Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1nc(-c2ccc(Cl)cc2Cl)cs1
Product: O=C(Nc1nc(-c2ccc(Cl)cc2Cl)cs1)c1cc(Cl)ccc1O
Yield: 8 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-(2,4-dichlorophenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.Cl[CH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[O:10][CH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: ClCc1ncccn1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ncccn2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 4-nitro-m-cresol (0.25 g, 1.6 mmol), 2-(chloromethyl)pyrimidine hydrochloride (0.40 g, 2.4 mmol) and potassium carbonate (0.50 g, 4.0 mmol) in N,N-dimethylformamide (6.0 mL) was stirred at 70° C. for 18 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford 2-[(3-methyl-4-nitrophenoxy)methyl]pyrimidine as crude material (0.32 g, y. 81%) as solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([NH:27][C:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]=1)[C:25]#[CH:26].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:32]2/[C:28]([NH:27][CH2:24][C:25]#[CH:26])=[N:29][C:30](=[O:33])[O:31]/2)[CH2:8][CH2:7]1
Reactant: C#CCNC1=NC(=O)OC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)O/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 1 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (339 mg) and 4-(prop-2-yn-1-ylamino)-1,3-oxazol-2(5H)-one (152 mg) in 2-propanol (3 mL) was added piperidinium acetate (160 mg) at room temperature. The reaction mixture was stirred at 90° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to give the title compound (4.40 mg)
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:29][CH3:30])[C:8]2[C:9]([CH2:16][NH:17][C:18]3[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][S:27][CH3:28])=[CH:20][N:19]=3)=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:34]([C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1)[CH3:35].O>CN(C)C=O>[F:43][C:42]([F:44])([F:45])[C:40]1[CH:41]=[C:36]([CH:34]([N:17]([CH2:16][C:9]2[C:8]([N:7]([CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:29][CH3:30])=[CH:13][CH:12]=[C:11]([O:14][CH3:15])[N:10]=2)[C:18]2[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][S:27][CH3:28])=[CH:20][N:19]=2)[CH3:35])[CH:37]=[C:38]([C:46]([F:47])([F:48])[F:49])[CH:39]=1
Reactant: CCN(CC1CCCC1)c1ccc(OC)nc1CNc1ncc(OCCSC)cn1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC1CCCC1)c1ccc(OC)nc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A solution of N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (168 mg, 0.39 mmol) in N,N-dimethylformamide (1 mL) stirred under ice cooling was added with sodium hydride (50% in oil, 24 mg, 1.4 mmol), and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to −78° C., added with a solution of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (250 mg, 0.78 mmol) obtained in Step 2 in N,N-dimethylformamide (0.5 mL), and the mixture was stirred for 12 hours with warming to room temperature. The reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the target compound, N-{1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (88.1 mg, 34%), as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][OH:9])=[O:5].[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31](Cl)(=[O:33])=[O:32]>>[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31]([NH:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][OH:9])=[O:5])(=[O:32])=[O:33]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Nc1ccccc1C(=O)N[C@H](CO)Cc1ccccc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1NS(=O)(=O)c1ccc2ccccc2c1

Procedure:
1.5 g (5.6 mmol) of (S)-2-amino-N-(3-phenylpropan-1-ol-2-yl)benzamide (intermediate 4a) were reacted with 2-naphthylsulfonyl chloride by the method of procedure 4b. 0.67 g of the product was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[OH:12])([O-])=O.[CH2:13](OC(OCC)OCC)C>[Pd].C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:11][O:10][C:6]1[C:5]2[O:12][CH:13]=[N:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc([N+](=O)[O-])c1O
Reactant: CCOC(OCC)OCC
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COc1cccc2ncoc12
Reaction time: 1.25 h
Yield: 85.2 %

