Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:3])[CH3:2].[C:33]([O:37][C:38]([N:40]1[CH2:45][C:44](OS(C(F)(F)F)(=O)=O)=[CH:43][CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>COCCOC.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>[C:33]([O:37][C:38]([N:40]1[CH2:41][C:42]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:32])[N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)=[CH:43][CH2:44][CH2:45]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC=C(OS(=O)(=O)C(F)(F)F)C1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)n(C(C)C)n1
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: COCCOC
Solvent: ClCCl
Solvent: O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4=CCCN(C(=O)OC(C)(C)C)C4)ccc2-3)n(C(C)C)n1
Temperature: 80 °C
Yield: 78.3 %

Procedure:
2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.496 g, 0.00110 mol), 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.550 g, 0.996 mmol) and sodium carbonate (0.317 g, 0.00299 mol) were dissolved in 1,2-dimethoxyethane (5.6 mL) and water (3.1 mL). The reaction was thoroughly degassed with N2. Tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.0000996 mol) was added and the reaction was heated to 80° C. for 3 hours. Water and dichloromethane were added and the mixture was extracted 3 times with dichloromethane. The organic layers were combined, dried with MgSO4 and concentrated. The crude was purified by flash chromatography to afford 5-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellow solid (396 mg). MS(ESI+) 508.2
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C.O>CS(C)=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:24]3[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:20]([CH3:19])[CH2:25]3)=[N:3][N:4]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Yield: 86.5 %

Procedure:
Heat a mixture of 1-chloro-4-(4-fluorophenyl)phthalazine (5.0 g, 19.3 mmol), (S)-tert-butyl 2-methylpiperazine-1-carboxylate (5.03 g, 25.1 mmol) and triethylamine (8.1 mL, 59.0 mmol) in DMSO (97 mL) at 115° C. for 3 d. Pour the reaction mixture into water, rinsing with CH2Cl2. Extract with Et2O. Wash the organic layer with water (2×), then dry over Na2SO4 and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 0 to 20% EtOAc in CH2Cl2) to provide the title compound as a pale yellow foam (7.05 g, 84%). ES/MS m/z 423.2 (M+1).
Reaction SMILES: [CH3:1]C(C)([O-])C.[Na+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](OC(F)(F)F)[CH:16]=2)[N:11]=[C:10]([N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[S:26](=[O:35])(=[O:34])[CH2:25][CH2:24]2)[CH:9]=1.[CH3:36][S:37][CH2:38][CH2:39][NH2:40]>O1CCOCC1.C(OCC)(=O)C.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]>[O:34]=[S:26]1(=[O:35])[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[CH2:29][N:23]([C:10]2[CH:9]=[C:8]([NH:40][CH2:39][CH2:38][S:37][CH3:36])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:1])[CH:16]=3)[N:11]=2)[CH2:24][CH2:25]1
Reactant: CC(C)(C)[O-]
Reactant: CSCCN
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A dried microwave process vial capped with a rubber septum was purged with argon and charged with tris(dibenzylideneacetone)dipalladium(0) (2.88 mg, 0.005 mmol), 1-(N,N-dimethylamino)-1′-(dicyclohexylphosphino)biphenyl (5.90 mg, 0.015 mmol) and sodium tert-butoxide (134 mg, 1.4 mmol). The tube was purged with argon, and a solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (370 mg, 1.0 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) and 2-(methylthio)ethylamine (128 mg, 1.4 mmol) in 1,4-dioxane (2.0 mL) was added. The mixture was heated with stirring in a sealed 5 mL of microwave process vial for 2 hour at 120° C. under microwave irradiation. After being cooled to room temperature, the reaction mixture was diluted with ethyl acetate, filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 1-10% methanol in dichloromethane) to afford 341 mg of the desired product (yield was 80%). MS obsd. (ESI+) [(M+H)+] 428.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([N:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:7][CH:6]=1>C1COCC1.CSC>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([CH3:1])[CH2:12][C:13]([N:15]2[C@H:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:9][CH:10]=1
Reactant: O=C(/C=C/c1ccc(Br)cc1)N1C(=O)OC[C@H]1c1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@H](CC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
To a stirred solution of copper(II) bromide dimethylsulfide complex (8.78 g, 42.7 mmol) in THF (60 mL) and dimethylsulfide (30 mL) was added methylmagnesium bromide (12.7 mL, 3.0M in diethyl ether, 38.1 mmol) at −40° C. The resultant mixture was stirred at −40° C. for 30 min, then warmed to −20° C. The product from Step A (3.53 g, 9.48 mmol) in THF (30 mL) was added to the above reaction mixture over 1 h at −20° C. The resultant mixture was stirred at −20° C. for 2 h, then slowly warmed to room temperature and stirred at room temperature for 12 h. The reaction was quenched by slow addition of saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with saturated aqueous brine and concentrated in vacuo. Purification by flash chromatography (silica gel, 83:17 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=1)=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 3-(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.94 (t, 3 H) 1.35-1.44 (m, 2 H) 1.61-1.68 (m, 2 H) 2.19 (s, 3H) 2.21 (s, 3 H) 4.07-4.13 (m, 2 H) 6.64 (s, 1 H) 7.66-7.70 (m, 1 H) 7.79 (d, 1 H) 8.18-8.20 (m, 1 H) 8.25 (d, 1H); MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-])=O.NC1C=CC=CC=1>C(O)C.C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Oc1cc(F)cc(F)c1
Solvent: C1CCOC1
Solvent: CCO
Solvent: Nc1ccccc1
Product: CCOC(=O)c1cc(N)ccc1Oc1cc(F)cc(F)c1
Yield: 100.9 %

