Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][CH3:12])=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.[Li]C(C)(C)C.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][C:19]([OH:18])([C:2]2[C:3]([CH2:11][CH3:12])=[N:4][N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=23)[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCc1nn2c(c1Br)CCCC2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCc1nn2c(c1C1(O)CCN(C(=O)OC(C)(C)C)CC1)CCCC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-α]pyridine (4.01 g, 17.6 mmol, from Step 3) in THF (20 mL) was added t-BuLi (1.7 M in pentane, 22.8 mL, 38.7 mmol) dropwise at −78° C. After stirring at −78° C. for 30 min., was added tert-butyl 4-oxo-1-piperidinecarboxylate (3.51 g, 17.6 mmol) in THF (10 mL) dropwise at −78° C. The mixture was stirred at −78° C. for 10 min. and at rt for 4 h. After the reaction was quenched with aqueous NH4Cl, the mixture was partitioned between EtOAc and water. Aqueous layer was extracted with EtOAc (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. Concentration was followed by purification by flash chromatography (hexanes: EtOAc=1:1, then 100% EtOAc) to give the title compound as a foamy solid. 1H NMR (500 Mz, CDCl3): δ 1.26 (t, 3H, J=7.4 Hz), 1.49 (s, 9H), 1.75-1.90 (m, 4H), 1.90-2.10 (m, 4H), 2.76 (q, 2H, J=7.6 Hz), 2.89 (t, 2H, J=6.4 Hz), 3.10-3.20 (br, 2H), 3.85-4.05 (br, 2H), 4.09 (t, 2H, J=6.2 Hz). ESI-MS 276 (M-t-Bu-H2O+H); HPLC C: 2.05 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:28][C:29]#[C:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:28]([N:9]1[CH2:8][CH2:7][C:6]([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1)[C:29]#[C:30][CH3:31]
Reactant: CC#CCBr
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(CC#CC)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
A mixture of 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (0.208 g,0.5 mmol), 1-bromo-2-butyne (0.044 ml, 0.53 mmol) and K2CO3 (0.138 g, 1.0 mmol)in 5.0 mL of DMF was stirred at room temperature for 6 h. The reaction was diluted with EtOAc and washed with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc:hexanes (1:1) to provide 0.183 g (85%) of the desired product as a pale yellow gum. Electrospray Mass Spec: 432.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH3:35][O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)CC)C.ClCCl.CO>C(#N)C>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: COCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.93 g, 1.97 mmol), 4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (1.04 g, 1.97 mmol), and triethylamine (1.5 mL, 10.76 mmol) in acetonitrile (20 mL). Heat to reflux. After 18 hours, cool and partition the reaction mixture between brine and dichloromethane. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.05 to give the title compound: Rf=0.49 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.1).
Reaction SMILES: O[C:2]1([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH:2]2[C:6]3[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=3[O:4][C:3]2([CH3:22])[CH3:21])=[CH:28][CH:27]=1
Reactant: COc1ccc(C2(O)c3cc(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C2c3cc(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)cc1
Yield: 82 %

Procedure:
Using N-(3-hydroxy-3-(4-methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 255, the title compound was synthesized in the same manner as in Example 271. Yield: 82%. Melting point: 169-170° C. (ethyl acetate-hexane).
Reaction SMILES: [CH:1](=[C:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]>C(Cl)Cl>[CH2:1]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC=C1CCCC1=O
Solvent: ClCCl
Product: CCCCCC1CCCC1=O
Temperature: 50 °C
Reaction time: 113 h
Yield: 68.9 %

Procedure:
In a 100 ml-volume three-way-cocked eggplant type flask whose atmosphere had been displaced with nitrogen was charged 735 mg (0.66 mmole) of [RuI(p-cymene)((+]-BINAP)]I, and 2.5 g (16 mmole) of 2-pentylidenecyclopentanone and 50 ml of methylene chloride were added thereto to form a solution. The solution was put in a 100 ml autoclave having been displaced with nitrogen and stirred at 50° C. under a hydrogen pressure of 60 kg/cm2 for 113 hours to conduct a hydrogenation reaction. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography using a mixed solvent of diethyl ether and hexane (1:4 by volume) as an eluent to obtain 1.7 g (percent yield 67%) of 2-pentylcyclopentanone.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]2[C@H:26]3[C@@H:22]([N:23]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=4)[C:24](=[O:27])[O:25]3)[CH2:21][S:20](=[O:40])(=[O:39])[CH2:19]2)=[CH:13][C:12]=1[F:41])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]2[C@H:26]3[C@@H:22]([N:23]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([CH3:37])([CH3:38])[CH3:36])[CH:30]=4)[C:24](=[O:27])[O:25]3)[CH2:21][S:20](=[O:39])(=[O:40])[CH2:19]2)=[CH:13][C:12]=1[F:41]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc(NC(=O)OCc5ccccc5)c(F)c4)CS(=O)(=O)C[C@@H]32)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc(N)c(F)c4)CS(=O)(=O)C[C@@H]32)c1

