Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:2].[NH2:18][CH2:19][CH:20]([OH:27])[CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24].C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:23]([N:22]([CH2:25][CH3:26])[CH2:21][CH:20]([OH:27])[CH2:19][NH:18][C:9]([C:5]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])=[O:11])[CH3:24]
Reactant: CCN(CC)CC(O)CN
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN(CC)CC(O)CNC(=O)c1c(C)[nH]c(C=O)c1-c1ccccc1
Yield: 25.7 %

Procedure:
A mixture of 5-Formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (1.0 gm, 4.36 mmol), 1-amino-3-diethylamino-2-propanol (950 mg, 6.54 mmol), DDC (900 mg, 4.36 mmol) and HOBt. (884 mg, 6.54 mmol) in chloroform (60 mL) was stirred at rt for 12 hrs. The reaction was poured into sat. Sodium bicarbonate (60 mL) and to it was added 1N NaOH (8 mL). It was then extracted with EtOAc (3×100 mL), washed with water and brine, dried and concentrated to give 400 mg of 5-Formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-2-hydroxy-propyl)-amide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]([Br:24])[N:17]=1)C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]([Br:24])[N:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Br)nc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(Br)nc1NC(=O)OC(C)(C)C

Procedure:
To a solution of the title compound and di-tert-butyl(6-bromo-3-methoxypyridin-2-yl)imidodicarbonate (7.19 g, approximate ratio of 43:57) in MeOH (55 mL) at rt was added K2CO3 (7.39 g, 53.5 mmol). After stirring at 55° C. for 1.5 h the mixture was cooled to rt and combined with a previous reaction mixture derived from title compound and di-tert-butyl(6-bromo-3-methoxypyridin-2-yl)imidodicarbonate (8.83 g, approximate ratio of 43:57) and filtered. The residue was washed with EtOAc and the filtrate was concentrated in vacuo. Purification by gradient flash chromatography, eluting with 10-25% EtOAc in heptane yielded the title compound (8.38 g, 27.6 mmol) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:36])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccc(F)cc2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccc(F)cc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(4-fluorobenzoyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.035 g, 0.085 mmol) and ammonium acetate (0.0655 g, 0.850 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.21 mL, 0.21 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C22H23ClFN4O (M+H)+: m/z=413.2; Found: 413.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]([O:15][CH3:16])=[O:14])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)n1ncc2c([N+](=O)[O-])cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)n1ncc2c(N)cccc21
Temperature: 80 °C

Procedure:
Methyl 4-nitro-1H-indazole-1-carboxylate 1.66 g, 7.5 mmol) and 10% Pd/C were combined in ethanol (20 mL) and exposed to a hydrogen atmosphere. The reaction mixture was heated at 80° C. for 20 minutes, allowed to cool to room temperature, and filtered through Celite. The filtrate was evaporated to provide title compound. 1H NMR (300 MHz, DMSO-d6) δ 6.1 (s, 2H), 6.41 (dd, 1H), 7.21 (m, 2H), 8.42 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:1]1[CH2:17][CH2:16][O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:2]1=2
Reactant: CCOC(=O)Cc1ccc(O)c(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of Ethyl 2-(3,4-dihydroxyphenyl)acetate (1.11 g, 5.66 mmol) and 1,2-dibromoethane (1.07 g, 5.69 mmol) in DMF (5 mL) was added cesium carbonate (3.71 g, 11.4 mmol). The reaction mixture was stirred for 2 hrs at 80° C. then cooled to room temperature. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:4˜1:2) as eluant.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:25]2[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([CH2:32][CH3:33])[CH:26]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)#[N:11].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:25]2[CH:30]=[C:29]([O:31][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:28]=[C:27]([CH2:32][CH3:33])[CH:26]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)#[N:11]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(O)cc(CC)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(Oc2ccccc2)c1
Reaction time: 60 h
Yield: 81.4 %

Procedure:
Copper(II) acetate (223 mg, 1.20 mmol), phenylboronic acid (164 mg, 1.32 mmol) and molecular sieve 4 Å were added to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-hydroxy-phenyl)-acetate (390 mg, 1.20 mmol) obtained in Example 200.1 in CH2Cl2 (12 ml). Pyridine (476 mg, 6.01 mmol) was added dropwise and the mixture was stirred for 60 h. under an atmosphere of air. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2). There were obtained 391 mg (81%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-phenoxy-phenyl)-acetate as beige crystals; MS: 401 ([M+H]+)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH2:19])[C:12]2=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH:13]([CH2:19][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[C:12]2=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: C=C1COc2ccc(OCc3ccccc3)cc2C1=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2cc(OCc3ccccc3)ccc2OCC1Cn1ccnc1
Yield: 64.6 %

