Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:33][CH3:34])[N:6]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.[CH3:35][NH:36][CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[CH3:35][N:36]([CH2:29][C:28]1[CH:31]=[CH:32][C:25]([CH2:24][N:21]2[CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][N:6]3[C:5]([O:33][CH3:34])=[N:4][C:3]4[C:7]3=[N:8][C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:10][C:2]=4[NH2:1])[CH2:23][CH2:22]2)=[CH:26][CH:27]=1)[CH3:37]
Reactant: CNC
Reactant: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(Cc4ccc(C=O)cc4)CC3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(Cc4ccc(CN(C)C)cc4)CC3)c2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.3 %

Procedure:
The compound (0.31 g, 1.66 mmol) obtained in Step (ii) was dissolved in THF (10 ml), and thereto were added at 0° C. dimethylamine (2M THF solution, 2.62 ml, 5.24 mmol) and sodium triacetoxy borohydride (0.56 g, 2.62 mmol), and the mixture was stirred at room temperature for 20 hours. The mixture was cooled to 0° C., and thereto was added a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted three times with chloroform/ethanol=3/1. The extract was dried over magnesium sulfate, concentrated, and purified by silica gel column (chloroform/methanol/28% aqueous ammonia=100/5/0 to 100/5/1) to give the title compound (0.28 g, 0.57 mmol) as a white solid. Yield: 87%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([CH2:14][NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(C2CCCCC2)CC1
Reactant: Nc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CNc2nccs2)(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
4-Cyclohexyl-4-formyl-piperidine-1-carboxylic acid tert-butyl ester, 3, (296 mg, 1.0 mmol) and 2-aminothiazole (103 mg, 1.0 mmol) are dissolved in toluene (15 mL), and the mixture was refluxed using a Dean-Stark apparatus overnight. The solution is then cooled to room temperature and sodium triacetoxyborohydride added. The reaction is stirred at room temperature for three hours and then diluted with ethyl acetate. The reaction mixture is washed with aqueous sodium bicarbonate and brine. The solvent is removed under reduced pressure and the residue purified by preparative HPLC to afford 312 mg (82% yield) of the desired compound. MS (ESI) m/z 380 (M+H+)
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][C:33]1[C:38]([C:39]([C:41]2[N:45]([CH3:46])[N:44]=[N:43][CH:42]=2)=[O:40])=[CH:37][CH:36]=[C:35]([CH3:47])[N:34]=1.O>O1CCCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:38]3[C:33]([CH3:32])=[N:34][C:35]([CH3:47])=[CH:36][CH:37]=3)([C:41]3[N:45]([CH3:46])[N:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 0.73 mL, 1.2 mmol) was added dropwise to a stirring solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (500 mg, 1.2 mmol, Intermediate 10) in tetrahydrofuran (10 mL) at −78° C. After 5 minutes, a solution of (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (250 mg, 1.2 mmol, Intermediate 19: step b) in tetrahydrofuran (1.6 mL) was added dropwise. After 5 minutes, the flask was placed into an ice-water bath. After 30 minutes, water (5 mL) was added and the mixture was allowed to warm to 23° C. The biphasic mixture was partitioned between half-saturated aqueous sodium chloride solution (100 mL) and ethyl acetate (100 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. The filtrate was concentrated and the residue was purified by RP-HPLC eluting initially with 5% acetonitrile-water (containing 0.05% trifluoroacetic acid), grading to 95% acetonitrile-water (containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid after partitioning the purified material between dichloromethane-saturated aqueous sodium bicarbonate solution, separating the layers, drying the organic layer with sodium sulfate, filtering the dried solution, and concentrating the filtrate to dryness. 1H NMR (600 MHz, CDCl3) δ ppm 8.08 (d, J=2.2 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.59-7.54 (m, 2H), 7.40-7.34 (m, 3H), 6.98-6.91 (m, 3H), 6.45-6.41 (m, 1H), 4.32 (s, 2H), 4.10 (s, 3H), 3.93 (s, 3H), 3.61 (s, 1H), 2.55 (s, 3H), 2.38 (s, 3H); MS (ESI): mass calcd. for C31H28ClN7O2, 565.2. m/z found, 566.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:32])[C:16](=[O:31])[C:17]([CH3:30])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[C:13]=2[C:12](=[O:33])[N:11]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:10]1=[O:43].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:14]1[N:15]([CH3:32])[C:16](=[O:31])[C:17]([CH3:30])=[C:18]2[C:13]=1[C:12](=[O:33])[N:11]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[C:10](=[O:43])[N:19]2[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cccc(Nc2c(C)c(=O)n(C)c3c2c(=O)n(Cc2ccc(OC)cc2)c(=O)n3-c2ccc(I)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc(-n2c(=O)n(Cc3ccc(OC)cc3)c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.7 %

