Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[F:25])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Fc1ccccc1CCl
Product: Fc1ccccc1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 59 %

Procedure:
The title compound (0.042 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-fluorobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H19ClFN3, 355.13; found, m/z 356.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.55-7.48 (br m, 4H), 7.39-3.37 (br m, 1H), 7.20-7.14 (m, 3H), 5.54 (s, 2H), 3.48-3.46 (br m, 2H), 3.40-3.38 (br m, 2H), 3.31-3.29 (br m, 2H), 3.13-3.11 (br m, 2H).
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O-])=O.Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>O>[N:20]1([CH2:19][CH2:18][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH2:6])=[CH:10][CH:11]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C

Procedure:
A stirred DMF suspension (5 mL) of 4-nitrophenol (0.5 g, 3.6 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.92 (5.4 mmol) and K2CO3 (1.24 g, 9 mmol) was heated at 80° for 3 hr. After cooling to RT, the reaction was diluted with H2O and extracted 3× with EtOAc. The combined EtOAc layers were washed 2× with H2O and dried over MgSO4. After concentration under vacuum, the resulting residue was chromatographed on silica gel, Gradient elution CH2Cl2 to 10% MeOH/CH2Cl2 eluted the 1-(2-(4-nitrophenoxy)ethyl)pyrrolidine (560 mg) as an orange oil. Further purification employing reverse phase chromatography (MeOH/H2O/0.1% TFA) yielded 413 mg of a yellow oil. Subsequent conversion of the aryl nitro substituent to the title aryl amine was accomplished following the procedure described in Example 6 step C. MS (ESI) 207 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24].O>CN(C)C=O>[C:22]([NH:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1)(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: Nc1nsnc1-c1c(Cl)cccc1Cl
Reactant: CC(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 60 °C
Yield: 36.5 %

Procedure:
To a solution of 0.49 g of 3-amino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole and 0.22 g of triethylamine in N,N-dimethylformamide, 0.27 g of isobutyryl chloride was added and the mixture was heated at 60° C. for 12 hours. After allowing to cool, the mixture was poured into water and was extracted with ether. The ether layer was washed twice with dilute hydrochloric acid, twice with water and twice with saturated aqueous sodium chloride solution. The resultant was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to obtain 0.23 g of 3-isobutyrylamino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH2:30])[CH:24]=1.FC(F)(F)C(O)=O>>[NH2:30][C:25]1[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=1[NH:29][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:21][CH:20]=1
Reactant: O=C(C=Cc1ccccc1)NCc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(F)cc1N
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(F)ccc1NC(=O)c1ccc(CNC(=O)C=Cc2ccccc2)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-cinnamoylaminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofunan (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 16 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give the title compound (0.45 g, 64%). 1H NMR (300 MHz, DMSO-d6): δppm: 4.42 (2H, d), 4.92 (2H, br.s), 6.62 (1H, t), 6.78 (2H, m), 7.01 (1H, t), 7.32 (5H, m), 7.54 (5H, m), 8.76 (1H, br.t), 9.58 (1H, br.s). IR (KBr) cm−1: 3306, 1618, 1517, 1308, 745. HRMS calcd for C23H20N3O2F: 389.4292. Found: 389.4294. MA calcd for C23H20N3O2F: C, 70.94%; H, 5.18%; N, 10.79%. Found: C, 70.72%; H, 5.18%; N, 10.88%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][C@@H:13]([N:23]2[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]2)[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:4][CH:3]=1.[CH:31](=O)[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Si:16]([O:15][CH2:14][C@H:13]([N:23]1[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]1)[CH2:12][CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][CH2:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:10]=2)[CH:6]=[CH:7]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: O=CCCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(N)cc21)n1cnc(C(N)=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(NCCCc3ccccc3)cc21)n1cnc(C(N)=O)c1
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Under N2, to a stirred solution of 1-[(R)-4-(6-aminoindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (164 mg, 0.383 mmol) in dichloromethane (10 ml) was added hydrocinnamaldehyde (51 mg, 0.383 mmol) at room temperature. The mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (114 mg, 0.536 mmol) was added to the mixture at room temperature and the resulting mixture was stirred for 5 hours. And then the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried (sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel (10 g) column chromatography eluted with chloroform/methanol (100:1 to 10:1) to give 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(6-(3-phenylpropylamino)indol-1-yl)-2-butyl]imidazole-4-carboxamide (52.6 mg, 25.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][C:31]([O:33]C)=[O:32])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:11]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][C:31]([OH:33])=[O:32])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:11]=1
Reactant: COC(=O)Cc1ccc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2ccc(CC(=O)O)cc2Cl)c1
Yield: 94 %