Procedure:
A mixture of 2-nitro-6-methoxyphenol (2.62 g, 15.5 mmol) (EP 333176) and 10% Palladium on carbon (130 mg) in ethanol (50.0 ml) was stirred under an atmosphere of H2 for 75min. The mixture was filtered through Celite® then immediately treated with p-toluenesulphonic acid (32.0 mg) and triethylorthoformate (6.45 ml, 38.8 mmol) then heated under reflux under an atmosphere of N2. After 20 h p-toluenesulphonic acid (30.0 mg) and triethylorthoformate (6.45 ml, 38.8 mmol) were added. After a total of 44 h heating, the reaction was allowed to cool and reduced in vacuo. The resulting residue was purified by flash chromatography (25:75 ethyl acetate/hexane) to give 1.97 g (85%) of the title compound as a yellow solid: m.p. 28-31° C.; IR (film) 1629, 1497, 1434, 1285, 1097; 1H NMR (CDCl3) δ 8.09 (1H, s), 7.40 (1H, d, J=8.0), 7.28 (1H, t, J=8.0), 6.89 (1H, d, J=8.0), 4.02 (3H, s); 13C NMR (CDCl3) δ 152.84, 145.82, 142.50, 139.99, 125.75, 113.42, 108.80, 56.97. Anal. Calcd. for C8H7N1O2. 0.1H2O: C, 63.65; H, 4.81; N, 9.29. Found: C, 63.43, H, 4.88, N, 9.05. M.S. (+FAB); 150 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][N+:11]([O-:13])=[O:12].[O:14]1[CH2:19][CH2:18][N:17]([CH:20]=[CH:21][C:22]#[N:23])[CH2:16][CH2:15]1.O1CCCC1>C(Cl)(Cl)Cl>[O:14]1[CH2:19][CH2:18][N:17]([CH:20]=[C:21]([C:22]#[N:23])[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[CH2:10][N+:11]([O-:13])=[O:12])[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])C=Cc1cccc(Cl)c1Cl
Reactant: N#CC=CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: N#CC(=CN1CCOCC1)C(C[N+](=O)[O-])c1cccc(Cl)c1Cl

Procedure:
5.0 g of 1-(2',3'-dichlorophenyl)-2-nitroethylene, 3.18 g of 3-morpholinoacrylonitrile and 30 ml of tetrahydrofuran (abs.) are refluxed for 24 hours, and the reaction solution is subsequently concentrated by evaporation. The resulting residue, dissolved in toluene/ethyl acetate (2:1 V/V), is chromatographed through silica gel, and from the eluate is thus obtained the finished product, m.p. 74°-77° C. IR (CHCl3) in cm-1 ; 2200 (CN), 1630 (C=C), 1560 (NO2). NMR (CDCl3) in ppm: 4.5 (m, 4H); 4.7 (m, 4H); 4.8 (ABX, 3H); 6.60 (s, 1H); 7.2-7.5 (m, 3H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:9]=[CH:10][CH:11]=1.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1>CCO>[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][N:23]1[CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:7]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: c1cc(OC[C@@H]2CO2)cc(-c2cccc3cccnc23)c1
Solvent: CCO
Product: O[C@H](COc1cccc(-c2cccc3cccnc23)c1)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 10.7 %

Procedure:
A mixture of (S)-8-(3-(oxiran-2-ylmethoxy)phenyl)quinoline (270 mg, 1 mmol), 1,2,3,4-tetrahydroisoquinoline (133 mg, 1 mmol) in EtOH (5 mL) was stirred at 120° C. under microwave heating for 30 minutes. After evaporation of the solvent, the residue was purified by prep-HPLC to afford the desired title compound (43.9 mg, Yield 14.6%). 1H NMR (400 MHz, MeOD): δ 8.80-8.79 (m, 1H), 8.38 (d, J=8 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.74-7.72 (m, 1H), 7.67-7.63 (m, 1H), 7.54-7.51 (m, 1H), 7.41-7.37 (m, 1H), 7.22-7.16 (m, 2H), 7.10-7.00 (m, 5H), 4.27-4.25 (m, 1H), 4.15-4.03 (m, 2H), 3.74 (s, 2H), 2.88-2.78 (m, 5H), 2.73-2.70 (m, 1H) ppm; ESI-MS (m/z): 411.1 [M+1]+.
Reaction SMILES: N1C=CN=C1.[CH2:6]=[CH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>O>[O:13]([CH:9]([CH2:10][CH:11]=[CH2:12])[CH2:8][CH:7]=[CH2:6])[Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: C=CCC(O)CC=C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Product: C=CCC(CC=C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Yield: 30 %