Procedure:
To a stirred solution of methyl 3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoate (3b) (3.20 g, 4.59 mmol) in THF (5 ml) and Methanol (10 ml), was added K2CO3 (2.54 g, 18.38 mmol) at RT. The reaction mixture was stirred at room temperature for 3 h under N2 atm. The solvents were evaporated in vacuo and the residue was suspended in water, the precipitated product was collected by filtration and dried under high vacuum to afford the titled compound (3c), (2.1 g). The crude product was carried forward for the next step without further purification.
Reaction SMILES: O[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>CN(C=O)C>[Cl:14][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ncnc(O)c1C(C)C
Solvent: CN(C)C=O
Product: Cc1ncnc(Cl)c1C(C)C
Temperature: 65 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
4-Hydroxy-5-isopropyl-6-methylpyrimidine (12.2 g, 80 mmol) was added to 50 ml phosphorous oxychloride and treated with ca. 0.1 ml DMF. The mixture was heated to 60-70° C. and stirred for 2h. After cooling the excess POCl3 was removed under vacuum, the residue was poured onto ice and the pH of the aqueous layer was adjusted to 7 by addition of NaOH and NaHCO3. The product was taken up in dichloromethane, washed with sat. sodium bicarbonate, dried (Na2SO4) and evaporated. The residue was purified by vacuum distillation to yield 8.5 g (62 percent yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][CH2:40]O)=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:40][CH2:39]/[CH:38]=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:32][CH:33]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OCC/C=C/c1ccc(Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 228 mg (1 mM) of (E)-4{-4-(1-imidazolylmethyl)phenyl}-3-buten-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 400 mg (73.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([CH2:8][NH:9][C:10](=[O:15])[CH2:11][O:12][CH2:13][CH3:14])=O)=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[O:15][C:10]([CH2:11][O:12][CH2:13][CH3:14])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOCC(=O)NCC(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCOCc1ncc(-c2ccc(Cl)cc2)o1
Temperature: 0 °C
Reaction time: 20 h
Yield: 88.8 %

