Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:30][CH2:29]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(CCCC2CC(c3cccc([N+](=O)[O-])c3)=NO2)CC1
Yield: 84.5 %

Procedure:
3-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl] propanal (23.8 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.5 mg, 0.262 mmol) and diisopropylethylamine. (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 31.2 mg (78.6%) of the target compound was obtained.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH3:19])[C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.C1N2CN3CN(C2)C[N:21]1C3.[Br-].[NH4+].C(O)(C)C>O>[Cl:18][C:15]1[CH:16]=[CH:17][C:4]2[N:3]([CH3:19])[CH2:2][CH2:1][N:21]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH:14]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CCN(C)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Br-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CN1CCN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
Reflux 0.005 moles of 2-(2-ethyl-methylamino)-5-chlorobenzophenone, 0.020 moles of hexamethylenetetramine and 0.020 moles of ammonium bromide together for 2 hours in 14 ml. of 85% (v/v) aqueous isopropyl alcohol. Pour the reaction mixture into water and extract the product with benzene. Wash the benzene solution with water, dry over anhydrous sodium sulfate, filter and evaporate to dryness. After recrystallization, 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine is obtained. The material gives a single spot by thin layer chromatography, and after drying under vacuum at 110° C., shows no depression on mixed melting point with an authentic sample.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=[O:37].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1COCC1.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]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([C:36]([C:32]2[O:31][CH:35]=[CH:34][CH:33]=2)=[O:37])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Reactant: O=C(Cl)c1ccco1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2ccco2)c1
Temperature: 50 °C
Yield: 50 %

Procedure:
Dissolve N-methyl-N-propyl-5-tributylstannanyl-isophthalamic acid methyl ester (500 mg, 1 mmol), furan-2-carbonyl chloride (0.12 mL), tris(dibenzylideneacetone)-dipalladium (0) (19 mg) and 2-(di-tert-butylphosphino)biphenyl (35 mg) in THF (6 mL) in a previously degassed, sealed vessel. Flush the mixture with nitrogen and heat the sealed mixture overnight at 50° C. Cool the reaction to room temperature and filter though a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, 0:100 to 38:62 ethyl acetate:hexanes) to give the title compound (50%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C:32](=[O:41])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[S:30])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([C:15]([O:17]C(C)(C)C)=[O:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[ClH:42].O1CCOCC1>>[ClH:42].[F:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C:32](=[O:41])[CH2:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)=[S:30])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c2cc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c2cc1C(=O)O
Temperature: 80 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
Compound 19a (385 mg) was dissolved in 4N HCl-dioxane solution (10 mL), and the solution was stirred at 80° C. for 4 hours. The precipitate in the reaction mixture was filtrated, to thereby yield compound 19b (245 mg, yield: 66%).
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[C:8]([C:10]2[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=2)[CH:9]=1>O>[Na+:2].[Na+:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[C:8]([C:10]2[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[CH:11]=2)[CH:9]=1.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[C:8]([C:10]2[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[CH:11]=2)[CH:9]=1
Reactant: O=C(O)CCCCc1cc(-c2cc(Cl)ccc2O)on1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCc1cc(-c2cc(Cl)ccc2O)on1
Temperature: 25 °C
Reaction time: 48 h
Yield: 107.1 %

Procedure:
Add a solution of NaOH (739 mg, 18.5 mmol) in water (3 mL) to a suspension of 5-[5-(5-chloro-2-hydroxy-phenyl)-isoxazol-3-yl]-pentanoic acid (2.73 g, 9.23 mmol) in water (5 mL) and stir at room temperature. Heat to 55° C. for 1 hour, filter hot solution, concentrate, place in 50-60° C. vacuum oven for 2 days. Scrape and crush solids, place in 50-60° C. vacuum oven overnight to afford the title compound (3.14 g, 100%). MS (IS) 296 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:43]([CH:45]1[O:47][CH2:46]1)Br>CC(CC)=O>[C:1]([O:5][C:6]([N:8]1[CH2:46][CH:45]([OH:47])[CH2:43][N:9]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: BrCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OC(C)(C)C

Procedure:
46.4 g of hydrazine-N,N'-dicarboxylic acid di-tert-butyl ester, 69.0 g of potassium carbonate, 3.3 g of potassium iodide, 20 ml of tetrabutylammonium fluoride (1 molar solution in tetrahydrofuran) and 21 ml of epibromohydrin are boiled under reflux for 48 hours in 400 ml of ethyl methyl ketone. The resulting suspension is concentrated, and 500 ml of diethyl ether are added thereto; the reaction mixture is then filtered and the tiltrate is concentrated. Purification of the crude product by means of column chromatography yields 27.1 g of the desired 4-hydroxy-pyrazolidine-N,N'-dicarboxylic acid di-tert-butyl ester in the form of white crystals; m.p. 100°-102° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[F:9][C:6]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([CH3:16])[C:3]([C:17]#[N:18])=[C:2]2[C:7]=1[O:8][C:24]([C:20]1[O:19][CH:23]=[CH:22][CH:21]=1)=[N:1]2
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: O=C(Cl)c1ccco1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)c(F)c2oc(-c3ccco3)nc2c1C#N
Temperature: 145 °C
Reaction time: 108 h
Yield: 30.7 %

