Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[NH:22])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)(O)[O-].[Na+].Br[CH2:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[CH2:29][C:30]([OH:35])([C:31]([F:34])([F:33])[F:32])[N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1F
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1F
Temperature: 72.5 °C
Yield: 63.5 %

Procedure:
To a mixture of 3-fluoro-4-methoxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (4.15 g, 12.9 mmol) and sodium bicarbonate (2.16 g, 25.8 mmol) in isopropanol (150 mL), 3-bromo-1,1,1-trifluoroacetone (4.8 mL, 45 mmol) was added. After heating the reaction mixture at 70-75° C. for 20 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture (7.8 g) was purified by chromatography (silica gel, toluene/ethyl acetate, 7/3) to give 2-(3-fluoro-4-methoxyphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (3.54 g, 64%) as a white solid: mp (DSC) 210° C. Anal. Calc'd. for C18H16N2SO4F4.0.1 PhCH3: C, 50.86, H, 3.83, N, 6.34. Found: C, 50.61, H, 3.64, N, 6.16.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].CI.[C:13](=O)([O-])[O-].[K+].[K+]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:13])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1ccccc1O
Agent: [K+]
Solvent: CI
Product: COc1ccccc1C(C)C

Procedure:
2-Isopropylphenol was reacted with methyl iodide in the presence of potassium carbonate to yield 1-isopropyl-2-methoxybenzene, which in turn was reacted with the solution of unisolated intermediate (CF3CO2)3I described above to form the bis-[3-isopropyl-4-methoxyphenyl]iodonium salt in 40-70% yield. The bis-[3-isopropyl-4-methoxyphenyl]iodonium salt precipitated as a gummy solid, making purification impracticable and contributing to the unpredictability of the yield.
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([C:15]1[CH:16]=[CH:17][C:18]2[O:24][CH2:23][C:22](=[O:25])[CH2:21][CH:20](S(C3C=CC=CC=3)(=O)=O)[C:19]=2[CH:35]=1)(=[O:14])[CH3:13].O.Cl>ClCCl>[C:12]([C:15]1[CH:16]=[CH:17][C:18]2[O:24][CH2:23][C:22](=[O:25])[CH:21]=[CH:20][C:19]=2[CH:35]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1ccc2c(c1)C(S(=O)(=O)c1ccccc1)CC(=O)CO2
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)c1ccc2c(c1)C=CC(=O)CO2

Procedure:
0.084 ml (1.05 equivalents) of 1,8-diazabicyclo[5.4.0]undec-7-ene is added at ambient temperature, under nitrogen, to 184 mg (0.53 mmol) of 7-acetyl-5-(phenylsulfonyl)-4,5-dihydro-1-benzoxepin-3(2H)-one, prepared according to example 14, in suspension in 20 ml of dichloromethane. From the addition of the base, the medium becomes translucent and slightly yellow. After addition of water and 1N hydrochloric acid, the phases are separated by settling and then the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with a saturated sodium hydrogencarbonate solution and then brine. After drying and then concentrating under vacuum, 90 mg (83%) of 7-acetyl-1-benzoxepin-3(2H)-one are obtained in the form of a white solid; M.p.=92–93° C.
Reaction SMILES: [C:1]([C:3]1[CH:44]=[CH:43][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:14]3[C:22]([O:23][CH:24]([F:26])[F:25])=[CH:21][C:20]([CH3:27])=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4C(OC(C)(C)C)=O)([O:12][CH3:13])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC(F)F)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(OC)C)N(COCC[Si](C)(C)C)C=2C=1)#N.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:26][CH:24]([F:25])[O:23][C:22]1[C:14]([C:10]([C:8]2[NH:7][C:6]3[CH:43]=[CH:44][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)([O:12][CH3:13])[CH3:11])=[C:15]2[C:19](=[C:20]([CH3:27])[CH:21]=1)[NH:18][CH:17]=[CH:16]2
Reactant: COC(C)(c1c(OC(F)F)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COC(C)(c1c(OC(F)F)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: COC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC(F)F)cc(C)c2[nH]ccc12
Temperature: 60 °C