Procedure:
A solution of 3.7 g of 6-benzyloxy-3-methylene-4-chromanone and 3.7 g of imidazole in 50 cc of DMF was heated at 60° C. for 1.5 hours. The reaction was allowed to cool, then poured into water and extracted with ethyl acetate. The combined organic layers were dried over Na and evaporated to give 4 g of crude product which was purified by recrystallization from CH2Cl2 /ether to give 3 g of title product, m.p. 108°-110° C. MS calculated for C20H18N2O3 : 334.1317; found: 334.1317.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[N:13]=1.[CH2:19]([C@H:21]1[O:23][CH2:22]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:21]3[CH2:22][O:23]3)=[CH:14][C:12]=2[N:13]=1
Reactant: ClC[C@@H]1CO1
Reactant: Oc1ccc2oc(-c3ccc(Cl)cc3Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(-c2nc3cc(OCC4CO4)ccc3o2)c(Cl)c1
Reaction time: 8 h

Procedure:
A mixture of 2-(2,4-dichlorophenyl)benzoxazol-5-ol, a compound of formula (g) (6.0 g, 36 mmol), (S)-(+)-epichlorohydrin (3.3 g, 315 mmol), a compound of formula (b) (20 ml, 182 mmol), and potassium carbonate (20 g, 144 mmol) in acetone (100 ml) was heated to reflux and stirred overnight. The solution was allowed to cool and filtered through Celite 512. The filtrate was evaporated under reduced pressure, to yield an oil. The oil was chromatographed on silica gel, eluting with 20% ethyl acetate/hexanes, to provide 2-(2,4-dichlorophenyl)-5-(oxiran-2-ylmethoxy)benzoxazole as a white solid (6.2 g, 28 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[Se:4][C:3]=1[C:11]#[N:12].C([OH:15])C>[OH-].[Na+]>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[Se:4][C:3]=1[C:11]([NH2:12])=[O:15]
Reactant: N#Cc1[se]c2ncccc2c1N
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1[se]c2ncccc2c1N
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a suspension of 3-aminoselenopheno[2,3-b]pyridine-2-carbonitrile (1.0 g) in aqueous sodium hydroxide solution (20 mL, 10%) was added ethanol (20 mL) and the mixture refluxed for 45 min. Ethanol was distilled off under vacuum (appr. 25 mL) and the mixture was allowed to cool to 5-10° C. The separated crystals and the solution was poured into ice cooled water and stirred for 15 min. The solid was filtered off, washed with cold water and dried to give the product as a pale yellow color solid (0.53 g, 50%), mp 256-260° C. 1H NMR (400 MHz, DMSO-d6): δ 8.60 (1H, d, J=3.6 Hz, H-6), 8.37 (1H, d, J=7.6 Hz, H-4), 7.47 (1H, dd, J=8.0, 4.8 Hz, H-5), 7.32 (2H, s, —CONH2), 7.09 (2H, s, —NH2); LC-MS (negative ion mode): m/z 238, 241 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].N1CCCCC1>CO>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1/[CH:11]=[CH:14]/[C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1C=O
Reactant: CC(=O)c1ccncc1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1[nH]c2ccccc2c1/C=C/C(=O)c1ccncc1
Yield: 69.6 %

Procedure:
To a dried 500 mL round bottom flask under argon, 2-methylindole-3-carboxaldehyde (400 mg, 2.51 mmol) was dissolved in anhydrous MeOH (10 mL). 4-Acetyl-pyridine (305 μL, 2.76 mmol, 1.1 equiv.) and piperidine (82 μL, 0.83 mmol) were added and the reaction was stirred under reflux. A red-orange precipitate gradually formed, and after twelve hours this solid was isolated by filtration, rinsed with chilled methanol and dried under vacuum, producing 458 mg (69%) of yellow solid. NMR: 1H NMR (600 MHz, d6-DMSO): δ 12.017 (s, 1H, N—H), 8.816-8.806 (dd, J1=4.5, J2=2.1, 2H, pyr-2,6H), 8.121-8.095 (d, J=15.6, 1H, C═CH), 8.077-8.063 (m, 1H, indole-4H), 7.975-7.965 (dd, J1=4.5, J2=1.5, 2H, pyr-3,5H), 7.489-7.464 (d, J=15.6, 1H, C═CH), 7.415-7.400 (m, 1H, indole-7H), 7.220-7.200 (m, 2H, indole-5,6H), 2.596 (s, 3H, methyl). 13C NMR (150 MHz, d6-DMSO): δ 188.0, 150.7, 145.6, 144.9, 139.5, 136.3, 125.8, 122.4, 121.50, 121.46, 120.4, 113.1, 111.7, 109.4, 11.9. Melting Point: 268-272° C. TLC: (ethyl acetate:hexanes 4:1) Rf=0.18. Elemental analysis calculated for C17H14N2O: C, 77.84; H, 5.38; N, 10.68. found: C, 77.96; H, 5.28; N, 10.59.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH2:19])=[O:18].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].Br[C:61]1[N:66]=[C:65]([CH2:67][N:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)[CH:64]=[CH:63][CH:62]=1>C(OCC)(=O)C.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]>[OH:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:61]3[CH:62]=[CH:63][CH:64]=[C:65]([CH2:67][N:68]4[CH2:73][CH2:72][O:71][CH2:70][CH2:69]4)[N:66]=3)=[C:3]([C:17]([NH2:19])=[O:18])[N:4]=2)=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(N)s2)cc1
Reactant: Brc1cccc(CN2CCOCC2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(Nc3cccc(CN4CCOCC4)n3)s2)cc1
Temperature: 25 °C

