Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH2:24]([N:26](CC)CC)C>C(O)C>[CH3:20][NH:19][C:14]1[N:13]=[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:17]=[C:16]([NH:26][CH3:24])[N:15]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(Cl)cc2)n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(Cl)cc2)nc(NC)n1
Temperature: 140 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
0.62 g (0.0019 mol) of 4-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 10 ml of ethanol, treated with 1.67 g (0.025 mol) of methylamine hydrochloride and 6.2 ml (0.044 mol) of triethylamine and stirred in an autoclave at 140° C. for 18 hours. The mixture was freed completely from solvent, the residue was partitioned in ethyl acetate/water and the insoluble constituents were filtered off under suction. The filter cake was recrystallized in methanol/diethyl ether. There was obtained 0.28 g (45%) of N-(2,6-bis-methylamino-pyrimidin-4-yl)-4-chloro-benzenesulfonamide as white crystals; m.p. 272-273° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:29](C(C)C)CC)(C)C.CS(Cl)(=O)=O>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24][NH2:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CO)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CN)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
To a 0° C. solution of 1.30 g of 1-(benzyloxycarbonyl)-2-hydroxymethyl-4-(tert-butyloxycarbonyl)-piperazine in 20 mL of CH2Cl2 was added 720 mg of diisopropylethylamine, then 510 mg of methanesulfonyl chloride. The mixture was allowed to warm to room temperature over 2 h, then diluted with 50 mL of EtOAc and washed with 25 mL of saturated NaHCO3, 2×25 mL of 1N HCl, 25 mL of saturated NaHCO3, and 25 mL of brine. The organic phase was dried over MgSO4 and concentrated to a yellow oil. This oil was dissolved in 10 mL of DMF and 360 mg of sodium azide was added. The mixture was heated to 100° C. and stirred overnight at this temperature, then cooled, diluted with 25 mL of EtOAc, and washed with 3×10 mL of water and 10 ml of brine. The organic phase was dried over MgSO4 and concentrated to an oily yellow solid. Of this solid, 475 mg was dissolved in 5 mL of 9:1 THF-water and 398 mg of triphenylphosphine was added. The mixture was heated to 50° C. and stirred at this temperature for 16 h, then cooled, poured into 30 mL of 1N HCl, and extracted with 2×10 mL of EtOAc. The aqueous phase was made very basic (pH>12) by addition of 5N NaOH, then extracted with 5×20 mL of EtOAc. The combined organic extracts were dried over MgSO4, and concentrated to yield 48 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ7.28-7.40 (m, 5H), 5.15 (ABq, J=12.4 Hz, 2H), 3.82-4.22 (m, 4H), 2.66-3.30 (m, 5H), 1.45 (br s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(Cl)(Cl)(Cl)[Cl:26]>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:26])=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][N:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2[nH]1
Reactant: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ccc(-c3ccc(C(F)(F)F)cn3)cc2c1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
N-Chlorosuccimimide (480 mg, 3.86 mmol) and 5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (800 mg, 2.4 mmol; see Example 8 (b)) were mixed in CCl4 (50 mL) and stirred at 80° C. for 2 h. The mixture was diluted with EtOAc and washed with Na2S2O3 (aq., sat.), NaHCO3 (aq., sat.), brine and dried over Na2SO4 Concentration gave the sub-title compound (870 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([CH3:22])[CH3:21])[N:9]=[C:10]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13](F)[CH:12]=3)[C:3]=12.O.[NH2:24][NH2:25]>CCCCO>[NH2:16][C:15]1[C:14]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([CH:20]([CH3:22])[CH3:21])[N:9]=3)=[CH:18][CH:17]=2)[NH:25][N:24]=1
Reactant: NN
Reactant: CC(C)n1nc(-c2ccc(C#N)c(F)c2)c2c(N)ncnc21
Solvent: CCCCO
Solvent: O
Product: CC(C)n1nc(-c2ccc3c(N)n[nH]c3c2)c2c(N)ncnc21
Temperature: 110 °C
Yield: 70 %