Procedure:
A solution of {4-[(3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-fluoro-phenyl}-carbamic acid benzyl ester (9.6 g, 15.8 mmol) in THF-MeOH 1:2 (150 mL) was hydrogenated over 10% Pd/C (0.7 g) for 4 h at 45° C. and 1 bar. The catalyst was filtered off over Celite and the filtrate is evaporated to provide the title compound as a colorless solid: TLC (toluene-EtOAc 3:1) Rf=0.26; UPLC RtD=1.596 min; ESIMS [M+NH4]+=478; 1H NMR (600 MHz, DMSO-d6): δ 7.38 (s, 1H), 7.32 (d, 1H), 7.27 (t, 1H), 7.13 (d, 1H), 6.83 (d, 1H), 6.69 (m, 2H), 5.02 (s, 2H), 4.42 (d, 1H), 4.22 (d, 1H), 4.11 (t, 1H), 3.67 (m, 2H), 3.46 (t, 1H), 3.01 (m, 2H), 2.79 (dd, 1H), 2.44 (m, 2H), 1.26 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH2:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:42])[CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:24][CH2:23]3)[CH:19]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH2:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:42])[CH:29]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:26][CH2:27]3)[CH:19]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(CCC2CCN(C(=O)C(c3ccccc3)c3ccccc3)CC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(CC(C(=O)O)c2cn(CCC3CCN(C(=O)C(c4ccccc4)c4ccccc4)CC3)cn2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
Ethyl 3-(6-aminopyridin-3-yl)-2-{1-[2-(1-diphenylacetylpiperidin-4-yl)ethyl]-1H-imidazol-4-yl}propionate (71 mg; 0.12 mmol) was dissolved in absolute ethanol (600 μl). 1N NaOH (128 μl; 0.12 mmol) was added thereto. The reaction mixture was stirred at RT for 16 h. It was then neutralized with 1N HCl (128 μl; 0.12 mmol) and concentrated under reduced pressure. It was taken up in methanol and filtered through a C18 column. The methanol was removed and acetonitrile was added and decanted twice, and the residue was then triturated with diethyl ether. The precipitate was filtered off and dried under high vacuum at 40° C. 3-(6-Aminopyridin-3-yl)-2-{1-[2-(1-diphenylacetylpiperidin-4-yl)ethyl]-1H-imidazol-4-yl}propionic acid (50 mg; 0.09 mmol) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-])=O.Cl>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9]
Reactant: Nc1ncnc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ncnc(Cl)c1N
Temperature: 85 °C
Yield: 37.1 %

Procedure:
Iron dust (1000 g, 17.9 mol) was added to a solution of the crude 6-chloro-5-nitropyrimidin-4-amine (500 g, 2.87 mol) in ethanol (5000 mL) and water (1000 mL). A catalytic amount of concentrated hydrochloric acid (10 mL) was slowly added to the reaction mixture over a period of 20 minutes. During the course of the addition the reaction temperature was observed to increase to 85° C. without external heating and the reaction mixture's color changed from yellow-brown to dark red. After the reaction mixture had cooled down to a temperature of 50° C., the slurry was filtered through a Celite pad, which was then washed with ethanol (3×250 mL). The resulting filtrate was concentrated under reduced pressure to give a yellow solid. This solid was then washed with hexane and dried under reduced pressure to give the title compound as a brown solid. (253 g, overall yield over two steps: 37.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.61 (s, 1H), 6.71 (broad s, 2H), 4.94 (broad s, 2H). MS (EI) for C4H5ClN4: 145 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:12][C:13]1[C:17](Cl)=[N:16][S:15][N:14]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:17]2[C:13]([Cl:12])=[N:14][S:15][N:16]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1nsnc1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2nsnc2Cl)CC1
Reaction time: 4 h
Yield: 106.2 %