Procedure:
A mixture of methyl 2-[3-chloro-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetate. (0.47 g), a 1N aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into water and acidified with 1N hydrochloric acid. The precipitated solid was collected by filtration and dried with air to give crystals (0.43 g, yield 94%) of 2-[3-chloro-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetic acid. Recrystallization from ethyl acetate-methanol gave colorless prism crystals. melting point: 150-151° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=O)([O-:3])=[O:2].C1(S([NH2:25])(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]#[N:25])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
A mixture of 21.2 grams (0.1 mole) of 2,4-dinitrobenzoic acid and 32.0 grams (0.21 mole) of benzenesulfonamide is stirred and heated in an oil bath at 205°-210° for 1 hour and then at 225° for 1 hour and allowed to cool to room temperature under a nitrogen atmosphere. The residue is shaken with methylene chloride and dilute NaOH solution and the methylene chloride layer separated and washed with water. The solvent is removed by distillation. There is obtained 6.05 grams (31%) of material melting at 88°-92°. Recrystallization from ethanol raises the melting point to 100°-2°. The infrared spectrum shows a weak nitrile band at 2200 cm-1.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)CCC>C1(C)C=CC=CC=1.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:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2ccccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ccccc2c1Cl

Procedure:
Prepared according to Procedure E using 2,4-dichloro-3-methylquinoline (1.038 g, 4.9 mmol), 2-(tributylstannyl)pyridine (2.0 g, 5.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol) in toluene (10.00 mL) to afford product as an off-white solid upon purification by precipitation from EtOAc and chromatography on silica gel, eluting with EtOAc gradient in hexane. Mass Spectrum (ESI) m/e=255.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][C:5](=O)[CH2:6][C:7]([O:9]CC)=[O:8].[N:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)=[N+:15]=[N-:16].[O-]CC.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:24]([NH:23][C:21]([C:20]1[CH:26]=[CH:27][C:17]([N:14]2[C:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:13])=[C:6]([C:7]([OH:9])=[O:8])[N:16]=[N:15]2)=[CH:18][CH:19]=1)=[O:22])[CH3:25]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)CCC(C)C
Agent: CC[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC(C)C)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 96.4 %

Procedure:
Ethyl 6-methyl-3-oxoheptanoate (1.08 g, 5.53 mmol, 1.25 eq.) obtained in Example 97a) and 4-azido-N-ethylbenzamide (0.842 g, 4.43 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (418 mg, 5.53 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 17 hr. 2% Aqueous sodium carbonate solution (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with water (20 ml) and washed with ethyl acetate-hexane (2:1, 40 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and stood still at 0° C. The precipitate was collected by filtration and washed with cold water and dried to give the title compound as a grayish white powder (1.41 g, 4.27 mmol, 96.3%).
Reaction SMILES: [CH:1]1([NH:4][CH3:5])[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:4]([CH:1]1[CH2:3][CH2:2]1)[CH3:5])(=[O:15])=[O:14]
Reactant: CNC1CC1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: ClCCl
Product: CN(C1CC1)S(=O)(=O)c1ccccc1Br
Temperature: 22 °C
Reaction time: 2 h

