Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=2)[CH2:3]1.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH:38][C:39](=O)[O:40]C1C=CC=CC=1>C1COCC1>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([C:21]([C:16]2[CH:15]=[C:14]3[C:19]([C:20]4[C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:39]([NH:38][C:34]6[S:33][CH:37]=[CH:36][N:35]=6)=[O:40])[CH2:3]5)=[CH:9][CH:10]=[C:11]([C:30]([NH2:32])=[O:31])[C:12]=4[NH:13]3)=[CH:18][CH:17]=2)=[O:22])[CH2:24][CH2:25]1
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(N4CCC[C@@H](N)C4)c23)CC1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(N4CCC[C@@H](NC(=O)Nc5nccs5)C4)c23)CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
A solution of (R)-4-(3-aminopiperidin-1-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 17-1, 23 mg, 0.053 mmol) and TEA (0.015 mL, 0.106 mmol) in THF (3 mL) was treated with phenyl thiazol-2-ylcarbamate (17.49 mg, 0.079 mmol). The mixture was stirred at 60° C. for 1.5 h, then at 70° C. for 2 h, then was concentrated and purified by preparative HPLC. The isolated TFA salt was partitioned between DCM and NaHCO3 (aq), and the organic phase was dried and concentrated to provide (R)-7-(4-methylpiperazine-1-carbonyl)-4-(3-(3-thiazol-2-ylureido)piperidin-1-yl)-9H-carbazole-1-carboxamide as a white solid (14 mg, 43%). 1H NMR (400 MHz, methanol-d4) δ 8.27 (1H, d, J=7.9 Hz), 7.87 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=1.1 Hz), 7.28 (1H, d, J=7.9 Hz), 7.18 (1H, br. s.), 6.93 (1H, d, J=3.7 Hz), 6.87 (1H, d, J=8.3 Hz), 4.25 (1H, br.), 3.82 (2H, br.), 3.41-3.68 (3H, m), 3.19 (3H, br.), 2.36-2.63 (4H, m), 2.33 (3H, s), 1.84-2.20 (3H, m), 1.71 (1H, br. s.). Mass spectrum m/z 561.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[NH2:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:7]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To 1.37 g of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 460 mg of 2-aminopyrazine, 277 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2.04 g of tripotassium phosphate and 248 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, was added 30 ml of 1,4-dioxane, and the mixture was subjected to degassing and was substituted with argon gas, and then was stirred at 100° C. for 2 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 960 mg of the objective compound as pale yellow powder.
Reaction SMILES: [Si]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21]4[N:26]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=5[O:36][CH3:37])[C:25](=[O:38])[C:24]([C:39]([O:41][CH3:42])=[O:40])=[CH:23][C:22]=4[CH2:43][CH3:44])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:37][O:36][C:29]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=1[CH2:27][N:26]1[C:21]([C:17]2[CH:18]=[CH:19][C:20]3[N:12]4[CH2:11][CH2:10][CH:9]([OH:8])[C:13]4=[CH:14][C:15]=3[CH:16]=2)=[C:22]([CH2:43][CH3:44])[CH:23]=[C:24]([C:39]([O:41][CH3:42])=[O:40])[C:25]1=[O:38]
Reactant: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc1n2CCC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of methyl 6-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)-1-(2,4-dimethoxybenzyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (1.7 g, 2.8 mmol) in THF (40 mL) was added a solution of TBAF (2.9 mL, 1M, 2.9 mmol). The dark red solution was stirred for 1 h at room temperature and then concentrated. The crude residue was purified on silica gel eluting with EtOAc to afford the title compound as yellow oil (1.3 g, 93%).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[C:8]([CH3:10])=[CH2:9].C(N(CC)CC)C>O>[C:13]([O:12][C:7](=[O:11])[CH:8]([CH3:10])[CH2:9][S:1][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=C(C)C(=O)OC(C)(C)C
Reactant: OCC(O)CS
Solvent: O
Solvent: CCN(CC)CC
Product: CC(CSCC(O)CO)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
To thioglycerol (0.835 mI), t-butyl methacrylate (10 ml) and triethylamine (1 ml) were added, followed by stirring at 60° C. for 48 hours. After cooling and addition of water, the reaction mixture was extracted with chloroform. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off, to yield the title compound (2.11 g, yield 84%) as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC(CON)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl 2-[(aminooxy)methyl]morpholine-4-carboxylate 156 (0.317 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 157 (0.35 g, 79%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26](=[O:33])(=[O:32])[N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:20]=4)[C:15]([CH3:35])([CH3:34])[CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26](=[O:32])(=[O:33])[N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:20]=4)[C:15]([CH3:35])([CH3:34])[CH2:14][NH:13]3)[CH2:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2(C)C
Agent: [BH4-]
Agent: [Na+]
Product: CCN(CC)S(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2(C)C
Product: Cl

