Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[OH-].[C:3]1([B+2])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1C1C=CC=C(C)C=1.O1CCOCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:20][CH:21]=1
Reactant: [B+2]c1ccccc1
Reactant: COc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cccc(-c2cc(C)ccc2C)c1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 94.2 %

Procedure:
An oven dried resealable Schlenk tube was purged with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 0.5 mol %), ligand 2 [Example 1] (5.9 mg, 0.015 mmol, 0.75 mol %), phenylboron dihydroxide (366 mg, 3.0 mmol), and potassium phosphate (850 mg, 4.0 mmol). The tube was purged with argon, and dioxane (6 mL), and 4-chloroanisole (0.24 mL, 2.0 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for two minutes, then heated to 100° C. with stirring until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (40 mL) and poured into a separatory funnel. The mixture was washed with 1 M NaOH (40 mL), and the layers were separated. The aqueous layer was extracted with ether (40 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel to give 347 mg (94%) of a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][C:29]([F:32])([F:31])[CH2:28][N:27]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[F:32][C:29]1([F:31])[CH2:28][NH:27][C@H:26]([CH2:25][N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])=[N:9]2)[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C[C@@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2S)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-4,4-difluoropyrrolidine-1-carboxylate (600 mg, 1.11 mmol, 1.00 equiv) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) dropwise. The resulting solution was stirred at room temperature for 2 h. The mixture was concentrated under vacuum to give 0.85 g (crude) of 1-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetic acid salt as a brown semi-solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[S:12]1[CH:16]=[CH:15][C:14]([C:17]([CH2:19][NH2:20])=[O:18])=[CH:13]1.C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH2:19][C:17]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)=[O:18])=[O:7])=[CH:4][CH:3]=1
Reactant: NCC(=O)c1ccsc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)c1ccc(F)cc1)c1ccsc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.5 %

Procedure:
16 g of 4-fluorobenzoyl chloride are dissolved in 50 ml of ethyl acetate, and the solution is added at a temperature below 10° C. under stirring to a mixture of 17.8 g of N-[(3-thienylcarbonyl)methyl]amine hydrochloride, 25 g of sodium bicarbonate, 100 ml of ethyl acetate and 200 ml of water. The mixture is further stirred at room temperature for 3 hours. The precipitated crystalls are collected by filtration, washed with water and then dried, whereby N-(4-fluorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine is obtained. On the other hand, the filtrate is washed with water, dried and then condensed under reduced pressure to remove solvent. The residue is washed with ether, whereby N-(4-fluorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine is further obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:13]1[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][CH:15]([C:26]([NH2:28])=[O:27])[NH:14]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(CC)CC)C.O>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:14]2[CH:15]([C:26]([NH2:28])=[O:27])[CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]=3[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)C1Cc2c([nH]c3ccccc23)CN1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2Cc3[nH]c4ccccc4c3CC2C(N)=O)cc1
Reaction time: 8 h

Procedure:
4-methoxy benzene sulphonyl chloride (495 gm, 2.4 mmol) in dry acetone (5 ml) was added to a stirred solution of dl 1,2,3,4-tetrahydro-9H-pyrido(3,4-b)indole-3-amide (0.430 gm, 1.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry DMF (5 ml) during 15 min and was allowed to stirr for 8 hrs. at room temperature (32° C.). Water was added to the reaction mixture and triturated to give 2-[4-methoxybenzenesulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid amide, which was purified by column chromatography over silica gel using 2% methanol chloroform as eluent. Yield=0.480 gm, (62.34%). m.p.=178-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[Cl:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:14][N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[Cl:1]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccc(Cl)c(Cl)c1
Yield: 73.1 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, 3,4-dichloro-benzaldehyde (5.6 g, 41.481=01) in ethanol (56 mL) was reacted with nitro methane (2.3 mL, 41.481 mmol), 10N NaOH solution (1.65 g, 41.481 mmol) at 0° C. for 1 hour to afford 5.1 g of the product (75% yield).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2C3C(=CC(Br)=CC=3)[C:5]([CH2:19][CH:20]=[CH2:21])([CH2:16][CH:17]=[CH2:18])[C:4]=2[CH:3]=1.[C:22]1([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:32]3[CH:33]=[CH:34][C:29]([N:28]([C:2]4[CH:14]=[CH:13][CH:12]=[CH:4][CH:3]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:30][C:31]=3[C:5]2([CH2:19][CH:20]=[CH2:21])[CH2:16][CH:17]=[CH2:18])=[CH:13][CH:14]=1
Reactant: C=CCC1(CC=C)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCC1(CC=C)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: 93 °C
Yield: 48 %

