Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[OH-].[Na+].[Pt]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][CH:3]=1
Reactant: OC(Cc1ccccn1)c1ccc(Br)cc1
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: OC(CC1CCCCN1)c1ccc(Br)cc1
Reaction time: 3 h

Procedure:
1 mmol of the compound obtained in Example 58 is dissolved in 20 ml of acetic acid, and 8 mg of platinum oxide are added. The hydrogenation is carried out starting from an initial pressure of 3 atmospheres at 24° C. After reacting for 3 hours, the catalyst is filtered off and washed with dichloromethane. The solvents are evaporated off and the residue obtained is dissolved in 10% sodium hydroxide solution and extracted with dichloro-methane. The organic phase is washed with water, dried over MgSO4 and then evaporated off to yield the title compound in the form of a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:37])[CH3:11])=[CH:6][CH:5]=1.CC(C)=[O:40].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][O:27][CH2:26][CH2:25][CH2:24][C@@:15]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13](=[O:37])[N:12]([C@H:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:2]([OH:40])=[O:1])=[CH:5][CH:6]=3)[CH3:11])[CH2:17][CH2:16]2)=[CH:34][CH:33]=1
Reactant: CC(C)=O
Reactant: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CCO)cc3)C(=O)O2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CC(=O)O)cc3)C(=O)O2)cc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of (R)-3-((S)-1-(4-(2-hydroxyethyl)phenyl)ethyl)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-1,3-oxazinan-2-one (260 mg, 0.517 mmol) in acetone (2 mL) was added Jones reagent (0.25 mL, 2.5 mol/L), and the formed mixture was stirred for 30 min. The mixture was extracted with EtOAc. The combined organic layer was concentrated to give crude 2-(4-((S)-1-((R)-6-(3-(4-methoxybenzyloxy)propyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)acetic acid (260 mg, 97%), which was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Br.[NH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])=[O:15].C(N(CC)CC)C.Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:12][CH2:13][C:14]([NH:16][C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=2[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])=[O:15])=[CH:4][CH:3]=1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(CNC(=O)Nc1ccc(Cl)cc1)Nc1ccccc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
A solution of p-chlorophenylisocyanate (756 mg, 4.92 mmol) in tetrahydrofuran (8 ml) is added to a solution of the salt 3a (1.341 g, 4 mmol) prepared in Preparation 3 in tetrahydrofuran (50 ml). Triethylamine (558 μl, 4 mmol) is added at 0° C., and the mixture is stirred at 0° C. for 30 minutes, and then at room temperature overnight. Water and then 10% hydrochloric acid are added, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried (sodium sulfate), and distilled under reduced pressure to remove solvent. The residue is recrystallized from dichloromethane/diisopropylether to obtain the objective compound 6y (1.48 g, 76%).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[S:17][C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:18]([C:16]1[S:17][C:13]([Br:12])=[CH:14][CH:15]=1)=[O:19])[CH2:4]2
Reactant: O=C(O)c1ccc(Br)s1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
Yield: 92.7 %

Procedure:
A mixture of (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride (4 g), 5-bromothiophene-2-carboxylic acid (4.25 g), 1-hydroxybenzotriazole hydrate (2.77 g), O-benzotriazol-1-yl-N,N,N′-tetramethyluronium tetrafluoroborate (6.6 g), and N,N-diisopropylethylamine (14 mL), in N,N-dimethylformamide (100 mL) was stirred at room temperature overnight. The solution was evaporated, and the residue was partitioned between aqueous sodium hydroxide and chloroform. The chloroform layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography on silica gel and eluted with 5%-20% 3.5N methanolic ammonia/chloroform mixtures. Evaporation of solvent gave yellow solid (5.87 g); MS (ES+) 315, 317 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20][NH:28][CH2:25][CH2:26][CH3:27])[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(Cl)cc2C1=O
Reactant: CCCN
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2cc(Cl)ccc2-3)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.3 %

Procedure:
A solution of 200 mg (0.54 mmol) of 8-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 4 ml of N,N-dimethylformamide was treated with 0.136 ml (1.65 mmol) of propylamine and stirred at room temperature under argon for 1.5 hrs. The solution was evaporated and the residue was triturated in 10 ml of water. The aqueous phase was extracted with methylene chloride and the combined extracts were washed twice with water, dried with sodium sulfate, filtered and evaporated. The combined crude products were chromatographed on 30 g of silica gel (ethyl acetate methylene chloride/methanol 9:1). There were obtained 126 mg of 8-chloro-3-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as a foam which was converted in acetonitrile with ethereal hydrochloric acid into the hydrochloride. By crystallization from hot acetonitrile there were obtained 102 mg (42%) of 8-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (1:1.8) of m.p. 230°-240° (dec.).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(O)C>[CH2:15]([N:17]([CH2:18][CH3:19])[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:16]
Reactant: Clc1nc2ccccc2n2ccnc12
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)c1nc2ccccc2n2ccnc12