Procedure:
4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorobenzonitrile (BA150, 20 mg, 0.07 mmol) was dissolved in n-BuOH (2 ml). Hydrazine monohydrate (0.400 ml) was added and the reaction was heated to 110° C. under an argon atomosphere and left stirring over night. Reaction mixture was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA154 (15 mg, 70% yield). ESI-MS (M+H)+ m/z calcd 309.2, found 309.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH3:23][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:25].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:25][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[CH:37][CH:38]=1)[CH3:23]
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)O)c1ccccc1F
Reactant: CN(C)Cc1ccccc1-c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)Cc1ccccc1-c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (60 mg, 0.19 mmol) and 4-(2-dimethylaminomethyl-phenyl)phenylamine (50 mg, 0.22 mmol) in pyridine (3 mL) cooled in an ice-bath, POCl3 (0.034 mL, 0.37 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (8 mg). MS 531.1 and 533.1 (M+H, Cl pattern).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]=1B(O)O>>[NH2:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([C:19]2[CH:18]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:16]=[CH:15][C:14]=2[F:13])=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Reactant: CCCOc1ccc(F)c(B(O)O)c1
Product: CCCOc1ccc(F)c(-c2nc(C(=O)O)c(N)cc2F)c1
Yield: 28 %

Procedure:
Method 1 was followed using 3-amino-6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2-fluoro-5-propoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)C12-DCM (0.05 equiv.) to give 3-amino-5-fluoro-6-(2-fluoro-5-propoxyphenyl)picolinic acid in 28% yield. LC/MS=309.1 (M+H), Rt=1.00 min.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11]Br)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>COCCO>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][N:28]2[CH2:29][CH2:30][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(CCN1CCC(c2ccccc2)CC1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 18.6 parts of 2,2-diphenyl-4-bromobutyronitrile, 10.0 parts of 4-phenylpiperidine, 8.0 parts of N,N-diisopropylethylamine and 200 parts by volume of 2-methoxyethanol is heated at reflux for 16 hours. The solution is then cooled and stripped in vacuum. The resulting residue is partitioned between dilute sodium hydroxide and ether. Extraction of the ether phase with dilute hydrochloric acid results in the precipitation of an oil. This oil and the aqueous phase of the partitioning are combined, treated with aqueous sodium hydroxide and extracted with 1:1 ether-benzene mixture. The ether-benzene extract is dried over sodium sulfate and stripped in vacuum to give a solid. Crystallization of the solid from a mixture of skelly B and ether provided 2,2-diphenyl-4-(4-phenylpiperidino)butyronitrile, melting at 88° - 89.5° C. and having the following formula ##STR7##
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OCc1cccnc1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2Cc1cccnc1

Procedure:
Compound IIn was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and pyridin-3-ylmethanol following the general procedure for the Mitsunobu reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].O[CH2:14][CH:15]([CH2:17]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]2[C:8]=1[CH:14]=[CH:15][CH:17]=[N:7]2
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(Cl)c2cccnc12
Yield: 67 %

Procedure:
In a similar fashion using route 10 general procedure 20, 5-chloro-4-fluoro-2-nitroaniline (1.0 g, 5.2 mmol), glycerol (1.5 g, 16.2 mmol), 3-nitrobenzensulfonic acid sodium salt (1.52 g, 6.7 mmol) and H2SO4/H2O (6 ml, 7:5) gave the title compound (790 mg, 67%) which was used in the next step without purification.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.[Br:12]Br>CC(O)=O>[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][CH2:2][CH2:3][CH:4]2[NH2:11]
Reactant: BrBr
Reactant: NC1CCOc2ccccc21
Solvent: CC(=O)O
Product: NC1CCOc2ccc(Br)cc21
Temperature: 25 °C