Procedure:
To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (475 mg, 0.758 mmol) in THF (7.6 mL) at room temperature, ethylenediamine (0.51 mL, 7.58 mmol) was added followed by TBAF (1M in THF, 7.6 mL, 7.6 mmol) and the reaction was stirred at 60° C. After 6 hours the reaction was cooled to room temperature, additional ethylenediamine (0.51 mL, 7.58 mmol) and TBAF (1M in THF, 7.6 mL, 7.6 mmol) were added and the reaction was stirred at 60° C. overnight. The reaction was cooled to room temperature, quenched with NH4Cl and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.68-12.85 (m, 1H) 11.19 (br. s., 1H) 8.09 (m) 7.83 (m) 7.69-7.74 (m) 7.47-7.58 (m) 7.31 (t, J=2.78 Hz, 1H) 6.89-6.96 (m) 6.70-6.77 (m) 6.46-6.58 (m) 3.01-3.17 (m, 3H) 2.46 (s, 3H) 2.07 (s, 3H). HRMS calcd. for C21H18F2N4O2 (M+H)+ 397.1471. found 397.1482.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:21][C:22](=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH3:20].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:19]([O:21][C:22](=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH3:20]
Reactant: CCOC(=O)CCCCCCCCCCBr
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 58 %

Procedure:
To a solution of 12.6 g (0.05 mole) 4,5-diphenyl-2-imidazolethiol in 125 ml dimethylformamide was added, dropwise, 14.2 g (0.05 mole) ethyl-11-bromoundecanoate in 40 ml dimethylformamide and the reaction mixture was stirred at reflux under nitrogen overnight. The cooled solution was poured into 5% sodium bicarbonate and ice and then extracted with ethyl acetate. The organic layer was backwashed with 5% sodium bicarbonate, water, and saturated sodium chloride solution, then dried over magnesium sulfate and the solvent was removed under vacuum. The residue was chromatographed using hexane:ethyl acetate (9:1). The resulting solid was triturated with hexane to give 13.58 g (0.029 mole) of the title compound as a white solid, mp=57°-59° C. 1HNMR(DMSO-d6): δ12.6(s,1H), 7.6-7.1(m,10H), 4.0(q,2H,J=8Hz), 3.5(t,2H,J=7Hz), 2.25(t,2H,J=7Hz), 1.8-1.1(m.21H).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Br[CH2:23][C:24]1[CH:35]=[CH:34][C:27]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:26]([CH3:36])[CH:25]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH3:36][C:26]1[CH:25]=[C:24]([CH2:23][N:5]([CH2:4][CH2:3][S:2][CH3:1])[C:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH:35]=[CH:34][C:27]=1[O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)COc1ccc(CBr)cc1C
Reactant: CSCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COc1ccc(CN(CCSC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
To a solution of N-[2-(methylthio)ethyl]-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (0.27 g, 0.864 mmol) in anhydrous MeCN (22 mL) under nitrogen at room temperature was added methyl [4-(bromomethyl)-2-methylphenoxy]acetate (0.248 g, 0.864 mmol) and N,N-diisopropyethylamine (0.15 mL, 0.864 mmol). The resultant mixture was heated to reflux and stirred for 3 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×30 mL) and water (30 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (20 g Silica cartridge), eluted with 1:99–1:33 EtOAc:cyclohexane afforded the title compound as a yellow oil (249 mg).
Reaction SMILES: [Na+].[I-].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:22][CH:21]1[CH:33]=[CH:34][N+:35]([O-:37])=[O:36])=[O:19])([CH3:16])([CH3:15])[CH3:14]>CO.CC#N>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[CH2:22][CH:21]1[CH:33]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([F:3])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)[CH2:34][N+:35]([O-:37])=[O:36])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C=C[N+](=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(C[N+](=O)[O-])c1c[nH]c2cc(F)ccc12
Reaction time: 72 h
Yield: 74.2 %