Procedure:
Using the method of Example 17.3, ethyl 5-nitro-2-(3,5-difluorophenoxy)benzoate (0.76 g) in ethanol (7 mL) and THF (3 mL) was converted to the corresponding aniline derivative which was obtained as an oil (0.696 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@@H:31]([C:44](O)=[O:45])[CH2:32][C:33]3[CH:42]=[C:41]([CH3:43])[C:36]4[NH:37][C:38](=[O:40])[O:39][C:35]=4[CH:34]=3)=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:47]=[CH:48][CH:49]=[CH:50][C:17]=2[NH:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:14]=[C:15]1[N:21]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C@H:31]([CH2:32][C:33]3[CH:42]=[C:41]([CH3:43])[C:36]4[NH:37][C:38](=[O:40])[O:39][C:35]=4[CH:34]=3)[C:44]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[O:45])=[O:29])[CH2:26][CH2:27]2)[CH2:20][CH2:19][C:18]2[CH:47]=[CH:48][CH:49]=[CH:50][C:17]=2[NH:16]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(c3ccc(F)cc3)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
234 mg (1.30 mmol) 1-(4-fluoro-phenyl)-piperazine were added to a solution of 600 mg (1.18 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 417 mg (1.30 mmol) TBTU, 183 μL (1.30 mmol) triethylamine in 10 mL DMF and the reaction mixture was shaken at RT. The reaction solution was purified by HPLC without any further working up, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH3:15][CH:16]([CH3:18])[O-:17].[Na+].O>CS(C)=O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:17][CH:16]([CH3:18])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a chilled (5° C.) solution of 118 g (0.5 mole) of 3-(trifluoromethyl)-4-chloronitrobenzene in 100 ml of dimethyl sulfoxide (DMSO) was added dropwise a solution containing 41 g (0.5 mole) of sodium isopropoxide in 300 ml of dimethyl sulfoxide. The dark reaction mixture was stirred at ambient temperature for one hour, poured into water and extracted with ether. The ether extracts were washed with water, dried and concentrated. Recrystallization of the residual liquid from hexane gave 115.5 g (92.7%) of white crystalline solid; m.p. 34°-36°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[F:21][C:22]([F:30])([F:29])[CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:28][CH:23]([C:24]([F:27])([F:26])[F:25])[C:22]([F:30])([F:29])[F:21]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)C(OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.2 %