Procedure:
A sealed tube was charged with a stir bar, 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (150 mg, 0.54 mmol), Pd2(dba)3 (30 mg, 0.023 mmol), X-PHOS (77 mg, 0.16 mmol), and potassium carbonate (82 mg, 0.60 mmol). The tube was evacuated, and backfilled with argon three times. A second vial was charged with 4-[(6-bromopyridin-2-yl)methyl]morpholine (Example 2, Step 1) (139 mg, 0.54 mmol) and evacuated and backfilled with argon three times. Fully degassed tert-amyl alcohol (1.2 mL) was added to the vial containing 4-[(6-bromopyridin-2-yl)methyl]morpholine and the resulting solution was transferred by syringe to the tube containing the rest of the reagents. The reaction vessel was cooled to room temperature, and the crude reaction mixture was taken up in ethyl acetate and washed with 100 mL water. The water layer was treated with concentrated ammonium hydroxide and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. To the filtrate was added 1.5 g of silica gel and the solvent was removed in vacuo. The compound on silica was purified via flash chromatography (silica, 0-3% methanol/ethyl acetate) to afford the title compound. 1H NMR (400 MHz CDCl3): δ 11.26 (s, 1H), 7.86 (d, 2H), 7.70 (s, 1H), 7.68 (d, 1H), 7.58 (s, 1H), 7.54 (d, 2H), 7.05 (d, 1H), 7.00 (d, 1H), 5.08 (s, 1H), 3.65 (s, 2H), 3.59 (m, 4H), 2.47 (m, 4H), 1.42 (s, 6H). LRMS (APCI) calc'd for C23H28N5O3S [M+H]+: 454.2, found 454.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[C:34]([O:38][C:39]([N:41]1[C:50]2[C:45](=[CH:46][C:47](Br)=[CH:48][N:49]=2)[CH2:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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]>[C:34]([O:38][C:39]([N:41]1[C:50]2[C:45](=[CH:46][C:47]([C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=3)=[CH:48][N:49]=2)[CH2:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(Br)cnc21
Reactant: CC(=O)c1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)c1cncc(-c2cnc3c(c2)CCCN3C(=O)OC(C)(C)C)c1
Temperature: 70 °C
Yield: 79.3 %

Procedure:
A vial containing 1-(5-bromo-pyridin-3-yl)-ethanone (1.59 g, 8.0 mmol), bis(pinacolato)diboron (2.53 g, 9.9 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) DCM complex (486 mg, 0.66 mmol) and potassium acetate (1.96 g, 19.9 mmol) in 1,4-dioxane (100 mL) is flushed with Ar, sealed tightly and heated to 70° C. for 16 h. The reaction mixture is cooled to room temperature and 6-bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (2.08 g, 6.6 mmol), aqueous sodium carbonate solution (2M, 9.9 mL, 19.9 mmol) and additional 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (486 mg, 0.66 mmol) are added. The mixture is flushed with Ar, sealed tightly and heated to 100° C. for 2 h. The reaction mixture is cooled to room temperature and partitioned between water and EtOAc. The layers are separated and the aqueous is further extracted with EtOAc. The combined organic layers are washed with brine and filtered through diatomaceous earth, rinsing well with EtOAc. The filtrate is dried (Na2SO4) and concentrated. The crude product is purified by silica gel column (25-100% EtOAc in heptane) to afford 6-(5-acetyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (1.85 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22]([O:24]C)=[O:23])[N:4]=[C:3]1[CH3:26].[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22]([OH:24])=[O:23])[N:4]=[C:3]1[CH3:26]
Reactant: COC(=O)c1nc(C)n(C)c1C(=O)NCCc1nc2ccccc2n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)c(C(=O)NCCc2nc3ccccc3n2C)n1C
Reaction time: 6 h
Yield: 95.7 %

