Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C([O:11][C@@H:12]([CH3:16])[C:13](Cl)=[O:14])(=O)C.[CH3:17][C@H:18]1[NH:23][C@@H:22]([CH3:24])[CH2:21][N:20]([C:25]2[N:26]([CH2:47][C:48]([F:51])([F:50])[F:49])[C:27]3[C:32]([N:33]=2)=[C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:30]=[C:29]([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)[N:28]=3)[CH2:19]1.C[O-].[Na+].CO>C(Cl)Cl.CO.C(Cl)Cl.CO>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:29]2[N:28]=[C:27]3[C:32]([N:33]=[C:25]([N:20]4[CH2:21][C@@H:22]([CH3:24])[N:23]([C:13](=[O:14])[CH:12]([OH:11])[CH3:16])[C@@H:18]([CH3:17])[CH2:19]4)[N:26]3[CH2:47][C:48]([F:50])([F:49])[F:51])=[C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[N:30]=2)=[CH:41][N:42]=1
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H](C)N1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(O)C(=O)N1[C@H](C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
Triethylamine (70.2 μl, 0.50 mmol) and (S)-(−)-2-acetoxypropionyl chloride (32.9 μl, 0.25 mmol) were added to a methylene chloride suspension (7.0 ml) of 5-[8-(cis-3,5-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (112.7 mg, 0.23 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 3 hours followed by the addition of (S)-(−)-2-acetoxypropionyl chloride (9.0 μl, 0.07 mmol) with ice cooling and the resulting mixture was stirred at room temperature for 1 day. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was dissolved in methylene chloride (7.0 ml) followed by the addition of triethylamine (140.3 μl, 1.01 mmol) and (S)-(−)-2-acetoxypropionyl chloride (65.7 μl, 0.50 mmol) with ice cooling, and the resulting mixture was stirred at room temperature for 1 day. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, a 25% by weight sodium methoxide-methanol solution (157.0 μl, 0.69 mmol) was added to a methanol (6.0 ml) solution of the resulting residue, and the resulting mixture was stirred at 50° C. for 22 hours. The resulting mixture was left standing to cool and then the reaction mixture was poured into methylene chloride and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (132.6 mg, 96%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([O:21][C:22]1[C:31]2[C:26](=[C:27]([NH:32]C(C)=O)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:36](Cl)(=[O:38])=[O:37])(=O)C>CC(C)=O>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[CH:25]=[CH:24][C:23]([S:36](=[O:38])(=[O:37])[NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:22]2[OH:21]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc2c(N)cccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
30 g of hexadecylamine was dissolved in 250 liters of acetone. To this solution was added gradually a solution of 40 g of 1-acetoxy-5-acetaminonaphthalene-2-sulfonyl chloride synthesized above in 150 ml of acetone while stirring, and, after completion of the addition, stirring was continued for about 1 hour at about 40° C. Then, the reaction solution was cooled with ice, and the precipitated crystals were collected by filtration and well washed with 1 liter of methanol. The crystals were refluxed for 8 hours together with 200 ml of ethanol, 30 g of sodium hydroxide and 100 ml of water. After being allowed to cool to room temperature, the solution was neutralized with acetic acid, and the crystals thus precipitated were collected by filtration and recrystallized from an ethanol-water mixture solvent to obtain 22 g (54% yield) of product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[N:11]1([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (50 mg) in dichloromethane (1 ml) was added trifluoroacetic acid (250 μl). The resulting solution was stirred at room temperature for 2 hrs. Reaction mixture was concentrated in vacuo and the residue was dissolved in acetonitrile and purified using the prep-HPLC to give the title compound trifluoroacetic acid salt as a white solid (6 mg).
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[N:4]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[N:5]=[CH:6][C:7]=1Cl.[C:18](=[O:21])([O-])[O-].[Na+].[Na+].[OH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3](=[O:17])[N:4]([CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[N:5]=[CH:6][C:7]=2[C:11]2[CH:12]=[CH:13][C:18]([OH:21])=[CH:10][CH:9]=2)=[CH:27][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: CC(c1ccccc1)n1ncc(Cl)c(Cl)c1=O
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(c1ccccc1)n1ncc(-c2ccc(O)cc2)c(-c2ccc(O)cc2)c1=O
Temperature: 80 °C
Yield: 78 %

Procedure:
the intermediate 1a (8.7 g, 32.3 mmol) is placed in presence of tetrakis(triphenylphosphine)palladium(0) (1.12 g, 0.97 mmol) and sodium carbonate (6.85 g, 64.7 mmol) in a mixture of 50 mL of toluene and 50 mL of ethanol and the mixture is heated to 80° C. 1.2 equivalent of 4-hydroxyphenylboronic acid is added and the mixture is heated under reflux for 5 h and 1.2 additional equivalent of 4-hydroxyphenylboronic acid is added and the reflux is maintained throughout the night. Following concentration to dryness, the residue is taken up with water and is extracted using AcOEt. After drying the organic layers and concentration to dryness, the residue obtained is purified by flash chromatography (CH2Cl2-MeOH, gradient 100-0 to 97-3 over 40 min.). 0.7g of minority compound 1 is obtained and 8.2g of solid corresponding to the majority substituted mono product 4-chloro-5-(4-hydroxyphenyl)-2-(1-phenylethyl)-pyridazin-3(2H)-one is obtained (yield:78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23](C1CCCCN1)[CH:22]=[CH:21]2>ClCCl.CO>[N:24]1([C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[CH:26][CH:27]=[C:18]([NH:17][C:14](=[O:16])[C:13]#[C:12][C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=4[Cl:1])[CH:19]=3)[N:24]=2)[CH2:25][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Nc1ccc2nc(C3CCCCN3)ccc2c1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc2nc(N3CCCCC3)ccc2c1

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and 6-amino-2-piperidin-2-ylquinoline. Yield: 170 mg (37.1% of theory); melting point: 176° C.-179° C.; C24H19ClF3N3O (M=457.88); calc.: molecular ion peak (M+H)+: 456/458; found: molecular ion peak (M+H)+: 456/458; Rf value: 0.62 (silica gel, dichloromethane/methanol (19:1)).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:19][N:18]=1>C(N(CC)CC)C.ClCCl>[CH2:5]([O:4][C:2]([N:19]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[C:17]([C:13]2[NH:12][CH:16]=[CH:15][CH:14]=2)=[N:18]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1c[nH]c(-c2n[nH]c3ncccc23)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)n1nc(-c2ccc[nH]2)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (150 mg) (Aldrich, Milwaukee, Wis.) was added to a mixture of 3-(1H-pyrrol-2-yl)-1H-pyrazolo[3,4-b]pyridine (120 mg) (from Example 2) and triethylamine (3 drops) in dichloromethane (DCM). After stirring at room temperature for one hour, the reaction was concentrated and purified on a silica gel column to give 3-(1H-pyrrol-2-yl)-pyrazolo[3,4-b]pyridine-1-carboxylic acid benzyl ester. It was then combined with di-morpholine methane (300 mg) (Aldrich, Milwaukee, Wis.), THF (2 mL), water (0.2 mL) and acetic acid (2 drops). The mixture was heated at 90° C. for 20 hours. The reaction was concentrated and purified on a silica gel column to give 30 mg of the titled compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH3:6])[CH3:5].[Na].[Cl:8][C:9]1[CH:22]=[CH:21][C:12]([C:13](=[N:15][O:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:14])=[CH:11][CH:10]=1>CN(C)C=O.O>[ClH:1].[CH3:5][N:4]([CH3:6])[CH2:3][CH2:2][O:20][C:18](=[O:19])[CH2:17][O:16][N:15]=[C:13]([CH3:14])[C:12]1[CH:21]=[CH:22][C:9]([Cl:8])=[CH:10][CH:11]=1
Reactant: CN(C)CCCl
Reactant: CC(=NOCC(=O)O)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NOCC(=O)OCCN(C)C)c1ccc(Cl)cc1
Product: Cl
Reaction time: 72 h

Procedure:
4.3 g of 2-chloro-N,N-dimethyl ethylamine was added to a suspension of 10 g of the sodium salt of (4-chloro-α -methylbenzylidene)amino-oxyacetic acid in 30 ml of dimethylformamide. The mixture was stirred for 72 hours. It was then diluted with water and extracted with diethylether. The resulting ethereal solution was extracted with 20 ml of 2N hydrochloric acid. The acid extract was then made basic with 30ml of 2N sodium hydroxide and extracted with diethylether. The latter ethereal extract was washed, dried over anhydrous sodium sulphate and after concentration by evaporation neutralized with alcoholic hydrochloric acid. When diethylether was added the hydrochloride of the (2-dimethyl-aminoethyl)ester of (4-chloro-α -methylbenzylidene) aminooxyacetic acid crystallized out. It was recrystallized from an alcohol-ether mixture; melting point 160° -162° C with decomposition.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:27](Cl)=[O:28])(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:27]([NH:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:28])(=[O:22])=[O:23]
Reactant: Cc1ccc(C(=O)Cl)cc1S(C)(=O)=O
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(C)c(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 3-methane-sulfonyl-4-methyl-benzoyl chloride. MS: 456.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([F:20])[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:16]2[CH:15]=[C:14]([F:13])[CH:19]=[C:18]([F:20])[CH:17]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1cc(F)cc(F)c1
Reactant: COC(=O)c1cc(Cl)ccc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1cc(F)cc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 3,5-difluorophenol: 1H-NMR (CDCl3) δ 8.00–7.90 (1H, m), 7.55–7.47 (1H, m), 7.08–7.00 (1H, m), 6.60–6.35 (3H, m), 3.81 (3H, s).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[SH:27][CH2:28][CH2:29][CH2:30]O.B(F)(F)F>>[O:1]1[C:3]2([CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:2][S:27][CH2:28][CH2:29][CH2:30]1
Reactant: OCCCS
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: FB(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CSCCCO4)c(F)c2)C(=O)O1

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.3 mmol) with 3-mercaptopropanol (0.36 mmol), BF3.etherate (catalytic) in tetrahydrofuran (10 ml) at 70-80° C. for 14 hours followed by silica gel column chromatographic purification to provide title compound in 48% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[N:7][CH:8]=1)#[N:2].[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:12][CH2:11][CH2:10][NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc(C#N)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(NCCN)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.0 g (15.25 mmol) of tert-butyl {2-[(5-cyanopyridin-2-yl)amino]ethyl}carbamate (Example 12A) are dissolved in 150 ml of dichloromethane, and 17.39 g (152.5 mmol) of trifluoroacetic acid are slowly injected. The mixture is stirred at RT for 16 h and then all volatile constituents are removed in vacuo. 4.3 g (91% of theory) of the product are obtained as a resin.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:33]O)[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([Cl:32])[CH:23]=1>>[Cl:32][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:33]=2)[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COC(=O)c1ccc(C(N)=NO)cc1Cl
Product: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(Cl)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Yield: 79.6 %

Procedure:
The title compound was prepared following procedure described for example 35, step 1, but starting from Intermediate 28 (1 076.46 mg; 4.20 mmol) and Intermediate 34 (960.27 mg; 4.20 mmol). The reaction mixture was cooled to RT and concentrated affording a brownish oil which was washed with MeOH (20 mL) affording a suspension that was filtered affording the title compound as a beige solid (1.5 g; 82%). 1H NMR (DMSO-d6, 300 MHz) δ 8.34 (d, J=1.5 Hz, 1H), 8.23 (d, J=1.3 Hz, 1H), 8.21 (dd, J=3.6, 1.7 Hz, 1H), 8.18 (dd, J=3.5, 1.8 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.37-7.27 (m, 3H), 7.15 (d, J=7.0 Hz, 1H), 4.23 (d, J=12.8 Hz, 1H), 4.16 (d, J=12.8 Hz, 1H), 3.92 (s, 3H), 3.25 (s, 3H), 2.04 (s, 3H). LC/MS (Method B): 449.1 (M+H)+. HPLC (Method A) Rt 6.14 min (Purity: 97.6%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[I:21]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[C:15]([I:21])[CH:16]=1
Reactant: Clc1ccc(CBr)c(I)c1
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2I)c1

Procedure:
1-(4-Chloro-2-iodo-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 1-Bromomethyl-4-chloro-2-iodo-benzene following General Procedure A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:25]2([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:32]>C(OCC)C.O1CCOCC1>[ClH:1].[ClH:32].[NH2:17][CH:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH:9]([C:25]2([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC1CCN(CC(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of tert-butyl {1-[2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate (130 mg, 0.28 mmol) (Example 13), in diethyl ether (2 mL) was treated with a 4 N solution of hydrogen chloride in dioxane (1 mL). The resulting solution was stored at 25° C. for 16 h, during which time crystals began to form. The mixture was transferred to the refrigerator where it was stored for an additional 16 h. The resulting crystals were collected, washed with diethyl ether, and dried in vacuo to yield 101 mg (82%) 1-[2-(4-aminopiperidin-1-yl)-1-(3,4-dichlorophenyl)ethyl]cyclohexanol dihydrochloride as a white solid. MS m/z 371/373/375 ([M+H]+); HRMS: calcd for C19H28Cl2N2O 2.00 HCl, 442.1112; found (ESI), 371.1642.
Reaction SMILES: CCOC(C)=O.[OH:7][N:8]=[CH:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CN1C(=O)CCC1.C1C(=O)N([Cl:36])C(=O)C1>O>[Cl:36][C:9](=[N:8][OH:7])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=NO
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(Cl)=NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 294.3 %

