Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)=[O:4].[N:16]1([CH2:22][CH2:23][CH2:24]O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:24][CH2:23][CH2:22][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: OCCCN1CCCCC1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(OCCCN3CCCCC3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
A mixture of 20.2 g (0.1 mol) 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (commercially available), 18.6 g (0.13 mol) 1-piperidinepropanol (commercially available), 50.4 g (0.2 mol) 1,1′-(azodicarbonyl)dipiperidine and 58 ml (0.2 mol) tri-n-butyl-phosphine in 400 ml THF was stirred at room temperature for 16 h. The suspension was filtered off and the filtrate evaoprated to dryness. The residue was taken up in 200 ml DCM and 400 g Isolute® HM-N (Argonaut Technologies Inc., support material for accelerated solvent extraction) was added and evaporated to dryness. The residue was chromatographed over silica eluting with a gradient formed from DCM/MeOH(2N NH3) 99/1 to 9/1. After evaporation the residue was treated with heptan/diethyl ether and the precipitate filtered of and washed again with heptan/diethyl ether. After drying under reduced pressure at 50° C. 25 g (76%) of the title compound was obtained as white solid. MS (m/e): 328.3 (MH+, 100%)
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]12[O:25][CH2:24][CH2:23][O:22]1)[CH3:2].[H][H]>C1C=CC=CC=1.[Pd]>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]12[O:22][CH2:23][CH2:24][O:25]1)[CH3:2]
Reactant: [H][H]
Reactant: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)C1=CCC21OCCO1
Agent: [Pd]
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC21OCCO1
Yield: 64.6 %

Procedure:
Hydrogenate 13β -ethyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaene (2.0 g.) in benzene (70 cc.) at atmospheric pressure using a 5% palladium on calcium carbonate catalyst (0.70 g.). Uptake of hydrogen ceases after 150 cc. has been absorbed. Isolate the product and recrystallize from 95% ethanol to obtain the title product (1.3 g.), m.p. 135°-137°; ultraviolet absorption peak at 2.78 mμ (15,100).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]1[C:17]([C:36]2[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)=[N:18][C:19]([NH:22][CH2:23][CH2:24][NH:25]C2C=CC(C(F)(F)F)=CN=2)=[N:20][CH:21]=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:25][CH2:24][CH2:23][NH:22][C:19]2[N:18]=[C:17]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)[C:16]([C:12]3[NH:11][CH:15]=[CH:14][N:13]=3)=[CH:21][N:20]=2)[N:3]=1
Reactant: N#Cc1cnc(Cl)nc1N
Reactant: N#Cc1ccc(-c2nc(NCCNc3ccc(C(F)(F)F)cn3)ncc2-c2ncc[nH]2)cc1
Product: N#Cc1ccc(-c2nc(NCCNc3ncc(C#N)c(N)n3)ncc2-c2ncc[nH]2)cc1

Procedure:
4-amino-2-[(2-{[4-(4-cyanophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]pyrimidine-5-carbonitrile was prepared from 4-amino-2-chloropyrimidine-5-carbonitrile using the general method for 4-{5-imidazolyl-2-[(2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amino]pyrimidin-4-yl}benzenecarbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:38])([F:37])[C:13]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:32][C:13]([OH:31])([CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([F:37])([F:11])[F:38])=[O:6]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 1 from 2-fluorobenzoic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[C:41]([O:42][CH3:43])=[CH:40][C:29]2[CH2:30][C:31](=[O:39])[N:32]([CH2:35][CH2:36][CH2:37]Cl)[CH:33]=[CH:34][C:28]=2[CH:27]=1>[OH-].[Na+].C(OCC)(=O)C>[CH3:24][O:25][C:26]1[C:41]([O:42][CH3:43])=[CH:40][C:29]2[CH2:30][C:31](=[O:39])[N:32]([CH2:35][CH2:36][CH2:37][N:2]([CH3:1])[CH:3]3[CH2:12][CH2:11][C:10]4[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[CH2:4]3)[CH:33]=[CH:34][C:28]=2[CH:27]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2
Reactant: CNC1CCc2cc(OC)c(OC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)C=C2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methylamino-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene (1.72 g, 0.0078 mol), triethylamine (1.09 ml, 0.0078 mol) and 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane (2.3 g, 0.0078 mol) is heated to a reaction temperature of 90° C. in steps within one hour and kept at this temperature for 2 hours. The initial suspension slowly changes into a clear solution and begins to precipitate in a jelly-like manner after about 30 minutes. The cooled reaction mixture is dissolved in 0.5M sodium hydroxide solution/ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over alumina (300 g), neutral, activity II, with methylene chloride and then with increasing quantities of ethanol (up to 20%). The hydrochloride is precipitated from a solution in acetone using ethereal hydrochloric acid. Yield: 1.39 g Mp: >125° C. (Decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][NH2:14].O>CCO>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([NH:14][CH3:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNc1cc(F)cc(F)c1[N+](=O)[O-]
Reaction time: 4 h
Yield: 83 %

Procedure:
1,3,5-Trifluoro-2-nitrobenzene (3.0 g, 16.90 mmol) was dissolved in EtOH (29.7 mL) and Methylamine 40% in Water (1.44 mL, 17.80 mmol) was added dropwise at 0° C. The color went from bright yellow to an orange precipitate within 20 min. After 4 h at RT. 0.66 mL of Methylamine was added (9 mmol). To complete the reaction, an additional 0.26 ml (3.6 mmol) of Methylamine was added after 2 h at RT. The completion was achieved within 20 min. Water (75 mL) was added to the reaction mixture and the solid was isolated by filtration, washed with water (2*10 mL) and dried over high vacuum to afford 2.64 g of 3,5-difluoro-N-methyl-2-nitrobenzenamine (Yield: 83%) as an orange solid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:8]=[N:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:5]1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:2][CH2:3][N:4]1[CH:8]=[N:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:5]1
Reactant: O=S(Cl)Cl
Reactant: OCCn1cnc(-c2cccnc2)n1
Product: ClCCn1cnc(-c2cccnc2)n1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
122 g (6.4 mmol) 1-(2-hydroxyethyl)-3-(3-pyridinyl)-1H-1,2,4-triazole were suspended in 15 ml thionyl chloride and heated at 70° C. for 45 minutes. Excess thionyl chloride was removed in vacuo and the residue was dissolved in water (100 ml). The aqueous solution was basified with NaHCO3 solution (10%) and the resulting slurry was stirred for 15 minutes. The product was isolated by filtration, washed with water and dried to give the desired product as a brownish solid. MS (EI): 208.1 (M+). 1H-NMR (DMSO-d6): 3.97 (t, 2H), 4.54 (t, 2H), 7.38 (m, 1H), 8.21 (s, 1H), 8.36 (m, 1H), 8.65 (m, 1H), 9.34 (d, 1H).
Reaction SMILES: CN(CCN(C)C)C.[C:9]([O:13][C:14](=[O:22])[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)([CH3:12])([CH3:11])[CH3:10].[C:23](=[O:25])=[O:24].[OH-].[Na+]>C1COCC1>[C:9]([O:13][C:14]([NH:15][C:16]1[C:21]([C:23]([OH:25])=[O:24])=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:22])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Agent: CN(C)CCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
n-Buli (1.6 M soln, 155 mL, 249 mmol) was added to a stirred solution of TMEDA (37.36 mL, 249 mmol) in THF at −40° C. The solution was allowed to come at room temperature over 10 min and stirred for another 10 min. The solution was cooled to −78° C. A solution of pyridine-4-yl-carbamic acid-tert-butyl ester (117) (22 g, 113.26 mmol) in THF was added slowly. The solution was allowed to come at room temperature within 3 h. After stirring at room temperature for 15 min the solution was again cooled to −78° C. and a freshly crushed dry ice was added. The solution was allowed to come at room temperature, stirred for 30 min and poured into ice cold 10% NH4Cl solution. The solution was basified by 1N NaOH solution and washed by dichloromethane. The pH of aqueous phase was adjusted to 4 by cold 10% HCl solution. The solids formed were filtered, washed by water and dried under vacuum at room temperature to yield 16.3 g (30%) 4-tert-butoxycarbonylamino-nicotinic acid (118) as white solids. MP: 260° C.; 1H-NMR (DMSO-d6): δ 1.49 (s, 9H), 8.23 (d, J=6.0 Hz, 1H), 8.55 (d, J=6.0 Hz, 1H), 8.96 (s, 1H); EIMS m/z 238 (M+1).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][C:16]1[CH:17]=[C:18]2[CH2:41][C:23]3([C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:24]3=[O:40])[O:22][C:19]2=[N:20][CH:21]=1>CC(C)=O>[O:40]=[C:24]1[N:25]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:38])[CH3:39])[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:31]2[C:23]21[O:22][C:19]1=[N:20][CH:21]=[C:16]([C:15]([OH:3])=[O:14])[CH:17]=[C:18]1[CH2:41]2
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(CO)cnc3O2)c2cccnc21
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(C(=O)O)cnc3O2)c2cccnc21

Procedure:
Freshly prepared Jones reagent was added drop wise to a solution of 5-(hydroxymethyl)-1′-((2-(trimethylsilyl)ethoxy)methyl)-3H-spiro[furo[2,3-b]pyridine-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (0.24 g, 0.60 mmol) in acetone (10 mL) at 0° C. until the starting material was completely consumed. The acidic mixture was neutralized carefully with saturated aqueous sodium bicarbonate solution and acidified with saturated aqueous citric acid solution to pH 5-6, then extracted with ethyl acetate (5×). The combined organic layers were dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane to give the title compound as a racemic mixture. MS: m/z=414.2 (M+1); 1H NMR (300 MHz, CD3OD): δ 8.70 (d, 1H, J=1.8 Hz), 8.34 (dd, 1H, J=1.5, 5.3 Hz), 8.29 (d, 1H, J=1.8 Hz), 7.89 (dd, 1H, J=1.5, 7.4 Hz), 7.19 (dd, 1H, J=5.3, 7.4 Hz), 5.26 (s, 2H), 3.78-3.65 (m, 4H), 0.95 (t, 2H, J=8 Hz), 0.005 (s, 9H).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=2)[O:10][C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[CH:26][CH:27]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1ccc(-c2cc(C(Cl)CC(C)C)c(C)o2)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (382 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (400 mg), sodium carbonate (170 mg) and sodium iodide (240 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 65% ethyl acetate/hexane) to give ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. The obtained ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.7 mL) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (153 mg, 25%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:9][CH3:11])=[CH:6][C:7]=1[F:8]
Reactant: Oc1cc(F)c(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)c(Br)cc1F
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 20 mL of DMF. To the stirred solvent were added 4-Bromo-2,5-difluorophenol (2.0 g, 9.6 mmol), K2CO3 (3.98 g, 28.8 mmol) and methyl iodide (1.63 g, 11.53 mmol), stirred at 45° C. for 15 minutes under nitrogen atmosphere. The RM was quenched with water, extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as white color solid (1.2 g, yield: 56.07%).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.N.P(Cl)(Cl)([Cl:23])=O>>[Br:1][C:2]1[C:3]([Cl:23])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cc1
Temperature: 106 °C
Reaction time: 16 h

Procedure:
255 mg of (RS)-S-{4-[(5-bromo-4-hydroxypyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide is suspended in 1.5 ml of phosphorus oxychloride and stirred for 3 hours at 106° C. and for 16 hours at room temperature. The mixture is poured into ice water, made alkaline with 25% ammonia solution while being cooled intensely (temperature <5° C.) and stirred for 1 hour in an ice bath. The precipitate is suctioned off, washed with water and dried at 60° C. 220 mg (81.8% of theory) of the product with a melting point of 170-173° C. is obtained.
Reaction SMILES: C(OC([NH:8][CH:9]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:10]1[N:14]2[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C:13]2=[N:12][N:11]=1)=O)(C)(C)C.CO.[ClH:35]>>[ClH:32].[ClH:35].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH:9]([C:10]2[N:14]3[CH2:15][CH2:16][NH:17][CH2:18][C:13]3=[N:12][N:11]=2)[NH2:8])=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccc(Cl)cc1)c1nnc2n1CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Product: NC(c1ccc(Cl)cc1)c1nnc2n1CCNC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of tert-butyl 3-((tert-butoxycarbonylamino)(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (0.652 g, 1.41 mmol) in MeOH (7.03 mL, 1.41 mmol) was saturated with HCl (g). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo to afford (4-chlorophenyl)(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine bishydrochloride as a foam (0.47 g, 99%). LCMS (APCI+) M+H+: 264 (50%), 266 (10%), 267 (3%); rt=1.76 minutes. 1H NMR (400 MHz, d6-DMSO) δ □10.62 (s, 1H), 10.18 (s, 1H), 9.43 (s, 3H), 7.57 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 6.13 (m, 1H), 4.51 (m, 2H), 4.44 (m, 1H), 3.56 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[N:24][OH:25])=[CH:12][CH:13]=1)=[O:6].N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>O1CCCC1>[C:36]([O:25][N:24]=[C:19]1[C:20]2[C:16](=[C:15]([O:14][C:11]3[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:26]=[CH:27][C:28]([Cl:29])=[C:2]([Cl:1])[CH:3]=4)=[CH:13][CH:12]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:18]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=NO)nc1)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)ON=C1CCc2c(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
650 mg of N1-{6-[(1-hydroxyimino-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl}benzamide obtained in Example 47 was dissolved in 10 ml of tetrahydrofuran. To the resulting reaction solution, 1.2 ml of pyridine and 0.7 ml of acetic anhydride were added and the mixture was stirred at room temperature. After 17 hours, the reaction solution was distilled off under reduced pressure and 15 ml of ethyl acetate and 15 ml of water were added to the resulting residue. Then, the deposited powder was isolated by filtration and washed in turn with water and ethyl acetate to obtain the titled compound (310 mg).
Reaction SMILES: [O:1]=[C:2]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[BH4-].[Na+].Cl>CO.O>[OH:1][CH:2]([C:26]1[CH:27]=[CH:28][C:29]([C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[CH:30][CH:31]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:25])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7]1
Reactant: CC(C)(CO)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(CO)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Dissolve 2-(4-(1-oxo-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl)-phenyl)-2-methylpropanol in methanol (450 mL) and stir for 15 minutes at room temperature. Add, by dropwise addition, a solution of sodium borohydride (2.25 g, 0.06 mol) in water (10 mL) over 15 minutes. Stir for another 30 minutes and cool in an ice-bath. Slowly add concentrated hydrochloric acid (4 mL) and water (8 mL) and stir for an additional 20 minutes. Evaporate the solvent in vacuo and partition the residue between methylene chloride (150 mL) and water (70 mL). Separate the organic phase and extract the aqueous phase with methylene chloride (25 mL). Wash the combined organic layers with water (2×50 mL), evaporate the solvent in vacuo and recrystallize (acetone) to give the title compound as white needles (9.53 g, 79%).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[Cl:17][C:18]1[CH:19]=[C:20]([F:42])[C:21]([C:40]#[N:41])=[C:22]([C:24]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[N:25]S(C(C)(C)C)=O)[CH:23]=1.Cl.CO>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]2[C:21]([C:40]([NH2:41])=[N:25][C:24]2([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[C:20]([F:42])[CH:19]=1
Reactant: COc1cccc(C(=NS(=O)C(C)(C)C)c2cc(Cl)cc(F)c2C#N)c1
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cc(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.2 %