Procedure:
To a solution of methyl 1,2-dimethyl-5-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethylcarbamoyl)-1H-imidazole-4-carboxylate (98 mg, 276 μmol) in THF (2 mL) and MeOH (1 mL) at room temperature was added LiOH (1M, 1.1 mL, 1.1 mmol). The reaction mixture was stirred at r. t. for 6 h. The reaction mixture was acidified with hydrochloric acid (1M, 1.5 mL), all volatiles were removed in vacuo and the residue was suspended in dichloromethane/MeOH (95:5) and filtered. The liquid was evaporated and dried in vacuo to give the product as colorless amorphous material (95 mg, 264 μmol, 95.9%) which was used without any further purification for the next step. MS: M=340.2 (M−H)−
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]([CH3:21])([CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]#[N:10].O.[OH-].[Na+]>C1COCC1>[CH2:14]([O:13][CH2:12][CH2:11][C:8]([CH3:21])([NH2:7])[CH2:9][NH2:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)(C#N)CCOCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)(CN)CCOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon and at 0° C., 1.59 ml (1.59 mmol) of lithium aluminium hydride (1 N solution in diethyl ether) were added to 0.5 g (2.45 mmol) of 2-amino-4-(benzyloxy)-2-methylbutanonitrile Example 260A in 25 ml of dry THF. The reaction solution was stirred first at 0° C. for 30 min and then for another 1 h whilst slowly warming to room temperature. 245 μl of water, 245 μl of 2 N aqueous sodium hydroxide solution and 490 μl of water were then added carefully. The precipitate was filtered off and washed with THF and methanol, the filtrate was concentrated and the residue was purified by silica gel chromatography (mobile phase: dichloromethane/2 N ammonia in methanol=20/1, isocratic). This gave 0.30 g of the target compound (96% pure, 57% of theory).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([C:21]3[CH:30]=[C:29]4[C:24]([CH2:25][CH2:26][N:27]([C:31](=[O:39])[CH2:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[CH2:28]4)=[CH:23][CH:22]=3)[N:18]=[C:17]([NH2:40])[N:16]=2)[CH2:11][CH2:10]1>>[CH:1]1([C:4]([N:36]2[CH2:35][CH2:34][CH:33]([CH2:32][C:31]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][C:21]([C:19]5[CH:20]=[C:15]([N:12]6[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]6)[N:16]=[C:17]([NH2:40])[N:18]=5)=[CH:22][CH:23]=4)[CH2:28]3)=[O:39])[CH2:38][CH2:37]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCN(C(=O)C5CC5)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 71, Step 4 starting from cyclopropanecarbonyl chloride (Aldrich, Cat. #C116807) and 4-(4-methylpiperazin-1-yl)-6-[2-(piperidin-4-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=518.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[O:16])=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(C#Cc2cccc(F)c2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(C#Cc2cccc(F)c2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of 4-((3-fluorophenyl)ethynyl)benzoic acid (2.0 g, 8.33 mmol) and DIPEA (2.38 g, 18.3 mmol) in DMF (35 mL) was added EDC (1.86 g, 10.0 mmol), HOBt (1.35 g, 10.0 mmol) and morpholine (1.07 g, 12.5 mmol). The reaction was stirred at room temperature for 18 h. The reaction was diluted with water (200 mL) and extracted with EtOAc (2×150 mL). The combined organic extracts were washed with water (2×100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (silica gel) using 0 to 90% EtOAc/hexanes to afford (4-((3-fluorophenyl)ethynyl)phenyl)(morpholino)methanone (2.35 g, 89%) as a light tan solid; 1H-nmr (400 MHz, CDCl3) δ 7.57 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.38-7.31 (m, 2H), 7.28-7.21 (m, 1H), 7.13-7.05 (m, 1H), 4.00-3.31 (bd s, 8H); LC (290 nM) 5.08 min (>98%); MS (ESI) m/z=310.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][S:21](=[O:33])(=[O:32])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:9]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>C(COC)OC>[OH:5][CH2:4][CH2:3][O:6][C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([NH:20][S:21](=[O:32])(=[O:33])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:9]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (17 mg, 60% dispersion in mineral oil) was added to ethylene glycol (1.2 ml) followed by addition of dimethoxyethane (0.5 ml). Stirring was continued for 30 min, then 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (45 mg, Referential Example 1e)) was added and the reaction mixture was heated to 80° C. for 48 h. The solvents were evaporated, water (10 ml) and a 10% solution of citric acid was added until the pH was 3 followed by extraction with EtOAc. The organic layers were dried over sodium sulfate and the solvent was evaporated. The crude product was purified by chromatography through silicagel with EtOAc to give 4-i-propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (38 mg). tR=4.56 min, (LC); [M+H]+=552.36 (ES+).