Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)[C:6]#[N:7].C1(C)C=CC=CC=1.CCO.C([O-])([O-])=O.[Na+].[Na+].B1([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)OC(C)(C)C(C)(C)O1>CCOC(C)=O.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.CO.C(Cl)Cl>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[CH:10][CH:9]=1)[C:6]#[N:7]
Reactant: CN(C)CCC(C#N)c1ccc(I)cc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: CN(C)CCC(C#N)c1ccc(-c2ccncc2)cc1
Temperature: 90 °C

Procedure:
To a solution of 4-dimethylamino-2-(4-iodo-phenyl)-butyronitrile (1.02 g, 3.2 mmol) in 2:1 toluene/EtOH (30 mL) was added 2M Na2CO3 (10 mL, 20 mmol), pyridine-4-boronic acid pinacol cyclic ester (1.0 g, 4.9 mmol), and Pd(PPh3)4 (116 mg, 0.31 mmol). The resulting mixture was heated at 90° C. under Ar for 16 h. TLC (10% MeOH/CH2Cl2) showed no starting material left. The mixture was diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO3 (50 mL×3), saturated aqueous NaCl (50 mL×3), dried over Na2SO4 and concentrated by rotary evaporation. The crude residue was purified using silica gel chromatography (2–10% MeOH/CH2Cl2 gradient) to give 4-dimethylamino-2-(4-pyridin-4-yl-phenyl)-butyronitrile as a brown oil, 680 mg (80%). 1H NMR (300 MHz, CDCl3): δ 8.79 (dd, 2H), 7.78 (d, 2H), 7.60 (m, 4H), 4.22 (dd, 1H), 2.61 (m, 1H), 2.46 (m, 1H), 2.37 (s, 6H), 2.24 (m, 1H), 2.15 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22]([NH:24][C:25]3[N:29]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[N:28]=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=3)=[O:23])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:50][O:51][CH2:52][C:53](Cl)=[O:54]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:37]([C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([O:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:53](=[O:54])[CH2:52][O:51][CH3:50])[CH:7]=3)=[CH:12][CH:13]=2)[N:29]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[N:28]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(N)c3)c3ccccc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cc(CCOc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Yield: 12.7 %

Procedure:
To a suspension of 1-(4-(2-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate D) (35 mg, 0.065 mmol) in DCM (0.5 mL) was added DIPEA (23 μl, 0.131 mmol) and methoxyacetyl chloride (7 μl, 0.072 mmol). The mixture was stirred at RT, until judged to be complete by LC-MS; diluted with saturated aq NaHCO3 (1.5 mL) and the layers were separated through a phase separator cartridge. The organics were collected, evaporated under reduced pressure and the residue subjected to SCX capture and release. The resulting residue was purified further by preparative RP HPLC to give N-(4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-2-yl)-2-methoxyacetamide (Example 18) as a white solid (5 mg, 13%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.37 (3H, s), 3.20 (2H, t), 3.37 (3H, s), 4.06 (2H, s), 4.38 (2H, t), 6.33 (1 H, s), 6.95 (1H, d), 7.19 (1H, dd), 7.33 (2H, m), 7.42-7.47 (3H, m), 7.54 (1H, m), 7.59 (1H, d), 7.87 (1H, d), 8.12 (1H, d), 8.18 (1H, bs), 8.23 (1H, d), 8.67 (1H, s), 8.84 (1H, s), 9.89 (1 H, s).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][S:10](O)(=[O:12])=[O:11].P(Cl)(Cl)(Cl)=O>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: CS(=O)(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(S(C)(=O)=O)cc1
Temperature: 122.5 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
Anisole (2.16.3 g, 2.0 moles) was mixed in a flask with anhydrous methane sulfonic acid (64.8 g, 1.0 mole) and phosphorus oxychloride (54.1 g, 0.56 mole) and was heated while stirring at 120-125° C. for 5 hours. A nitrogen purge was used to sweep out HCl gas as it formed. Subsequent treatment of the reaction mixture after cooling was the same as in Example 1. The washed and dried product solution was then heated in a distillation unit with a fractionating column to remove unreacted anisole. Products remaining in the distillation unit were finally diluted with N-butanol and crystallized from this solvent. A yield of 35% of methyl p-methoxyphenyl sulfone was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]1=2.O[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCOC(C)=O>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CC=C(c2cccs2)c2cc(C(=O)O)ccc21
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1

