Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:3]=1[NH2:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:26]([O:29][CH2:30]C)(=O)C.CCCCCC>C(OC)(OC)OC>[CH3:26][O:29][CH:30]=[N:13][C:3]1[C:4]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)Cc1cccc(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCC
Solvent: COC(OC)OC
Product: COC=Nc1c(Cl)cccc1CS(C)(=O)=O

Procedure:
The 2-chloro-6-methanesulfonylmethyl-phenylamine (2.04 g, 0.019 mole) of Step 4 was suspended in 15 ml trimethyl orthoformate and p-toluenesulfonic acid hydrate (0.21 g) was added. The reaction mixture was brought to reflux and heated at this temperature for 3 h. The reaction was monitored by tlc (3:7 ethyl acetate:hexane, silica gel) which showed the appearance of a new slightly less polar spot. At the end of 3 h, the reaction was cooled and evaporated to dryness to afford N-(2-Chloro-6-methanesulfonylmethyl-phenyl)-formimidic acid methyl ester.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)C=CC=CC=1.[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([CH:47]=O)=[N:43][C:44]=1[O:45][CH3:46].O>O1CCCC1>[Cl:38][C:39]1[C:44]([O:45][CH3:46])=[N:43][C:42](/[CH:47]=[CH:19]\[CH:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:41][CH:40]=1
Reactant: c1ccc([P+](CC2CCOCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1nc(C=O)ccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(/C=C\C2CCOCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
A solution of lithium hexamethyldisilazide in tetrahydrofuran (1 M, 10 mL) was added to a solution of triphenyl(tetrahydro-2H-pyran-4-ylmethyl)phosphonium iodide (5.51 g) in tetrahydrofuran (20 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. A solution of 5-chloro-6-methoxypyridine-2-carbaldehyde (1.3 g) in tetrahydrofuran (20 mL) was slowly added to the reaction solution, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3-chloro-2-methoxy-6-[(Z)-2-(tetrahydro-2H-pyran-4-yl)ethenyl]pyridine as a colorless powder (1.62 g, 60%).
Reaction SMILES: [C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]=[CH2:20])[CH:5]=1)(=[O:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:1]([C:4]1[C:16]([O:17][CH3:21])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]=[CH2:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCC#N
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCc1cc(C(C)=O)c(OC)cc1OCCCCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.6 %

Procedure:
A mixture of 1.365 g of 5-(4-acetyl-5-hydroxy-2-allylphenoxy)pentanenitrile, 0.966 g of potassium carbonate, and 1.42 g of methyl iodide in 50 ml of dimethylformamide was stirred together at room temperature for 5 hours. The mixture was partitioned between dilute hydrochloric acid and ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to provide 1.2 g of the desired title product, m.p.=40°-42° C. NMR, MS.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][CH:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=2)=[N:4][N:3]=1.CO.[OH-].[Na+]>C1COCC1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][CH:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)=[N:4][N:3]=1
Reactant: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(OC2CCN(C)C2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc(Oc3cc(OC4CCN(C)C4=O)cc(C(=O)O)c3)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
A solution of Methyl 3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-5-(1-methyl-2-oxopyrrolidin-3-yloxy)benzoate (7 g) (Intermediate 2) in a mixture of THF and to methanol (1:1 ratio) was treated with a solution of sodium hydroxide (2 g) in water and the reaction mixture was stirred for 1 h at room temperature. The resulting solution was concentrated under vacuum to remove THF and methanol, diluted with water, and washed with EtOAc. The aqueous phase was cooled and acidified with 0.1N HCl and extracted with DCM, combined organic extracts washed with brine, dried over Na2SO4 and concentrated in vacuo to give the product (3.5 g) as white solid.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].[CH3:26][O:27][CH2:28][CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>CC(=O)OCC.C1COCC1>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:29][CH2:28][O:27][CH3:26])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2]
Reactant: COCCO
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCCOC)cc3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg (119 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 19 μL (241 μmol) 2-methoxyethanol, 66 mg (251 μmol) diphenyl-2-pyridylphosphine and 10 ml THF are placed under protective gas. At 0° C. 58 mg (252 μmol) DBAD are added and then the mixture is stirred overnight at RT. Then it is diluted with EA and extracted with 10% sodium carbonate solution. The organic phase is stirred with 20 mL of 4N HCl for 5 min and then extracted. The organic phase is washed with saturated saline solution and then the solv. is eliminated i.V. The residue is purified on silica gel. (Eluant: DCM/MeOH/ammonia) The solv. of the corresponding fractions is eliminated i.V. and the residue is crystallised with cyclohexane/EA.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Yield: 79 %