Procedure:
A mixture of 2,8 g of 4-chloroimidazo[1,2-a]quinoxaline (example 1) and 9.8 ml of diethylamine in 40 ml of ethanol is refluxed for 4 h. After evaporating the solvent, the residue is taken up in chloroform and washed with water and saturated NaCl, then dried and evaporated, thereby obtaining 2.2 g of raw product that is subsequently chromatographed on SiO2 (eluent: CH2Cl2): after recrystallization from n-hexane there are obtained 1.3 g of 4- diethylaminoimidazo[1,2-a]quinoxaline. m.p. (DSC)=91.7° C. (onset); IR (KBr): 2976, 1518, 1425, cm-1 ; 1H-NMR (CDCl3): δ7.9 (1H,s), 7.7÷7.4 (3H,m), 7.35÷7.05 (2H,m), 4.15 (4H,q), 1.3 (6H,t); UV (EtOH): λmax =231, 250, 293, 305, 332, 348 nm. Elementary analysis for C14H16N4 (m.w. 240.31): calcd. C 69.97, H 6.71, N 23.31%; found C 69.99, H 6.80, N 23.13%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[Cl-].[CH2:12]1[CH2:16]OC[CH2:13]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:16][CH:12]=[CH2:13])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: C1CCOC1
Agent: [Cl-]
Product: C=CCC(O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the aldehyde from Step F (7.97 g, 39.1 mmol) in 40 mL of THF at −78° C. under argon was added dropwise a solution of allymagnesium chloride in THF (23.4 mL, 46.9 mmol, 2M). After one hour, another portion of allymagnesium chloride solution was added (5 mL, 10 mmol). After an additional 30 minutes, the solution was quenched with saturated aqueous ammonium chloride, warmed to room temperature, and poured into ethyl acetate. The solution was washed with washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([NH:19]C(=O)OC(C)(C)C)[N:15]=[CH:16]2)=[CH:11][N:10]=1>ClC(Cl)C>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([NH2:19])[N:15]=[CH:16]2)=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2cnc(Cl)cc2cn1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: Nc1cc2cnc(Cl)cc2cn1
Reaction time: 4 h
Yield: 91.5 %

Procedure:
Trifluoroacetic acid (0.43 mL, 5.5 mmol) was added to a solution of tert-butyl 7-chloro-2,6-naphthyridin-3-ylcarbamate (410 mg, 1.4 mmol) in dichloroethane (7 mL). After 4 hours, the reaction mixture was concentrated in vacuo, diluted with methylene chloride (50 mL), and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-100% ethyl acetate in heptane) to afford the title compound as a yellow solid (230 mg, 86%), which was used in the next step without further purification.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][S:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Sc1ccccn1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3ccccn3)C(=O)O)cc2)cc1

Procedure:
Example 47 is prepared from 2-mercaptopyridine and 1d using the procedure described for compound 20.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C)=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=1)[N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][CH:2]([CH3:22])[CH:3]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=1)[N:4]1[CH:8]=[N:7][CH:6]=[N:5]1
Reactant: CC(=O)Nc1ccc(C(C(C)C)n2cncn2)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1cncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
A mixture of 20 parts of intermediate 17, namely N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2-nitrophenyl]acetamide and 200 parts of a hydrochloric acid solution 2N was stirred for 12 hours at room temperature. The reaction mixture was poured into 500 parts of water and the whole was neutralized with a concentrated potassium carbonate solution. The product was extracted with dichloromethane (3×130 parts). The combined extracts were dried, filtered and evaporated to dry. The residue was crystallized from 2,2'-oxybispropane, yielding 18.5 parts (97.7%) of 4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2-nitrobenzenamine; mp. 206° C. (interm. 18).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=2[C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>>[C:1]1([CH2:7][C:8]2[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=2[C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([Cl:28])=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Product: O=C(Cl)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1

Procedure:
A mixture of 2.0 g of 4-[[2-(phenylmethyl)benzoyl]amino]benzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 1.53 g of the desired product as an oil. M+ =346 as methyl ester.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:16]=4[F:23])[C:13](=[O:24])[CH:12](C(OCC)=O)[C:11]3=[O:30])=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:16]=4[F:23])[C:13](=[O:24])[CH2:12][C:11]3=[O:30])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C1C(=O)C(c2cc(F)cc(F)c2F)N(c2ccc3[nH]cnc3c2)C1=O
Agent: Cl
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1cc(F)cc(F)c1F

Procedure:
The compound was synthesized starting from ethyl 1-(1H-benzo[d]imidazol-5-yl)-2,4-dioxo-5-(2,3,5-trifluorophenyl)pyrrolidine-3-carboxylate (which may be prepared in accordance with the procedure described for Intermediate 7; 0.036 g, 0.086 mmol) and 5 N aqueous hydrochloric acid (3 ml) according to the method described in Method 1, step 3.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2C(=O)C=[N+]=[N-])[N:3]=1.CO.[C:19]([O:22][CH2:23]C)(=[O:21])[CH3:20]>C(N(CC)CC)C.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[CH3:23][O:22][C:19](=[O:21])[CH2:20][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]2
Reactant: [N-]=[N+]=CC(=O)c1cccc2nc(Cl)ccc12
Reactant: CCOC(C)=O
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc2nc(Cl)ccc12
Yield: 55 %

Procedure:
A mixture of 2.17 g (9.37 mmol) 1-(2-chloro-quinolin-5-yl)-2-diazo-ethanone and 20 mL methanol was brought to reflux. A solution of 0.20 g (0.87 mmol) silver benzoate in 1 mL triethylamine was added to the reaction mixture. After 10 min at reflux, TLC analysis (ethyl acetate, silica, Rf prod 0.8) showed starting material consumed. The solvent was removed under reduced pressure and the resulting black residue was purified on 100 g 230-400 mesh silica eluting with 1:1 hexanes/ethyl acetate to give 1.20 g (5.09 mmol, 55%) of (2-chloro-quinolin-5-yl)-acetic acid methyl ester as a white amorphous solid. MS (APCI) m/z 236 (M, 100% abundance), 238 (M+2, 32% abundance). 1H NMR (400 MHz) CDCl3 8.31 (d, J=8.9 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.74 (m, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 4.05 (s, 2H), 3.68 (s, 3H).
Reaction SMILES: [OH-].[K+].F[C:4]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:5]=1[N:6]([CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:7]([CH3:10])[CH2:8][OH:9].C(OC=C(C(OCC)=O)C(OCC)=O)C.O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:28][C:25]1[CH:24]=[CH:23][C:5]2[N:6]([CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:26]=1[F:27]
Reactant: CCOC(=O)C(=CN(c1ccc(F)c(F)c1F)[C@@H](C)CO)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OC[C@@H]1C)C(=O)OCC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide (180 mg) and tetrabutylammonium hydrogensulfate (90.4 mg) were dissolved in DMF (15 ml) by heating to 60° C. and a solution of diethyl [2,3,4-trifluoro[(1S)-2-hydroxy-1-methylethyl]anilino]methylenemalonate (1 g, 99.8% ee) and diethyl ethoxymethylenemalonate (120 mg) in DMF 85 ml) was added thereto. The obtained mixture was stirred at the same temperature for 2 hours. After adding water, the liquid reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography. Thus, 852 mg (99.8% ee) of the title compound was obtained as a yellow oily substance. Various spectral data was identical with those described in Japanese Patent No. 2,769,174.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:37][N:23]([S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])[C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCCC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@@H]3CCCC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To the stirred solution of 125 mg of tert-butyl trans-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylate in 4 mL of N,N-dimethylformamide was added 133 mg of potassium carbonate, followed by 68 mg of iodomethane. The suspension was stirred at room temperature over night. After removal of the volatile material in vacuo, 80 ml of ethyl acetate was added. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was to provide 121 mg (97% yield) of tert-butyl trans-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylate after flash column chromatography eluting with ethyl acetate/hexane (3:7). MS: 525.2 (M+H)+
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][CH2:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][CH:21]([C:26]([O:28]C)=O)[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1.[CH3:32][NH2:33]>CO.O1CCCC1>[CH3:32][NH:33][C:26]([CH:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:31][CH:30]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:28]
Reactant: CN
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Dimethyl 2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonate (3.00 g, 7.08 mmol) synthesized according to the method described in WO95/18125 was dissolved in methanol-tetrahydrofuran (1:1, 100 ml), and 40% aqueous methylamine solution (50 ml) was added. The mixture was stirred at room temperature for 0.5 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=1:2) to give the title compound (1.50 g, yield 50%) as a white solid.
Reaction SMILES: C([C:3]1[C:8]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[C:18]([C:30]34[CH2:39][CH:34]5[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]5)[CH2:31]3)[CH2:37]4)[CH:17]=2)[N:4]=1)C.B(Br)(Br)Br>C(Cl)Cl>[C:30]12([C:18]3[CH:17]=[C:16]([C:5]4[N:6]=[CH:7][C:8]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][N:4]=4)[CH:21]=[CH:20][C:19]=3[OH:22])[CH2:37][CH:36]3[CH2:38][CH:32]([CH2:33][CH:34]([CH2:35]3)[CH2:39]1)[CH2:31]2
Reactant: CCOC(=O)CNc1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)nc1CC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CNc1cnc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Yield: 102.1 %

Procedure:
A solution of ethyl 2-[3-(1-adamantyl)-4-benzyloxyphenyl]-5-(carbethoxymethylamino)pyrimidine (51 mg, 0.10 mmol), 1.0 M BBr3 (0.56 mmol) in CH2Cl2 (0.6 mL) and CH2Cl2 (1.4 mL) was stirred at −78° C. under argon for 2 h, quenched with H2O (10 mL) and extracted with EtOAc (100 mL). The extract was washed (water and brine) and dried. After solvent removal at reduced pressure, the residue was chromatographed (1:4 EtOAc/hexane) to give 41.6 mg (99%) of 2-[3-(1-adamantyl)-4-hydroxyphenyl]-5-(carbethoxymethylamino)pyrimidine as a pale-tan solid, mp 190° C. (dec). IR 3432, 2904, 1708, 1211 cm−1; 1H NMR (CDCl3) δ 1.32 (t, J=7.2 Hz, 3H, OCH2CH3), 1.79 (bs, 6H, AdCH2), 2.09 (bs, 3H, AdCH), 2.21 (m, 6H, AdCH2), 4.30 (q, J=7.2 Hz, 2H, OCH2CH3), 4.60 (m, 1H, NH), 4.72 (s, 2H, NHCH2CO), 5.85 (s, 1H, OH), 6.71 (d, J=8.4 Hz, 1H, 5′-ArH), 8.03 (dd, J=8.4 Hz, 2.1 Hz, 1H, 6′-ArH), 8.27 (d, J=2.1 Hz, 1H, 2′-ArH), 8.45 ppm (s, 2H, 4-ArH, 6-ArH). HRMS calcd C24H29N3O3 [M+H]+ 408.2287. found 408.2291.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH:36]1([C:39]2[C:47]3[C:46]([NH2:48])=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]([CH2:49][C:50]3[CH:54]=[CH:53][N:52]([CH:55]([CH3:57])[CH3:56])[N:51]=3)[N:40]=2)[CH2:38][CH2:37]1.[OH-].[Na+]>CN1C(=O)CCC1>[CH:36]1([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][C:46]=3[NH:48][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:22])[N:41]([CH2:49][C:50]3[CH:54]=[CH:53][N:52]([CH:55]([CH3:57])[CH3:56])[N:51]=3)[N:40]=2)[CH2:37][CH2:38]1
Reactant: CC(C)n1ccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)n1ccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (130 mg, 0.411 mmol) was added NMP (10 mL). The solution was cooled to 0° C. and 2,4,6-trichlorobenzoyl chloride (65.6 μl, 0.411 mmol) was added dropwise. The cold bath was removed once the addition was complete. The reaction mixture was stirred for 1 hour during which time a cloudy suspension formed. 3-Cyclopropyl-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (90 mg, 0.305 mmol) was added and the reaction mixture was heated at 88° C. for 11 hours. The mixture was cooled to ambient temperature and NMP was removed by vacuum distillation to give an oily residue. To this was added 10% NaOH aqueous solution (10 mL) and the resulting clear solution was stirred at 80° C. for 30 minutes. The solution was cooled to ambient temperature and extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure and the residue was triturated with Et2O (50 mL). The resulting solids were collected by filtration, washed with Et2O (40 mL) and dried under vacuum to give the final product (125 mg). MS (ES+APCI) m/z=582 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:18]=[C:17]([CH:19]=[CH2:20])[S:16][CH:15]=3)[CH:9]=2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[CH2:19]([C:17]1[S:16][CH:15]=[C:14]([C:10]2[CH:9]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:13]=[CH:12][N:11]=2)[CH:18]=1)[CH3:20]
Reactant: C=Cc1cc(-c2cc(N3CCN(C)CC3)ccn2)cs1
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(-c2cc(N3CCN(C)CC3)ccn2)cs1

Procedure:
A solution of 1-Methyl-4-[2-(5-vinyl-thiophen-3-yl)-pyridin-4-yl]-piperazine in ethanol was treated with a catalytic amount of 10% palladium on carbon and placed under an H2 atmosphere at room temperature. The resulting mixture was filtered and concentrated to yield the title compound.