Procedure:
A solution of 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid (Compound E6, 50.0 mg, 0.177 mmol), ethyl 4-hydroxybenzoate (38.2 mg, 0.230 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44.0 mg, 0.230 mmol), and 4-N,N-dimethylaminopyridine (28.0 mg, 0.230 mmol) in 2.0 mL DMF was stirred overnight at room temperature. EtOAc (50 mL) was added and the solution washed with H2O, 5% HCl, saturated aqueous NaCO3, and saturated aqueous NaCl before being dried over MgSO4. Removal of the sovents under reduced pressure and column chromatography (10% EtOAc-hexanes) of the residual oil afforded the title compound as a colorless solid.
Reaction SMILES: C1C(=O)N([O:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]2[S:19][CH2:18][C@@H:17]3[NH:20][C:21]([NH:23][C@H:16]23)=[O:22])=[O:10])C(=O)C1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:10][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[C@@H:16]2[C@@H:17]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:19]1)=[O:8]
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)ON2C(=O)CCC2=O)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 3 h

Procedure:
3A-LK resin (0.1 g, 0.065 mmol) was washed with DMF. The ivDde protecting group was removed with 4% NH2NH2 in DMF (5 min, 10 min). After washing with DMF (3×5 mL), MeOH (3×15 mL), and DMF (3×5 mL), a solution of biotin-OSu (67 mg, 0.195 mmol) and DIEA (68 μL, 0.39 mmol) in DMF (2 mL) was added to the beads. The coupling proceeded at room temperature for 3 h. Kaiser test was negative. The beads were washed with DMF (5×5 mL), MeOH (3×5 mL), and DCM (3×5 mL). The beads were then dried under vacuum for 1 h before adding a cleavage mixture of 95% TFA: 2.5% water: 2.5% triisopropylsilane. The cleavage reaction was conducted at room temperature for 2 h. The liquid was collected and precipitated with diethyl ether. The crude product was purified using preparative RP-HPLC and lyophilized to give the designed product. ESI-MS, m/z 1699 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[F:14][C:15]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:15]=3[F:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(F)c1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(F)c3F)ccc12
Yield: 14 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (156 mg, 0.601 mmol), 2,3-difluorobenzylamine (0.074 mL, 0.646 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (104 mg, 0.167 mmol) and NaOtBu (134 mg, 1.39 mmol) in DMA (6 mL) was heated at 80° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2,3-difluoro-benzylamino)-2H-phthalazin-1-one (27 mg) as an off white solid, 1H (400 MHz, CDCl3) δ: 4.45 (s, 2H), 6.84 (d, 1H), 6.96 (m, 2H), 7.03 (m, 2H), 8.01 (d, 1H), 11.00 (s, 1H) ppm; m/z (M+1) 321.91.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][OH:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=[O:22])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1NC1CCN(Cc2ccccc2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccccc1NC1CCN(Cc2ccccc2)CC1
Yield: 83.3 %

Procedure:
A mixture of N-(1-benzyl-4-piperidinyl)-o-hydroxymethylaniline (2.9 g), chloroform (100 ml) and manganese dioxide (12 g) is refluxed for 1 hour. After cooling, the mixture is filtered and the filtrate is concentrated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane) to give N-(1-benzyl-4-piperidinyl)-o-formylaniline (2.4 g) as yellow powders, m.p. 87°-90° C.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][S:5]([CH3:8])(=[O:7])=[O:6].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>N1C=CC=CC=1>[C:8]1([S:5]([N:4]([S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])[C:3]2[CH:9]=[CH:10][C:11]([S:5]([CH3:8])(=[O:7])=[O:6])=[CH:12][C:2]=2[I:1])(=[O:7])=[O:6])[CH:11]=[CH:12][CH:2]=[CH:3][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CS(=O)(=O)Nc1ccccc1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 197.4 %

Procedure:
To a solution of the compound obtained in Example 8 (3) (2.20 g) in pyridine (7.4 ml), benzenesulfonyl chloride (1.57 g) was added and the mixture was stirred at 15 to 30° C. for 1 hour and at 60° C. for 1 hour. Further, to the mixture was added benzenesulfonyl chloride (1.57 g) and the mixture was stirred at 60° C. for 15 hours, and then poured into a saturated aqueous ammonium chloride solution. The precipitates were filtered off, washed with water and ether successively and dried under reduced pressure to obtain 4.22 g of the desired products as a white crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3O)[N:9]=1)[CH3:2].[NH2:29][CH2:30][CH2:31][S:32]([N:35](C)[CH3:36])(=[O:34])=[O:33]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3[NH:29][CH2:30][CH2:31][S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[N:9]=1)[CH3:2]
Reactant: CN(C)S(=O)(=O)CCN
Reactant: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4O)no2)cc1OCC
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4NCCS(=O)(=O)NC)no2)cc1OCC

