Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[CH:14]OC)[C:6](=[O:17])[N:5]1[C:18](=[O:20])[CH3:19])(=[O:3])[CH3:2].Cl.[NH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([OH:30])[CH:29]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)/[C:7](=[CH:14]/[NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([OH:30])[CH:29]=2)/[C:6](=[O:17])[N:5]1[C:18](=[O:20])[CH3:19])(=[O:3])[CH3:2]
Reactant: COC=C1C(=O)N(C(C)=O)N(C(C)=O)c2ccccc21
Reactant: COc1ccc(CN)cc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(CN/C=C2\C(=O)N(C(C)=O)N(C(C)=O)c3ccccc32)cc1O
Temperature: 25 °C
Reaction time: 120 h
Yield: 53.6 %

Procedure:
To a suspension of 1,2-diacetyl-4-methoxymethylene-1,4-dihydro-2H-cinnolin-3-one (0.18 g, 0.66 mmol) and 5-(aminomethyl)-2-methoxyphenol hydrochloride (0.13 g, 0.66 mmol) in tetrahydrofuran (5 mL) is added triethylamine (0.21 mL). After the addition of a few drops of N,N-dimethylformamide, the reaction mixture is stirred for five days at room temperature. The solvent is then evaporated under reduced pressure to give a maroon oil, which is then purified by via semi-preparative HPLC (Prodigy ODS3 column, 40% MeCN/60% water/0.01% trifluoroacetic acid to 70% acetonitrile over 1 hour at 10 mL/min) to give (4Z)-1,2-diacetyl-4-{[(3-hydroxy-4-methoxybenzyl)amino]methylene}-1,4-dihydrocinnolin-3(2H)-one (0.14 g, 54%) as a straw-colored foam, which is crushed to a powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH:3]=1.[Li]CCCC.[CH3:18][S:19]SC.O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:19][CH3:18])=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CSSC
Reactant: Brc1ccc2ccc(Br)cc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc2ccc(Br)cc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.8 %

