Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].CN(C)C=O>O>[O:23]=[C:21]1[C:20]2[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18](=[O:28])[N:22]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]
Reactant: CCOP(=O)(Cc1cccc(CBr)c1)OCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1cccc(CN2C(=O)c3ccccc3C2=O)c1)OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.3 %

Procedure:
A mixture of diethyl [3-(bromomethyl)benzyl]phosphonate (10 g), potassium phthalimide (5.77 g) and N,N-dimethylformamide (100 ml) was stirred at room temperature for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated Recrystallization of the residue from ethyl acetate-hexane gave diethyl {3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzyl}phosphonate (9.40 g, 78%) as colorless prism crystals. melting point: 100-101° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl[C:18]1[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1.[H-].[Na+]>CN(C)C=O>[C:4]([C:3]1[CH:12]=[CH:13][C:14]([O:16][C:18]2[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH:23]=2)=[CH:15][C:2]=1[OH:1])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(=O)c3ccccc3)c(O)c2)ccc1[N+](=O)[O-]
Yield: 22.6 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2,4-dihydroxybenzophenone (4.5 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6.0 g), sodium hydride (55 wt. %, 1.75 g) and anhydrous N,N-dimethylformamide (130 ml) and the reaction mixture was purified to give the title compound (2.2 g).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][NH:28][CH3:29]>>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][N:28]([CH3:29])[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNCCN(C)C
Reactant: CN(C)CCNc1cccc2c1C(=O)c1cccc(Cl)c1C2=O
Product: CN(C)CCNc1cccc2c1C(=O)c1cccc(N(C)CCN(C)C)c1C2=O
Yield: 43.4 %

Procedure:
This procedure was carried out as described previously in Example 19, using Compound 17 (500 mg, 1.52 mmol) and N,N,N′-trimethylethylenediamine (988 μL, 7.6 mmol). The dye was obtained as a red solid (260 mg) after Biotage purification using a gradient of methanol in chloroform. Abs (max, PBS pH 7.4)=530 nm; Em=646 nm. The structure of Compound 41 is given below:
Reaction SMILES: [CH:1]([N:3]([CH3:19])[CH:4]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:2].[CH3:20]C(C)([O-])C.[K+].COS(OC)(=O)=O>O1CCCC1>[CH:1]([N:3]([CH3:19])[CH:4]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:20])=[O:2]
Reactant: Cc1ccsc1C(Cc1ccccc1O)N(C)C=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: COc1ccccc1CC(c1sccc1C)N(C)C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To an ice-water chilled solution of 5.10 g of N-formyl-2-hydroxy-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 100 ml of tetrahydrofuran, was added 2.24 g of potassium t-butoxide and then a solution of 2.52 g of dimethylsulfate and 25 ml of tetrahydrofuran dropwise, with stirring. The mixture was stirred at ice-bath temperature for 30 min, at room temperature for one hr, and at reflux for 30 mins. Additional dimethylsulfate and potassium t-butoxide were added and the mixture was refluxed for 20 min. The reaction mixture was decanted into 40 ml of water and basified with 10% sodium hydroxide solution. The mixture was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was combined with a previous sample. The combined residue Was purified by preparative H:PLC (Water Associates Prep LC/System 500, silica gel, material applied as a solution in dichloromethane, eluted with ethyl acetate-hexane (1:1,200 ml/min flow rate). The appropriate fractions were combined and concentrated. The residue crystallized during refrigerated storage. Recrystallization from cyclohexane afforded 3.5 g of the product, mp 80°-83° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][C:34]=1[C:50]1[CH:55]=[CH:54][C:53]([C:56]([O:58][CH3:59])=[O:57])=[CH:52][C:51]=1[CH3:60].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Cl-].[Na+].O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:36]4[C:37]([O:39][CH3:40])=[CH:38][C:33]([F:32])=[C:34]([C:50]5[CH:55]=[CH:54][C:53]([C:56]([O:58][CH3:59])=[O:57])=[CH:52][C:51]=5[CH3:60])[CH:35]=4)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: COC(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)c(OC)cc2F)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)c(C)c1

