Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([SiH2][O:7][C:8](C)(C)[CH:9]1[CH2:23][C:12]2=[C:13]3[C:18](=[N:19][CH:20]=[C:11]2[O:10]1)[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[N:14]3)(C)(C)C>CO>[CH3:22][O:21][C:15]1[CH:16]=[CH:17][C:18]2[C:13]([N:14]=1)=[C:12]1[CH2:23][CH:9]([CH2:8][OH:7])[O:10][C:11]1=[CH:20][N:19]=2
Reactant: COc1ccc2ncc3c(c2n1)CC(C(C)(C)O[SiH2]C(C)(C)C)O3
Agent: Cl
Solvent: CO
Product: COc1ccc2ncc3c(c2n1)CC(CO)O3
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
A 2.0 N hydrochloric acid aqueous solution (5 mL) is added at room temperature to a stirred solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalene (600 mg, 1.7 mmol, 1.0 eq) in methanol (20 mL). After 2 hours stirring at room temperature, solvent is removed, the residue is extracted with dichloromethane (3×30 mL) and water (30 mL) and the pH is adjusted to 8 by the addition of a saturated sodium carbonate aqueous solution. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to afford (8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalene-2-yl)-methanol as an off-white solid (400 mg, 99% yield).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.[C:23]([C:27]1[CH:31]=[C:30]([NH2:32])[O:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24].CC([O-])(C)C.[K+]>O1CCOCC1>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[C:12]([CH:15]=3)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=2)[O:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: N#Cc1cc(-c2ccnc(F)c2)ccc1OC1CCOCC1
Reactant: CC(C)(C)c1cc(N)on1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(Nc2cc(-c3ccc(OC4CCOCC4)c(C#N)c3)ccn2)on1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 46 %

Procedure:
100 mg of 5-(2-fluoropyridin-4-yl)-2-(tetrahydropyran-4-yloxy)benzonitrile are suspended in 6 ml of dioxane in a 50 ml three-necked flask under N2, 52 mg of 3-tert-butylisoxazol-5-ylamine and 79 mg of KOtBu are added. The yellow solution is stirred at 80° C. for 2.5 h. For work-up, the reaction mixture is evaporated in a rotary evaporator, the residue is taken up in ethyl acetate and water and extracted. The collected organic phases are dried, filtered and evaporated. The crude product is purified by preparative HPLC, giving the desired product in 46% yield; HPLC-MS Rt. [min] 2.556; HPLC-MS [M+H] 419;
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[O-2].[Ca+2]>COCCOCCOC>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:22]([CH:19]3[CH2:21][CH2:20]3)[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[NH:10][C:11]=12
Reactant: NC1CC1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Agent: [Ca+2]
Agent: [O-2]
Solvent: COCCOCCOC
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The process according to claim 4, wherein 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide is heated with cyclopropylamine in the presence of 1 to 2 mol of calcium oxide in diglyme to 135° to 145° C. for 6 to 7 hours, the reaction mixture is then cooled down to 20° to 30° C. and filtered, the filter cake is washed with diglyme and the combined filtrates are concentrated, the residue is then diluted with diglyme and this solution is added to a solution or suspension of sodium hydride in diglyme, heated to 130° to 140° C., and the reaction mixture is kept at a temperature of 130° to 140° C. for 30 minutes to one hour and then the reaction medium is distilled off, the residue is hydrolysed at a temperature of 50° to 80° C. and then cooled to a temperature of about 25° C. and mixed with an inert solvent and an organic acid and the reaction mixture is stirred for about 1 hour at 10° to 25° C., the resultant suspension of the product is separated, washed with an inert solvent, followed by water and alcohol to give nevirapine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([O:18]C)[N:15]=[C:14]3[S:20][C:21]([CH3:31])=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)=[C:21]([CH3:31])[S:20][C:14]=3[NH:15][C:16](=[O:18])[CH:17]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(-c2c(C)sc3nc(OC)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl
Solvent: CO
Product: COc1cccc(-c2c(C)sc3[nH]c(=O)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A solution of 3-chloro-N-{2-methyl-6-(methyloxy)-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}benzenesulfonamide (Example 115) (98 mg, 0.206 mmol) in 37% HCl (2 mL, 24.35 mmol) was heated to 100° C. under nitrogen atmosphere overnight. The reaction mixture was cooled to RT, diluted with MeOH and concentrated in vacuo. The residue was purified by MDAP (acidic conditions), to afford the title compound (58 mg). LCMS (A) m/z: 461 [M+1]+, Rt 1.27 min (acidic).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(OCC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].[OH-].[Na+]>O.C(OCC)(=O)C>[C:16]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=CC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 13.8 g. (0.10 mol) of m-nitroaniline in 100 ml. of diethyl ether and 30 ml. of ethyl acetate was added 9.0 g. (0.10 mol) of acryloyl chloride and a solution of 4.0 g. (0.10 mol) of sodium hydroxide in 20 ml. of water. The mixture was stirred overnight (18 hours) at ambient temperature and the precipitate filtered to give N-propenoyl-3-nitroaniline.
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]([NH2:13])=[O:12].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/B(O)O)=[CH:18][CH:17]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:7]([N:6]1[C:2](/[CH:23]=[CH:22]/[C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[C:3]([C:11]([NH2:13])=[O:12])[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1ncc(C(N)=O)c1Br
Reactant: COc1ccc(/C=C/B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(/C=C/c2c(C(N)=O)cnn2C(C)(C)C)cc1
Yield: 16.3 %