Procedure:
A mixture of 2,7 dibromo-9,9-diprop-2-enylfluorene (40.4 g, 0.1 mol), diphenylamine (8.5 g, 0.05 mol), bis(dibenzylideneacetone)palladium(0) (0.3 g, 0.522 mmol), bis(diphenylphosphino)ferrocene (0.32 g, 0.57 mmol) sodium t-butoxide (5.6 g, 0.058 mol) and toluene (350 mL) was heated at 93° C. for 18 hours under nitrogen, and cooled. The mixture was diluted with toluene and water, and the toluene phase was dried and concentrated. The residue was chromatographed over 850 g of alumina. Elution with heptane led to the recovery of unreacted dibromo-diallylfluorene, 13.38 g, 33%, m.p. 134-137° C. Elution with 10% toluene-heptane yielded the desired product, m.p. 151-153° C., 11.74 g, 48% yield. Two successive recrystallizations from hexanes did not raise the m.p., 150.4-152.8° C. Mass Spec: m/z 491,493 (M+). IR (KBr): 3068, 2977,1639,1589,1489 cm−1. Anal. Calcd. for C31H26BrN; C, 75.61%; H, 5.32%; N, 2.84%; Br, 16.23%. Found: C, 75.56%; H, 5.27%; N, 2.68%. (Br- 17.1%). This reaction also produced some 2,7-bis(diphenylamino)-9,9-diallylfluorene, 1.09 g, m.p. 179-183° C. Mass Spec: m/z 580 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]1[O:6][CH2:5]1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]([OH:6])[CH2:5][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: Clc1ccccc1C1CO1
Reactant: NCCCCCCO
Solvent: CO
Solvent: CCOC(C)=O
Product: OCCCCCCNCC(O)c1ccccc1Cl
Yield: 41 %

Procedure:
From 2-chlorostyrene oxide and 6-amino-1-hexanol. Working up by means of chromatography (ethyl acetate/methanol 1:1). Yield: 41%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([CH2:20][O:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[CH2:17][C:16]2=[O:32])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[CH2:17][C:16]2=[O:32])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OCc4ccccc4)cc3)C2)cc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 94.8 %

Procedure:
Methyl 4-[1-(4-benzyloxyphenyl)-2-pyrrolidon-4-yl]methoxybenzoate (2.00 g) is dissolved in a mixed solvent of chloroform (50 ml) and methanol (20 ml), and thereto is added 10% palladium-carbon (0.2 g). The mixture is stirred at room temperature at atmospheric pressure under hydrogen atmosphere for 22 hours. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is crystallized from 50% aqueous methanol (about 20 ml) to give the desired product (1.50 g), m.p. 141°-144° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[NH3:34]>>[S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29]([NH2:34])=[O:31])[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1
Reactant: N
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(N)=O
Yield: 88 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with ammonia to give the title compound as a white solid (170 mg, 88%); NMR Spectrum 1.67 (d, 3H), 5.14 (q, 1H), 5.79 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.50 (s, 1H), 7.56 (br s, 1H), 7.79-7.72 (m, 3H), 7.90 (br s, 1H), 8.10 (s, 1H), 8.51 (m, 2H), 9.04 (s, 1H), 10.80 (br s, 1H); Mass spectrum MH+ 446.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]=[C:6]2[CH2:13][NH2:14]>CO.CC(O)=O.[Ni]>[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[CH2:13][NH2:14]
Reactant: NCC1=CCOc2ccc(F)cc21
Agent: [Ni]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: NCC1CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 1-(6-fluoro-2H-chromen-4-yl)methanamine hydrochloride (1.36 g, 7.6 mmol) in MeOH (20 mL) and AcOH (10 mL) was added Raney Nickel (760 mg) at room temperature. The suspension was stirred at rt overnight under 50 psi of H2. The reaction mixture was filtered and concentrated. The residue was dissolved in DCM and washed with sat. NaHCO3, dried (Na2SO4), and concentrated to give 490 mg (36%) of the title compound as a green oil. [M+H] calc'd for C10H12FNO, 182. found 182.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(S(OC)(=O)=O)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]=[CH:8][C:7]1=[O:12]
Reactant: O=C1CCCCN1Cc1ccc(F)c(Cl)c1
Agent: COS(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1C=CCCN1Cc1ccc(F)c(Cl)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a cold (−20° C.) solution of 1-(3-chloro-4-fluorobenzyl)piperidin-2-one (340 g, 1.41 mol) in anhydrous tetrahydrofuran (5 L) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide (3.09 L, 3.09 mol; 1M in THF) was added over a period of 40 minutes with the temperature of the reaction maintained at −20° C. After the addition was complete, the reaction mixture was stirred at −20° C. for one hour. Methyl benzene sulfonate (231 mL, 1.69 mol) was added to the reaction mixture over a period of 30 minutes. The reaction mixture was stirred at −20° C. for 30 minutes. The product mixture was diluted with ethyl acetate (4 L) and washed with water (four times; 2 L each time). The organic extract was concentrated under vacuum. The residue was dissolved in toluene (4 L), treated with solid sodium carbonate (500 g), and heated at 100° C. for one hour. The product mixture was diluted with ethyl acetate (4 L) and washed with water (4 times; 2 L each). The organic extract was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a gradient of 0-60% EtOAc in heptane. Collection and concentration of appropriate fractions provide the title compound as oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[N:11]=[CH:12]/[CH:13]2[C:18](=[O:19])OC(C)(C)OC2=O)[CH:6]=[N:7][C:8]=1[O:9][CH3:10].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:10][O:9][C:8]1[N:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[NH:11][CH:12]=[CH:13][C:18]2=[O:19]
Reactant: COc1cc(/N=C/C2C(=O)OC(C)(C)OC2=O)cnc1OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COc1cc2[nH]ccc(=O)c2nc1OC
Temperature: 200 °C

