Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:17]([Cl:24])=[C:18](N)[CH:19]=[CH:20][C:21]=1Br)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][C:19]([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:34]=2)=[CH:18][C:17]=1[Cl:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1c(Br)ccc(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c2)CC1
Temperature: 80 °C

Procedure:
A mixture of the product of Example 60A (380 mg, 1.23 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (380 mg, 1.23 mmol) and sodium carbonate (391 mg, 3.69 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed and heated at 80° C. for 16 hours. After cooling to ambient temperature and concentration, the residue was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate (3×35 mL). The combined organic phase was washed with saturated brine, dried over sodium carbonate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 8/1 petroleum/ethyl acetate to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=1[C:38]([F:41])([F:40])[F:39]>CN(C=O)C.CCOC(C)=O>[F:39][C:38]([F:40])([F:41])[C:29]1[CH:30]=[C:31]([C:34]([F:37])([F:35])[F:36])[CH:32]=[CH:33][C:28]=1[CH2:27][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)cc21
Temperature: 70 °C

Procedure:
To a mixture of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.130 g, 0.5 mmol) and K2CO3 (0.069 g, 0.500 mmol) in DMF (1 mL) was added 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (0.154 g, 0.500 mmol). The mixture was heated at 70° C. overnight, taken up in EtOAc, washed with water (thrice) and brine. The organics were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound an orange solid (0.195 g). LCMS m/z 486.3 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1>>[N:25]1([CH2:2][C:3]2[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:11]=3)=[O:8])=[CH:5][CH:4]=2)[CH:29]=[CH:28][CH:27]=[N:26]1
Reactant: c1cn[nH]c1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cn2cccn2)cc1

Procedure:
70 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 36 mg of 1H-pyrazole via Procedure P. The reaction was evaporated to dryness and purified by reverse phase HPLC to yield 4-((1H-pyrazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 389.3 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.[OH-].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)=[CH:28][CH:27]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(C=O)cc2)C1)c1cc(F)cc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(CN3CCCC3)cc2)C1)c1cc(F)cc(F)c1
Reaction time: 20 h
Yield: 51.1 %

Procedure:
0.75 g of (RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine and then 0.68 g of sodium triacetoxyborohydride are added to a solution of 0.10 g of pyrrolidine in 20 cm3 of 1,2-dichloroethane. After 20 hours at room temperature, 2 cm3 of 1 N sodium hydroxide are added, the product is extracted with 100 cm3 of dichloromethane, the organic phase is washed twice with 50 cm3 of water and then 50 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1 cm, height 13 cm), at an argon pressure of 0.5 bar with acetate as eluent and collecting 20 cm3 fractions. Fractions 10 to 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.39 g of (RS)-1-{(4-chlorophenyl)-[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 1.65 (4H, m, 2CH2), 2.40 (4H,m, 2NCH2), 3.02 (3H,s, SCH3), 3.50 (2H, s, NCH2Ph), 3.85 (2H, s, NCH2), 4.20 (2H, S, NCH2), 4.75 (1H, s, NCH), between 7.15 and 7.40 (9H, m, 9CH arom.), 7.48 (2H, d, J=7 Hz, 2CH arom.)].
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:14][C@H:13]2[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[C:7]1=[O:15])C.[NH3:17]>CO>[O:15]=[C:7]1[C@@H:8]2[C@@H:13]([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:14][N:6]1[CH2:5][C:4]([NH2:17])=[O:3]
Reactant: CCOC(=O)CN1C[C@@H]2CCCC[C@@H]2C1=O
Reactant: N
Solvent: CO
Product: NC(=O)CN1C[C@@H]2CCCC[C@@H]2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of cis-octahydro-1-oxo-2H-isoindole-2acetic acid ethyl ester (17.79 g, 0.079 mole) in methanol (100 ml) is saturated with anhydrous ammonia and the solution is stirred 18 hours at room temperature. The solution is concentrated at reduced pressure to yield a gummy solid. Recrystallization from acetonitrile yields pure cis-octahydro-1-oxo-2H-isoindole-2-acetic acid amide, with mp 142°-144° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8](O)=[S:9])=[N:5][N:4]=[N:3]1.[CH2:11]1[CH2:21][CH2:20][N:19]2[C:14](=NC[CH2:17][CH2:18]2)[CH2:13][CH2:12]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:18]([N:19]([CH:14]1[CH2:13][CH2:12][CH2:11][CH2:21][CH2:20]1)[C:8](=[S:9])[CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[CH3:17]
Reactant: Cn1nnnc1CC(O)=S
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCN(C(=S)Cc1nnnn1C)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
2-(1-Methyl-1,2,3,4-tetrazol-5-yl)thio-acetic acid (45 mmole) is dissolved in tetrahydrofuran (50 ml) and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmole) under ice-cooling and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethyl-cyclohexylamine under ice-cooling, and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the resulting residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-ethyl-N-cyclohexyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-acetamide (yield: 52%) which is recrystallized from ether-petroleum ether, white prisms, m.p. 69°-71° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: OC1CCN(Cc2ccc(Br)cc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccc(Br)cc2)CC1)c1ccc(Cl)cc1
Yield: 81.5 %