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylthio)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 38, 158.7 mg, 0.299 mmol), methyl 2′-fluoro-4′-methoxy-2-methyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (144 mg, 0.359 mmol), K2CO3 (0-329 mL, 0.658 mmol), 1,1′-bis(diphenylphosphino) ferrocene-palladium dichloride dichloromethane adduct (36.7 mg, 0.045 mmol) and 1,4-dioxane (7 mL) were sealed in a microwave vessel and subjected to microwave irradiation at 140° C. for 20 min. LCMS trace of aliquot indicated completion of reaction. The reaction crude was combined with Crude-D1 and Crude-D2. The combined crude mixture was worked up with brine, extracted with EtOAc, dried (Na2SO4), filtered and evaporated to afford a dark mixture. The resulting dark mixture was purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted with a EtOAc/hexanes gradient mixture (0% to 30%). Related fractions were pooled and evaporated into 256 mg of yellow glass. TLC and LCMS trace indicated this yellow glass was not pure. The yellow glass was purified by preparative TLC (silica gel) developed with a EtOAc/hexanes mixture (30% EtOAc/hex, v/v) to give a yellow glass of 175 mg. This yellow glass was further purified by preparative TLC (silica gel, EtOAc/CH2Cl2, 2.5%, v/v) to give a yellow glass as the titled compound. LCMS calc.=723.16; found=724.03 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CN(C)[C@@H]1CCN(CC2C=CC(C(O)=O)=CC=2)C1.[C:40]([O:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1)(=[O:42])[CH3:41]>CCOC(C)=O>[C:40]([O:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](=[O:49])[NH:1][C:2]2[CH:7]=[C:6]([C:8]3[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=3)[CH:5]=[CH:4][C:3]=2[NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])=[CH:46][CH:45]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2=CC(=O)CC2)cc1N
Agent: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)O)cc2)C1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C(=O)Nc2cc(C3=CC(=O)CC3)ccc2NC(=O)OC(C)(C)C)cc1
Yield: 30 %

Procedure:
Following the same procedure as described in Example 1, step 6 (scheme 1), but substituting compound 4 for compound 258 and compound 7 for 4-acetoxybenzoic acid, title compound 259 was obtained as a yellow oil in 30% yield [after flash chromatography (eluent: 30% AcOEt in hexanes)].
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:19])=[C:9]([CH:18]=1)[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11].[CH3:20][C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:19][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:3][C:24]([C:21]2([CH3:20])[CH2:23][CH2:22]2)=[O:25])=[CH:18][C:9]=1[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11]
Reactant: CC1(C(=O)O)CC1
Reactant: NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C(=O)NCc2ccc(Cl)c(C(=O)Nc3ncc[nH]3)c2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
Dissolve 5-(aminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide dihydrochloride (100 mg, 0.35 mmol, 1.0 equiv) and 1-methylcyclopropanecarboxylic acid (45.3 mg, 0.45 mmol, 1.3 equiv) in DMF (0.697 mL), add triethylamine (82.5 μL, 0.59 mmol, 1.7 equiv) and BOP (231 mg, 0.52 mmol, 1.5 equiv). Stir the mixture at 60° C. overnight, and purify the crude mixture by flash chromatography on silica gel eluting with a 20% to 60% EtOAc/hexanes gradient. Recrystallize the material from EtOAc, filter, and wash with EtOAc to provide the title compound as a white solid (116 mg, 55%). 1H NMR (DMSO-d6, 400 MHz) δ 11.76 (br s, 2H), 8.13 (t, 1H, J=6.0 Hz), 7.43 (d, 1H, J=8.2 Hz), 7.39 (d, 1H, J=1.3 Hz), 7.29 (dd, 1H, J=8.2, 1.3 Hz), 6.74 (br s, 2H), 4.25 (d, 2H, J=6.0 Hz), 1.26 (s, 3H), 0.93 (app q, 2H, J=3.1 Hz), 0.50 (app q, 2H, J=3.2 Hz). MS (m/z) (35Cl/37Cl) 333/335 (M+1).