Procedure:
To a solution of CeCl3.7H2O (6.06 g, 40.6 mmol) and NaI (2.44 g, 16.2 mmol) in MeOH (200 mL) was added SiO2 (30 g). The resulting pale yellow solution was evaporated to dryness to afford a fine yellow powder. To this solid was added 6-fluoroindole (6.59 g, 48.7 mmol) and a solution of 77 (15.1 g, 40.6 mmol) in anhydrous CH3CN (150 mL). The heterogeneous reaction mixture was evaporated to dryness and allowed to stand 72 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and additional silica gel (150 mL) was added. The mixture was concentrated to dryness and the product was eluted by flash silica gel chromatography (15-25% EtOAc/hexanes) to afford 78 (15.3 g, 75%) as an inseparable mixture of diastereomers. Mass spectrum, m/z [508.2] (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H:40]([O:43]CCC)[CH2:39][CH2:38]2)CCCCC1.[CH:47]1(N([C@H]2CC[C@H](OC)CC2)C(=O)NC2SC(SCC(O)=O)=CN=2)CCCC1.O[C@H]1CC[C@H](C2C=CC=C3C=2C(=O)NC3=O)CC1.BrCCC.C1(=O)CCCCC1.COC(=O)CN(S(C1SC(N)=NC=1)(=O)=O)C>>[CH:24]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([O:43][CH2:40][CH2:39][CH3:38])[CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH3:47])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CCCO[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: COC(=O)CN(C)S(=O)(=O)c1cnc(N)s1
Agent: O=C1NC(=O)c2c1cccc2[C@H]1CC[C@H](O)CC1
Solvent: CCCBr
Solvent: O=C1CCCCC1
Product: CCCO[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)N(C)CC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-propoxy-cyclohexyl)-amine (prepared according to the procedure described for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Step 1) using (trans-4-hydroxy-cyclohexyl)-isoindole-1,3-dione, 1-bromopropane and cyclohexanone) and [(2-amino-thiazole-5-sulfonyl)-methyl-amino]-acetic acid methyl ester to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[C:7]#[N:8].[N:16]([O-])=O.[Na+].[ClH:20]>C(O)(=O)C>[Cl:20][C:7]1[C:6]2[S:5][C:4]3[CH:9]=[CH:10][CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:3]=3[C:2]=2[N:1]=[N:16][N:8]=1
Reactant: N#Cc1sc2cccc([N+](=O)[O-])c2c1N
Reactant: O=N[O-]
Reactant: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2sc3c(Cl)nnnc3c12

Procedure:
The process of Example 2 was followed in general, using 4.4 g. of 3-amino-4-nitrobenzo[b]thiophene-2-carbonitrile and 1.7 g. of sodium nitrite in 60 ml. of concentrated hydrochloric acid and 60 ml. of glacial acetic acid. The product was recrystallized from a dimethylformamide, and the yield was 4.0 g. of purified 4-chloro-9-nitro[1]benzothieno[3,2-d]-v-triazine, m.p. 171°-173° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.N[C:37]1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.CC1C=CC=CC=1N=C=S>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:37])=[S:35])=[CH:12][CH:13]=3)[CH:18]=2)[C:22]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Agent: Cc1ccccc1N=C=S
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4C)cc3)ccc2C1=O

Procedure:
The compound of example 272 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 2-methyl phenyl isothiocyanate. The compound of example 272 was used directly without isolation, for the preparation of compound of example 273.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:16][C:17]1[CH:18]=[C:19]([CH:27]=[C:28]([F:31])[C:29]=1[F:30])[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22]1>>[CH3:15][C:13]1[N:12]=[CH:11][N:10]([C:5]2[CH:4]=[CH:3][C:2]([NH:26][C:23]3[CH:24]=[CH:25][N:21]([CH2:20][C:19]4[CH:18]=[C:17]([F:16])[C:29]([F:30])=[C:28]([F:31])[CH:27]=4)[N:22]=3)=[CH:9][C:6]=2[C:7]#[N:8])[CH:14]=1
Reactant: Nc1ccn(Cc2cc(F)c(F)c(F)c2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4cc(F)c(F)c(F)c4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(3,4,5-trifluoro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a white solid (Yield=56%). MS ISP (m/e): 409.3 (100) [(M+H)+].
Reaction SMILES: CO[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH2:8][C:7]1=[O:18].[BrH:19].C(O)(=O)C>O>[Br:19][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH2:8][C:7]1=[O:18]
Reactant: COCCCN1C(=O)CC(=O)Nc2ccccc21
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(=O)N(CCCBr)c2ccccc2N1
Temperature: 60 °C
Reaction time: 4.7 h