Procedure:
0.27 g (0.001 mol) of 1-(4-bromo-benzyl)-piperidin-4-ol and 0.359 ml (0.0025 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.16 ml (0.00125 mol) of 4-chlorobenzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.333 g (81.5%) of 1-(4-bromo-benzyl)-piperidin-4-yl 4-chloro-benzoate was obtained as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:12]12[O:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][NH:14][CH2:13]2.[OH-].[Na+]>O>[C:1]1([CH2:7][C:8]([N:14]2[CH2:13][CH:12]3[O:19][CH:16]([CH2:17][CH2:18]3)[CH2:15]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CC2CNCC1O2
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Cc1ccccc1)N1CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phenylacetyl chloride (15.46 grams, 0.1 mole) (Aldrich Chemical Co., Inc., Milwaukee, Wisconsin) was slowly added to a mixture of 8-oxa-3-azabicyclo(3.2.1)octane hydrochloride (product of Example 3) (14.96 grams, 0.1 mole) and sodium hydroxide (10 grams) in 300 ml water at 10° C. After the addition of phenylacetyl chloride, the reaction mixture was stirred at room temperature for 2 hours. The crystalline solid (22.1 grams, 95.6%) which separated was filtered off, washed with water, and finally recrystallized from a blend of about 30% petroleum ether (boiling point 30°-60° C.) and 70% diethyl ether (v/v) to yield the product 3-phenylacetyl-8-oxa-3-azabicyclo(3.2.1)octane which had a melting point of 106°-106.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][NH:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:24]([O:26][CH3:27])=[O:25]>N1C=CC=CC=1.C(Cl)Cl>[CH3:27][O:26][C:24]([N:16]1[C:17]2[CH2:18][CH:19]3[N:11]([S:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)(=[O:9])=[O:10])[CH:12]([CH2:22][N:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20]3)[C:13]=2[CH:14]=[N:15]1)=[O:25]
Reactant: COC(=O)Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CNCC1c1cn[nH]c1C2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1CC2Cc3c(cnn3C(=O)OC)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
12-(4-Chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene (204 mg, 0.602 mmol) was dissolved in pyridine (1 mL) and cooled to 0° C. Methyl chloroformate (0.139 mL, 1.80 mmol) was added over 15 minutes and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (10 mL), washed with aqueous HCl (5 mL, 1 N) and aqueous NaHCO3 (5 mL), dried (Na2SO4), filtered and concentrated under vacuum to give 275 mg of 12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-5,10-dicarboxylic acid dimethyl ester as a brown oil. Retention time (min)=1.704, method [1], MS (ESI) 455.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2cccc(O)c2Cl)OC1(C)C
Agent: Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1cccc(B2OC(C)(C)C(C)(C)O2)c1Cl
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (830 g, 3.26 mol) in dry DMF (4.15 L) was added potassium carbonate (1126.4 g, 8.15 mol) under an inert atmosphere. Me2SO4 (402 mL, 4.24 mol) was added slowly to control the resulting exotherm (addition over 30 minutes gave a temperature rise from 28° C. to 55° C.) and after complete addition the reaction was stirred for 10 minutes. The reaction mixture was added to stirring HCl (5.98 L, 2 N, aq.) very slowly to control effervescence and the resulting precipitate stirred for 2 hours. The solids were filtered and washed with water (1 L) and dried in a vacuum oven over drying agent for 4 days to give 2-(2-chloro-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 7a as a white powder (746.7 g, 2.78 mol, 85%).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[CH2:13]([O:15][CH2:16][CH2:17][C:18](O)=O)[CH3:14].[OH-].[Na+]>>[CH2:13]([O:15][CH2:16][CH2:17][C:18]1[N:4]2[C:5]3[C:10]([CH:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH3:14]
Reactant: NNc1ccc2ccccc2n1
Reactant: CCOCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOCCc1nnc2ccc3ccccc3n12