Procedure:
There were supplied 6.5 g of imidazole manufactured by Wako Pure Chemical Industries, Ltd. to a 100 mL-two neck flask, and thereto, 50 mL of anhydrous N,N-dimethylformaide manufactured by Wako Pure Chemical Industries, Ltd., and 5.78 mL of 1,6-heptadien-4-ol manufactured by Aldrich Chemical Company were added. The obtained mixture was cooled down to 0° C. To the mixture, 6.5 g of tert-butyldimethylsilyl chloride manufactured by Tokyo Chemical Industry Co., Ltd. were added, and the resultant mixture was stirred for 12 hours at a room temperature. Then, an excess amount of water was added thereto, thereby terminating the reaction. A product contained in the reaction mixture was extracted with hexane, and the obtained organic extract was dried over anhydrous sodium sulfate manufactured by Nacalai Tesque, Inc. The dried hexane solution was distilled in vacuo, thereby obtaining 2.88 g (yield: 30%) of 4-(tert-butyldimethylsiloxy)-1,6-heptadiene as clear colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>C(Cl)(Cl)Cl>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C@@H:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCl)CC[C@H]2c2ccc(F)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCCn3ccnc3)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=428.5 (M+H+) and [α]D20=−68.5° (c=0.3050 in chloroform), was prepared in accordance with the general method of example 82b from (2R,5S)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-imidazole.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[NH2:23][CH2:24][C@H:25]([CH:42]([CH3:44])[CH3:43])[CH2:26][C@H:27]1[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[N:28]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].[OH-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:23][CH2:24][C@H:25]([CH:42]([CH3:44])[CH3:43])[CH2:26][C@H:27]1[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[N:28]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:11]
Reactant: COCCCOc1ccccc1C(=O)O
Reactant: CC(C)[C@@H](CN)C[C@H]1COC(C)(C)N1NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H]1COC(C)(C)N1NC(=O)OC(C)(C)C)C(C)C
Reaction time: 1 h

Procedure:
The solution of 2.99 g of 2-(3-methoxypropoxy)benzoic acid [179992-98-4] and 3.95 ml of triethylamine in 60 ml of dichloromethane is cooled to 15° C. and admixed with 3.70 g of bis-(2-oxo-3-oxazolidynyl)phosphinoyl chloride. The mixture is stirred over 1 hour and subsequently admixed with the solution of 2.22 g of tert-butyl 4(S)-(2(S)-aminomethyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carbamate in 3 ml of dichloromethane and 0.703 g of 4-dimethylaminopyridine, and stirred overnight. The reaction mixture is poured onto 1M NaOH and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.29 (1:1 EtOAc-heptane); Rt=5.49 (gradient I).
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[Br:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1>>[Br:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=3[CH3:26])=[O:17])[C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: O=c1cc(OCc2ccc(Br)cn2)cc[nH]1
Product: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccc(Br)cn2)cc1=O
Yield: 98 %

Procedure:
4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared following preparation 1c employing 4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.C[Si]([N:36]=[C:37]=[O:38])(C)C>ClCCl.CN(C)C=O>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([NH2:36])=[O:38])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(N)=O)cc3)nc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
8-(4-Amino-benzyl)-3-butyl-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione (25 mg, 0.06 mmol) was dissolved in 95:5 dichloromethane/N,N-dimethylformamide (2 mL), and treated with trimethylsilyl isocyanate (Aldrich) (47 μl, 0.3 mmol). The reaction was stirred at room temperature for 18 h. The reaction was then concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford the desired product. LCMS, m/z(M+H)=464.98.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].COCCN(S(F)(F)[F:33])CCOC>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2([F:33])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cn2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccc(C#N)cn2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a solution of tert-butyl 4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound 26.2, 1 g, 3.13 mmol, 1.00 equiv, 95%) in dichloromethane (50 mL) under nitrogen at −78° C. was added dropwise a solution of bis(2-methoxyethyl)aminosulfur trifluoride (830 mg, 3.75 mmol, 1.20 equiv) in dichloromethane (10 mL) during the course of 1 min. The resulting mixture was stirred for 1 h at −78° C. The reaction was then carefully quenched by dropwise addition of water and washed with 2×20 mL of sodium bicarbonate(aq) followed by 3×20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10) to yield 0.38 g (38%) of the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][C:7]1[CH:12]=[C:11]([C:13](=O)[CH3:14])[CH:10]=[CH:9][N:8]=1>CO>[CH3:6][C:7]1[CH:12]=[C:11]([C:13](=[N:2][OH:3])[CH3:14])[CH:10]=[CH:9][N:8]=1
Reactant: NO
Reactant: CC(=O)c1ccnc(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=NO)c1ccnc(C)c1