Procedure:
Prepared using General Procedure 14 from 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol 60 and 2-amino-N,N-dimethylethanesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:19]([CH:21]([CH2:24][CH3:25])[CH:22]=[O:23])[CH3:20].CCOC(C)=O>C1COCC1.Cl>[CH2:19]([CH:21]([CH2:24][CH3:25])[CH:22]([C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=[CH:11][CH:12]=1)[OH:23])[CH3:20]
Reactant: COc1ccc(-n2cccn2)cc1
Reactant: CCC(C=O)CC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ccnn1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a chilled reaction vessel at −78° C. containing 1-(4-methoxyphenyl)-1H-pyrazole (Tetrahedron Lett. 39(19), 2941-2944, (1998)) (1.096 g, 6.3 mmol) in THF (40 mL) was added a solution of n-butyllithium (2.5M in hexanes, 2.5 mL, 6.4 mmol) dropwise and the mixture was stirred for 1 h. 2-Ethylbutyraldehyde (0.93 mL, 7.5 mmol) was then added dropwise and, after 15 min, the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with 0.1N HCl and stirred for 15 min, then poured into a separatory funnel containing EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, EtOAc/hexane, 1:4) to yield a pure oil in 68% yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:32][CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:32]([N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])[CH3:33]
Reactant: CCI
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with iodoethane and cesium carbonate in N,N-dimethylacetamide to give N-ethyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 520.9 ([M+NH4]+)
Reaction SMILES: [CH3:1][N+:2]([O-:17])=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](C)[CH:11]=1)[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.C[C:19]1[CH:20]=[C:21]([O:25][CH2:26][CH:27]=[CH2:28])[CH:22]=[CH:23][CH:24]=1>>[C:10]1([C:3]2([CH2:4][N:5]3[CH:9]=[N:8][CH:7]=[N:6]3)[CH2:28][CH:27]([CH2:26][O:25][C:21]3[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=3)[O:17][N:2]2[CH3:1])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=CCOc1cccc(C)c1
Reactant: Cc1cccc(C(Cn2cncn2)=[N+](C)[O-])c1
Product: CN1OC(COc2ccccc2)CC1(Cn1cncn1)c1ccccc1

Procedure:
Compound 3 (R1 =R2 =H) was prepared by a procedure similar to that described in Example 1 by reacting N-methyl-1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide (1, R1 =H) with allyl phenyl ether (2, R2 =H). The resulting cis- and trans-diastereomeric mixture of the title compound was flash-chromatographed on neutral silica gel using chloroform-methanol (99:1 by volume) as eluent. Isomer A has a melting point 68°-75° C. (ethyl acetate-hexane, 1:1 by volume).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.CCOC(C)=O.[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[F:18][C:15]([F:16])([F:17])[C:14]([C:11]1[CH:10]=[CH:9][C:8]([N:7]2[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]2[CH3:1])=[CH:13][CH:12]=1)([OH:20])[CH3:19]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1CNCCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Yield: 70.2 %

Procedure:
A 500 mL round-bottomed flask was charged with tert-butyl (3S)-3-methyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (8.33 g, 21.5 mmol) and 200 mL of EtOAc. To this was added 20 mL of 4N HCl (80 mmol) in dioxane. After 12 h at reflux, the resulting white precipitate was collected and dried under reduced pressure to give 1,1,1-trifluoro-2-(4-((2S)-2-methyl-1-piperazinyl)phenyl)-2-propanol dihydrochloride (5.45 g) as a white solid.
Reaction SMILES: N1C=C(C(O)=O)C=C(C(O)=O)C=1.[CH3:13][C:14]1[O:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH2:25][CH2:26][O:27][C:28]1[C:36]2[CH:35]=[CH:34][S:33][C:32]=2[C:31]([CH:37]=[C:38]2[S:42][C:41](=[O:43])[NH:40][C:39]2=[O:44])=[CH:30][CH:29]=1>>[CH3:13][C:14]1[O:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH2:25][CH2:26][O:27][C:28]1[C:36]2[CH:35]=[CH:34][S:33][C:32]=2[C:31]([CH2:37][CH:38]2[S:42][C:41](=[O:43])[NH:40][C:39]2=[O:44])=[CH:30][CH:29]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)c2sccc12
Agent: O=C(O)c1cncc(C(=O)O)c1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12
Temperature: 260 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
The content of the 1500 ml glass reactor was heated to 260° C. with a metal bath, while the content of the 1000 ml glass flask was heated to 145° C. The solution of 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-, diethyl ester was transferred within 1 to 2 minutes to the stirred solution of 5-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione. The temperature dropped to 220-230° C. and the mixture was heated again to 260° C. After 10 to 15 minutes 5-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione was completely converted, and the metal bath removed. When the reaction mixture reached a temperature of 90° C., 650 ml of a mixture of n-heptane and ethanol (9:1) was added via a dropping funnel within 10 minutes. The mixture was seeded with 5-{[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl]methyl}-2,4-thiazolidinedione and crystallization started at 50° C. The suspension was cooled to 0° C. and stirred at that temperature for 5 h. The crystals were filtered off and washed with 4 portions of ethanol each 125 ml. The wet material was dried at 140° C., 10 mbar for 15 h, which afforded 89.1 g of white crystalline 5-{[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl]methyl}-2,4-thiazolidinedione with a purity of 96.5% according to HPLC analysis, corresponding to a corrected yield of 92.5%.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>>[C:1]1([C:11]([Cl:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 1.03 g of 1-naphthoic acid and 4.86 g of thionyl chloride was stirred at 50° C. for 2 hours. An excess of thionyl chloride was removed under reduced pressure to give 1-naphthoyl chloride. A solution of 1-naphthoyl chloride in 10 ml of benzene was added dropwise to mixture of 1.06 g of N-methyl-4-tert-butylbenzylamine, 2 ml of pyridine and 10 ml of dry benzene and was stirred for 5 hours. The resultant was poured into water and extracted with benzene, and the benzene solution was washed successively with 3 % aqueous solution of sodium bicarbonate, 3 % hydrochloric acid and water, and then dried over anhydrous sodium sulfate. Oily product (1.74 g, amide) was obtained by distilling away benzene and was crystallized by leaving as it was.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C@H:4]([NH:13]C(=O)OC(C)(C)C)[C:3]1=[O:21].[ClH:22]>O1CCOCC1>[ClH:22].[NH2:13][C@H:4]1[CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3]1=[O:21]
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(=O)[C@@H](N)CCc2ccccc21
Reaction time: 4 h

Procedure:
4.36 g of 7a (15.01 mmol) are taken up in a 250 ml round-bottomed flask and 110 ml of a solution of hydrochloric acid in dioxane (4M) are added. The mixture is stirred for 4 h at AT under argon. After the solvent has been evaporated off, the solid is disintegrated with 25 ml of isopropyl ether, and filter-dried over sintered glass. After drying, 3.1 g of amine 8a in hydrochloride form are obtained, which amine is used directly for the following step.
Reaction SMILES: Br[C:2]1[C:3]([C:16]#[N:17])=[N:4][N:5]([CH2:13][CH2:14][CH3:15])[C:6]=1[CH2:7][C:8]([C:11]#[N:12])([CH3:10])[CH3:9].Cl.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:17][C:16]1[C:3]2=[N:4][N:5]([CH2:13][CH2:14][CH3:15])[C:6]([CH2:7][C:8]([CH3:9])([CH3:10])[C:11]#[N:12])=[C:2]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1
Reactant: Nc1ccccc1B(O)O
Reactant: CCCn1nc(C#N)c(Br)c1CC(C)(C)C#N
Agent: Cl
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)C#N
Reaction time: 1 h
Yield: 54.7 %

Procedure:
A modification of the method described in Example 1283 was used to couple 4-bromo-5-(2-cyano-2-methylpropyl)-1-propyl-1H-pyrazole-3-carbonitrile (1.48 g, 5.00 mmol) with 2-aminophenylboronic acid hydrochloride (1.73 g, 10.0 mmol). The reaction was completed in one hour. The coupling product was purified by IFC (silica cartridge, eluting with 40% to 60% ethyl acetate in hexane). The reaction with hydrogen chloride was heated at reflux for a total of about seven hours. 3-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2,2-dimethylpropanenitrile (840 mg) was obtained as a white solid, mp 248-250° C.
Reaction SMILES: Cl.[CH2:2]([NH2:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[P:15](Cl)([Cl:18])([Cl:17])=[O:16].Cl>>[CH2:2]([NH:14][P:15]([Cl:18])([Cl:17])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCN
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: CCCCCCCCCCCCNP(=O)(Cl)Cl
Reaction time: 5 h

Procedure:
n-Dodecylamine hydrochloride (44.4 g, 0.2 mol) and phosphorus oxychloride (91.4 mL, 1.0 mol) were reacted under nitrogen. A clear solution formed within 30 minutes, and the evolution of hydrogen chloride was observed. Heating at reflux was continued for 5 hours. Excess phosphorus oxychloride was removed by distillation in vacuum (40 to 5 torr, 24° to 50° C.) forming N-(n-dodecyl)phosphoramidic dichloride as a viscous liquid. The following spectroscopic data were obtained from the liquid:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: Cc1cc(-c2ccccc2Cl)ccc1CO
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution (4-bromo-2-methylphenyl)methanol (1 eq.) from Benzyl nitrile III.1 (Step 1) and 2-chlorophenylboronic acid (1.2 eq.) in n-propanol (0.1M) was added palladium acetate/triphenyl phosphine (1:3; 0.05 eq.) and aqueous Na2CO3 (2M; 3 eq.). The mixture was stirred at 80° C. for 2 h, cooled to room temperature, poured in water and extracted with EtOAc. The organic extract was washed with, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 75% in 30 min) to afforded the desired compound.