Procedure:
A solution of 5-bromo-1-tert-butyl-1H-pyrazole-4-carboxamide (100 mg, 0.41 mmol), trans-2-(4-methoxyphenyl)vinylboronic acid (108 mg, 0.61 mmol), S-phos (3.34 mg, 8.13 μmol), palladium(II) acetate (0.912 mg, 4.06 μmol) and tripotassium phosphate (173 mg, 0.81 mmol) in THF (2 mL) was stirred under an argon atmosphere at 40° C. for 14 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 3→100% ethyl acetate/hexane) to give (E)-1-tert-butyl-5-(4-methoxystyryl)-1H-pyrazole-4-carboxamide (20 mg, 0.067 mmol, 16.4%) as a white powder.
Reaction SMILES: [CH:1]1[C:6]([O:7][C@@H:8]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]([OH:17])[C@H:9]2[OH:18])=[C:5]([OH:19])[CH:4]=[C:3]2[O:20][C:21]([CH:23]=[CH:24][C:2]=12)=[O:22].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[I-].[K+]>CN(C)C=O>[CH2:25]([O:19][C:5]1[CH:4]=[C:3]2[C:2]([CH:24]=[CH:23][C:21](=[O:22])[O:20]2)=[CH:1][C:6]=1[O:7][CH:8]1[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]([OH:17])[C@H:9]1[OH:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: O=c1ccc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(O)cc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OC3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(OCc3ccccc3)cc2o1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
Esculin (1.0 g), benzyl chloride (1.0 g), potassium carbonate (0.7 g), catalytic amounts of 18-crown-6-ether and potassium iodide, and dimethylformamide (40 ml) were placed in an eggplant-shaped flask (100 ml). The mixture was reacted while stirred at 60° C. for 8 hours. The reaction mixture was concentrated under reduced pressure and the residue was poured into ice water. The precipitated crystals were filtered out and recrystallized from methanol to obtain 7-benzyloxy-6-D-glucopyranosyloxycoumarin (VIII-2) (melting point=184° to 186° C., mass spectrum (M+)=430, yield=86.4%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH:25](O)[CH2:26][C:27]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)=[O:28])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)C([O-])=O.Cl.C(=O)([O-])O.[Na+]>C(O)C>[N:5]1[C:4]2[CH2:8][CH2:9][CH2:10][C:3]=2[C:2]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([C:27](=[O:28])/[CH:26]=[CH:25]/[CH2:24][CH:21]3[CH2:22][CH2:23][N:18]([CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:19][CH2:20]3)=[CH:30][CH:31]=2)=[N:7][CH:6]=1
Reactant: Nc1ccc(C(=O)CC(O)CC2CCN(Cc3ccccc3)CC2)cc1
Reactant: Clc1ncnc2c1CCC2
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Solvent: CCO
Product: O=C(/C=C/CC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3)cc1
Temperature: 60 °C
Yield: 34 %

Procedure:
30 ml of ethanol and 0.58 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine were added to 1.21 g of 4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline·trifluoroacetate, 1 ml of an ethanol solution of hydrochloric acid (containing 0.29 g of hydrochloric acid) was added thereto and the mixture was stirred under heating at 60° C. for 40 minutes. Then, a saturated sodium hydrogen carbonate aqueous solution was added thereto and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 0.40 g of the title compound as yellow powder.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:12]=2[S:13][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>ClC(Cl)(Cl)Cl>[Br:1][CH2:24][C:21]1[CH:22]=[CH:23][C:11]2[C:10]([Cl:9])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:13][C:12]=2[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc2cc(C)ccc2c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc2cc(CBr)ccc2c1Cl
Yield: 102.3 %