Procedure:
tert-Butyllithium (1.7 M in pentane, 6.59 mL, 11.20 mmol) was added dropwise to THF (10 mL) at −100° C. under an argon atmosphere. A solution of 4-bromo-2-trifluoromethylpyridine (1.266 g, 5.60 mmol) in THF (1 mL) was added dropwise followed by the addition of N-((5-chloro-2-cyano-3-fluorophenyl)(3-methoxyphenyl)methylene)-2-methylpropane-2-sulfinamide (2 g, 5.09 mmol) in THF (6 mL). The resulting reaction mixture was left on the thawing cooling bath for 30 min then the cooling bath was removed and the mixture was stirred at rt for 1.5 h. Hydrogen chloride in methanol solution (20.36 mL, 25.45 mmol) was added and the mixture was stirred at rt for 1 h. The mixture was concentrated and purified on a silica gel column eluted with 0-10% 0.1M NH3 in MeOH in DCM to afford 870 mg (39%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[C:13]([OH:16])(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:5][C:4]([C:3]1[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:2]=1[CH3:1])=[O:7])(=[O:15])[CH3:14]
Reactant: Cc1ccc(C(=O)CCl)c(C)c1
Reactant: CC(=O)O
Product: CC(=O)OCC(=O)c1ccc(C)cc1C

Procedure:
Following the procedure of Example 1,5 grams of 2,4-dimethylphenacyl chloride are reacted with 5 grams of acetic acid to obtain 2,4-dimethylphenacyl acetate, m.p. 43°-45° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([OH:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([C:52]([O:54][CH3:55])=[O:53])=[CH:49][C:50]=1O)=[O:45]>C1COCC1>[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([C:52]([O:54][CH3:55])=[O:53])=[CH:49][C:50]=1[O:22][CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])[CH3:21])=[O:45]
Reactant: COC(=O)c1cc(O)c(C(=O)OC)s1
Reactant: CC(O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(C)c2ccccc2Cl)c(C(=O)OC)s1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
Diethyl azodicarboxylate (1.29 g, 7.41 mmol, 1.3 Eq.) was added to a stirred solution of 1-(2-Chloro-phenyl)-ethanol (893 mg, 5.70 mmol, 1.0 Eq.), triphenylphosphine (1.94 g, 7.41 mmol, 1.3 Eq.) and 3-hydroxythiophene-2,5-dicarboxylic acid dimethyl ester (1.23 g, 5.70 mmol, 1.0 Eq.) in anhydrous THF (20 mL) at 0° C. under nitrogen and the reaction allowed to warm to ambient temperature overnight. The crude reaction mixture was concentrated in vacuo and purified by column chromatography (10% EtOAc/Petroleum ether) to give the sub-title compound as a white solid (1.94 g, 5.6 mmol, 93%); 1H NMR (400 MHz, CDCl3) δ 1.71 (3H, d), 3.89 (3H, s), 3.95 (3H, s), 5.80 (1H, q), 7.20-7.32 (3H, m), 7.39 (1H, d), 7.66 (1H, d).