Procedure:
2-Amino-3-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one. 1-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 105 part a to d except using 3,5-dichloro-2-nitrobenzaldehyde (2.1 g) and decaborane (0.41 g) in part a to yield [2-(tert-butyldimethylsilanyloxy)propyl]-(3,5-dichloro-2-nitrobenzyl)amine (1.2 g, 32%). 3,5-Dichloro-2-nitrobenzaldehyde (2.2 g, 79%) was prepared by nitration of 3,5-dichlorobenzaldehyde (2.2 g) in a mixture of nitric acid (1.5 mL) and sulfuric acid (8 mL) at 0° C. for 30 minutes.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][C:4]2[C:13](=[O:21])[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:3]1=2.[CH2:22](I)[CH3:23]>>[O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]([CH2:22][CH3:23])[C:4]2[C:13](=[O:21])[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:3]1=2
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]c2c(=O)oc3ccccc3c2c1=O
Product: CCOC(=O)c1cn(CC)c2c(=O)oc3ccccc3c2c1=O
Yield: 75.4 %

Procedure:
Prepared from ethyl 1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]-pyridine-2-carboxylate (9.5 g, 0.033 mole) and ethyl iodide (20.8 g, 0.134 mole) by the method described for Ex. 6. Recrystallization from dimethylformamide gives white crystals (7.8 g, 75%), m.p. 180-181.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[C:29]1([C:35]2[CH:39]=[CH:38][NH:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O.Cl>[CH3:26][C:23]1[C:22]([CH2:27][N:37]2[CH:38]=[CH:39][C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:36]2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1Cn1ccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-[4′-(4-Bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.132 g, 0.3 mmol) and 3-phenyl-1H-pyrazole (0.043 g, 0.3 mmol) were combined in DMF. Sodium hydride (60% in mineral oil; 0.014 g, 0.35 mmol) was added, and the reaction was stirred at room temperature for 1.5 hours. Once no starting material was seen by analytical LCMS, the mixture was diluted with EtOAc and 1N aqueous HCl. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with H2O and brine, and then dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:6])[CH:4]=[CH2:5].[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CN=C1.O>CN(C=O)C.ClCCl>[Si:7]([O:1][CH2:2][CH:3]([CH3:6])[CH:4]=[CH2:5])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: C=CC(C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(C)CO[Si](C)(C)C(C)(C)C
Yield: 96.8 %

Procedure:
Commercially available 1-hydroxy-2-methyl-3-butene (1.91 g) was silylated with 5 g t-butyldimethylsilyl chloride and 4.7 g imidazole in 5 mL DMF and 5 mL dichloromethane for 3 hours. The mixture was poured into water and extracted with 9:1 hexane:ether. The extracts were combined and concentrated to afford 4.3 g 1-t-butyldimethylsilyloxy-2-methyl-3-butene which was used without further purification. The silyloxybutene and 3 mg Sudan 7B red dye were dissolved in 50 mL dichloromethane and treated at -78° C. with ozone until the red color was discharged. The solution was then warmed to room temperature for 30 minutes before cooling back to -78° C. A solution of 2.0M ethyl magnesium bromide (30 mL) in THF was added over 10 minutes and the resulting mixture was warmed to room temperature for 45 minutes before cautious addition of aqueous ammonium chloride at low temperature to quench the excess Grignard reagent. Extraction of the mixture with ether and evaporation of the solvent yielded 3.96 g residual oil confirmed by NMR to be the desired product. This was dissolved in 20 mL of methanol with 475 mg of p-toluenesulfonic acid monohydrate and stirred at 20° C. for 2 hours. The methanol was then removed in vacuo and the residual product was flash chromatographed on 400 g of silica gel (1:1 hexane:ethyl acetate) to yield 1.1 g of 1,3-dihydroxy-2-methyl-pentane as a diastereomeric mixture (by NMR). Subsequent conversion to the title phosphonium iodide was accomplished following the procedure set forth in Preparations Y and Z.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][C@@H:11]([C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](OC=O)(=[O:41])C>C1COCC1>[CH2:1]([O:8][N:9]([CH2:10][C@@H:11]([C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:39]=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC=O
Reactant: COc1ccc(N2CCN(C(=O)[C@H](CNOCc3ccccc3)CC(C)C)CC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)CN(C=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 81 %