Procedure:
Catalytic azobisisobutylnitrile (AIBN, 0.28 g) and N-bromosuccinimide (4.8 g, 26.8 mmol) were added to a solution of ethyl 3-chloro-6-methylbenzo[b]thiophene-2-carboxylate (Preparation 9, 6.5 g, 25.5 mmol) in tetrachloromethane (50 ml), under a nitrogen atmosphere. The mixture was heated to reflux for 5 hours, cooled, and then loaded onto a silica gel column. The product was eluted with a gradient mixture of dichloromethane and hexane (initially 30:70 increasing to 50:50, and then 70:30). The solvent was removed under reduced pressure to leave the title compound as a colourless solid (8.7 g)
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].N([O-])=O.[Na+].[Na+].[I-:22].CCO>O.Cl>[I:22][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)c1ccc2ccc(I)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of sodium 7-aminonaphthalene-2-sulfonate (Pfaltz and Bauer, 1.00 g, 4.06 mmol) in water (6.0 mL) and conc. HCl (2.0 mL) was cooled to 0° C. A premixed solution of NaNO2 (280 mg, 4.06 mmol) in water (2.0 mL) was added slowly, maintaining the temperature close to 0° C. The reaction mixture was stirred at 0° C. for 1 h. A solution of NaI (609 mg g, 4.06 mmol) in water (3.0 mL) and conc. HCl (1.0 mL) was then added dropwise over 30 min, maintaining a temperature close to 0° C. The reaction mixture was stirred at room temperature for 2 h and then heated to 90° C. for 1 h. The reaction mixture was cooled to room temperature, treated with EtOH (10.0 mL) and concentrated in vacuo. EtOH (10 mL) was added and the mixture was filtered to give the title compound (1.07 g, 79%) as a tan solid. 1H NMR (DMSO-d6) δ 8.45 (s, 1H), 8.09 (s, 1H), 8.76 (d, J=8.6 Hz, 1H), 7.80-7.68 (m, 3H); MS(ESI−) m/z 333.2 (M−H)−.
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl>C1COCC1.CO.O>[C:4]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)[CH2:13]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 93.7 %

Procedure:
LiOH.H2O (1.14 g, 27.26 mmol) and water (5 mL) was added to a solution of 324 (4.36 g, 13.62 mmol) in THF (15 mL) and MeOH (15 mL). The reaction mixture was stirred at room temperature for 22 h, diluted with water and acidified with HCl (pH 4-5). The precipitate obtained was collected by filtration and rinsed with water to give the title compound 325 (3.91 g, 94% yield) as a white solid.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1.[NH3:24]>>[NH2:24][C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1
Reactant: N
Reactant: CCCOc1ccccc1-c1nc2nnc(SC)nc2c(=O)[nH]1
Product: CCCOc1ccccc1-c1nc2nnc(N)nc2c(=O)[nH]1

Procedure:
5,6-Dihydro-3-methylthio-5-oxo-7-(2-propoxyphenyl)pyrimido[5,4-e][1,2,4]triazine (0.7 g) was heated for 30 hours with ethanolic ammonia (50 ml) at 100° C. in a pressure vessel. The cooled mixture was filtered to give the crude product (0.21 g) which was recrystallized from ethanol to give the pure title compound, m.p. 322-325° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:40][O:41][C:42]1[CH:47]=[C:46]([NH2:48])[CH:45]=[CH:44][N:43]=1.CCN(CC)CC>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4]([NH:48][C:46]1[CH:45]=[CH:44][N:43]=[C:42]([O:41][CH3:40])[CH:47]=1)=[O:6]
Reactant: COc1cc(N)ccn1
Reactant: O=C(O)c1cc(OC(F)(F)F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2cc(OC(F)(F)F)ccc2F)ccn1
Yield: 64.9 %

Procedure:
A solution of 2-fluoro-5-(trifluoromethoxy)benzoic acid (5.3 g, 23.47 mmol), HATU (8.92 g, 23.47 mmol), 2-methoxypyridin-4-amine (2.9 g, 23.47 mmol) and Et3N (13.09 mL, 93.88 mmol) in dichloromethane (47.4 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-50%) to yield 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethoxy)benzamide (5.03 g, 65%) as a white solid. ESI-MS m/z calc. 330.06. found 331.1 (M+1)+; Retention time: 1.48 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.10 (m, 1H), 7.73 (dd, J=5.1, 3.2 Hz, 1H), 7.66 (m, 1H), 7.55 (t, J=9.2 Hz, 1H), 7.21 (dd, J=3.7, 1.8 Hz, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:6]=2[N:7]=1.B(O)(O)[C:25]1[CH:33]=[N:32][C:28]2[NH:29][CH:30]=[CH:31][C:27]=2[CH:26]=1>>[CH3:17][N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:11][C:9]1[S:8][C:6]2[N:7]=[C:2]([C:25]3[CH:26]=[C:27]4[CH:31]=[CH:30][NH:29][C:28]4=[N:32][CH:33]=3)[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5]=2[CH:10]=1
Reactant: CN(Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1)S(C)(=O)=O
Reactant: OB(O)c1cnc2[nH]ccc2c1
Product: CN(Cc1cc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc2s1)S(C)(=O)=O
Yield: 6 %