Procedure:
To an AcOEt (270 ml) solution of the (S)-t-butyl 2-((hydroxyimino)methyl)pyrrolidine-1-carboxylate (32.0 g) obtained in Example 2-(1), NMP (43.1 ml) was added and after adding NCS (21.94 g) in three divided portions at 20- to 30-min intervals at 30 to 40° C., the resulting mixture was stirred at room temperature for 0.5 hour. The same reaction was carried out in a total of four runs using the same quantities. To the reaction mixture, water (400 ml) was added and the organic layer was separated. The separated organic layers were combined, washed with water (1.2 L×2), dried (MgSO4), filtered and concentrated to give a crude product (pale yellow solid, 174 g), which was washed with AcOEt/hexane (AcOEt/hexane=140 ml/840 ml) and dried to give the titled compound (109.3 g, colorless solid.)
Reaction SMILES: C[O:2][C:3](=[O:23])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)=[N:5]/[O:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Li+].O>CO.C(Cl)(Cl)Cl>[Cl:22][C:14]1[CH:13]=[C:12](/[C:4](=[N:5]\[O:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)/[C:3]([OH:23])=[O:2])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COC(=O)/C(=N/OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reaction time: 1 h

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid methyl ester (144 mg, 0.40 mmol) was dissolved in methanol (4 mL) and cooled in an ice bath. A 2.0 N solution of lithium hydroxide in water (0.60 mL, 1.2 mmol) was added dropwise. After stirring 1 h, the reaction mixture was diluted with chloroform (50 mL) and washed with 0.1 M aqueous potassium bisulfate (25 mL). The aqueous phase was extracted with chloroform (30 mL) and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to afford (E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid which was used in the next step without further purification: H1-NMR (400 MHz, CDCl3) δ=1.65 (4H, m), 1.88 (4H, m), 3.31 (3H, s), 4.97 (1H, m), 7.58 (1H, dd, J=8.2 Hz, J=1.1 Hz), 7.67 (1H, d, J=1.1 Hz), 8.19 (1H, d, J=8.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[NH:11][C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:23].Br[CH2:29][C:30]#[N:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]([CH2:29][C:30]#[N:31])[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:23]
Reactant: CN(C)C(=O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: N#CCBr
Product: CN(C)C(=O)c1c2c(c(O)c(=O)n1CC#N)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
The title compound was prepared in a manner similar to that described for 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (Example 13, step 6), wherein bromoacetonitrile was employed in place of 2-iodopropane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:13]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)=O.O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CS(C)=O>O1CCOCC1>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([CH:13]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH3:31])[N:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[C:10](=[O:11])[NH:12]2)=[CH:16][CH:17]=1)#[N:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(=O)Nc1cc(Cl)cc(Cl)c1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(C)N(c2cc(Cl)cc(Cl)c2)C(=O)NC1c1ccc(C#N)cc1

Procedure:
Under argon, 30.8 mg (0.15 mmol) N-(3,5-dichlorophenyl)urea are stirred together with 39.3 mg (0.3 mmol) 4-formylbenzonitrile, 39 mg (0.3 mmol) ethyl 3-oxo-butanoate and 90 mg trimethylsilylpolyphosphate in 0.5 ml dioxan at 80° C. for 4 hours. After adding a small amount of DMSO, the reaction mixture is filtered and purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% conc. aq. ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; flow rate 25 ml/min; wavelength: 220 nm; injection volume: approx. 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:22]([S:12][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Sc1nnc(-c2ccccc2)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1ccc(CSc2nnc(-c3ccccc3)o2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 5-phenyl-[1,3,4]oxadiazole-2-thiol (3.1 g, 17.4 mmol; Aldrich) in ethanol (30 mL) was cooled to 0° C. and treated with diisopropylethylamine (3.1 mL, 17.4 mmol; Aldrich). The suspension cleared. Benzyl bromide (2.08 mL, 17.4 mmol; Aldrich) was then added, and the mixture was allowed to warm to room temperature. After 45 minutes, the resulting precipitate was collected by filtration and dried to afford the title compound.