Procedure:
450 μl of N-cyclopropyl-N-methylamine are added dropwise with cooling to a solution of 640 mg of 2-bromobenzenesulfonyl chloride in 2.5 ml of DCM. The mixture is subsequently stirred at 22° C. for 2 h, extracted twice with 5 ml of 1N sodium hydroxide solution, the organic phase is dried over magnesium sulfate, filtered and evaporated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[N:12]=1)([CH3:4])([CH3:3])C.ClC(O[C:24]1[CH:29]=CC=C[CH:25]=1)=O.O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C1COCC1>[C:1]1([O:5][C:6](=[O:19])[NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[N:12]=2)[CH:3]=[CH:29][CH:24]=[CH:25][CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COCCOCc1csc(NC(=O)OC(C)(C)C)n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COCCOCc1csc(NC(=O)Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-butyl 4-((2-methoxyethoxy)methyl)thiazol-2-ylcarbamate (Intermediate III, 3.4 g, 0.018 mol) was dissolved in pyridine (50 mL) and a catalytic amount of DMAP was added (0.2 g, ˜10 mol %). To this mixture a solution of phenyl chloroformate (2.27 mL, 1 eq.) in THF (50 mL) was added drop wise and the resulting reaction mixture was stirred for 3 hours at ambient temperature. Then, H2O was added and the diluted mixture was extracted with EtOAc. Dried the organic layer over Na2SO4, filtered and concentrated in vacuo. Purification over SiO2 eluting with 1:1 EtOAc/heptane gave 2.4 gram of the product as a yellow fluffy solid. 1H-NMR (300 MHz, DMSO-d6) δ 11.70 (s, br, 1H), 7.42 (d, 1H), 7.37 (m, 1H), 7.08 (m, 3H), 4.59 (s, 2H), 4.38 (d, 2H), 3.30 (s, 2H), 3.23 (t, 2H), 1.75 (q, 2H), 0.97 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[I-:12].[K+].C(OCC)(=O)C>C(O)(=O)C>[Cl:8][C:7]1[C:2]([I:12])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: [I-]
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc(I)c(Cl)c1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of 2,3-dichloro-5-nitropyridine (9.75 g) and potassium iodide (29 g) in acetic acid (120 mL, degassed with nitrogen) was heated to 100° C. for 1.5 hours under nitrogen. The brown solution was cooled to room temperature and then ethyl acetate (300 mL) added. The organic phase was separated and washed with water (2×100 mL) and dilute aqueous sodium sulfite (100 mL). Evaporation of the solvent gave crystalline 3-chloro-2-iodo-5-nitro-pyridine (13.11 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+:20]>>[OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[Na+:20]
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(O)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)[O-])c1ccc(-c2ccccc2)c(O)c1

Procedure:
2-(2-hydroxy-4-biphenylyl)propionic acid was mixed with an equivalent amount of aqueous sodium hydroxide. The mixture was evaporated to dryness to give sodium 2-(2-hydroxy-4-biphenylyl)propionate, m.p. 230 (decomposed) °C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][NH:11][CH3:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][NH:11][CH2:12][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: CNCc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(CNCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of the compound (630 mg) obtained in Example 42 and triethylamine (768 mg) in acetonitrile (20 ml), benzyl bromide (778 mg) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h and, after addition of water, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1) to give 925 mg of the titled compound (yield, 95%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7](Br)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]>CC(C)=O>[CH2:7]([O:8][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([O:4][CH2:1][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:12]=1)[CH:7]=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Br)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 34 %

Procedure:
To a mixture of DHBD (24.4 g, 177 mmol) and potassium carbonate (12.2 g, 88.5 mmol) heated at reflux under argon in dry acetone (200 ml) was added dropwise over 12 hours a solution of BzBr (43.4 g, 30.2 ml, 248 mmol) in dry acetone (30 ml). Thin layer chromatography showed very little DHBD after the addition was complete. The reaction mixture was evaporated to dryness and the residue partitioned between dichloromethane/water. The aqueous layer was further extracted with dichloromethane (3×100 ml) and the combined dichloromethane layers extracted with aqueous sodium hydroxide (1N, 3×100 ml). Evaporation of the dichloromethane layers gave 18.1 g of essentially pure 3,5-dibenzyloxybenzaldehyde (34.0% based on DHBD). The sodium hydroxide extracts were acidified with glacial acetic acid, extracted with chloroform (3×100 ml), and the combined chloroform extracts dried and evaporated to dryness. The residue was recrystallized from methanol/water to give 14.5 g of compound XVI (36.0% based on DHBD).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:15])=[O:14])[CH2:6][CH:5]1[OH:22])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH:4]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:15])=[O:14])[CH2:6][CH:5]1[OH:22]
Reactant: CC1(C)CC(N=[N+]=[N-])C(O)CN(S(=O)(=O)c2ccccn2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(N)C(O)CN(S(=O)(=O)c2ccccn2)C1
Temperature: 45 °C
Yield: 45 %