Procedure:
4-Amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (100 mg, 0.41 mmol) was dissolved in xylene (10 ml), then at room temperature, triethylamine (70 μl), 2-furoyl chloride (49 μl, 0.50 mmol), pyridinium paratoluenesulfonate (31 mg, 0.12 mmol) were added. Next, this mixture liquid was stirred at 145° C. for 108 hours, then cooled to room temperature. This reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was separated, and this was extracted twice with ethyl acetate. The organic layers were combined, this was washed with saturated brine, dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=4:1), and the entitled compound (40 mg, 31%) was obtained as a white solid.
Reaction SMILES: [C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32]Cl>CN(C=O)C>[CH2:7]([N:21]([CH2:31][CH3:32])[CH2:20][CH2:19][CH2:18][O:23][C:16]1[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:21]4[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH:11]=[CH:12][CH:13]=3)[CH3:1]
Reactant: Oc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 95 %

Procedure:
To a mixture of (1R)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (3.67 g, 12.19 mmol) in DMF (90 mL) is added potassium carbonate (8.4 g, 60.9 mmol) and 1-bromo-2-chloroethane (5.0 mL, 60.9 mmol). The mixture is heated to 85° C. for 24 h. The temperature is then increased to 95° C. and heated for 4 h. Mechanical stirring is employed and the reaction heated an additional 1.5 h. The mixture is then partitioned between water and Et2O. The layers are separated and the organic layer washed with water (100 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography with silica gel using hexane/CH2Cl2 (60/40) gave 2.4 g (54%) of the title compound.
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[O:24][CH3:25])(C)[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>C(O)C.O>[CH3:25][O:24][C:11]1[C:12]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][CH:14]=[CH:15][C:10]=1[CH:3]([CH3:1])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(C#N)c1cccc(Sc2ccccc2Cl)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(Sc2ccccc2Cl)cccc1C(C)C(=O)O
Yield: 67 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenylthio)phenyl]propionate (3.3 g) and potassium hydroxide (1.5 g) in ethanol (60 ml) and water (30 ml) was refluxed under heating for 48 hours. After cooling, ethanol was distilled off from the reaction mixture. To the residue was added water, and the aqueous solution was washed with diethyl ether, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and then evaporated under reduced pressure to give oily 2-[2-methoxy-3-(2-chlorophenylthio)phenyl]propionic acid (1.9 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([C:26](O)=[O:27])=[CH:23][CH:24]=4)[N:19]=[CH:18][CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.[C:29]([O:33][C:34](=[O:41])[NH:35][CH2:36][C:37]([NH2:40])([CH3:39])[CH3:38])([CH3:32])([CH3:31])[CH3:30].C(Cl)CCl.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[C:29]([O:33][C:34](=[O:41])[NH:35][CH2:36][C:37]([CH3:39])([NH:40][C:26]([C:22]1[CH:21]=[C:20]2[C:25]([C:16]([C:9]3[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)=[N:12][N:11]4[CH2:13][CH2:14][CH2:15][C:10]=34)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1)=[O:27])[CH3:38])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(C(=O)O)ccc24)CCC3)n1
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(C(=O)NC(C)(C)CNC(=O)OC(C)(C)C)ccc24)CCC3)n1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a solution of 4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid (0.16 g, 0.43 mmol), (2-amino-2-methyl-propyl)-carbamic acid tert-butyl ester (0.09 g, 0.47 mmol), EDC (0.09 g, 0.47 mmol), 1-hydroxybenzotriazole (0.06 g, 0.47 mmol) in dichloromethane (8.6 mL) is added N,N-diisopropylethylamine (0.25 mL, 1.29 mmol). The mixture is stirred at room temperature for 18 hand concentrated in vacuo. The residue is taken up in ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on SiO2 (methanol/dichloromethane/2:98) to yield the title compound 0.21 g (91%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1B(O)O>>[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: CS(=O)(=O)NCc1cncc(Br)c1
Product: Cn1c(-c2cncc(CNS(C)(=O)=O)c2)cc2ccccc21