Procedure:
To a solution of (2S)—N-(benzyloxy)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-4-methylpentan-1-amine (122 mg; 0.29 mmol; 1.0 eq.) and triethylamine (123 μL; 0.86 mmol; 3.0 eq.) in THF (2 mL) was added formic acetic anhydride (63 mg, 0.72 mmol, 2.5 eq., prepared as described in Krimen et al., in Organic Syntheses Coll. Vol 6, p8. The solution was stirred for 4.5 h at room temperature. The solvents were evaporated and the residue purified by column chromatography (Silicagel, 1/1 EtOAc/c-Hex) to give the title product as a colorless oil (105 mg, 81%). HPLC, Rt: 3.17 min (purity: 100%). M+(LC-MS (ESI)): 454.4.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F-:11].[K+].CCOCC>CN(C=O)C>[F:11][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(CF)c1ccccc1
Temperature: 100 °C
Yield: 39.8 %

Procedure:
A mixture of 2-bromoacetophenone (20.00 gm, 100 mmol) and KF (8.82 gm, 152 mmol) in dry DMF (35 ml) was heated at 100° C. for 1 hour. Additional KF (2.26 gm) was added and heating of the mixture continued for 4 more hours. The dark-red solution was cooled, poured into Et2O and washed with H2O (twice) and brine. The ethereal solution was dried (Na2SO4), filtered, and stripped to yield a dark red oil. The oil was distilled to collect a fraction boiling between 62°-64° C. at 1 mm Hg which was 91 molar percent the title compound and 9 molar percent acetophenone (6.00 gm). Flash chromatography (Merck SiO2, 10% EtOAc in hexane) afforded the pure title compound (5.50 gm, 45%) as a liquid that solidifies near room temperature.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH:16]([OH:18])[C@@H:15]([NH:19][C:20](=[O:34])[C@@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@H:12]1[CH3:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)C[C@H](NC(C1C=C2C(=CC=1)N=CC=C2)=O)C(=O)N[C@H]1CC[C@@H](C)N(S(C2C=CC=CN=2)(=O)=O)CC1O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][C:16](=[O:18])[C@@H:15]([NH:19][C:20](=[O:34])[C@@H:21]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@H:12]1[CH3:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)CC1O
Agent: CC(C)C[C@H](NC(=O)c1ccc2ncccc2c1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)CC1=O

Procedure:
Following the procedure of Example 12 (m), except substituting “(2R,5S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepane-1-carboxylic acid benzyl ester” for “quinoline-6-carboxylic acid {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide gave the title compound: 1H NMR: 7.40-7.35 (m, 5H), 5.26 (m, 1H), 5.13 (dd, 1H), 4.91-4.78 (m, 2H), 4.47 (m, 1H), 4.12 (m, 1H), 3.64 (dd, 1H), 2.32 (m, 1H), 2.10 (m, 1H), 1.70-1.52 (m, 5H), 1.45 (s, 9H), 1.12 (d, 3H), 0.96 (s, 3H), 0.94 (s, 3H); Electrospray mass spec: M+H+=512.2.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])(=[O:33])=[O:32])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To an ice cooled solution of 2.04 g (10 mmol) of Boc-homopiperazine, 1.32 g (10 mmol) of DIPEA in 80 ml of methylene chloride was added a solution of 2.18 g (10 mmol) of 2-chlorophenylsulfonyl chloride in 40 ml of methylene chloride. Then the reaction mixture was stirred at RT overnight. The organic phase washed with HCl aq, water, dried over sodium sulphate and evaporated to dryness to give 3.7 g of compound as yellow oil.
Reaction SMILES: C([C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:10](=[N:26][N:27]([CH2:30][CH3:31])[C:28]=3[CH3:29])[C:11]([N:19](C([O-])=O)C([O-])=O)=[N:12][C:13]=2[C:14]=1C(C)(C)C)(C)(C)C.C(C1C=CC2C3C(=NN(CCC)C=3C)C(N(C([O-])=O)C([O-])=O)=NC=2C=1C(C)(C)C)(C)(C)C.[C:64]1(=[O:70])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1.C1(=O)CCC1>>[NH2:19][C:11]1[C:10]2=[N:26][N:27]([CH2:30][CH3:31])[C:28]([CH2:29][C:64]3([OH:70])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]3)=[C:9]2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:14][C:13]=2[N:12]=1
Reactant: CCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Reactant: O=C1CCCCC1
Agent: CCCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Agent: O=C1CCC1
Product: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCCCC1

