Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([C:14]2[CH:27]=[CH:26][C:17]3[O:18][C:19]([CH3:25])([CH3:24])[C@@:20]4([CH3:23])[O:22][C@H:21]4[C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:28][N:29]1[C:34](=[O:35])[CH:33]=[CH:32][C:31]([OH:36])=[N:30]1.N1C=CC=CC=1>O1CCOCC1>[CH3:28][N:29]1[C:34](=[O:35])[CH:33]=[CH:32][C:31]([O:36][C@H:21]2[C@@:20]([OH:22])([CH3:23])[C:19]([CH3:25])([CH3:24])[O:18][C:17]3[CH:26]=[CH:27][C:14]([S:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)(=[O:13])=[O:12])=[CH:15][C:16]2=3)=[N:30]1
Reactant: Cn1nc(O)ccc1=O
Reactant: COc1ccc(S(=O)(=O)c2ccc3c(c2)[C@@H]2O[C@]2(C)C(C)(C)O3)cc1OC
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)c2ccc3c(c2)[C@@H](Oc2ccc(=O)n(C)n2)[C@](C)(O)C(C)(C)O3)cc1OC
Yield: 42.8 %

Procedure:
(3S,4S)-3,4-Dihydro-6-(3,4-dimethoxyphenyl)sulphonyl-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (3.0 g) (see Preparation 25) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (2.0 g) (see J.Org.Chem, 1971, 36, 3372) were suspended in dry 1,4-dioxane (30 ml), pyridine (0.61 g) was added and the mixture heated under reflux (a calcium chloride drying tube was attached to the flask) for 2 days. The solvent was removed under reduced pressure, the residue stirred with 5% methanol/dichloromethane and filtered. The filtrate was evaporated and the crude product chromatographed on silica eluting with 2.5:97.5 methanol: dichloromethane as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxo-pyridazin-6-yl)oxy-6-(3,4-dimethoxyphenyl)sulphonyl-3-hydroxy-2,2,3-trimethyl-2H-benzo[b]pyran (1.7 g) as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[H][H]>[Ni].C(O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2sc3ccc(F)cc3c2c1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2sc3ccc(F)cc3c2c1

Procedure:
A mixture of 14.33 g. (0.0605 mole) of 2-fluoro-8-nitrodibenzothiophene in 550 ml. of ethanol and about one-half teaspoonful (about 2.5 ml.) of Raney nickel is hydrogenated at about 30 psi of hydrogen gas in a Paar apparatus for about 48 hours. The mixture is filtered, and the filtrate is evaporated to dryness under vacuum to provide white needles of 2-amino-8-fluorodibenzothiophene, m.p. 131°-132° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2[nH]ncc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of methyl 1H-indazole-5-carboxylate (10 g, 56.82 mmol) in methanol (80 ml) was added a solution of sodium hydroxide (9.09 g, 227.28 mmol) in water (30 ml) with stirring overnight at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum, then quenched by the addition of water (30 ml), and the pH adjusted to 6 with HCl (3N). The solids were collected by filtration to afford 1H-indazole-5-carboxylic acid as a yellow solid (8.6 g, 93%). LC/MS (ES, m/z): [M+H]+ 163.0
Reaction SMILES: C(O[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[C:21]([CH2:29][CH3:30])=[N:22][O:23][C:24]=3[C:25]=2[CH2:26][CH2:27][CH3:28])=[C:8](C)[C:7]=1[CH3:32])(=O)CC.[Li+].[OH-:34]>CO>[CH3:32][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[C:21]([CH2:29][CH3:30])=[N:22][O:23][C:24]=3[C:25]=2[CH2:26][CH2:27][CH3:28])[CH:10]=[CH:11][C:6]=1[CH:8]([CH3:7])[C:9]([OH:12])=[O:34]
Reactant: [OH-]
Reactant: CCCc1c(OCCCOc2ccc(OC(=O)CC)c(C)c2C)ccc2c(CC)noc12
Agent: [Li+]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(C)C(=O)O)c(C)c2)ccc2c(CC)noc12
Temperature: 50 °C