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.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.[K+].[Si:70]([O:77][CH:78]1[CH2:83][CH2:82][CH:81]([NH2:84])[CH2:80][CH:79]1[F:85])([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71]>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].COCCOC>[Si:70]([O:77][CH:78]1[CH2:83][CH2:82][CH:81]([NH:84][C:2]2[C:14]3[C:13]4[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=4[NH:7][C:6]=3[C:5]([C:16]#[N:17])=[CH:4][N:3]=2)[CH2:80][CH:79]1[F:85])([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(N)CC1F
Reactant: N#Cc1cnc(Cl)c2c1[nH]c1ccc(F)cc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ncc(C#N)c3[nH]c4ccc(F)cc4c23)CC1F
Temperature: 85 °C

Procedure:
A flask containing 1-chloro-8-fluoro-5H-pyrido[4,3-b]indole-4-carbonitrile (Example 38 Step 4, 250 mg, 1.02 mmol), BINAP (95 mg, 0.15 mmol), Pd2(dba)3 (47 mg, 0.051 mmol), and KOtBu (365 mg, 3.26 mmol) was evacuated and refilled with nitrogen (×3). Degassed DME (5 mL) and 4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorocyclohexanamine (327 mg, 1.32 mmol) were added to the mixture. The reaction mixture was heated to 85° C. overnight, cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried (sodium sulfate), concentrated, and purified by flash chromatography to afford the title compound. LRMS (APCI) calc'd for (C24H30F2N4OSi) [M+H]+, 457.2. found 457.1.
Reaction SMILES: N(C1C=C(C2SC(C(NCC([CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])(NS(C3C(C)=CC(C)=CC=3C)(=O)=O)C(N)=O)=O)=CC=2)C=CC=1)C(N)=N.N.N(C1C=C(C2SC(C([NH:61][CH2:62][C:63](CCO)([NH:67][S:68]([C:71]3[C:76]([CH3:77])=[CH:75][C:74]([CH3:78])=[CH:73][C:72]=3[CH3:79])(=[O:70])=[O:69])[C:64]([NH2:66])=[O:65])=O)=CC=2)C=CC=1)C(N)=N>>[NH2:61][CH2:62][CH:63]([NH:67][S:68]([C:71]1[C:72]([CH3:79])=[CH:73][C:74]([CH3:78])=[CH:75][C:76]=1[CH3:77])(=[O:69])=[O:70])[C:64]([NH:66][CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])=[O:65]
Reactant: Cc1cc(C)c(S(=O)(=O)NC(CCO)(CNC(=O)c2ccc(-c3cccc(NC(=N)N)c3)s2)C(N)=O)c(C)c1
Reactant: CC(=O)OCCC(CNC(=O)c1ccc(-c2cccc(NC(=N)N)c2)s1)(NS(=O)(=O)c1c(C)cc(C)cc1C)C(N)=O
Agent: N
Product: CC(=O)OCCNC(=O)C(CN)NS(=O)(=O)c1c(C)cc(C)cc1C

Procedure:
3-{[5-(3-Guanidino-phenyl)-thiophene-2-carbonyl]-amino}-2-(2,4,6-trimethyl-benzenesulfonylamino)-2-acetoxyethyl propionamide (X-9) was treated with excess methanolic ammonia resulting in the formation of 3-{[5-(3-Guanidino-phenyl)-thiophene-2-carbonyl]-amino}-2-(2,4,6-trimethyl-benzenesulfonylamino)-2-hydroxyethyl propionamide (X-9).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:16][CH2:15][C:14]([CH2:18][OH:19])([CH3:17])[CH2:13]1.[H-].[Na+].I[CH3:23].O>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:16][CH2:15][C:14]([CH2:18][O:19][CH3:23])([CH3:17])[CH2:13]1
Reactant: CI
Reactant: CC1(CO)CCN(CC2COc3ccccc3O2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1(C)CCN(CC2COc3ccccc3O2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 56 mg (0.21 mmol) of [1-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-yl]-methanol in 1.5 ml of tetrahydrofuran was added to a flask containing 58 mg (2.40 mmol) of sodium hydride, previously washed with heptane under argon. The reaction mixture was stirred at 60° C. for 2 h, cooled to 0° C. followed by dropwise addition of a solution containing 16 μl (0.25 mmol) of iodomethane in tetrahydrofuran (0.5 ml). The reaction mixture was allowed to warm to room temperature and the stirring was continued for 1½ h. Water was slowly added and tetrahydrofuran was evaporated off and the water phase was extracted with dichloromethane (3×25 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification by column chromatography (silica gel, ethyl acetate/heptane, 7:13) yielded the desired pure methyl ether.