Procedure:
To 4.9 g of the compound of Example 208, 25 ml of 30% hydrobromic acid-acetic acid solution is added and the resulting mixture is stirred at 60° C. for 4.7 hours. The resulting mixture is poured into water and the resultant is subjected to extraction with ethyl acetate. The organic layer is washed with aqueous sodium carbonate solution and brine and dried. The resultant is purified by silica gel column chromatography (ethyl acetate) to obtain 3.3 g of (209).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1.[NH:13]1[CH2:18][CH2:17][C:16]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH2:19]2)[CH2:15][CH2:14]1.C(N(CC)CC)C.O>CN(C)C=O>[N:8]1([C:5]2[N:4]=[N:3][C:2]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[O:20][CH2:19]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Clc1ccc(-n2ccnc2)nn1
Reactant: c1ccc2c(c1)OCC21CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)OCC21CCN(c2ccc(-n3ccnc3)nn2)CC1
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 73.7 %

Procedure:
3-Chloro-6-(1H-imidazol-1-yl)pyridazine (180 mg), spiro[1-benzofuran-3,4′-piperidine] (200 mg) and triethylamine (0.42 mL) were dissolved in N,N-dimethylformamide (1 mL), and the solution was stirred at 160° C. under irradiation of microwave for 20 min. Water (10 mL) was added, and the resulting precipitate was collected by filtration, and recrystallized from ethyl acetate-hexane to give the object product (245 mg, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:14]([SiH2:18][O:19][C:20]([CH3:30])([CH3:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[C:22]=1[NH2:28])([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:28][C:22]1[C:21]([C:20]([CH3:30])([CH3:29])[O:19][SiH2:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:26][CH:25]=[CH:24][C:23]=1[NH:27][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][N:9]=1)=[O:13]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(N)c1N
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(NC(=O)c2n[nH]c3ncc(Br)cc23)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid Compound 1c (1.0 g, 4.13 mmol) and 3-(tert-butyl-dimethyl-silanyloxymethyl)-benzene-1,2-diamine Compound 6a (1.05 g, 4.17 mmol), HATU (1.58 g, 4.16 mmol) and DIPEA (2.5 mL, 35.9 mmol) in DMF (50 mL) was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL), then sequentially washed with hydrochloric acid (20 mL, 1M), water (30 mL×3) and brine (20 mL). The organic solution was evaporated to dryness in vacuo and purified by silica gel chromatography (10% to 50% of ethyl acetate in hexanes) to yield 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid [2-amino-3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-amide Compound 6b (1.21 g, 61% yield) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 8.91 (d, 1H, J=2.1 Hz), 8.73 (s, 1H), 8.67 (d, 1H, J=2.1 Hz), 7.47 (d, 1H, J=7.2 Hz), 7.01 (d, 1H, J=7.2 Hz), 6.83 (t, 1H, J=7.2 Hz), 4.78 (s, 2H), 0.95 (s; 9H), 0.11 (s, 6H); MS (ESI) m/z: 477 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[CH:9]([C:11]([F:14])([F:13])[F:12])=O.S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][C:7]=1[CH:9]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[Cl:8])[C:11]([F:14])([F:13])[F:12]
Reactant: Clc1cccc(Cl)c1
Reactant: O=CC(F)(F)F
Agent: O=S(=O)(O)O
Product: FC(F)(F)C(c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Yield: 76 %