Procedure:
12.78 g (50 mmol) of N-[(4-chlorobenzoyl)methyl]-2-ethoxyacetamide were dissolved in 32.5 ml of concentrated sulphuric acid while stirring and cooling intermittently so that the temperature did not rise above room temperature. The mixture was held at room temperature for 20 hours, then poured on to 600 ml of ice/water and extracted three times with 150 ml of diethyl ether each time. The combined ether extracts were washed with 100 ml of saturated sodium hydrogen carbonate solution, then dried over magnesium sulphate, filtered and evaporated to give 10.55 g (89%) of 5-(4-chlorophenyl)-2-ethoxymethyloxazole in the form of a syrup.
Reaction SMILES: CS(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([C:24]([O:27]C)([CH3:26])[CH3:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH:29]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1.[CH2:37](O)[CH2:38][OH:39]>>[NH2:29][C@@H:17]1[CH2:16][CH2:15][C@@H:14]([C:8]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=2[F:6])[CH2:20][N:19]2[C:21]([C:24]([CH3:25])([O:27][CH2:37][CH2:38][OH:39])[CH3:26])=[CH:22][N:23]=[C:18]12
Reactant: OCCO
Reactant: COC(C)(C)c1cnc2n1C[C@H](c1c(F)cccc1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Product: CC(C)(OCCO)c1cnc2n1C[C@H](c1c(F)cccc1F)CC[C@H]2N
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Methanesulfonic acid (78 μL, 1.19 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,6-difluorophenyl)-3-(1-methoxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (104 mg, 0.24 mmol) in ethylene glycol (4 mL) and the mixture heated to 60° C. After 18 h, the reaction mixture was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×), and the combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated. MS 366.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]([CH:10]([CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12][C:13](O)=[O:14])[CH3:9])=[O:7].C(N(CC)CC)C.[NH2:45][C@H:46]([CH2:51][OH:52])[CH2:47][CH:48]([CH3:50])[CH3:49].C(P(=O)(OCC)OCC)#N>CN(C)C=O>[OH:52][CH2:51][C@@H:46]([NH:45][C:13](=[O:14])[CH2:12][CH2:11][CH:10]([N:8]([C:6](=[O:7])[C:5]1[CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=1)[CH3:9])[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:47][CH:48]([CH3:50])[CH3:49]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](N)CO
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CO)NC(=O)CCC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 120 mg (0.23 mmol) of 4-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-5,5-diphenyl-pentanoic acid (example 32 h) and 45 μl (0.32 mmol) of triethylamine in 4 ml of N,N-dimethylformamide at 0° C. is treated with 36 μl (0.28 mmol) of (S)-leucinol, followed by 45 μl (0.28 mmol) of diethyl cyanophosphonate. After stirring for 4 h at room temperature, the reaction mixture is concentrated, diluted with ethyl acetate, and then washed with saturated sodium bicarbonate solution. The aqueous layer is further extracted with ethyl acetate (3×). The organic layers are combined, dried with sodium sulfate and concentrated. The residue is then purified by flash chromatography (98:2 to 95:5 methylene chloride/methanol) to give the title compound as a white solid (mixture of diastereomers). TLC: methylene chloride/methanol (95:5) Rf =0.22, 0.19
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccn1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and methyl (S)-2-amino-3-(2-pyridyl)propionate hydrochloride (Synthetech), the tide compound was prepared as a solid (mp=121-124° C.). The reaction was monitored by tlc (Rf=0.39 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:13]C(=O)C)([CH3:12])[CH3:11])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH2:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)NC(C)(C)c1ccnc(C2CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(N)c1ccnc(C2CC2)n1
Temperature: 25 °C
Yield: 35.8 %

Procedure:
Heat a solution of N-[1-(2-cyclopropyl-pyrimidin-4-yl)-1-methyl-ethyl]-acetamide (4.5 g, 20.5 mmol) and aqueous 5N HCl (125 mL) to 100° C. for 18 hours. Cool the mixture to room temperature. Extract the reaction with diethyl ether (2×) then make the aqueous layer alkaline with aqueous 5N NaOH. Extract the aqueous layer with diethyl ether (3×), dry the combined organic layers over sodium sulfate, filter, and concentrate under reduced pressure to give 1-(2-cyclopropyl-pyrimidin-4-yl)-1-methyl-ethylamine (1.3 g, 36%) as a dark yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.45 (d, J=5.6 Hz, 1H), 7.12 (d, J=5.6 Hz, 1H), 2.30 (m, 1H), 1.76 (br s, 2H), 1.41 (s, 6H), 1.09 (m, 2H), 1.02 (m, 2H).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[C:10]3[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=3[N:12]=[CH:13][N:14]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:27]O.C([O-])(=O)C.[NH4+].N>CO.[Zn].C(Cl)(Cl)Cl.CO.O>[CH:1]1([CH:7]([C:9]2[C:10]3[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=3[N:12]=[CH:13][N:14]=2)[NH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: C[Si](C)(C)CCOCn1ccc2c(C(=O)C3CCCCC3)ncnc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(C(N)C3CCCCC3)ncnc21
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Cyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone (406 mg, 1.13 mmol) in methanol (10 ml) was stirred with hydroxylamine hydrochloride (395 mg, 5.66 mmol) for 4 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in ethanol (3.0 mL), mixed with ammonium acetate (105 mg, 1.36 mmol), water (3 mL) and aqueous ammonia (5 mL) and refluxed with zinc powder (600 mg, 9.17 mmol) for 4 hours. The reaction mixture was allowed to cool to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hi Flash column amino type manufactured by Yamazen Corporation: chloroform/methanol=20/1 (v/v)) to give the title compound as a yellow oil (390 mg, yield 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:28]1([CH2:34][C:35]([N:37]=[C:38]=[O:39])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.CCCCCC>[CH3:25][N:23]([CH2:22][CH:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:39])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1)[CH3:24]
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (60.6 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.64 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) to provide the titled compound (59.5 mg, 68%) as white powder.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[CH:7][CH:6]=1>O.[Ag]=O>[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]([OH:1])=[O:14])=[CH:7][CH:6]=1
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: [OH-]
Agent: O=[Ag]
Agent: [Na+]
Solvent: O
Product: COc1ccc(Oc2cccc(C(=O)O)c2)cc1
Yield: 61.7 %