Procedure:
A solution of methyl-2-methyl-4-(3-(3-(Ethyl)-7-(propyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)-phenyl propionate (11.5 mg, Step A) was dissolved in MeOH (0.5 mL)and 1M LiOH (0.10 mL) was added. The resulting solution was warmed to 50° C. for 2 hours, cooled and concentrated. The residue was partitioned between ethyl acetate and 1 M Hcl. The organic fraction was removed, dried and concentrated to give the title compound as a colorless oil (10.7 mg) NMR (CDCl3); δ 7.40 (d,2H), 7.11 (d,2H), 6.95 (d,2H), 6.85 (d,2H), 1.43 (t,3H), 1.18 (d,2H), 0.95 (t,3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[OH-].[NH4+:13]>O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:13]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [OH-]
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A stirred solution of 3,4-difluoronitrobenzene (2.00 g, 12.57 mmol) in ammonium hydroxide (20 ml, 28% in water) was heated at 150° C. in a sealed flask for 3.5 hrs. The mixture was cooled to room temperature, and the resulting suspension was diluted in water, shaken for 15 min, the solid was isolated by filtration, rinsed with water, air-dried, and dried under high vacuum to afford title compound 337 (1.76 g, 90% yield) as a yellow crystalline solid. MS (m/z): 157.0 (M+H)+. and 179.0 (M+Na)+..
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:15][O:16][CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15][O:16][CH3:17])=[CH:19][CH:20]=1
Reactant: COCC(c1ccc(F)cc1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC(c1ccc(F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a solution of 4-(tert-butyloxycarbonyl)-1-[1-(4-fluorophenyl)-2-methoxyethyl]piperazine (1.46 g, 4.3 mmol) in CH2Cl2 (40 mL) was added trifluoroacetic acid (4 mL), and the mixture stirred at room temperature for 3 h. The solvent was evaporated and the residue azeotroped with toluene (2×20 mL). The residue was partitioned between EtOAc (2×50 mL) and Na2CO3 solution (sat., 50 mL). The combined organic phases were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH:NH3 (90:10:1), to afford the piperazine (0.95 g, 92%) as a pale yellow oil. 1H NMR (360 MHz, CDCl3) δ2.37-2.55 (4H, m), 2.86-2.89 (4H, m), 3.29 (3H, s), 3.45-3.48 (1H, m), 3.61 (1H, dd, J=9.9 and 5.2 Hz), 3.71 (1H, dd, J=9.9 and 5.8 Hz), 7.00 (2H, dd, JHA-HB =8.7 Hz and JHA-F =8.7 Hz), 7.27 (2H, dd, JHB-HA =8.7 Hz and JHB-F =5.6 Hz). MS (ES+) (239, M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH3:15]>CO>[N+:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH2:15])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Reactant: N
Solvent: CO
Product: Nc1ncnc2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.6 g of 4-chloro-7-nitroquinazoline in 50 ml 7N ammonia in methanol was stirred overnight at rt and concentrated to dryness. The solid was suspended in water, filtered, rinsed with water followed by ether and dried overnight in vacuum oven to provide 0.98 g of 7-nitroquinazolin-4-amine (compound 98-2).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH3:12])=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>>[Br:13][CH2:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2ccc(Cl)cc12
Product: Clc1ccc2cccc(CBr)c2c1

Procedure:
Using general procedure A (Exp. 1.3.), 7-chloro-1-methyl-naphthalene was reacted with N-bromosuccinimide to give 1-bromomethyl-7-chloro-naphthalene as a white solid. MS: 253.9 ([M]+).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])(C)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH2:9][NH2:8]
Reactant: COc1ccccc1OCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccccc1OCCN

Procedure:
Under an atmosphere of Nitrogen, 3N HCl (3 ml) was added to a solution of [2-(2-methoxy-phenoxy)-ethyl]-carbamic acid tert-butyl ester (320 mg, 1.20 mmol) in dioxane (3 ml). The mixture was heated to reflux (2 h). Upon cooling, the reaction mixture was taken up in ethyl acetate, and extracted several times with H2O. The combined H2O extracts were then made alkaline by addition of NaOH 2N, and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4), and the solvent was evaporated. The obtained product (180 mg, 90%) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH2:10][C@@H:9]2[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.C(O)C>O=[Pt]=O.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:11][CH2:10][C@@H:9]2[C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc([C@H]2CC[C@H](c3ccc([N+](=O)[O-])cc3)N2c2ccc(F)cc2)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc([C@H]2CC[C@H](c3ccc(N)cc3)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.9 %