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])C.[OH-].[Na+]>C(O)C>[C:23]1([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:4]([OH:29])=[O:3])=[CH:22][CH:21]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: CCCCCCCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 23.5gof α-[p-(1-cyclohexenyl)-phenoxy]-dodecanoic acid ethyl ester in 150 ml of ethanol are added 100 ml of 2N sodium hydroxide solution and the mixture stirred for 2 hours at room temperature. The ethanol is stripped off in vacuo and the residue partitioned between 2N hydrochloric acid and ether. The organic phase is washed until neutral, dried over sodium sulphate and evaporated to dryness. Distillation of the residue at 0.04 mm yields in the fraction boiling at 190°-197° C the α-[p-(1-cyclohexenyl)-phenoxy]-dodecanoic acid of the formula ##STR18## (m.p. 70°-72° C).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.CN(C)C(=O)C.Cl.Cl[CH2:19][C:20]1[N:21]=[C:22]([CH3:25])[S:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[N:6]([CH2:19][C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc(CCl)cs1
Reactant: Clc1nc2ccccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(Cn2c(Cl)nc3ccccc32)cs1
Temperature: 75 °C
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a mixture of 15.5 pans of 2-chloro-1H-benzimidazole and 235 parts of N,N-dimethylacetamide there were added 22 pans of 4-(chloromethyl)-2-methylthiazole monohydrochloride and 25.4 pans of sodium carbonate. The whole was stirred for 18 hours at 75° C. and was then poured into water. The product was extracted with 4-methyl-2-pentanone and the extract was washed with water, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 11.3 parts (42.8%) of 2-chloro-1-[(2-methyl-4-thiazolyl)methyl]-1H-benzimidazole (interm. 1). In a similar manner there was also prepared 2-chloro-1-[(6-methyl-2-pyridinyl)methyl]1H-benzimidazole (interm. 2).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:18]=[C:19]([CH2:23][C:24](O)=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CCOC(C)=O>[N+:14]([C:17]1[CH:18]=[C:19]([CH2:23][C:24]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An oven-dried, round-bottom flask was charged with tert-butyl piperazine-1-carboxylate (1.1 eq), 3-nitrophenylacetic acid (7A, 1.0 eq), EDC (1.2 eq), and HOBT (1.2 eq). The flask was flushed with nitrogen, and N,N-dimethylformamide (about 0.5 M 7A in DMF) and triethylamine (2.0 eq) were added by syringe. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc, and washed 4 times with H2O, twice with 1 N aq. KHSO4, once with saturated NaHCO3, and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Tert-butyl 4-(2-(3-nitrophenyl)acetyl)piperazine-1-carboxylate (7B) was isolated as a solid (80%) and used without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C@H:7]([CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[NH:19][N:18]=[N:17][C:16]=2[N:15]([CH3:23])[C:13]1=[O:14])(=[O:5])[CH3:4].[CH3:25]I>CS(C)=O>[C:3]([O:6][C@H:7]([CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:25])[N:18]=[N:17][C:16]=2[N:15]([CH3:23])[C:13]1=[O:14])(=[O:5])[CH3:4]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]nnc2n(C)c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nnn2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