Procedure:
A round bottom flask was charged with (E)-5-((5,6-dimethoxypyridin-3-ylimino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (450 mg, 1460 μmol) and 4.2 mL diphenyl ether. A reflux condenser was attached, and the solution was heated at 200° C. for 0.5 h. Upon cooling, hexane was added and the solids were filtered and washed with hexane. 6,7-dimethoxy-1,5-naphthyridin-4(1H)-one was isolated as a tan solid. MS [M+H]=207
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:7][O:8][CH:13]([C:12]2[CH:15]=[CH:16][CH:17]=[C:10]([F:9])[CH:11]=2)[O:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC(CO)CO
Reactant: O=Cc1cccc(F)c1
Solvent: Cc1ccccc1
Product: CCCC1COC(c2cccc(F)c2)OC1
Yield: 32.6 %

Procedure:
2-Propyl-1,3-propanediol (138.0 g; 1.17 mol) and 3-fluorobenzaldehyde (138.0 g; 1.11 mol) were dissolved in toluene (1.5 liters), and PTS (7 g) was added. The mixture was refluxed for 3 hours while being dehydrated with a Dean-Stark's device. The resultant reaction mixture was washed sequentially with saturated sodium bicarbonate solution and saturated brine, and then dried over magnesium sulfate. Subsequently, the solvent was evaporated. The residue was recrystallized twice from heptane, to thereby obtain 81.2 g (362 mmol) of 5-propyl-2-(3-fluorophenyl)-1,3-dioxane. The yield of the compound from 3-fluorobenzaldehyde was 32.6%.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[O:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH2:35])=[CH:32][CH:33]=2)[CH:28]=[N:27]1>>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:35][C:31]1[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=1)[N:26]([CH2:25][C:21]1[O:20][CH:24]=[CH:23][N:22]=1)[N:27]=[CH:28]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Reactant: Nc1ccc2c(cnn2Cc2ncco2)c1
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ncco4)c3)c12)C(=O)N(C)C
Yield: 80 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (212 mg, 0.81 mmol) and 1-(1,3-oxazol-2-ylmethyl)-1H-indazol-5-amine (1 equivalents) were reacted to give the title compound as a beige foam (295 mg, 80%); NMR spectrum (CDCl3) 1.73 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.71 (s, 2H), 6.81 (d, 1H), 7.09 (s, 1H), 7.48-7.53 (m, 2H), 7.58-7.62 (m, 2H), 7.88 (d, 1H), 8.07 (s, 1H), 8.41 (s, 1H), 8.61 (s, 1H), 10.92 (br s, 1H); Mass spectrum MH+ 458.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[CH:19]1([C:22]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=2)[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH:19]1([C:22]2[N:23]=[CH:24][C:25]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=3[C:10]#[C:11][C:12]3[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=3)=[CH:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: OB(O)c1ccc(C2CC2)nc1
Reactant: CCc1nccc(Cl)c1C#Cc1ccc(N)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCc1nccc(-c2ccc(C3CC3)nc2)c1C#Cc1ccc(N)nc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 150 mg (0.58 mmol) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using 142 mg (0.87 mmoL) 2-cyclopropyl-pyrid-5-yl boronic acid, 4.5 mg (0.03 mmol) Pd(PPh3)4 and 154 mg (1.11 mmol) K2CO3 in a mixture of 6.0 mL DME and 1.5 mL water. The reaction mixture is stirred twice under microwave irradiation at 150° C. for 120 min. The reaction mixture is concentrated in vaccuo and the crude product is purified by chromatography on silica gel using a DCM/MeOH-gradient. Yield: 68 mg (34%).