Procedure:
A stirred solution of 189 (5.72 g, 20.0 mmol) in THF (80 mL) was treated dropwise at −78° C. with n-BuLi (2.5 M in hexanes, 8.40 mL, 21.0 mmol) under N2. The mixture was stirred at −78° C. for 20 min, then treated slowly with dimethyl disulfide (2.16 mL, 24 mmol) and allowed to warm to room temperature. The solvent was removed under reduced pressure to give a residue that was shaken with water, and the resulting solid was crystallised fom petroleum ether to give 2-bromo-7-(methylsulfanyl)naphthalene (199) (4.14 g, 82%): mp 80-81° C.; 1H NMR [(CD3)2SO] δ 8.11 (d, J=1.9 Hz, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.54 (dd, J=8.72, 2.0 Hz, 1H), 7.44 (dd, J=8.6, 2.0 Hz, 1H), 2.58 (s, 3H). Anal. (C11H9BrS) C, H, S.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])=[CH2:9]>CC(C)=O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:3][CH:2]=1
Reactant: C=C(C)c1ccc(O)cc1
Reactant: Oc1ccccc1
Solvent: CC(C)=O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
According to the present invention the following reactions are conducted simultaneously in a reaction system comprising step I of the process: reaction of phenol with acetone, reaction of phenol with p-isopropenylphenol resulting from thermal decomposition of process by-products and recycled to the reaction system, and isomerizational rearrangement of process by-products to obtain bisphenol A in the presence of a micro- and macroporous cation-exchange resin catalyst mixture. Step II of the process comprises cooling the post-reaction mixture together with water and acetone to obtain a precipitate of bisphenol-A/phenol in phenolic solution. Step III of the process comprises separation of the precipitate into crystalline bisphenol-A/phenol adduct and phenolic mother liquor I. The crystalline adduct is washed with the phenolic liquor and step IV follows, wherein the bisphenolA/phenol adduct obtained in step III is dissolved in the phenolic solution and the resulting mixture is cooled to obtain a bisphenol-A/phenol precipitate in phenolic solution. Step V comprises separation of the precipitate obtained in step IV into the crystalline bisphenol-A/phenol adduct and mother liquor II to be turned back to step III of the process. The bisphenol-A/phenol crystalline adduct is then washed with phenolic solution and step VI follows, wherein a high-purity bisphenol A is recovered by removal of phenol from the bisphenol-A/phenol adduct obtained in step V. Step VII of the process consists in distillation of the phenolic mother liquor I obtained in step III, and removal of acetone, water and part of phenol therefrom. Dewatered phenol liquor is turned back to step I of the process to the reaction zone and step VIII follows, consisting of thermal catalytic decomposition of part of the mother liquor I obtained in step(s) III and/or VII, resulting in a distillate comprising phenol, isopropenylphenol and process by-products. Step IX consists of catalytic rearrangement of the reactive components of the distillate obtained in step VIII, while leaving the p-isopropenylphenol contained therein substantially intact and the rearranged distillate is recycled to step I of the process.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33].CCOCC>CO.C1COCC1>[ClH:33].[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: NCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
{4-[4-(2-tert-Butoxycarbonylaminoethoxy)phenyl]butyl}carbamic acid benzyl ester 1 (11.0 g, 24.9 mmol) was dissolved in methanol (110 mL) and THF (20 mL). 12N Hydrochloric acid (40 mL) was added dropwise, and the reaction was allowed to stir. After 1.5 h, ether (200 mL) was added, and the reaction was suction filtered to collect a white solid. The solid was washed with ether, air dried, and dried under vacuum. This afforded 7.6 g, (82%) of 7 as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.39 (br s, 11H), 1.52 (m, 2H),
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH2:19]([S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:28][CH:27]=1)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][N:34]([C:7]([C:6]3[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=3[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:33][CH2:32]2)=[N:28][CH:27]=1)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)s1
Yield: 54 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 54%). MS (m/e): 530.3 (M+H+, 35%), 547.5 (M+NH4+, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[N:8][C:7]3[CH:10]=[CH:11][S:12][C:6]=3[N:5]2[CH:13]=1.[I:14]N1C(=O)CCC1=O>C(Cl)Cl>[I:14][C:13]1[N:5]2[C:6]3[S:12][CH:11]=[CH:10][C:7]=3[N:8]=[CH:9][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cn2c(cnc3ccsc32)n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Cc1nc2cnc3ccsc3n2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.7 %

Procedure:
A mixture of 7-methylimidazo[1,2-a]thieno[3,2-e]pyrazine (30 mg, 0.16 mmol), and N-iodosuccinimide (39 mg, 0.17 mmol) in methylene chloride (1.2 mL) was stirred at 25° C. for 16 h. The product was purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (15 mg, 30%). LCMS calculated for C9H7IN3S (M+H)+: m/z=315.9. Found: 316.0. 1H NMR (CDCl3, 400 MHz) δ 8.89 (1H, s), 7.55 (1H, d, J=5.6 Hz), 7.35 (1H, d, J=5.6 Hz), 2.55 (3H, s) ppm.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.I[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[C:15]1([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: c1cn[nH]c1
Reactant: Ic1cccc2ccccc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc2c(-n3cccn3)cccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1H-pyrazole (300 mg, 4.4 mmol), iodonaphthalene (1.1 g, 4.4 mmol), copper (I) iodide (126 mg, 0.66 mmol), Cs2CO3 (2.15 g, 6.6 mmol) in DMF (5 mL) was evacuated and filled with nitrogen twice. The reaction was then stirred at room temperature for 30 minutes and then at 120° C. for 2 days. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, filtered through silica gel and concentrated to give 1-(naphthalen-1-yl)-1H-pyrazole as pure solid. (800 mg, 93%).
Reaction SMILES: [CH2:1]([Cl:3])Cl.[Li]CCCC.[OH:9][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].CC(C)C[B:20]([O-:22])[O-:21]>C1COCC1.CC(OC)(C)C.[Cl-].[Cl-].[Zn+2]>[OH:9][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[Cl:3][CH:1]([B:20]([O-:22])[O-:21])[CH2:11][CH:10]([CH3:13])[CH3:12]
Reactant: ClCCl
Reactant: CC(C)CB([O-])[O-]
Agent: CC(C)(O)C(C)(C)O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)CC(Cl)B([O-])[O-]
Temperature: -100 °C
Reaction time: 1 h
Yield: 189.3 %