Procedure:
A reaction vessel was charged with 0.42 g of 3,5-dichloro-4-(4-bromobutyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.25 g of 1,1,1,3,3,3-hexafluoro-2-propanol, 0.17 g of potassium carbonate and 10 ml of N,N-dimethylformamide. After stirring at room temperature for 48 hours, the reaction mixture was poured into water and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated. The residue was subjected to silica gel chromatography, which afforded 0.077 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(1,1,1,3,3,3-hexafluoro-2-propyloxy)butyloxy)benzene (yield, 15%), nD24.0 1.4805.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1.[NH2:17][NH2:18].O>C(O)C>[NH:17]([C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1)[NH2:18]
Reactant: Clc1cc2c(nn1)-c1ccccc1CCC2
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1cc2c(nn1)-c1ccccc1CCC2
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of the compound of formula (Df), 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine, (4.3 g, 18.6 mmol) and anhydrous hydrazine (11.7 mL, 370 mmol) in 45 mL of ethanol was refluxed for 16 h. After cooling to ambient temperature, 5 mL of water was added and the volatiles were then evaporated. To the solid residue was added cold water (about 80 mL). After sonication for 10 min, the resulting solid was collected by filtration and washed with cold water three times. After freeze-drying, the compound of formula (D-1), 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine, (4.14 g, 98%) was obtained as a slight yellow solid, 1H NMR (300 MHz, CD3OD) δ: 7.59 (m, 1H), 7.39-7.26 (m, 3H), 7.04 (s, 1H), 2.54 (t, J=6.9 Hz, 2H), 2.47 (t, J=6.9 Hz, 2H), 2.18 (quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 227 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.Cl.[CH3:58][NH:59][CH3:60].[CH2:61](N(CC)CC)C>CN(C)C=O.COC(C)(C)C>[CH3:58][N:59]([CH3:61])[CH2:60][CH2:41][CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:53]=[CH:54][CH:55]=[CH:56][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CNC
Reactant: CCN(CC)CC
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCCN(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 0.40 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}ethoxy)piperidine-1-carboxylate (Example 26b), 0.82 g of dimethylamine hydrochloride and 1.39 ml of triethylamine in 4 ml of N,N-dimethylformamide is stirred at 65° C. over 16 hours. The reaction mixture is cooled to room temperature, diluted with tert-butyl methyl ether, washed with 1N HCl (2×) and 0.5N NaOH, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (1:2 EtOAc-heptane); Rt=5.47.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[O-:10][CH2:11][CH3:12].[Na+].OCCCl>C(O)C>[OH:10][CH2:11][CH2:12][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9]
Reactant: CSc1ccccc1O
Reactant: CC[O-]
Agent: OCCCl
Agent: [Na+]
Solvent: CCO
Product: CSc1ccccc1OCCO

Procedure:
o-Hydroxythioanisole (14.1 g., 0.1 mole) is dissolved in sodium ethoxide (6.8 g., 0.1 mole) in absolute ethanol (100 ml.) and stirred as β-hydroxyethyl chloride (8.1 g., 0.1 mole) is added. The reaction mixture is refluxed for 2 hours and cooled. The o-(β-hydroxyethoxy)-thioanisole is extracted.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[CH:19]=[CH:20][CH2:21][OH:22])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.[NH2:26][C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)=[O:28].C1(N=C=NC2CCCCC2)CCCCC1.CN(C=O)C>CN(C)C1C=CN=CC=1.O.CCOCC>[NH2:26][C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([O:22][CH2:21][CH:20]=[CH:19][CH:18]([O:17][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:7]3[CH:6]=[N:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=3)=[CH:25][CH:24]=2)[CH3:23])=[O:34])=[CH:31][CH:30]=1)=[O:28]
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C=CCO)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C=CCOC(=O)c1ccc(C(N)=O)cc1)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
A mixture of 1.5 g (4.2 mmol) of the pentenol obtained in Example 3 above, 1.04 g (6.3 mmol) of 4-(aminocarbonyl)benzoic acid, 1.30 g (6.3 mmol) of dicyclohexylcarbodiimide (DDC), 0.05 g of 4-(dimethylamino)pyridine and 20 ml of DMF was stirred at room temperature overnight. An additional 0.3 g of DCC and 0.25 g of 4-(aminocarbonyl)benzoic acid were added and the mixture was stirred an additional 20 hours. The mixture was then poured into ether, water added and filtered. The filtrates were separated, and the organic layer washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and evaporated to dryness. The residue was purified by preparative scale HPLC, eluting with a 3:2 hexane:acetone mixture to give 0.55 g of the desired product as a tan, glassy solid, m.p. 144°-148° C. (Compound 29).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].[Br:7][CH2:8][CH:9](Br)[O:10][CH2:11][CH3:12].O.Cl>CCOCC>[Br:7][CH2:8][CH:9]([O:10][CH2:11][CH3:12])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCOC(Br)CBr
Reactant: CCCC[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCCCC(CBr)OCC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.68 moles of n-butylmagnesium bromide, as a 1.7 M solution in ether, is added dropwise a solution of 300 g. of 1,2-dibromo-2-ethoxyethane in 750 ml. of ether during a period of 2 hours at -15° C. The resulting mixture is stirred for one hour while warming to 20° C., then cooled to 0° C., and treated while stirring with 500 ml. of water, followed by 100 ml. of 4N hydrochloric acid. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The residue is distilled to provide a colorless liquid, b.p. 83°-84° C., 18 mm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([S:38](C)=O)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([SH:38])=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(S(C)=O)cn2)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(S)cn2)cc1
Yield: 118.4 %

Procedure:
A solution of 4-tert-butyl-N-{6-[2-(5-methylsulfinylpyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (471 mg) in trifluoroacetic anhydride (5 ml) and methylene chloride (5 ml) is refluxed for 30 minutes, and the mixture is evaporated to remove the solvent. The residue is dissolved in methanol/triethylamine (1:1) (20 ml), and concentrated to dryness under reduced pressure. The residue is dissolved in chloroform, washed with saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to give 4-tert-butyl-N-{6-[2-(5-mercaptopyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide as pale yellow foam (529 mg).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([N:13]2[C:17]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][C:15]([C:23]([F:26])([F:25])[F:24])=[N:14]2)[CH:8]=1)(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C>[N:27]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([N:13]2[C:17]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][C:15]([C:23]([F:26])([F:25])[F:24])=[N:14]2)[CH:8]=1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of 38 (0.695 mmol) in DMF (4.6 mL) at room temperature was added sodium azide (136 mg, 2.085 mmol) drop wise. The resulting solution was allowed to stir for 1 h at 60° C. The mixture was quenched with water and extracted with ethyl acetate, washed with brine (two times), dried (MgSO4) filtered and concentrated. Compound 39 (205 mg, 88%) was isolated as a brown oil and used as is for the next step. LRMS (ESI): calc. 334.1; found 335.1 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.C(=O)(O)[O-].[Na+].[N+]([O-])(O)=O.CC1C=C(C)[N:34]([C:38](N)=[NH:39])N=1>C(O)C>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:38]([NH2:39])=[NH:34]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Yield: 50 %

Procedure:
A mixture of 5-amino-3-[(7-azaindol-3-yl)methylene]-2-oxindole (2.773 g, 10 mmol) and sodium bicarbonate (0.168 g, 2 mmol) in refluxing ethanol (100 ml) was treated with 3,5-dimethylpyrazole-1-carboxamidine nitrate (3.018 g, 15 mmol) for 20 h. The solvent was removed from the cooled solution, and the residue was chromatographed on silica gel with gradient elution (1 to 5% EtOH in CHCl3) to afford pure title compound in about 50% yield.