Reaction SMILES: [CH:1]([N:4]([CH3:24])[C:5]1[C:6]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[CH:1]([N:4]([CH3:24])[C:5]1[C:6]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3cn[nH]c3)c(N(C)C(C)C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(1H-pyrazol-4-yl)quinoxaline-6-carboxylate (130.0 mg, 0.40 mmol,) in methanol (20 mL) and water (1 mL) was added lithium hydroxide hydrate (50.0 mg, 1.12 mmol). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was diluted with water (10 mL) and adjusted to pH 5 with citric acid (1N). The product were collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(1H-pyrazol-4-yl)quinoxaline-6-carboxylic acid as yellow solid (64.7 mg, 52%).
Reaction SMILES: C1(COC([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([CH2:20][CH2:21][NH:22]C(OCC3C=CC=CC=3)=O)=[CH:18][CH:19]=2)=O)C=CC=CC=1>[Pd]>[NH2:22][CH2:21][CH2:20][C:17]1[N:16]=[CH:15][C:14]([CH2:13][CH2:12][NH2:11])=[CH:19][CH:18]=1
Reactant: O=C(NCCc1ccc(CCNC(=O)OCc2ccccc2)nc1)OCc1ccccc1
Agent: [Pd]
Product: NCCc1ccc(CCN)nc1
Yield: 55 %

Procedure:
(Phenylmethoxy)-N-[2-(6-{2-[(phenylmethoxy)carbonylamino]ethyl}(3-pyridyl))ethyl]carboxamide (3.6 mmol) and 10% palladium on carbon (1.0 g, 62 mole %) were combined and hydrogenation was carried out in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, 2-[6-(2-aminoethyl)-3-pyridyl]ethylamine, (55%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C.C(OCC)C>O1CCCC1>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Cl
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)OB(c2cc(F)c(Cl)cc2F)OC1(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
1-Bromo-4-chloro-2,5-difluorobenzene (1.11 g, 4.9 mmol) was dissolved in tetrahydrofuran (THF; 15 mL) and cooled to −10° C. A 2.0M solution of isopropyl-magnesium chloride (2.7 mL, 5.4 mmol) in THF was added dropwise via a syringe. The reaction mixture was stirred at −10° C. for 1 hour, allowed to warm toward 0° C. for 1 hour, then cooled to −10° C. again. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.4 mmol) in THF (1.0 mL) was then added dropwise and the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydroxide twice. The aqueous phases were combined, acidified to pH 3 with concentrated HCl, and extracted with dichloromethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.97 g, 72.3% yield) that was used without further purification: 1H NMR (CDCl3): δ 7.45 (dd, 1H), 7.09 dd, 1H), 1.36 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27]CC)=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH2:24][C:25]([OH:27])=[O:26])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:21])=[O:22])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(OCC(=O)O)cc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-chlorophenyl)-6-hydroxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (500 mg), ethyl bromoacetate (0.2 ml), and potassium carbonate (245 mg) in N,N-dimethyl formamide (1 ml) was stirred at 80° C. for 3 hours. The mixture was cooled and poured into ice-water. The separated solid was filtered and dissolved in a mixture of ethanol (15 ml) and tetrahydrofuran (15 ml). To the solution containing 2-(4-chlorophenyl)-6-ethoxycarbonylmethoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide was added aqueous 1N-sodium hydroxide solution (2.2 ml) in one portion at ambient temperature. The solution was stirred for one hour at ambient temperature and concentrated in vacuo. The residue was extracted with methylene chloride. The organic layer washed with brine, dried, and evaporated to give the crude product, which was crystallized from methanol to yield 2-(4-chlorophenyl)-6-carboxymethoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (213 mg).