To a suspension of sodium hydride (22 mg, 0.91 mmol) in anhydrous dimethylsulfoxide (4.0 ml) was added (R)-1-(5-acetoxyhexyl)-3-methyl-8-azaxanthine (225 mg, 0.728 mmol). After stirring at room temperature for 30 min, the mixture was treated with methyl iodide (524 mg, 3.64 mmol). After stirring at room temperature overnight, the reaction was quenched by addition of saturated aqueous sodium chloride solution (20 ml) and then extracted with ethyl acetate (3x 15 ml). The combined extracts were washed with water (10 ml), with saturated aqueous sodium chloride solution (10 ml) and dried over magnesium sulfate. TLC showed that there were two products in this mixture. After evaporation of the solvent under reduced pressure, the crude products were purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to provide (R)-1-(5-acetoxyhexyl)-3,7-dimethyl-8-azaxanthine (74 mg, 31% yield) followed by (R)-1-(5-acetoxyhexyl)-3,8-dimethyl-8-azaxanthine (66 mg, 28% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:33])[N:5]2[C:10]=1[C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)=[N:8][C:7]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1)=[N:6]2>[Pd]>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:10]3=[C:2]([CH3:1])[N:3]=[C:4]([CH3:33])[N:5]3[N:6]=2)=[CH:29][CH:28]=1
Reactant: COc1cc(Nc2nc(-c3ccc([N+](=O)[O-])cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: [Pd]
Product: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
620 mg (1.38 mmol) of 5,7-dimethyl-2-(4-nitrophenyl)-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-4-amine from example 17A are hydrogenated in the presence of 200 mg of palladium on carbon (10% strength) analogously to example 1.
Reaction SMILES: [H-].[Na+].O.[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.Br[CH2:10][C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][N:12]=1>CCCCCC.CN(C)C=O>[N:4]1([CH2:10][C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: c1c[nH]cn1
Reactant: BrCc1noc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: c1ccc2c(Cn3ccnc3)noc2c1
Temperature: 85 °C

Procedure:
Sodium hydride (50% in mineral oil, 3.4 g, 0.071 mole) is washed free of mineral oil with hexane (3×30 mL) and suspended in dimethylformamide (100 mL). This suspension is well stirred and maintained near room temperature (water bath) during the dropwise addition of a solution of imidazole (4.8 g, 0.071 mole) in dimethylformamide (25 mL). The reaction mixture is stirred at room temperature for 1 hour when 3-bromomethyl-1,2-benzisoxazole (15.0 g, 0.071 mole) is added all at once. The mixture is then heated at 85° C. for 8 hours. The solvent is evaporated in vacuo and the residue is taken up in methylene chloride (200 mL) and washed with water (3×50 mL). The organic solution is dried over anhydrous sodium sulfate, filtered and evaporated to give 3-[(1H-imidazol-1-yl)methyl]-1,2-benzisoxazole, which is purified by recrystallisation from isopropanol, m.p. 52°-55° C. The free base is converted to the hydrochloride salt m.p. 145°-146° C., when its solution in isopropanol is treated with a small excess of ethereal hydrogen chloride.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH:10]1[CH2:12][O:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].C(OC)=O.CO>O>[CH3:1][N:2]([CH2:9][CH:10]([OH:11])[CH2:12][N:13]=[N+:14]=[N-:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(CC1CO1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: COC=O
Solvent: CO
Product: CN(CC(O)CN=[N+]=[N-])c1ccccc1
Yield: 91.1 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 1.65 g of N-methyl-N-phenylaminomethyloxirane (prepared as described in Preparation 88), 3.29 g of sodium azide, 15 ml of methyl formate and 63 ml of an 8:1 by volume mixture of methanol and water were used, to give 1.9 g of the title compound as a pale yellow oil having an Rf value of 0.09 (on silica gel thin layer chromatography, using a 1:15 by volume mixture of ethyl acetate and hexane as the developing solvent).