Procedure:
4-Azido-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-3-ol from Example 92f (0.4 g, 1.23 mmol) was dissolved in THF (50 ml) and H2O (0.2 ml). PPh3 (0.48 g, 1.85 mmol) was added to this solution. The reaction mixture was stirred at 45° C. over night. TLC showed no starting material left. THF was evaporated, azeotroped with toluene (2×'s). The resulting thick oil was dissolved in MeOH, treated with HCl in ether to adjust pH to acidic. More ether was added and the solution turned cloudy. 0.22 g white precipitate of the title compound was collected. (45% yield); 1H-NMR (400 MHz, CD3OD): •8.68(m, 1H), 8.10-7.93(m, 2H), 7.62(m, 1H), 3.90(m, 1H), 3.68(m, 1H), 3.40-2.90(m, 4H), 1.82(m, 1H), 1.53(d, 1H), 1.05(s, 6H)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].I[C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1>>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([N:4]([C:1](=[O:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: COc1cccc(I)c1
Product: COc1cccc(N(C(C)=O)c2ccccc2)c1
Yield: 67 %

Procedure:
Using acetanilide (3.7 g) and 3-iodoanisole, a reaction was made in the same manner as is 1) of Production Example 2. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:3 to 1:2) produced 3-methoxy-N-phenylacetanilide (4.44 g; yield, 67%) as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>CN(C)C=O.[Cu]>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: C#CC(C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Agent: [Cu]
Solvent: CN(C)C=O
Product: C#CC(C)(C)Nc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 16 h

Procedure:
To a mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication No. WO 88/08424, 5.40 g), cuprous chloride (1.00 g), copper powder (1.00 g), and dry dimethylformamide (25 ml) under nitrogen at 0° is added a solution of 3-chloro-3-methyl-1-butyne (2.00 g) in dry dimethylformamide (5 ml) in 4 portions over 15 min. The resulting mixture is then stirred at 20°-25° for 16 hrs, concentrated, and diluted with methylene chloride (75 ml) and water (20 ml). The layers are separated and the aqueous phase is extracted with methylene chloride (25 ml). The combined organic phase is washed with saline (20 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue which is chromatographed on silica gel (70-230 mesh, 500 g), eluting with a gradient of ethyl acetate/hexane (10/90-20/80). Pooling of fractions giving an Rf =0.31 (ethyl acetate/hexane, 25/75) and removal of solvent under reduced pressure gives the title compound, NMR (CDCl3) 7.75, 7.47, 6.94, 4.61, 3.56, 3.00, 2.39, 1.64 and 1.48 δ.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[C:2]=1[C:10]([OH:12])=[O:11]>[OH-].[Na+].[Ni].[Al]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH:2]1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cccnc1C(=O)O
Agent: [Ni]
Agent: [Al]
Agent: [Na+]
Product: O=C(O)C1CCCNC1C(=O)O
Reaction time: 96 h

Procedure:
Dissolve pyridine-2,3-dicarboxylic acid (20 g, 120 mmol) in 0.5N aqueous sodium hydroxide (900 mL). Add nickel/aluminum powder (45 g) in portions over 3 hours. Stir for 4 days, filter off the catalyst to yield the title compound in clear solution. The resulting free amine is not isolated.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=1[CH2:6][OH:7])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:12][C:8]1[C:5]([CH2:6][OH:7])=[C:4]([NH:3][CH3:1])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(NC=O)c1CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1cccc(C)c1CO
Yield: 49.4 %

Procedure:
A solution of 2-formamido-6-methylbenzyl alcohol (1.9 g) in tetrahydrofuran (26 ml) was added dropwise to a suspension of lithium aluminum hydride (0.873 g) in tetrahydrofuran (17 ml) at room temperature over a period of 10 minutes. After being refluxed for 4.5 hours, the excess reagent was decomposed with a small amount of water and the resulting precipitates were filtered off by suction. The filtrate was evaporated in vacuo and the residue was recrystallized from carbon tetrachloride to give 6-methyl-2-methylaminobenzyl alcohol (0.86 g).