Procedure:
1 mol (374 g) of α,α-bis-(2,4-dichlorophenyl)-β,β,β-trifluoroethane (obtained by condensation of m-dichlorobenzene with fluoral in the presence of concentrated sulfuric acid) is dissolved in 800 ml of "glyme". There is then added with stirring 80 g of 1,2,4-triazole, and at 80°-85° there is subsequently added dropwise 250 ml of 60% KOH. The reaction mixture is refluxed for about a further 3 hours. After cooling, the aqueous phase is separated and discarded. The organic phase is concentrated by evaporation, and the residue is subjected to molecular distillation under high vacuum. The substance distills over at 180° and 0.1 Torr as colourless oil, which solidifes on cooling to form a solid resin. The yield is about 76%. The compound can be crystallised from a mixture of cyclohexane and methanol: m.p. 84°-86°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:9][N:8]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.O>C(OCC)(=O)C.C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:9][N:8]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc(N)cc1
Temperature: 80 °C
Yield: 59.7 %

Procedure:
A stirred solution of 1-benzoyl-4-(4-nitro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (10 g, Reference Example 9) in a mixture of ethyl acetate (324 ml) and ethanol (78 ml), at 24° C., was treated portionwise with tin chloride (30.65 g) then heated at 80° C. for 4 hours. After cooling to 24° C. the mixture was treated with water (400 ml), then with aqueous sodium bicarbonate solution (125 ml, 5%) and then filtered through a pad of celite washing twice with ethyl acetate (300 ml). The aqueous layer from the filtrate was separated and extracted twice with ethyl acetate (300 ml). The combined organic phases were dried over magnesium sulphate and evaporated (40° C. and 2.7 kPa). The residue was triturated with diethyl ether (100 ml) affording the title compound (5.48 g) as a white powder. 1H-NMR [250 MHz, (CD3)2SO at 373° K.]: δ 1.14 (t, J=7 Hz, 3H); 3.24 (m, 1H); 3.40 to 3.60 (m, 2H); 3.73 (dd, J=11 and 8.5 Hz, 1H); 3.80 to 4.00 (m, 2H); 4.08 (q, J=7 Hz, 2H); 6.58 (d, J=8 Hz, 2H); 6.98 (d, J=8 Hz, 2H); 7.40 to 7.60 (m, 5H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[CH:27]1([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:40]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH2:32][CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:39][CH:38]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: Nc1ccc(OCC2CCCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: O=C1N(c2ccc(OCC3CCCC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
Light Brown crystalline solid. MS (ESI): 503.2 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 4-cyclopentylmethoxy-phenylamine.
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].Cl>>[C@@H:11]12[O:12][CH2:2][C@H:3]([O:4]1)[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@@H:9]2[OH:10]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Product: O[C@@H]1[C@H](O)[C@@H]2OC[C@H](O2)[C@H]1O
Yield: 35.5 %

Procedure:
A mixture of L-gulose (1) (33 g, 0.127 mol) and 0.5 N HCl (330 mL, 0.165 mol) was refluxed for 20 hours. The mixture was cooled and neutralized to pH 6 by a resin (Dowex-2, HCO3-form) with air bubbling. The resin was recycled by washing with 10% HCl, water, methanol, water and saturated NaHCO3 solution. The reaction mixture was filtered and the resin was washed with water (500 mL). The combined filtrate was concentrated to dryness and dried in vacuo overnight. The residue was purified over a column (5 cm depth, silica gel, mesh, CHCl3—CH3OH, 10:1) to give a slightly yellow solid, which was recrystallized from absolute alcohol to give a colorless solid (2) [Rf=0.43 (CHCl3—CH3OH, 5:1), 7.3 g, 35.52%]. The L-gulose Rf=0.07, 11 g) obtained was recycled to give (2) (5 g, total yield 60%): mp 142.5–145° C.; 1H NMR (DMSO-d6) δ 3.22–3.68 (m, 4H, H-2, -3, -4 and -6a), 3.83 (d, J6b,6a=7.25 Hz, 1H, Hb-6), 4.22 (pseudo t, J5,6a=4.61 and 4.18 Hz, H, H-5), 4.46 (d, J2-OH,2=6.59 Hz, 1H, 2-OH, exchangeable with D2O), 4.62 (d, J3-OH,3=5.28 Hz, 1H, 3-OH, exchangeable with D2O), 5.07 (d, J4-OH,4=4.84 Hz, 1H, 4-OH, exchangeable with D2O), 5.20 (d, J1,2=2.19 Hz, 1H, H-1). [α]D25−50.011 (c, 1.61, CH3OH).