Procedure:
N′-[2-({1-[1-(4-Chlorophenyl)cyclobutyl]-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]-N,N-diethylsulfuric diamide hydrochloride was prepared analogously to example 65 using N′-[2-({1-[1-(4-chlorophenyl)cyclobutyl]-4,4-dimethyl-3,4-dihydroisoquinolin-7-yl}oxy)ethyl]-N,N-diethylsulfuric diamide (68 mg, 0.13 mmol) and sodiumborohydride (10 mg, 0.26 mmol). Yield: 60 mg (0.11 mmol, 82%, colorless foam).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([Br:10])=[CH:5][C:3]=1[NH2:4].[C:11](N1C=CN=C1)(N1C=CN=C1)=S.[NH:23]([C:25](=[O:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1)=[O:27])[NH2:24].CCN=C=NCCCN(C)C>CN(C=O)C.O>[Br:10][C:6]1[C:7]([F:9])=[CH:8][C:2]([F:1])=[C:3]([NH:4][C:11]2[O:41][C:25]([C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[CH:33][CH:34]=3)=[O:27])=[N:23][N:24]=2)[CH:5]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Br)c(F)cc1F
Reactant: NNC(=O)C(=O)Nc1ccc(N2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1nnc(Nc2cc(Br)c(F)cc2F)o1
Reaction time: 16 h
Yield: 35.1 %

Procedure:
2,4-Difluoro-5-bromoaniline (208 mg, 1.04 mmol) was added to a solution of thiocarbonyldiimidazole (185 mg 1.04 mmol) in DMF (10 mL) and the mixture was stirred for 16 h. 2-Hydrazino-N-(4-morpholin-4-ylphenyl)-2 oxoacetamide (Intermediate 27, 211 mg, 0.8 mmol) was added and the mixture was stirred at 80° C. until a clear solution was obtained. EDAC (306 mg, 1.6 mmol) was added and stirring was continued for a further 1 h. The mixture was cooled then diluted with water (25 mL) and the resulting precipitate was filtered and dried to give the title compound the title compound (135 mg) as a solid;
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH2:11][NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCC1CCCCC1
Reactant: CCOC(CN)OCC
Product: CCOC(CNCC1CCCCC1)OCC
Reaction time: 8 h
Yield: 29.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-5 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with bromomethylcyclohexane (2.77 ml, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform:methanol=100:0 to 98:2) to obtain the title compound (1.36 g, 30%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[CH:23]1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]3[C:26]4[CH:27]=[CH:28][C:29]([C:31]5[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=5)=[CH:30][C:25]=4[N:24]=[CH:23]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: NCCn1cnc2cc(C3=NNC(=O)CC3)ccc21
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: O=C1CCC(c2ccc3c(c2)ncn3CCNCC(O)COc2ccc(CCOCC3CC3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[C:20]([O:27][CH3:28])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([C:24]([NH:32][O:30][CH3:31])=[O:25])[CH:21]=[C:20]([O:27][CH3:28])[N:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CON
Reactant: COc1cc(C(=O)O)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Agent: Cl
Product: CONC(=O)c1cc(OC)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-6-methoxypyrimidine-4-carboxylic acid (Example 174) and methoxylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=O.[F:22][C:23]([F:31])([F:30])[C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[F:22][C:23]([F:31])([F:30])[C:24]([C:25]1[C:26]([CH3:27])=[N:1][C:2]2[C:3]([C:13]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[CH:4][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=2)=[O:29]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccc(F)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 96 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(4-fluoro-phenyl)-methanone [example A9] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 96%; MS: m/z=417 (M).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[O:13][CH3:14])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C#Cc1ccccc1OC
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1ccccc1OC)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 80 %

Procedure:
The title compound was synthesized from (2-methoxy-phenyl)-propynoic acid ethyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in a 80% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.45 (m, 1H), 7.28–6.95 (m, 4H), 6.85–6.60 (m, 4H), 6.49 (m, 2H), 6.25 (s, 1H), 4.39 (m, 2H), 4.09 (q, 2H, J=7.2 Hz), 3.68 (s, 2H), 3.58 (s, 1H), 3.80 (m, 2H), 3.20 (m, 2H), 2.70 (m, 2H), 1.89 (m, 2H), 1.50 (s, 9H), 1.25 (t, 3H, J=6.8 Hz). Mass Spectrum (LCMS, ESI) calculated for C30H32N3O4 498.2 (M-Boc+H); found 498.4.
Reaction SMILES: Br[C:2]1[C:3]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[N:4][C:5]2[N:6]([N:25]=[CH:26][C:27]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:7]=1[N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C.C([Sn](CCCC)(CCCC)[C:49]([O:51]CC)=[CH2:50])CCC>O1CCOCC1.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>[NH2:8][C:7]1[N:6]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:5]2[N:4]=[C:3]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)[C:2]=1[C:49](=[O:51])[CH3:50]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn2c1N
Temperature: 100 °C