Procedure:
A mixture of THF (2 L) and DCM (55.3 g, 0.651 mol) was cooled to −100° C. n-BuLi (260.7 mL, 2.5 M in n-hexane, 0.651 mol) was added dropwise into the reaction mixture maintaining at −100° C. Pinacol 2-methylpropane-1-boronate ([2]; 100 g, 0.543 mol) was added into the reaction mixture. The resulting mixture was keep at −100° C. for one hour. A solution of ZnCl2 (136.3 g, 1.0 mol) in THF (500 mL) was added dropwise to the reaction over a period of 60 minutes. The resulting mixture was keep at −100° C. for one hour, the reaction mixture was warmed up to room temperature and keep at room temperature overnight. The reaction was diluted with MTBE (750 mL) and was washed twice with saturated NH4Cl (2 L each). The organic layer was dried overnight over MgSO4 before filtering and evaporating. n-Heptane (250 mL) was added into the mixture and was filtered and evaporated providing the product as an oil (119.5 g, 0.514 mol). 1H NMR (300 MHz, CDCl3) δ 3.48 (dd, J=9.8, 6.1 Hz, 1H), 1.93-1.71 (m, 2H), 1.61 (td, J=8.1, 4.0 Hz, 1H), 1.33-1.24 (m, 12H), 0.95-0.87 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 84.5, 42.8, 25.8, 24.8, 23.1, 21.5.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([I:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([I:11])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)cc1I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)cc1I
Reaction time: 2 h

Procedure:
A catalytic amount of DMF (approximately 3 drops) was added to a stirred mixture of 4-chloro-2-iodobenzoic acid (24.47 g, 86.63 mmol) and oxalyl chloride (11.34 mL, 129.9 mmol) in DCM (100 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours and then concentrated in vacuo to give 4-chloro-2-iodobenzoyl chloride as a yellow oil that solidified upon standing (26.07 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](Cl)[N:18]=3)[C:13](=[O:21])[C:12]([C:22]([OH:24])=[O:23])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8].Cl.Cl.[NH2:27][CH:28]1[CH2:31][NH:30][CH2:29]1.CN1CCCC1.C(OCC)C>C(#N)C.C(O)C>[NH2:27][CH:28]1[CH2:31][N:30]([C:17]2[N:18]=[C:19]3[C:14]([C:13](=[O:21])[C:12]([C:22]([OH:24])=[O:23])=[CH:11][N:10]3[C:4]3[C:5]([F:9])=[CH:6][C:7]([F:8])=[C:2]([NH2:1])[CH:3]=3)=[CH:15][CH:16]=2)[CH2:29]1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3ccc(Cl)nc32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Solvent: CCOCC
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3ccc(N4CC(N)C4)nc32)c(F)cc1F
Temperature: 80 °C
Yield: 57.2 %

Procedure:
With stirring at 80° C., 100 mg of 1-(3-amino-4,6-difluorophenyl)-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was added to a solution of 61 mg of 3-aminoazetidine dihydrochloride and 119 mg of N-methylpyrrolidine in 3 ml of acetonitrile. The solution was stirred at 80° C. for 2 hours and 50 minutes. After the reaction solution was allowed to cool down, decantation with diethyl ether was carried out. The solid was dispersed by adding a small amount of ethanol and collected by filtration. The solid was washed with ethanol and then diethyl ether to give 63 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([C:17](OC)=[O:18])=[CH:9][O:8]1)[CH3:5])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.CC(C)=O>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([CH2:17][OH:18])=[CH:9][O:8]1)[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC[C@@H](C)[C@@H]12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(C)O[C@@H]1OC=C(CO)[C@H]2CC[C@@H](C)[C@@H]12
Yield: 81.5 %

