C)C=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1.Cl.Cl.C(OC(C1C(NN)=NNC=1)=O)C>>[CH2:42]([O:49][C:50]([C:52]1[CH:53]=[N:54][NH:55][C:56]=1[N:57]1[C:3](=[O:2])[NH:4][C:5]([CH:6]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:34])([CH3:33])[CH3:35])([CH3:31])[CH3:30])[C:17]=2[F:36])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2)=[N:58]1)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCCO[Si](C)(C)C(C)(C)C)c1F
Reactant: NNc1[nH]ncc1C(=O)OCc1ccccc1
Agent: CCOC(=O)c1c[nH]nc1NN
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCCO[Si](C)(C)C(C)(C)C)c1F
Agent: Cl
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(C#N)cc2)c2nn(-c3[nH]ncc3C(=O)OCc3ccccc3)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Example (177b), except that (2-{3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphenyl}-2-(4-cyanophenylimino)-1-methylsulfanylethylidene)carbamic acid methyl ester (Example (163c)) and 5-hydrazino-1H-pyrazole-4-carboxylic acid benzyl ester bishydrochloride were used instead of respectively (2-{3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester and 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester bishydrochloride, to give the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])[C:2]#[CH:3].[OH2:18]>N1C=CC=CC=1CO.CC([O-])=O.CC([O-])=O.[Cu+2].O>[N+:15]([C:6]1[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]([F:11])=[CH:10][C:5]=1[NH:4][CH2:1][C:2]#[C:3][C:3]#[C:2][CH2:1][NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:13])=[O:18])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])([O-:17])=[O:16]
Reactant: O
Reactant: C#CCNc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OCc1ccccn1
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(NCC#CC#CCNc2cc(F)c([N+](=O)[O-])cc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of Cu(OAc)2.H2O (1.5 g) in pyridinemethanol (1:1, 10 ml) was added N-(2-propynyl)-2,4-dinitro-5-fluoroaniline (1.00 g, 4.18×10-3 mole). The reaction mixture was stirred at room temperature for 17 hours. The mixture was poured into excess water and filtered. The crude solid was chromatographed on a silica column, eluting with chloroform ethyl acetate. Soxhlet recrystallization of the resulting solid from ethyl acetate afforded yellow crystals, m.p. 225° C. dec. Yield: 0.21 g (12%). I.R. (KBr): 3360 (NH), 1680 and 1315 cm-1 (Ar-NO2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.[CH3:18][O:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27](Br)=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:21].[C:32](=O)([O-])[O-].[K+].[K+].Cl>O.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.C(O)C.CN(C=O)C>[CH3:18][O:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([C:7]3[CH:6]=[CH:5][C:4]([OH:17])=[CH:3][C:2]=3[CH3:1])=[CH:28][CH:29]=2)[N:24]([CH3:32])[CH:23]=1)=[O:21]
Reactant: COC(=O)c1c[nH]c2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: COC(=O)c1cn(C)c2cc(-c3ccc(O)cc3C)ccc12
Temperature: 85 °C
Yield: 87 %

Procedure:
A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (2.36 g, 10.1 mmol), 6-bromo-1H-indole-3-carboxylic acid methyl ester (1.8 g, 6.71 mmol), tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.26 mmol), DMF (27 mL), ethanol (13.5 mL) and 2M aqueous potassium carbonate (13.5 mL) is heated to 85° C. for 4 hours. The reaction is cooled to room temperature and diluted with water and acidified with 1 N HCl. The resulting solution is extracted with ethyl acetate. The combined organic layers are washed with brine and dried over anhydrous magnesium sulfate and concentrated. The residue is purified with flash chromatography eluting with 25→40% ethyl acetate/heptane to give 1.73 mg (87%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:21]([O-])=O)[CH:8]=2)[O:3]1>[Pd].CO>[CH3:1][C:2]1([CH3:24])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(Oc2ccnc(O)c2)C1O
Agent: [Pd]
Solvent: CO
Product: CC1(C)Oc2ccc(N)cc2C(Oc2ccnc(O)c2)C1O

Procedure:
A solution of 1 g of 2,2-dimethyl-4(2-hydroxy-4-pyridyloxy)-6-nitro-3-chromanol in 25 of methanol is hydrogenated at 20° and 1 bar on 0.5 g of 5% Pd-C to completion. This mixture is filtered, evaporated and 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3-chromanol is obtained.