Procedure:
To a solution of the product from Example 38B (2.34 g, 5.74 mmol) in 1:1 ethanol:THF (60 ml) in a 250 mL stainless steel pressure bottle was added PtO2 (0.47 g, 2.06 mmol) and the resulting mixture was placed under H2 pressure (30 psi) and stirred at rt. for 90 min. The mixture was filtered through a nylon membrane and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-65% ethyl acetate in hexanes to give the title compound as a solid (0.736 g, 37%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH2:7])[CH2:2]1.[OH-].[Na+].[CH3:10][NH:11][C:12](=[N:15][N+:16]([O-:18])=[O:17])OC.Cl>C(#N)C.O>[CH3:10][NH:11][C:12]([NH:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[N:15][N+:16]([O-:18])=[O:17]
Reactant: NCC1CCOC1
Reactant: CNC(=N[N+](=O)[O-])OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCC1CCOC1
Reaction time: 4 h

Procedure:
[(3-tetrahydrofuryl)methyl]amine (38.0 g, 0.38 mole) and 56.99 g of water were mixed, and the resulting mixture was cooled to 5 degree centigrade. Furthermore, 3.05 g (0.07 mole) of 1N NaOH was added to the solution, and then N,O-dimethyl-N′-nitroisourea (49.2 g, 0.37 mole) was introduced to the solution. The suspension was stirred at 5 degree centigrade for 4 hours, and then heated to 10 degree centigrade, and further stirred for 10 hours. 35% hydrochloric acid (6.7 g, 0.07 mole) was added to the suspension so that the pH became not more than 4. Water and acetonitrile were added to the above suspension for complete dissolution. The resulting solution was analyzed by HPLC and as a result, the reaction yield of the titled compound was 86%.
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14](Cl)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C[C@H](NC(=O)c1ccc(Br)c(Cl)n1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)c1ccc(Br)c(Oc2ccc(F)cc2)n1)C(N)=O
Temperature: 120 °C
Yield: 37.9 %

Procedure:
5-Bromo-6-chloro-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide (50 mg, 143 μmol) was dissolved in DMF (0.5 mL) to give a colorless solution. 4-Fluorophenol (19.3 mg, 172 μmol) and sodium carbonate (45.6 mg, 430 μmol) were added successively to give a yellow solution. The reaction mixture was stirred at 120° C. over the weekend, cooled to ambient temperature and poured into 40 mL water. The mixture was extracted with isopropyl acetate (2×40 mL), organic phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 2.0 mm, isopropyl acetate) to give the title compound (23 mg, 38%) as colorless oil, MS (ESI): m/e=421.9 [M−H]−.
Reaction SMILES: [Cl-].[Li+].[CH2:3]([Sn](CCCC)(CCCC)C=C)[CH2:4]CC.O1CCCC1.FC(F)(F)S(O[C:29]1[CH2:30][C@H:31]2[C@@H:38]([CH:39]=1)[C:33]1([O:37][CH2:36][CH2:35][O:34]1)[CH2:32]2)(=O)=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.O>[CH:3]([C:29]1[CH2:30][C@H:31]2[C@@H:38]([CH:39]=1)[C:33]1([O:37][CH2:36][CH2:35][O:34]1)[CH2:32]2)=[CH2:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(OC1=C[C@@H]2[C@H](C1)CC21OCCO1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC1=C[C@@H]2[C@H](C1)CC21OCCO1

Procedure:
Lithium chloride (1.97 g, 46.4 mmol), tetrakis(triphenylphosphine)palladium (0) (0.36 g, 0.31 mmol), and tributyl(vinyl)tin (2.47 mL, 8.50 mmol) were added to a tetrahydrofuran solution (60 mL) of (±)-(1R,5S)-spiro[bicyclo[3.2.0]hept-3-ene-6,2′-[1,3]dioxolan]-3-yl trifluoromethanesulfonate (2.32 g, 7.73 mmol). The mixture was heated to reflux for 2 hours, and water was then added to the reaction solution, followed by extraction with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (990 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11](Br)=[N:10][N:9]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1.[CH3:28][NH:29][CH3:30].CO>CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([N:29]([CH3:30])[CH3:28])=[N:10][N:9]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(=O)Nc1cccc(-n2nc(Br)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)Nc1cccc(-n2nc(N(C)C)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 150 °C
Yield: 11 %