Procedure:
A degassed mixture of 6-bromo-5-morpholino-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (141 mg, 0.20 mmoL), tributyl(1-ethoxyvinyl)tin (112 mg, 0.31 mmoL), Pd(PPh3)4 (24 mg, 0.02 mmoL) in Dioxane (4 mL) was heated at 100° C. for 2 days. The mixture was cooled to room temperature and filtered through short plug of 10% KF/SiO2. The crude Stille coupling product obtained after concentrating the filtrate was then treated with 3 mL of 1:1 mixture of TFA and H2O at room temperature for 30 min. Concentration and purification by prep-LC afforded 1-(7-amino-5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone. LCMS tR=3.32 Min. Mass calculated for, M+ 388.1, observed LC/MS m/z 389.1 (M+H).
Reaction SMILES: CN(C)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][O:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[C:27]3[CH:28]=[CH:29][C:30]([O:32]CC4C=CC=CC=4)=[CH:31][C:26]=3[S:25][N:24]=2)[CH2:18]1>ClCCl>[CH3:14][O:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[C:27]3[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=3[S:25][N:24]=2)[CH2:18]1
Reactant: COC[C@@H]1CN(c2nsc3cc(OCc4ccccc4)ccc23)C(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: COC[C@@H]1CN(c2nsc3cc(O)ccc23)C(=O)O1
Temperature: -8 °C
Yield: 88.1 %

Procedure:
8.7 ml (68 mmol) of dimethylaniline and 6.9 g (0.051 mol) of aluminium chloride are added in three portions over 4 hours to a solution of 2.10 g (5.67 mmol) of (S)-5-methoxymethyl-3-[6-(phenylmethoxy)-1,2-benzisothiazol-3-yl]oxazolidin-2-one in 76 ml of dichloromethane, which solution is cooled at -8° C. The mixture is poured into ice-water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. After purification by chromatography on a silica column with dichloromethane and methanol, in proportions of 99:1, and trituration in diisopropyl ether, 1.4 g of product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:39])[C:12]2[CH:17]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[C:14]([C:24]3[O:25][C:26]([C:29](O)([CH3:37])[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:28]=3)[CH:13]=2)[CH3:9])=[CH:4][CH:3]=1.[N-:40]=[N+]=[N-].[Na+].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:39])[C:12]2[CH:17]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[C:14]([C:24]3[O:25][C:26]([C:29]([NH2:40])([CH3:37])[CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:28]=3)[CH:13]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)c1cc(-c2ccc(C(C)(O)Cc3ccccc3)o2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C[C@@H](NC(=O)c1cc(-c2ccc(C(C)(N)Cc3ccccc3)o2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1

Procedure:
To a solution of Example 50 (0.080 g, 0.15 mmol) in 1 mL CHCl3 was added a suspension of sodium azide (0.094 g, 1.45 mmol) in TFA (0.06 mL, 0.73 mmol). The solution progressively turned dark over 1 h to afford a mixture of desired product and a byproduct resulting from dehydration. Concentrated and used as is in next reaction. LCMS [M+H]+=575.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:23][CH:24]([NH2:27])[CH2:25][OH:26]>>[OH:26][CH2:25][CH:24]([NH:27][C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])[CH3:23]
Reactant: CC(N)CO
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)n(C)n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC(C)CO)n(C)n1
Yield: 70 %

Procedure:
As described for example 85b, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (60 mg, 0.2 mmol), was converted, using DL-2-amino-1-propanol instead of ethanolamine, to the title compound (48 mg, 70%) which was obtained as a colorless oil. MS: m/e=351.3 [M+H]+.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].N1C=CN=C1.C([Si](C)(C)Cl)(C)(C)C.O>CN(C=O)C>[CH2:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=2)[C:6](=[O:11])[CH2:5]1
Reactant: O=C1CCc2c(O)cccc21
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 4-hydroxy-1-indanone (25.0 g, 169 mmol) and imidazole (28.7 g, 422 mmol) in DMF (500 ml) was added tert-butyldimethylchiorosilane. The reaction mixture was stirred overnight at room temperature and treated with water (500 ml) and extracted with diethyl ether (500 ml). The organic phase was collected and dried over sodium sulfate. Evaporation gave a yellow oil which was distilled under reduced pressure to give indanone (1) (35.44 g, 135 mmol, 79.9%) as a colourless oil (120–121° C./0.1 mbar).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.S(=O)(=O)(O)O.[Br:23]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:23][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[C:7]([NH2:12])=[N:8][CH:9]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)cc1OCc1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
32.6 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 4A; 138 mmol, 1 equivalent) were suspended in 552 ml of 10% strength sulphuric acid, and the mixture was cooled to 0° C. 8.5 ml of bromine (165 mmol, 1.2 equivalents) were dissolved in 85 ml of acetic acid and then, over a period of 90 min, added dropwise to the ice-cooled reaction solution. After the dropwise addition had ended, the mixture was stirred at 0° C. for 90 min and then diluted with 600 ml of ethyl acetate, and the aqueous phase was separated off. The aqueous phase was re-extracted with ethyl acetate and the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried and concentrated. The residue was dissolved in dichloromethane and chromatographed on silica gel (petroleum ether/ethyl acetate gradient as mobile phase). This gave 24 g (55% of theory) of the title compound. LC-MS (Method 1): Rt=0.96 min
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[N:21]2)=[CH:17][CH:16]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[N:21]2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)cn2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]methanol (2.82 g), activated manganese dioxide (6.00 g), and tetrahydrofuran (50 ml) was stirred at room temperature for 2 hours. After the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-carbaldehyde (2.63 g, yield: 94%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).