Procedure:
N-(5-Bromo-pyridin-3-ylmethyl)-methanesulfonamide and N-methyl-indoleboronic acid are processed according to the method described in Example 100 to give N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 3.03 (s, 3H), 3.82 (s, 3H), 4.45 (s, 2H), 6.70 (s, 1H), 7.13 (t, J=7.5 Hz, 1 H), 7.23-7.31 (m, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.10 (t, J=2.0 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.72 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 316.1108 [(M+H)+ Calcd for C16H18N3O2S: 316.1120].
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)=[CH:53][C:52]=1[F:64])#[N:50]>CN(C=O)C>[C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=2)=[CH:53][C:52]=1[F:64])#[N:50]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: N#Cc1ccc(-c2cccc(N)c2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1F
Temperature: 25 °C
Yield: 15.4 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-cyano-3′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.004 g of product in 15% yield: LCMS (ESI) m/z 401 (MH+).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:7])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(C)ccc1F
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(=O)(=O)NC(C)(C)C)cnn23)c1
Yield: 83.1 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (1.29 g, 2.89 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (0.73 g, 4.06 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (1.40 g, 95%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:21])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5]([OH:7])=O.C(N(C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH3:42]>C(#N)C>[F:21][C:9]1[CH:8]=[C:4]([C:5]([N:46]2[CH2:47][CH2:48][N:43]([CH2:41][CH3:42])[CH2:44][CH2:45]2)=[O:7])[CH:3]=[C:2]([F:1])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CCN1CCNCC1
Reactant: COc1ccc(CNc2c(F)cc(C(=O)O)cc2F)cc1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(C(=O)c2cc(F)c(NCc3ccc(OC)cc3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
To a solution of 3,5-difluoro-4-(4-methoxy-benzylamino)-benzoic acid (9.00 g, 30.7 mmol) obtained in Step B in acetonitrile (150 ml), N-ethyldiisopropylamine (16.0 ml, 92.1 mmol), HOBt (4.15 g, 30.7 mmol) and WSCI (5.88 g, 30.7 mmol) were added, followed by stirring at room temperature for 10 minutes. To this, 1-ethyl-piperazine (4.68 ml, 368 mmol) was added, followed by stirring at room temperature for 62 hours. N-Ethyldiisopropylamine (5.35 ml, 30.7 mmol), HOBt (2.07 g, 15.3 mmol) and WSCI (2.94 g, 15.3 mmol) were added at room temperature, followed by stirring for 22 hours. The solvent was distilled off under reduced pressure, followed by dissolution in ethyl acetate (300 ml), which was washed with saturated aqueous sodium chloride solution (100 ml) and saturated sodium hydrogencarbonate aqueous solution (100 ml). Subsequently, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 25/1), to obtain the desired compound as a brown oil (11.8 g, 99%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=3)[NH:13][CH:12]2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C2Nc3cc(OC)ccc3C(=O)N2c2ccc(OCCCl)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc3cc(OC)ccc3c(=O)n2-c2ccc(OCCCl)cc2)cc1

Procedure:
To a solution of 8.1 g (0.0185 mol) of 3-[4-(2-chloro-ethoxy)-phenyl]-7-methoxy-2-(4methoxy-phenyl)-2,3-dihydro-1H-quinazolin-4-one in 300 mL of toluene was added 4.2 g (0.0185 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The reaction mixture was stirred and heated to reflux for 2 hours. The toluene was removed in a rotary evaporator. Ethanol (300 mL) was added to the reaction flask which was allowed to stir at room temperature overnight. The precipitate was collected by vacuum filtration and amounted to 6.9 g. The product (mp 186-187° C.) was used in the next step without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:30])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[CH2:31]([CH2:33][NH2:34])[OH:32]>CS(C)=O>[OH:32][CH2:31][CH2:33][NH:34][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:30])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4cn(C)nn4)ccc3C)csc12
Solvent: CS(C)=O
Product: Cc1ccc(-c2cn(C)nn2)cc1OCc1csc2c(C(=O)NCCO)cnc(N)c12
Temperature: 160 °C

Procedure:
A solution of 4-amino-3-[2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.050 g, 0.11 mmol) (from Example 23 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160° C. for 2 hours in a microwave reactor. The reaction mixture was purified by C18 column eluting with acetonitrile-water to give 4-amino-3-[2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 31.0 mg, 60%).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(=O)=O.C([O:15][C:16]([C:18]1([CH3:31])[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1)=O)C.OS([O-])(=O)=O.[K+]>C1COCC1>[C:27]([O:26][C:24]([N:20]1[CH2:21][CH2:22][CH2:23][C:18]([CH2:16][OH:15])([CH3:31])[CH2:19]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Product: CC1(CO)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
6.14 ml (1.2 M in toluene, 7.37 mmol) of DIBALH was dropped to a dry ice cooled (−30° C.) solution of 1.00 g (3.69 mmol) crude 3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester in 2 ml of THF. The reaction was warmed up (0° C. for 1 h), continued for 3 h, cooled (−15° C.) and treated again with 0.61 ml (1.2 M in toluene, 0.74 mmol) of DIBALH. After 1 h the reaction was warmed up to 0° C. and neutralized with aqueous 10% KHSO4 solution. The mixture was extracted with ether (3×), the organic phases were washed with a aqueous 10% NaCl solution, dried (Na2SO4) and evaporated to give after flash silica gel column (n-heptane/EtOAc 9:1) 0.61 g (73%) of the title compound as yellow oil. MS: 230.0 (MH+).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][O:20][CH2:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][O:20][CH2:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: COCC1Cc2ccccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COCC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 37.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 326 mg of 2-(methoxymethyl)indoline and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 143 mg of 2-{2-[2-(methoxymethyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a beige powder, the characteristics of which are the following: