Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:26])([OH:25])[CH2:12][N:13]2[CH2:18][CH:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].O>CN(C=O)C>[CH3:26][C@@:11]1([CH2:12][N:13]2[CH2:18][CH:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:25][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CC=C(c2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CC=C(c3ccccc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.2 %

Procedure:
(S)-1-(2-Chloro-4-nitro-imidazol-1-yl)-2-methyl-3-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)propan-2-ol prepared in Example 275 (0.492 g, 1.31 mmol) was dissolved in DMF (8 ml). To the solution, sodium hydride (63 mg, 1.57 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 3 hours. To the reaction mixture, water was added. After extraction with ethyl acetate, the organic phase was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/acetone=4/1) and recrystallized from methylene chloride-ethyl acetate to afford (S)-2-methyl-6-nitro-2-(4-phenyl-1,2,3,6-tetrahydropyridin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole (0.059 g, yield 13%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:14]#[C:13][CH2:12][OH:15]
Reactant: Brc1ccc2ccccc2c1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCC#Cc1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
A mixture of 2-bromonaphthalene (19.83 g), CuI (1.59 g), 2-propyn-1-ol (10 ml) and dichlorobis(triphenylphosphine)palladium (II) (2.00 g) in triethylamine (300 ml) was stirred under argon atmosphere at 50° C. for 72 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate and the extract was washed with water and brine, dried over Na2SO4and concentrated in vacuo. The residue was chromatographed on silica gel (hexane:ethyl acetate=5:2) followed by recrystallization from hexane-ethyl acetate to give the titled compound (14.92 g) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]([C:35]4[CH:39]=[CH:38][O:37][N:36]=4)C(OCC(Cl)(Cl)Cl)=O)[O:22][C:21]3=[O:40])=[CH:16][C:15]=2[F:41])[CH2:10]1)=[O:7]>C(O)(=O)C.O.[Zn]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:35]4[CH:39]=[CH:38][O:37][N:36]=4)[O:22][C:21]3=[O:40])=[CH:16][C:15]=2[F:41])[CH2:10]1)=[O:7]
Reactant: COCCOC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COCCOC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
3-(4-(3(S)-(2-Methoxyethoxycarbonylamino)pyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one (400 mg, 0.5 mM) was stirred in a mixture of acetic acid (10 ml) and water (2 ml). Zinc dust (203 mg, 3.1 mM) was added, and the mixture stirred 30 minutes at ambient temperature. The mixture was filtered through celite, and the residue after evaporation partitioned between ethyl acetate (10 ml) and aqueous sodium bicarbonate (15 ml). The organic phase was washed with sodium bicarbonate (2×15 ml), water (15 ml), dried (magnesium sulfate), and evaporated. The crude product was purified by chromatography on a 10 g Biotage silica column, eluting with a gradient from dichloromethane to ethyl acetate. Relevant fractions were combined to give the desired product (141 mg).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30]([OH:38])(=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:30]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:38])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1ccccc1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with benzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-benzoyl-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 470 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:28]([O:27][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[CH:20][CH:21]=2)=[CH:11][CH:12]=1)[C:4]([OH:30])=[O:3])[CH3:29]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(NS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(NS(C)(=O)=O)cc2)cc1)C(=O)O
Yield: 104.3 %

Procedure:
2-Ethoxy-3-{4-[2-(4-methanesulfonylaminophenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 62) (0.554 g; 1.27 mmole) was dissolved in tetrahydrofuran (5.7 ml). Lithium hydroxide hydrate (0.137 g; 3,26 mmole) was dissolved in water and added in portions during 30 minutes at room temperature. The reaction mixture was kept in the refrigerator over night. Tetrahydrofuran was evaporated in vacuo. The water residue was washed with ethyl acetate, acidified with hydrochloric acid (1M) to pH 1-2 and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.54 g (yield 100%) of 2-ethoxy-3-{4-[2-(4-methanesulfonylaminophenyl)ethoxy]phenyl}propanoic acid.
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:15][C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[CH2:10][C:11]([O:13][CH3:14])=[O:12])(C(C)(C)C)(C)C.F>>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1/[CH:18]=[CH:17]/[C:16](=[O:27])[CH2:15][C@@H:9]([OH:8])[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C[C@@H](CC(=O)/C=C/c1ccc(Cl)cc1Cl)O[Si](C)(C)C(C)(C)C
Agent: F
Product: COC(=O)C[C@H](O)CC(=O)/C=C/c1ccc(Cl)cc1Cl

Procedure:
For instance, methyl (3R,6E)-3-[(tert-butyldimethylsilyl)oxy]-7-(2,4-dichlorophenyl)-5-oxo-6-heptenoate (which is one of the compounds of the formula (1)) is subjected to the tert-butyldimethylsilyl removing step using hydrogen fluoride in the manner as described in Japanese Patent Provisional Publication H5 (1993)-178841, to give methyl (3R,6E)-7-(2,4-dichlorophenyl)-3-hydroxy-5-oxo-6-heptenoate. The obtained ester is then subjected to Syn reduction using diethylmethoxyborane and sodium borohydride (NaBH4), to give methyl (3R,5S,6E)-7-(2,4-dichlorophenyl)-3,5-dihydroxy-6-heptenoate. Subsequently, thus obtained ester is treated with sodium hydroxide and hydrochloric acid in the manner as described in Journal of Medicinal Chemistry, 1985, vol. 28, No. 3, pp. 347-358, to give (+)-trans-(E)-6-[2-(2,4-dichlorophenyl)ethenyl]3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-on which has the 3-hydroxy-3-methylglutaryl Coenzyme A reductase preventive action.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:39])[CH3:38]>ClCCl>[CH:37]([N:40]1[CH2:45][CH2:44][N:43]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:42][CH2:41]1)([CH3:39])[CH3:38]
Reactant: CC(C)N1CCNCC1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2cc3c(cn2)ncn3-c2cc(O[C@H](C)c3ccccc3C(F)(F)F)c(C(N)=O)s2)CC1

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 128.2 mg of 1-isopropylpiperazin in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 61b (760 mg, 4.49 mmol), NBS (878 mg, 4.93 mmol) and DBPO (54 mg, 0.23 mmol) in carbon tetrachloride according to Method A. Crude product was purified by flash chromatography on silica-gel using hexane/ethyl acetate (8:1) as eluent. White solid. Yield: 297 mg, 73%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=4.54 (s, 2H), 7.42-7.53 (m, 3H), 7.71-7.77 (m, 1H), 7.80-7.85 (m, 1H), 7.98-8.04 (m, 2H), 8.72-8.76 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=29.7, 120.6, 127.0, 128.4, 128.8, 130.1, 137.6, 138.5, 149.6, 157.36; (ESI): m/z=249.66 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:6][CH:7]=1.C([BH3-])#N.[Na+].[CH3:30][C:31]([CH3:33])=O>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:31]([CH3:33])[CH3:30])[CH2:21][CH2:20]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(NCC2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]-5-methylbenzamide from Example 204 (1.0 g, 2.78 mmol) in 20 mL of acetone and 6 mL of 95:5 methanol-acetic acid was treated with sodium cyanoborohydride (0.70 g, 11.1 mmol). After stirring at room temperature for 24 h, the reaction mixture was applied to a 10 g SCX column, washed with methanol and eluted with 1 N ammonia in methanol. The yellow fractions were combined and concentrated in vacuo, affording 0.76 g (69%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[BH4-].[Na+].Cl>CO.C(O)(=O)C>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[CH:10][CH:9]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NCCCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNCCCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of 3-amino-propan-1-ol (15.0 g, 200 mmol) in methanol (300 ml) was added para-methoxybenzaldehyde (28.6 g, 210 mmol) and a few drops of acetic acid at room temperature. The mixture was stirred at room temperature for 2 hours and cooled to 0° C. After the addition of sodium borohydride (11.4 g, 300 mmol), the mixture was stirred at room temperature for another 2 hours and acidified with 3N hydrochloric acid. The biphasic mixture was stirred at room temperature for 10 minutes. The organic solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous phase was washed with ethyl acetate and basified with 6N sodium hydroxide. Extraction with chloroform was performed and the organic phase was dried over sodium sulfate followed by concentration in vacuo to afford 3-(4-methoxy-benzylamino)-propan-1-ol as pale yellow oil (16.4 g, 42%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:22]([Cu])#[N:23].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[C:22]([C:5]1[C:4]2[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[N:15][O:16][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)#[N:23]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(I)c2c(-c3cccs3)noc2c1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3cccs3)noc2c1O
Temperature: 110 °C
Yield: 57.9 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (310 mg, 0.745 mmol) and CuCN (200 mg, 2.24 mmol) were added to 5 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (4 mL, 15% aqueous solution) and EtOAc (100 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 136 mg of the title compound. MS: (+) m/z 316.29 (M+1).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[C:11]([OH:15])([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>O>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:7]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(C)(C)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.4 %

Procedure:
8.55 ml (64.69 mmol) of 4-toluoyl chloride are added dropwise to 10.52 ml (109.96 mmol) of tert-butanol and 10.46 ml (129.37 mmol) of pyridine while cooling in ice. The mixture is stirred at room temperature for 12 hours. After reaction is complete, water is added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with sodium bicarbonate solution, water and sodium chloride solution, dried over sodium sulphate and evaporated. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 50:1). 7.76 g (40.36 mmol, 62% yield) of the title compound are obtained as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccn1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1c[nH]cn1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2ncccn2)cn1
Yield: 72 %

Procedure:
As described for Example 40, 3-(3-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (100 mg, 0.41 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (95 mg, 72%) which was obtained as an off-white solid. MS: m/e=322.4 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1nc(C(C)(C)C)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Yield: 29.8 %

Procedure:
According to the procedure described in Example 161C, 3-tert-butyl-1-methyl-1H-pyrazol-5-amine (1.0 g, 6.5 mmol), and K2CO3 (1.17 g, 8.5 mmol) in THF (15 mL) were reacted with phenyl chloroformate (1.12 g, 7.2 mmol). The crude product was purified by silica gel chromatography with 0-50% EtOAc/hexane gradient to afford phenyl 3-tert-butyl-1-methyl-1H-pyrazol-5-ylcarbamate as solid (0.53 g, 31%). 1H NMR (300 MHz, DMSO-d6) δ 10.2 (s, 1H), 7.43 (m, 2H), 7.25 (m, 3H), 6.06 (s, 1H), 3.66 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 274 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[C:17][Si](C)(C)C)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]#[CH:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#CCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of (3-(4-benzyloxy-phenyl)-prop-1-ynyl)-trimethyl-silane (911 mg, 3.09 mmol) described in Manufacturing Example 29-2-1 in methanol (20 mL) was added potassium carbonate (854 mg, 6.18 mmol) at room temperature, which was stirred for 4 hours and 10 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain the title compound (618 mg, 90%).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-])=O)[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Ni]>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH2:14])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2ccc(N)cc2[nH]1
Yield: 88.5 %

Procedure:
To a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) in MeOH (10 mL) was added Raney Nickel (0.2 g). The mixture was hydrogenated under 1 atm of hydrogen at room temperature for 3 h. The reaction mixture was filtered and the filtrate was concentrated. The residue washed with petroleum ether to give 2-tert-butyl-1H-indol-6-amine (1.0 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.46 (s, 1H), 6.25 (dd, J=1.8, 8.1 Hz, 1H), 5.79 (d, J=1.8 Hz, 1H), 4.52 (s, 2H), 1.24 (s, 9H); MS (ESI) m/e (M+H+) 189.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][OH:25])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH3:37]N(C)C=O.[H-].[Na+].CI>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][O:25][CH3:37])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methanol (0.30 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.030 g) at 0° C. After stirring the reaction mixture at 0° C. for 30 min, methyl iodide (0.11 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-furyl)-4-{[2-methoxy-4-({[4-(methoxymethyl)-1-phenyl-1H-pyrazol-3-yl]oxy}methyl)phenoxy]methyl}-5-methyl-1,3-oxazole as colorless crystals (0.20 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: [C:1]([C:4]([C:15](=[O:17])[CH3:16])=[CH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH3:14])(=O)[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=1>C(O)(C)C>[C:15]([C:4]1[CH:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=2[CH3:14])[C:20]2[C:21](=[O:25])[NH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:1]=1[CH3:2])(=[O:17])[CH3:16]
Reactant: CC(=O)C(=Cc1ccc(C#N)cc1C)C(C)=O
Reactant: Nc1cc[nH]c(=O)c1
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1C

Procedure:
1.10 g (4.84 mmol) of 4-(2-acetyl-3-oxobut-1-en-1-yl)-3-methylbenzonitrile are taken up in 30 ml of isopropanol and, after addition of 592 mg (4.84 mmol) of 4-aminopyridin-2(1H)-one, heated at the reflux temperature for 72 h. The mixture is then concentrated, and the residue is again taken up in isopropanol and filtered through silica gel with isopropanol as eluent. The residue after concentration of the filtrate is mixed with a little methanol and crystallized. The precipitated product is filtered off, washed with diethyl ether and dried under high vacuum. 348 mg (22.5% of theory) of the title compound are obtained.
Reaction SMILES: CC[N:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[F:8][C:9]([F:15])([F:14])[CH2:10]CC=O>>[F:15][C:9]([F:8])([F:14])[CH2:10][CH2:7][CH2:6][NH:3][CH2:4][CH2:5][CH2:10][C:9]([F:15])([F:14])[F:8]
Reactant: CCN(CC)CC
Reactant: O=CCCC(F)(F)F
Product: FC(F)(F)CCCNCCCC(F)(F)F

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, 4,4,4-trifluorobutan-1-amine, HCl (598 mg, 4.00 mmol), Et3N (550 μL, 4.00 mmol) and 4,4,4-trifluorobutanal (504 mg, 4.00 mmol) provided a colorless oil which was used directly in the preparation of Example 129. MS(ESI+) m/z 192.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](Cl)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>ClC(Cl)C.C(O)(C)(C)C>[Br:1][C:2]1[S:10][C:9]2[C:8]([NH:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Clc1ncnc2cc(Br)sc12
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Temperature: 25 °C
Yield: 121.7 %

Procedure:
6-Bromo-4-chloro-thieno[3,2-d]pyrimidine (7.73 g, 31 mmol) was dissolved in 50 mL of dichloroethane and 50 mL of t-butyl alcohol, and 5-aminoindole (4.09 g, 31 mmol) were added. The reaction mixture was refluxed for 14 hours, cooled to room temperature, and concentrated in vacuo to afford 13.02 g of (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine. The crude material was used without further purification (83% purity). 1H NMR (400 MHz, DMSO) d 11.1 (s, 1H), 9.62 (s, 1H), 8.38 (s, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 7.35 (m, 2H), 7.10 (d, 1H), 6.40 (s, 1H); LC-MS: 345, 347 (MH+); HPLC RT: 3.77 minutes.