Procedure:
Methyl (1S, 4aS, 7R, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[c]pyran-4-carboxylate (3.00 g, 0.011 mol) obtained in Example 24 was dissolved in 70 mι of anhydrous tetrahydrofuran, and while the reaction mixture was being cooled with ice and stirred, 14.8 mι of diisobutylaluminum hydride (1.5M toluene solution) was added dropwise. The reaction mixture was stirred at the same temperature for 2 hours, 1.6 mι of acetone was added dropwise and the reaction mixture was again stirred for 20 minutes. Furthermore, 2 mι of 3% sodium hydroxide solution was added dropwise and the reaction mixture was stirred for 1 hour. After magnesium sulfate was added, the reaction mixture was further stirred for 20 minutes, unnecessary matters were filtered by a celite and the solvent was distilled off under a reduced pressure. A colorless oily substance was thus obtained, i.e., (1S, 4aS, 7R, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4-(hydroxymethyl)-7-methylcyclopenta[c]pyran (2.18 yield=81.5%). This (1S, 4aS, 7R, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro- 4(hydroxymethyl)-7-methylcyclopenta[c]pyran had the following physicochemical properties:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1.[OH:26][C:27]1[C:31]([CH:32]=[O:33])=[CH:30][N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:32]([C:31]1[C:27]([O:26][CH2:2][C:3]2[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=3[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=2)=[N:28][N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=1)=[O:33]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(CCl)cc2OC)c(C)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3C=O)cc2OC)c(C)o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
A mixture of ethyl (2E)-3-{4[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (2.50 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.22 g), potassium carbonate (0.90 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (2E)-3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate as colorless crystals (1.81 g, yield 54%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 150-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20]#[N:21])[CH2:5][N:6]1[CH2:9][CH:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1.Cl.[NH2:23][OH:24].C(=O)(O)[O-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20](=[N:23][OH:24])[NH2:21])[CH2:5][N:6]1[CH2:9][CH:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)c(Cl)c2)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)c(Cl)c2)C1
Reaction time: 5 h
Yield: 96.3 %

Procedure:
A solution of tert-butyl 1-(3-chloro-4-cyanobenzyl)azetidine-3-carboxylate (0.133 g, 0.434 mmol) in isopropanol (1.2 mL) with hydroxylamine hydrochloride (0.060 g, 0.868 mmol) and sodium bicarbonate (0.146 g, 1.74 mmol) was stirred at 90° C. for 6.5 hrs. HPLC and LCMS indicated the reaction was only 33% complete after 20 minutes. Additional hydroxylamine hydrochloride (0.060 g) and sodium bicarbonate (0.146 g) were added and heating was continued for 5 hrs. The isopropanol was removed under reduced pressure, and the reaction mixture was diluted with ethyl acetate and washed with water (2×), washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded tert-butyl 1-(3-chloro-4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (142 mg) of a tan viscous taffy. The compound had an HPLC ret. time=0.795 min.−Column. PHENOMENEX® S5 4.6×30 mm (2 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=340.11.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[O:5][CH2:6][C:7]([NH2:9])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[O:5][CH2:6][CH2:7][NH2:9]
Reactant: Cc1ccc(OCC(N)=O)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(OCCN)cc1C
Yield: 27.4 %