Procedure:
A solution of chroman-4-ylamine (2.550 g, 17.09 mmol) in AcOH (50 mL) at RT was treated with Br2 (3.01 g, 0.96 mL, 18.8 mmol) drop-wise. The reaction was stirred at RT until HPLC analysis showed complete consumption of starting material. The mixture was diluted with H2O (100 mL) and NaOH was added until the solution became basic. The aqueous layer was extracted with EtOAc until tlc analysis of the aqueous layer showed no evidence of the title compound. The combined organics were dried over MgSO4 and concentrated in vacuo to yield the crude compound, which was purified by flash column chromatography to afford the pure title compound. MS (APCI pos) 229 (M+H).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>[Cl-].[Zn+2].[Cl-].O>[C:1]([C:4]1[O:5][C:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(CCl)cc1
Reactant: CC(=O)c1ccco1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CC(=O)c1ccc(Cc2ccc(F)cc2)o1
Temperature: 85 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
To 258 g (0.94 mol) of a 50% aqueous solution of zinc chloride were added 69.3 g of water, 99.0 g (0.90 mol) of 2-acetylfuran and 260 g (1.80 mol) of 4-fluorobenzylchloride. The mixture was stirred at 85° C. for 6 hours. The reaction mixture was cooled and extracted with ethylacetate. The extract was washed with 1N hydrochloric acid, washed with an aqueous sodium hydrogencarbonate solution and removed under reduced pressure. The obtained residue was distilled under reduced pressure to give 145.4 g of crude 2-acetyl-5-(4-fluorobenzyl)furan (106-121° C./0.4 mmHg). The crude product was recrystallized from isopropylalcohol/n-hexane to give 84.4 g of 2-acetyl-5-(4-fluorobenzyl)furan. Yield: 43%.
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C(O)CCc1ccccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
Methyl iodide (51 g, 22.4 ml, 0.24 mole) was added to a stirred mixture of 3-(2-bromophenyl)propanoic acid (36.7 g, 0.16 mole, prepared as described by F. G. Holliman and F. G. Mann J Chem. Soc. 9, 1960) and anhydrous potassium carbonate (33 g, 0.24 mole) in dry N,N-dimethylformamide (250 ml) and the mixture was stirred at ambient temperature overnight. After removal of the solvent in vacuo the residue was partitioned between ether and water and the ethereal phase washed with aqueous sodium thiosulphate and then brine and dried (MgSO4). Evaporation gave a pale yellow oil which distilled at 116°-118° C. (0.2 mm) to give 36.91 g (95%) of the title ester as a colourless oil, νmax 2950, 1740, 1570, 1470, 1440 cm-1, δ(CDCl3), 2.63 (2H, m, ArCH2), 3.07 (2H, m, CH2CO2), 3.70 (3H, s, CH3), 7.12 (3H, m, arom), 7.50 (1H, d, arom).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].Cl.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([N:5]4[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]4=[O:9])=[CH:18][CH:17]=3)=[O:16])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@@H]4C(C)C)cc3)CC2)c(C)c1
Yield: 69.3 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (S)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (496 mg) described in Preparation Example 80 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (455 mg) described in Preparation Example 64, the title compound (583 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([OH:9])[C:6](=[O:8])[CH:7]=1.Cl.CC(C)=O.CC1(C)OC2C=C3OC(C)(C)OC3=CC=2O1>O.[Fe]>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([OH:9])=[CH:4][C:3]=1[OH:10]
Reactant: O=C1C=C(O)C(=O)C=C1O
Agent: [Fe]
Agent: CC1(C)Oc2cc3c(cc2O1)OC(C)(C)O3
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Oc1cc(O)c(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,5-Dihydroxy-1,4-benzoquinone (10.00 g, 71.43 mmol) was suspended in water (200 ml, distilled) followed by HCl (6 mL, 142.86 mmol, conc.). Iron (4.00 g, 71.43 mmol, powder) was added and the mixture was stirred 30 minutes at room temperature. The solution was filtered and the solution evaporated to dryness. The product was isolated as a grey brown powder containing some iron complexes. Yield 14.80 g. The product is used as such in the reaction with acetone and P2O5 (Example 5) with no negative effects.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[C:22]3[C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[N:13]=1.O>CN(C=O)C>[C:29]([C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([NH:18][C:14]3[N:15]=[C:16]([N:4]4[CH:5]=[C:6]([CH:7]=[O:8])[C:2]([CH3:1])=[N:3]4)[CH:17]=[CH:12][N:13]=3)[CH:20]=2)[N:24]([CH3:28])[CH:23]=1)(=[O:33])[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1n[nH]cc1C=O
Reactant: CC(C)C(=O)c1cn(C)c2ccc(Nc3nccc(Cl)n3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(C(=O)C(C)C)cn4C)n2)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 3-methyl-1H-pyrazole-4-carbaldehyde (273 mg, 2.48 mmol) in anhydrous DMF (5 mL) was added 60% NaH (130 mg, 3.25 mmol) at 0° C. After being stirred for 30 min at room temperature, it was cooled to 0° C. To this, was added intermediate 5 (542 mg, 1.65 mmol) and then stirred for 6 hours at 60° C. Quenching the reaction by addition of ice and 20 mL of water resulted precipitation of brown solids. The resulted solids were collected by filtration, rinsed with water and the dried in vacuo to provide the desired intermediate 6 as a brown solid (424 mg, 80%); MS (ESI) m/z 403 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])C)[CH:9]=[CH:10][CH:11]=1.[Se](=O)=O.[C:23]([O-:26])(O)=[O:24].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[C:23]([OH:26])=[O:24])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C([O-])O
Reactant: CC(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: O=[Se]=O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cccc(C)c1COc1cccc(C(=O)C(=O)O)c1
Temperature: 100 °C