Procedure:
To a suspension of 10.6 g of silver oxide in 75 ml of water were added 7 g of sodium hydroxide. Ten grams of 3-(4-methoxyphenoxy)benzaldehyde were added in dropwise fashion and the reaction mixture was heated to 60°-70° C. for one hour. The mixture was filtered, the filtrate was acidified to pH 2 with hydrochloric acid, and the resulting precipitate was recovered by filtration. Crystallization from ethanol/water afforded 6.6 g of the desired subtitle intermediate, m.p. 141°-143° C.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].O.S([O-])([O-])=O.[Na+].[Na+].[Br:30]Br>C(O)(=O)C>[CH2:1]([CH:3]([NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([Br:30])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(CC)Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h

Procedure:
EPAQ (20.02 g) was dissolved in hot acetic acid. In a separate flask, bromine (12.03 g) was dissolved in acetic acid (ca. 10 mL). The bromine solution was slowly added to the dye solution. The reaction was allowed to proceed for 1/2 hour with occasional shaking The reaction mixture was poured into water (600 mL), and aqueous sodium sulfite was added to discharge the bromine. The aqueous solution was decanted off. The solid was dissolved in methylene chloride, then concentrated, and slowly added to cold methanol, whereupon a solid precipitated.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([NH2:40])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]3[CH:3]=[C:2]([NH:40][C:34]4[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[CH:33]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc(N)cc1OC
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Product: COc1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1OC
Yield: 71 %

Procedure:
The title compound was prepared in 71% yield from compound (10) and 3,4-dimethoxyphenyl amine using the method described for Preparation 35. 1H-NMR (CDCl3, 500 MHz): δ 1.46 (s, 9H), 1.68 (s, 9H), 3.90 (s, 3H), 3.91 (s, 3H), 6.45 (br s, 1H, NH), 6.56 (d, J=0.95 Hz, 1H), 6.89 (m, 2H), 6.96 (m, 1H), 7.45 (m, 1H), 7.81 (d, J=0.63 Hz, 1H), 8.20 (d, J=0.95 Hz, 1H), 8.42 (d, J=0.95 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH3:14])[C:5](/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18])=[CH:4][C:3]=1[O:21][CH3:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH3:14])[C:5](/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18])=[CH:4][C:3]=1[O:21][CH3:22])(=[O:25])[CH3:24]
Reactant: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(OC(C)=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.1 g of (E)-3-(4-hydroxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid was dissolved in 20 ml of pyridine and 2 ml of acetic anhydride was added, followed by stirring at room temperature overnight. The reaction mixture was concentrated in vacuo and the resultant crystals were filtered and washed with ethyl acetate to obtain 7.5 g of the titled compound as colorless crystals.