Procedure:
2.50 g (13.9 mmol) of (3,4-dimethylphenoxy)acetamide obtained in step 3 was dissolved in 50 ml of dry tetrahydrofuran, and added slowly to a solution of 1.05 g (27.8 mmol) of LiAlH4 in 70 ml of dry tetrahydrofuran. The reaction mixture was refluxed for 5 hours and then 5 ml of water and 5 ml of 1N sodium hydroxide were added to decompose the remaining LiAlH4. The resultant mixture was passed through a Celite™ layer and the filtrate was evaporated under a reduced pressure to produce a residue, which was distilled under a reduced pressure to obtain 0.63 g (yield 28%) of the title compound as a colorless oil.
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:6]1)(=O)C.[OH-].[Na+].O>CO>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C@@H:7]2[CH2:8][CH2:9][C@H:5]([OH:4])[CH2:6]2)[CH:11]=1
Reactant: CC(=O)O[C@H]1CC[C@@H](c2cccnc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O[C@H]1CC[C@@H](c2cccnc2)C1
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of (1S,3R)-3-(3-pyridyl)cyclopentyl acetate (5.43 g, 26.5 mmol) in MeOH (80 ml) was added 1N NaOH aq. (26 mL) at 4° C., and stirred for 2 h at same temperature. To the reaction mixture was added H2O and then extracted with CH2Cl2 four times, and the combined layers were dried over Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (EtOAc) to yield (1S,3R)-3-(3-pyridyl)cyclopentanol (3.99 g, 92%) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)/[CH:5]=[N:17]/[S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: O=Cc1cc(F)cc(Br)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cc(F)cc(Br)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 3-bromo-5-fluorobenzaldehyde (5 g, 24.63 mmol) and (S)-2-methylpropane-2-sulfinamide (3.28 g, 27.1 mmol) in DCE (82 mL) was added copper(II) sulfate (anhydrous) (7.86 g, 49.3 mmol). The suspension was stirred under nitrogen at 60° C. overnight. The reaction mixture was cooled down, filtered through a plug of celite, and rinsed with DCM. The filtrate was concentrated to yield the crude product. The crude product was purified by flash chromatograph eluting with 0-30% EtOAc in heptane to yield the product (S,E)-N-(3-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide (7.5 g, 24.49 mmol, 99% yield) as a light yellow color oil. LCMS (m/z): 306.1/308.1 (MH+), 1.04 min.
Reaction SMILES: C(OC(=O)[N:7]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[N:23]=[N:22][NH:21][N:20]3[CH2:24][CH2:25][CH2:26][CH3:27])[CH:17]=2)[NH:12][C:11]=1[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:36]([NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[N:23]=[N:22][NH:21][N:20]3[CH2:24][CH2:25][CH2:26][CH3:27])[CH:17]=2)[NH:12][C:11]=1[C:28]1[CH:29]=[C:30]([CH3:35])[CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCCCN1NN=NN1c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(Cc3ccccc3)C(=O)OC(C)(C)C)c2c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCN1NN=NN1c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of benzyl-{2-[5-(2-butylpentazol-1-yl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-ethyl}carbamic acid tert-butyl ester (57 mg in 3.5 mL methylene chloride) at 0° C. was added 0.12 mL anisole followed by 0.80 mL trifluoroacetic acid and the mixture stirred at 0° C. After 1.5 hours, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene to give the crude title compound in quantitative yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[C:7]([CH3:13])[N:6]=2.[H-].[Na+].I[CH3:17]>CN(C)C=O>[OH:1][CH2:2][C:3]1[N:4]([CH3:17])[C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[C:7]([CH3:13])[N:6]=2
Reactant: CI
Reactant: Cc1cc(C)c2nc(CO)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2nc(CO)n(C)c2n1
Yield: 53.5 %

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 2.6 g of 2-hydroxymethyl-5,7-dimethyl-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 85), 0.64 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.2 g of iodomethane and 80 ml of dimethylformamide were used. After working up the product as described in Preparation 15, the resulting crude product was purified by column chromatography through silica gel, using a 1:6 by volume mixture of ethanol and ethyl acetate as the eluent, followed by recrystallization from ethyl acetate, to give 1.5 g of the title compound, melting at 178°-179° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#N)N=1)(=[O:3])C.[CH:12](=O)[C:13]1C=CC=CC=1>>[C:8]1([CH:9]=[CH:4][CH:1]=[O:3])[CH:7]=[CH:6][CH:10]=[CH:13][CH:12]=1
Reactant: CC(=O)c1cccc(C#N)n1
Reactant: O=Cc1ccccc1
Product: O=CC=Cc1ccccc1

Procedure:
reacting said 2-acetyl-6-cyanopyridine with a benzaldehyde for a time period and under conditions sufficient to form the corresponding 3-phenyl-2-propen-1-one; and