Procedure:
To a stirred solution of 1-(3-(2,6-Dimethylbenzyloxy)-phenyl)-ethanone (WO 02/100341, 5 g, 20 mmol) in pyridine (20 ml) was added selenium dioxide (3.492 g, 31 mmol) diluted in pyridine (20 ml). The reaction mixture was heated at 100° C. for 3 hours, decanted from selenium metal and concentrated in vacuo to give orange oil, which solidified at room temperature. The solid was dissolved in saturated NaHCO3 (40 ml) and stirred with decolorizing carbon (0.5 g) for an hour at room temperature. The reaction mixture was filtered through celite and aqueous filtrate was acidified using 6N HCI (6 ml). A gray precipitant (6.3 g) was filtered and dried in vacuo at 40° C. for 2 hours. The acidified filtrate was washed with ether (2×75 ml), dried over Na2SO4, filtered, and concentrated to yield a white solid (0.5 g). Recrystallization using carbon tetrachloride afforded 4.9 g of the title compound with pyridine as an impurity. The semipure material (4.2 g) was dissolved in ethyl acetate (150 ml) and washed with 5% HCl (2×50 ml). The organic layer was dried over Na2SO4, filtered and concentrated to yield a yellow solid (3.9 g). The solid was recrystallized with carbon tetrachloride (30 ml) to afford the title compound (3.03 g) as a light yellow solid.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][I:21])[OH:19])[CH3:9].CN(C1C=CC=CN=1)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl.C(OCC)(=O)C>[C:31]([O:18][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][I:21])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:16][CH3:17])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COC1C(O)CCC(O)(CI)C1C1(C)OC1CC=C(C)C
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC1C(OC(C)=O)CCC(O)(CI)C1C1(C)OC1CC=C(C)C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
In dichloromethane (5 ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (2.08 g). To the solution were added dimethylaminopyridine (0.74 g) and acetic anhydride (0.58 ml). The mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 ml), which was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the solvent was purified by means of a silica gel column chromatography (carrier 100 g, developing solvent: ethyl acetate - hexane=1:3) to afford 4-O-acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-iodomethyl-3-methoxy-1,4-cyclohexanediol (2.19 g: yield 95%) as a colorless oily product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=2)[CH2:11]1.C1([O:27][C:28](=O)[NH:29][C:30]2[CH:35]=[C:34]([C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH:33]=[C:32]([CH2:42][CH3:43])[CH:31]=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH2:42]([C:32]1[CH:31]=[C:30]([NH:29][C:28]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[CH2:8][NH:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[CH2:11]2)=[O:27])[CH:35]=[C:34]([C:36]2[N:40]([CH3:41])[N:39]=[N:38][N:37]=2)[CH:33]=1)[CH3:43]
Reactant: N[C@@H]1CCCC[C@H]1CNC1CCc2cc(F)ccc2C1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(NC(=O)N[C@@H]2CCCC[C@H]2CNC2CCc3cc(F)ccc3C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.6 %

Procedure:
A mixture of N-{[(1S,2R)-2-aminocyclohexyl]methyl}-(2RS)-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine (60 mg, 217 μmol) and phenyl[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]carbamate (54 mg, 217 μmol) in acetonitrile (2 mL) was treated with triethylamine (75 μL, 540 μmol). After being stirred at room temperature for 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonia, to provide an amorphous solid (50 mg, 45%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:18]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([S:26](Cl)(=[O:28])=[O:27])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]>O1CCOCC1.C(N(CC)CC)C>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:26]([C:25]4[CH:24]=[CH:23][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a stirred solution of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (which was obtained in Example 214) (2.8 g, 11.9mol) in 1.4-dioxane (150 mL) and triethylamine (7 mL) was added a solution of N-acetylsulfanilyl chloride (3.5 g, 15 mmol) in 75 mL of 1,4-dioxane at room temperature. The reaction was stirred for 18 hours. The reaction mixture was concentrated. The residue was dissolved in methylene chloride and washed with diluted hydrochloric acid. The white solid in water layer was collected and dried to give the title compound as a white solid (2.5 g, 43%); 1H NMR (300 MHz, DMSO-d6) δ 1.92 (brs, 4H), 2.06 (s, 3H), 3.68 (brs, 4H), 3.93 (s, 4H), 7.06 (d, J=8.4 Hz, 2H), 7.33 (brs, 2H), 7.68 (d, J=9.0 Hz, 2H), 7.71 (d, J=9.0Hz, 2H), 10.24 (brs, 1H), 10.38 (s, 1H); MS (ES) m/z: 432.3 (MH+); HRMS Calcd. for C21H25N3O5S(M+): 431.1515. Found: 431.1530.