Procedure:
(2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl-n-methyl-N-(methylsulfonyl)methaneamine and 1H-pyrrolo[2,3-b]pyridin-5-yl-5-boronic acid were reacted following General Procedure A to produce 417 in 6.0% yield MS (Q1) 459.2 (M)+
Reaction SMILES: C(OC(=O)[N:7]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)=[O:19])=[CH:13][CH:12]=1)(C)(C)C.[ClH:30].COC1CCCC1>C1COCC1>[ClH:30].[CH:26]1([CH2:25][NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(NC(=O)c2cn[nH]c2)cc1
Agent: Cl
Solvent: COC1CCCC1
Solvent: C1CCOC1
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCC2CC2)cc1)c1cn[nH]c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl(cyclopropylmethyl)(trans-2-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate (72 mg) was dissolved in THF (0.5 mL), and the mixture was ice-cooled to 0° C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (4.5 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (45 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C(N)[CH2:17][NH2:18]>CN(C)C=O.O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:17]#[N:18])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: NCCN
Reactant: Nc1c([N+](=O)[O-])ccc2c(Br)cccc12
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc2c(N)c([N+](=O)[O-])ccc12
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 1,6 g (5,9 mmol) 1-amino-5-bromo-2-nitronaphthalene in 50 ml dimethylformamide was added 1,1 g (11,8 mmol) cuprous cyanide. The reaction mixture was refluxed for 5 h, and then poured into a solution of 2,5 ml ethylenediamine in 80 ml water. Stirring was continued for 15 min., and then the precipitate was filtered off and washed with water and boiling ethyl acetate to give 1,0 g (80%) 1-amino-5-cyano-2-nitronaphthalene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:34][C:33]5[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=5[F:31])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: Fc1ccc(C[Zn+])c(F)c1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(F)cc3F)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,4-difluoro-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 3): tR=0.98 min; Mass spectrum (ESI+): m/z=541 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1)=O>C(O)(=O)C>[CH3:19][C:15]1[N:14]=[C:13]([C:11]2[N:3]3[N:4]=[CH:5][CH:6]=[C:2]3[N:1]=[CH:9][CH:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cc[nH]n1
Reactant: Cc1cccc(C(=O)C=CN(C)C)n1
Solvent: CC(=O)O
Product: Cc1cccc(-c2ccnc3ccnn23)n1

Procedure:
A mixture of 0.84 g. of 3-aminopyrazole and 1.90 g. of 3-dimethylamino-1-(6-methyl-2-pyridyl)-2-propen-1-one and 25. ml. of glacial acetic acid is heated on a steam bath for 4 hours. The solvent was removed under reduced pressure. The residue is dissolved in dichloromethane and the solution passed through a short column of hydrous magnesium silicate. The element is concentrated and diluted with hexane to give 1.15 g. of crystals, m.p. 126°-127° C.
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.[Br:22][C:23]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[Br:22][C:23]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:24]=1[CH2:25][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: FC(F)(F)c1ccc(CBr)c(Br)c1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccc(C(F)(F)F)cc1Br
Yield: 78 %

Procedure:
Compound 55.2 was prepared as described for example 6.2, by reacting compound 1.1 with 2-bromo-4-trifluoromethylbenzyl bromide. 4-[3-(2-Bromo-4-trifluoromethylbenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained in a yield of 78%. 1H NMR: 8.36, d, 1H, 8.25, s, 1H, 8.1, d, 1H, 8.05, s, 1H; 7.85, d, 1H, 7.73, d, 1H, 4.7, s, 2H, 1.48, s, 6H.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:17])[C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:6][CH:7]=1.[CH2:18]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:17][C:4]1[C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:6][CH:7]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:28][CH:29]=2)[CH:3]=1
Reactant: CCCCCCCCOc1ncc(Br)cc1Cl
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2cnc(OCCCCCCCC)c(Cl)c2)cc1
Yield: 64.8 %

Procedure:
3.16 g (9.86 mmol) of 5-bromo-3-chloro-2-octyloxypyridine, 2.47 g (9.86 mmol) of 4-octyloxybenzeneboronic acid, 0.11 g (0.10 mmol) of tetrakis(triphenylphosphine)-palladium(0) and 2.09 g (19.72 mmol) of sodium carbonate are heated at 80° C. for 3 hours in 90 ml of toluene, 60 ml of ethanol and 30 ml of water. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate and evaporated, and the product is purified by chromatography (silica gel/hexane:ethyl acetate 9:1), giving 2.85 g of 3-chloro-2-octyloxy-5-(4-octyloxyphenyl)pyridine. ##STR22##