Procedure:
2-Hydrazinoquinoline (50.0 grams; about 0.3 mole) and 3-ethoxypropionic acid (100 grams; about 0.85 mole) were mixed and refluxed for eight hours. The reaction mixture was then allowed to cool and made basic with 50 percent sodium hydroxide. A precipitate, the desired 1-(2-ethoxyethyl)-s-triazolo(4,3-a)quinoline, formed. It was separated by filtration and recrystallized from ethanol, m.p., 93°C. The identity of the product was confirmed by NMR and by microanalysis.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([OH:22])=[C:15]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH:16]=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:30])([F:29])[S:25](O)(=[O:27])=[O:26].N1C=CC=CC=1>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:15]([CH:16]=[O:17])[C:14]=1[O:22][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)c(O)c1OCCCOCc1ccccc1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1OCCCOCc1ccccc1

Procedure:
Synthesized according to the methods of general procedure 6 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-Benzyloxy-propoxy)-2-hydroxy-4-methyl-benzaldehyde (0.3 g, 1.0 mmol), trifluoromethanesulfonic acid (0.34 mL, 2.0 mmol), pyridine (0.25 mL, 3.1 mmol), dichloromethane (15 mL). Purification: flash column chromatography (10-15% EtOAc/hexane): yield 0.25 g (59%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.14 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.42-7.29 (m, 6H), 4.53 (s, 2H), 4.07 (t, J=6.4 Hz, 2H), 3.71 (t, J=6.1 Hz, 2H), 2.40 (s, 3H), 2.07-2.22 (m, 2H). 19F NMR (400 MHz, CDCl3) δ (ppm): −73.63 (s).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:8](=[O:21])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:10]=[CH:11][C:12]=2Cl)=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>>[N:24]([C:12]1[CH:11]=[N:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8](=[O:21])[C:7]=1[O:6][C:5]1[CH:22]=[CH:23][C:2]([Br:1])=[CH:3][CH:4]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1c(Oc2ccc(Br)cc2)c(Cl)cnn1-c1ccc(Cl)cc1
Agent: [Na+]
Product: [N-]=[N+]=Nc1cnn(-c2ccc(Cl)cc2)c(=O)c1Oc1ccc(Br)cc1

Procedure:
Obtainable by general method 13 from 7.55 g (18.3 mmol) of the compound from Example 10A with 5.96 g (91.6 mmol) of sodium azide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9](N)=[O:10]>>[C:2]1([NH:1][C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1
Reaction time: 0.75 h

Procedure:
After 45 minutes at 160° C., the solution contained 0.050 mole each of methyl N-phenyl carbamate and aniline, representing quantitative urea alcoholysis.
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([OH:4])[CH3:3].[H][H]>[C].[Pd].C(O)C>[CH3:3][C:2]([CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6]1)([OH:4])[CH3:1]
Reactant: CC(C)(O)c1cc2ccccc2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(O)C1Cc2ccccc2O1
Yield: 65.8 %

Procedure:
Into 200 ml of ethanol, was dissolved 10.3 g of 2-(1-methyl-1-hydroxyethyl)benzofuran. To the solution, was added 1.1 g of 10% palladium carbon. Hydrogen was introduced into the mixture with shaking at atmospheric pressure and at room temperature until no more hydrogen had been absorbed (it took 6 hours). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was distilled under reduced pressure to obtain 6.86 g of the intended product boiling at 78°-95° C./0.4 mmHg.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][C:5]([CH3:9])=[N:4]1)[CH3:2].[OH-].[Ca+2].[OH-].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O1CCOCC1.O>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[C:5]([CH3:9])=[N:4]1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCn1nc(C)cc1O
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCn1nc(C)c(C(=O)c2ccccc2)c1O
Temperature: 110 °C
Reaction time: 3.5 h