Procedure:
1-[(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]cyclohexanol was prepared according to the method of Example 1 Part F using di(tert-butyl)2-ethyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate in lieu of di(tert-butyl)1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicabonate and cyclohexanone in lieu of cyclobutanone. The crude product was recrystallized from acetonitrile to provide 0.560 g of 1-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]cyclohexanol as a white powder, mp 211.5-213° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([OH:38])[CH2:35][C:36]#[CH:37].[C:39]1(=O)[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12>C1(C)C=CC=CC=1>[CH2:39]([N:43]1[C:34](=[O:38])[C:35]2[C:41](=[CH:45][CH:46]=[CH:37][CH:36]=2)[C:42]1=[O:44])[CH2:40][C:48]#[CH:47]
Reactant: C#CCCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C#CCCN1C(=O)c2ccccc2C1=O
Temperature: -5 °C
Reaction time: 0.83 h
Yield: 80.5 %

Procedure:
Diisopropyl azodicarboxylate (316 g, 1.56 mol) was added to a solution of triphenylphosphine (PPh3) (393 g, 1.50 mol), 3-butyn-1-ol (105 g, 1.50 mol) and phthalimide (200 g, 1.36 mol) in toluene (1600 mL) which was pre-cooled with a −5° C. cooling bath at such a rate that temperature of the reaction mixture was kept between 15-25° C. The addition time was 50 min. The cooling bath was removed after the addition was finished. The reaction mixture was allowed to warm to 15-25° C. and stirred for 1 h. Then methanol (800 mL) was added. The mixture was stirred for 30 min and then filtered. The crude product was washed with methanol and dried to give a white solid (218 g) in 80% yield 99.8% purity by area. 1H NMR (DMSO-d6): δ 7.88 (m, 4 H), 3.72 (t, 2 H, J=7.0 Hz), 2.83 (t, 1 H, J=2.7 Hz), 2.55 (m, 2 H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9]>CN(C=O)C.ClCCl>[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1Cl

Procedure:
Thionyl chloride (2.48 ml, 10 eq) and DMF (2 drops) were added to a solution of 2-chloronicotinic acid (535 mg, 3.4 mmol) in dichloromethane (3 ml). The mixture was heated at reflux overnight then concentrated in vacuo and azeotroped with toluene (2×5 ml) to give 2-chloronicotinoyl chloride as a yellow oil. A solution of this acid chloride in dichloromethane (5 ml) was added dropwise to a solution of Intermediate 5 (750 mg, 2.69 mmol) and NMM (355 μl, 1.2 eq) in dichloromethane (15 ml) at 00. Dimethylaminopyridine (catalytic) was added and the mixture stirred at room temperature for 2 h. The mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with aqueous NaHCO3 (2×50 ml). The organic phase was dried (MgSO4) and concentrated in vacuo, to give the title compound. δH (CDCl3) 10.55 (1H, s), 8.51 (1H, m), 8.05 (1H, m), 7.67 (1H, m), 7.57 (3H, m), 7.2 (2H, m), 4.24 (1H, m), 3.62 (3H, s), 3.08 (2H, m), 1.03 (9H, s); m/z (ESI, 70V) 418 (M++H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([CH:12]=1)[C:9](O)=[O:10].C[N:26](C=O)C>S(Cl)(Cl)=O>[CH3:2][O:3][C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([CH:12]=1)[C:9]([NH2:26])=[O:10]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCN1CCCC1
Reactant: CN(C)C=O
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
A solution of 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (9.63 g, 24 mmol) in thionyl chloride (20ml) and DMF (50 μl) was heated at 45° C. for 1.5 hours. The excess thionyl chloride was removed by evaporation and by azeotroping with toluene (×2). The resulting solid was suspended in THF (250 ml) and methylene chloride (100 ml) and ammonia was bubbled though the mixture for 30 minutes and the mixture stirred for a further 1.5 hours at ambient temperature. The volatiles were removed by evaporation, the residue was dissolved in water and applied to a Diaion (trade mark of Mitsubishi) HP20SS resin column and eluted with water/methanol (100/0 to 95/5). The solvent was removed by evaporation from the fractions containing product and the residue was dissolved in a minimum of methanol and the solution was diluted with ether. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 5-methoxy-2-nitro4-(3-(pyrrolidin-1-yl)propoxy)benzamide (7.23 g, 73%).
Reaction SMILES: Br[C:2]1[C:3]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]1([CH3:39])C=CC=C[CH:34]=1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[N:5]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:4]=[C:3]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:2]=2[CH:39]2[CH2:33][CH2:34]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Br
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C1CC1
Yield: 44 %

Procedure:
To a solution of ethyl 4-bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (68) (500 mg, 1.1 mmol) in aqueous toluene, tetrakis(triphenylphsophine)palladium (122 mg, 0.11 mmol) and potassium carbonate (510 mg, 3.9 mmol) were added. The reaction mixture was placed under microwave irradiation with the temperature set to 140° C. The resulting solution was filtered with syringe filter, and then solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography to obtain the title compound (283 mg, 44%) as white solid.