Procedure:
According to Scheme 2 Step 4: To a solution of 2(C) (100 mg, 0.22 mmol) in 0.5 mL of DMF was added dimethylamine 2M solution in methanol (0.56 mL, 1.11 mmol). The reaction was heated 5 h at 150° C. under microwave irradiation. The reaction mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were washed successively with water, with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 5 g column (Eluant: DCM/MeOH 98/2). 10 mg, (11% yield) of N-(3-(4-(4-chlorobenzyl)-6-(dimethylamino)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 2(D) were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([C:27](=[O:28])[NH:26][CH2:24][CH3:25])=[CH:30][CH:31]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: CCNC(=O)c1ccc(B(O)O)cc1
Product: CCNC(=O)c1ccc(-c2cc3cc(C4CCN(C(=O)OC(C)(C)C)CC4)oc3cn2)cc1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-ethylcarbamoyl-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. LC (method 4): tR=1.68 min; Mass spectrum (ESI+): m/z=450 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.BrC1C=CC=CC=1CBr.[Br:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[CH2:39]Br>>[Br:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[CH2:39][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: Clc1ccc(CBr)c(Br)c1
Agent: BrCc1ccccc1Br
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccc(Cl)cc1Br

Procedure:
Compound 109.2 was prepared as described for example 1.2, by reacting compound 1.1, instead of 2-bromobenzyl bromide, with 2-bromo-1-bromomethyl-4-chlorobenzene (prepared by N-bromosuccinimide bromination from 2-bromo-4-chloro-1-methylbenzene; 1H NMR: 7.82, d, 1H; 7.65, s, 1H, 7.5, d, 1H, 4.72, s, 2H). 4-[3-(2-Bromo-4-chlorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained. (Molecular weight 498.99 (C20H14BrClF3N3O2); retention time Rt=2.30 min. [B]; MS (ESI): 541.04 (MH++CH3CN).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:24][PH:25]([O-])([O-:29])[O:26][CH2:27][CH3:28].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C@H:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:5]1[CH:6]=[CH:7][C:2]([P:25]([CH3:24])(=[O:29])[O:26][CH2:27][CH3:28])=[CH:3][CH:4]=1
Reactant: CCO[PH](C)([O-])[O-]
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1ccc([C@@H](N[S@](=O)C(C)(C)C)c2ccc(F)cc2F)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
To (R)—N—((R)-(4-bromophenyl)(2,4-difluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 20-c, (1 g, 2.5 mmol), ethyl methylphosphite (0.54 g, 5 mmol) and Et3N (0.63 g, 6.25 mmol) in THF (10 ml) was added PdCl2(dppf) (183 mg). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into ethyl acetate and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel to give compound, 20-d, (dichloromethane:methanol=50/1) to provide the product (866 mg, 81%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH:19]C(=O)OC(C)(C)C)[CH3:18])=[C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[ClH:27]>O1CCOCC1>[ClH:27].[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1C1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccn(C)c2cc1C1CCOCC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl (1-(1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (515 mg, 1.361 mmol) in dioxane (5 mL) was added 4.0 M HCl in 1,4-dioxane (3.40 mL, 13.6 mmol) at 23° C. The mixture was stirred for 30 minutes at 23° C. Additional 4.0 M HCl (3.40 mL, 13.6 mmol) was added at 23° C. and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated via rotary evaporation, re-suspended in Et2O (5 mL), filtered, and rinsed with Et2O. The resulting solid was dried in vacuo to give an HCl salt of the title compound as a yellow solid (403 mg, 100%). ESI-MS m/z [M+H]+ calc'd for C15H21N3O, 260; found 260.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[O:36][CH:37](C)C)[CH2:25][CH2:24]2)[CH2:4][CH2:3][CH2:2]1.ClC1N=CN=C(N)C=1OC>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:20])[F:21])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[O:36][CH3:37])[CH2:25][CH2:24]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)Oc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Agent: COc1c(N)ncnc1Cl
Product: COc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine using 6-chloro-5-methoxypyrimidin-4-amine
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:23]O.C([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:23])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Stir 5 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde together with 1.29 of hydroxylamine hydrochloride and 1.52 g of anhydrous sodium acetate in 15 ml of dimethylformamide for 1.5 hours at room temperature. Then add 2.85 g of phosphorus oxychloride dropwise to the resulting reaction mixture, the temperature of which rises to 40° C. Stir for 1 hour and then confirm that the reaction is complete by a thin layer chromatograph. Allow the solution to stand overnight and then pour onto 90 ml of ice water. Stir for 30 minutes at room temperature and then for 30 minutes at 40° C. Draw off the formed precipitate by vacuum filtration, wash the precipitate well with water and dry to obtain a 98% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carbonitrile [m.p. 190° to 192° C].