Procedure:
A suspension of 1.4 g of 2-ethyl-5-methyl-2H-pyrazol-3-ol, 1.6 g of calcium hydroxide and 1.3 ml of benzoyl chloride in 70 ml of 1,4-dioxane was stirred at 110° C. for 3.5 h. 1 ml of water was added and the mixture was stirred at 110° C. for 2 h. 25 ml of 2N hydrochloric acid was added. The mixture was stirred at room temperature for 16 h and extracted three times with 60 ml of ethyl acetate. The combined extracts were dried over magnesium sulphate, filtered and evaporated to give 3.1 g of (1-ethyl-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-phenyl-methanone as a yellow oil which was used without further purification. Mass spectrum (ES) m/z 231 [M+H]+, 272 [M+H+CH3CN]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]4[CH2:23][CH2:22]4)[C:13]3=[O:24])[N:8]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]2=[N:6][CH:7]=1.[C:30]([Zn]C#N)#[N:31].C(N(CC)CC)C>O1CCOCC1>[CH:21]1([N:14]2[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:12]([CH2:11][C:9]3[N:8]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]4=[N:6][CH:7]=[C:2]([C:30]#[N:31])[CH:3]=[C:4]4[N:10]=3)[C:13]2=[O:24])[CH2:23][CH2:22]1
Reactant: N#C[Zn]C#N
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(Br)cnc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(C#N)cnc21
Temperature: 25 °C

Procedure:
The mixture of compound 16 (0.5 g, 1 mmol), Dichloro(diphenylphosphinoferrocene)palladium (78.7 mg, 0.108 mmol), dicyanozinc (0.505 g, 4.3 mmol) and triethyl amine (0.6 mL, 4.3 mmol) in dioxane (10 mL) under nitrogen atmosphere was irradiated for 1 h in a microwave reactor at 125° C. The resulting mixture was allowed to cool down to room temperature then filtered over dicalite. The filtrate was evaporated to dryness. The ρεστδνε was purified by column chromatography using EtOAc/MeOH 8-2. The title compound 27 was isolated as a white solid (200 mg, 45%). m/z=402 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][CH:19]1[CH2:21][O:20]1>CC(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:18][CH:19]1[CH2:21][O:20]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OCC1CO1
Reaction time: 48 h
Yield: 20 %

Procedure:
To a stirred solution of 139 parts of 2-nitrophenol and 138 parts of potassium carbonate in 640 parts of 2-propanone are added dropwise 215 parts of 2-(chloromethyl)oxirane. Upon completion, stirring is continued for 2 days at reflux. The formed precipitate is filtered off and the filter-cake is washed with 2-propanone. The filtrate is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and petroleumether (1:1 by volume). The product is filtered off and dried, yielding 38 parts (20%) of 2-(2-nitrophenoxymethyl)oxirane; mp. 56° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.[CH2:29]([NH2:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>COCCO.C(O)(C)C>[S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=1)([OH:45])(=[O:44])=[O:43].[C:23]1(/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:35][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:6][CH:7]=2)=[C:12](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:13]([F:16])([F:15])[F:14])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Reactant: CCCCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Solvent: CC(C)O
Product: CCCCCCNCCOc1ccc(/C(=C(\c2ccccc2)C(F)(F)F)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
2.23 g (5 mmoles) of (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, prepared as described in Example 7, are dissolved in a mixture of 5.0 g (50 mmoles) of n-hexylamine and 10 ml of 2-methoxyethanol. The mixture is boiled for 30 minutes, then evaporated, and the residue is passed through a chromatographic column filled with 50 g of silica gel. The column is eluted with benzene. The fractions which are chromatographically uniform are combined and evaporated, the residue is dissolved in 5 ml of isopropanol, and a solution of 1.20 g (6 mmoles) of p-toluenesulfonic acid in 6 ml of isopropanol is added. The separated crystals are filtered off and washed with ether. 2.14 g (91.8%) of the aimed compound are obtained; m.p.: 151°-153° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[CH:4]=[N:3][C:2]([N:38]6[CH2:43][CH2:42][O:41][CH2:40][CH2:39]6)=[CH:7][N:6]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: C1COCCN1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CCOCC5)cn3)C4)n[nH]c2c1
Yield: 48 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (100 mg, 154 μmol) and morpholine, (34 mg, 386 μmol) using the method of Example 32. The crude material was purified by HPLC Method F to afford (42 mg, 38%) of the title compound as off-white solid.