Procedure:
To 4.03 g. (58.4 mmoles) of hydroxylamine hydrochloride in 27 ml. of a 2 N sodium hydroxide solution was added 3.95 g. (29.2 mmoles) of 2-methyl-4-acetylpyridine and the resulting mixture heated on a steam bath, methanol being added to keep the mixture homogeneous. The mixture was heated for an additional 5 minutes and was then cooled. The resulting precipitate was filtered, washed with water and dried 3.95 g. (90%), m.p. 151°-152° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[F:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[K+].[K+]>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>[F:35][C:36]1[C:41]([C:7]2[CH:8]=[C:9]3[C@@:20]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)[CH:18]=4)[O:13][C:10]3=[CH:11][CH:12]=2)=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)cc1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)cc1
Yield: 72.8 %

Procedure:
A vial was charged with (S)-2′-amino-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (45.0 mg, 0.092 mmol), 2-fluoropyridin-3-ylboronic acid (38.7 mg, 0.275 mmol), potassium carbonate (229 μL, 0.458 mmol), and Pd(PPh3)4 (5.29 mg, 4.58 μmol). The vial was flushed with Ar (g), then dioxane (458 μL) (actual amount as 1 mL) and water (0.5 mL) were added in sequence. The vial was sealed and placed in an 80° C. oil bath for 2 hours. The mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12-g Redi-Sep column with 0-5% MeOH/DCM to give (S)-7-(2-fluoropyridin-3-yl)-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (29.53 mg, 0.067 mmol, 73.6% yield) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].[ClH:12].Cl[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:12])=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cl
Reactant: Cc1cc(C=NO)ccc1Br
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: Cc1cc(C(Cl)=NO)ccc1Br
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
In a solution of 82.0 g of 4-bromo-3-methylbenzaldoxime in 450 mL of tetrahydrofuran, 120.0 g of concentrated hydrochloric acid was added dropwise under cooling with ice and with stirring over 45 minutes. Then, 220 mL of 8% sodium hypochlorite aqueous solution was added dropwise over 75 minutes carefully so that the temperature of the reaction mixture would not exceed 5° C. After the completion of the addition dropwise, it was continued to stir at a temperature of 10° C. or less for further 90 minutes. After the completion of the reaction, the reaction mixture was blown with nitrogen gas for 45 minutes, then precipitated insoluble material was filtered off, tetrahydrofuran was distilled off under reduced pressure. The residual aqueous solution was extracted with 240.0 g of ethyl acetate, and the organic phase was washed with water (240 mL×2). The insoluble material was filtered off, the solvent was distilled off under reduced pressure to obtain 93.5 g of the aimed product as pale yellow crystal.
Reaction SMILES: [CH:1]([C:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)([CH3:5])[CH3:4])=O.[CH2:11]([O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14](/[CH:16]=[CH:1]/[C:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)([CH3:5])[CH3:4])=[O:15])[CH3:12]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)n1ccnc1
Product: CCOC(=O)/C=C/C(C)(C)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A mixture of 0.75 g of 1-(1-formyl-1-methylethyl)imidazole (prepared as described hereafter), 1.80 g of ethoxycarbonylmethylidenetriphenylphosphorane and 9 ml of chloroform was stirred overnight at room temperature. After evaporation under reduced pressure, the residue was purified by column chromatography on silica gel using a mixture of chloroform and ethanol (49:1) as eluent to give 0.79 g of the title compound having the following physical characteristics:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].CO[C:10]([C:12]1([CH3:36])[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH:26]([F:28])[F:27])[CH:21]=3)[NH:16][C:15]=2[CH:14]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[NH:13]1)=[O:11]>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6](=[O:7])[N:13]2[CH:14]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=3)[C:15]3[NH:16][C:17]4[C:22]([C:23]=3[CH2:24][C:12]2([CH3:36])[C:10]1=[O:11])=[CH:21][C:20]([O:25][CH:26]([F:28])[F:27])=[CH:19][CH:18]=4
Reactant: O=C=NCCCCl
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(OC(F)F)cc23)C(c2cccc(O)c2)N1
Product: CC12Cc3c([nH]c4ccc(OC(F)F)cc34)C(c3cccc(O)c3)N1C(=O)N(CCCCl)C2=O

Procedure:
The title compound is prepared analogously to the procedure described for example 22, using chloro propyl isocyanate and (1RS,3SR)-6-(1,1-difluoro-methoxy)-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester. MS: m/z (MH+)=490.0
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:9]([O-])=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1>[Pd].CO>[NH2:9][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(O)c(N)n1

Procedure:
3-Hydroxy-6-methyl-2-nitropyridine (3.5 g.) in 75 ml. of methanol was reduced over 1 g. of 5% palladium-on-carbon catalyst. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give 2-amino-3-hydroxy-6-methylpyridine which was used directly in the next step.