Procedure:
Piperidine-4-carboxylic acid ethyl ester (14.0 mL, 91 mmol) was dissolved in DMF (15.0 mL) and heated to 100 C. 3,4-Dichloro-1,2,5-thiadiazole (4.0 mL, 42 mmol) was added and the mixture heated at 100 C. for 4 h. The reaction mixture was poured into 1N HCl and extracted with EtOAc (4×). The combined EtOAc extractions were washed with H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give 12.3 g (105%) of 1-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid ethyl ester which was used without further purification. 1H NMR (CDCl3) 4.30-4.13 (m, 2H), 4.06-3.93 (m, 2H), 3.12-2.99 (m, 2H), 2.59 (m, 1H), 2.03 (m, 4H), 1.42-1.26 (m, (3H) ppm. LC-MS (MH+)=276.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-:12].C([Br:16])(=O)C.O.C([O-])(O)=O.[Na+]>CCOC(C)=O.C(Cl)(Cl)Cl>[Br:16][C:6]1[CH:7]=[C:2]([CH3:1])[N+:3]([O-:12])=[C:4]([CH3:11])[CH:5]=1
Reactant: CC(=O)Br
Reactant: Cc1cc([N+](=O)[O-])cc(C)[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cc(C)[n+]1[O-]
Temperature: 75 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A mixture of 2.4 g of 2,6-dimethyl-4-nitropyridine 1-oxide and 16.5 mL of acetyl bromide was stirred at 75° C. under a CaCl2 drying tube for 4 h. The mixture was added to ice with H2O, CHCl3, and EtOAc and solid NaHCO3 was added to pH=7-8. The aqueous layer was extracted with CHCl3 (3×), and the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1 to 5) % MeOH/CHCl3 provided 1.39 g of 4-bromo-2,6-dimethylpyridine 1-oxide as a pale brown solid in 48% yield.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24](=[O:34])[CH2:25][CH2:26][S:27][C:28]1[S:32][C:31]([NH2:33])=[N:30][CH:29]=1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][CH2:26][S:27][C:28]1[S:32][C:31]([NH:33][C:8](=[O:10])[C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:30][CH:29]=1)[CH3:22]
Reactant: CCOC(=O)CCSc1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Product: CCOC(=O)CCSc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
(R)-3-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester was prepared from (R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and 3-(2-aminothiazol-5-ylsulfanyl)-propionic acid ethyl ester as described in Example 1. 1H_NMR (CD3OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.40 (s, 1H), 4.08 (q, 2H), 3.96 (t, 1H), 3.09 (s, 3H), 2.92 (t, 2H), 2.57 (t, 2H), 2.21 (m, 1H), 1.88-1.48 (m, 8H), 1.22-1.17 (m, 5H); HPLC-MS: m/z: 511 (M+1).
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[NH:10][CH:9]=[N:8][C:7]=2[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[CH3:20]>>[CH3:1][N:10]1[C:11](=[O:13])[C:12]2[C:4]([CH3:3])=[C:5]([CH3:20])[N:6]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=[CH:9]1
Reactant: CI
Reactant: Cc1c(C)n(-c2ccccc2)c2nc[nH]c(=O)c12
Product: Cc1c(C)n(-c2ccccc2)c2ncn(C)c(=O)c12
Yield: 62.4 %

Procedure:
The starting material was prepared as described in Example 3 by the alkylation with methyl iodide of 5,6-dimethyl-7-phenyl-3H,7H-pyrrolo-[2,3-d]pyrimidin-4-one (see US Patent 4,229,453). There was thus obtained 3,5,6-trimethyl-7-phenyl-3H-7H-pyrrolo-[2,3-d]pyrimidin-4-one (62.4% yield) m.p. 207°-208° C.; microanalysis, found: C, 71.0; H, 6.2; N, 16.3%; C15H15N3 requires C, 71.1; H, 5.97; N, 16.6%; NMR: CDCl3 ; 2.1(3H, s, CH3), 2.4-2.5(3H, s, CH3), 3.5-3.6(3H, s, N-CH3), 7.25-7.6(5H, complex, aromatic), 7.7-7.8(1H, s, C-H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:36]([O:38]C)=[O:37])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:22])=[CH:18][C:17]4[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CI.[H-].[Na+].[CH3:44]NC(N)=O>CN(C=O)C.CO.CO.C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:36]([OH:38])=[O:37])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]([CH3:44])[CH:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[O:22])=[CH:18][C:17]4[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)NC1CCOCC1)=Cc1cc(OC)ccc1-3
Reactant: CNC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(C(=O)N(C)C1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21

Procedure:
Prepared from methyl 13-Cyclohexyl-3-(methyloxy)-6-((tetrahydro-2H-pyran-4-ylamino)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate by methylation using MeI and NaH in DMF in a similar manner as described before; Analytical thin layer chromatography (5% MeOH/CH2Cl2) Rf=0.50; Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=529.32, HPLC Rt=1.995 min.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=[O:17].[Mg+2].OO.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>CC(C)=O.C[Re](=O)(=O)=O.C(OCC)(=O)C>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)([O-])[O-]
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: C[Re](=O)(=O)=O
Agent: O=C(O)C(=O)O
Agent: OO
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: ON(Cc1ccccc1)Cc1ccccc1
Yield: 102.7 %

Procedure:
Dibenzylamine (3.0 g, 0.0152 mole) was added with ethyl acetate (15 ml) and anhydrous magnesium sulfate (3 g), and the mixture was stirred under ice cooling. A solution of methyltrioxorhenium (0.0114 g, 0.0457 mmole) dissolved in 35% aqueous hydrogen peroxide (1.8 g, 0.018 mole) was added dropwise to the mixture over 1 hour so as to keep internal temperature at 5° C. to 10° C. After the reaction mixture was stirred at the same temperature for 1 hour, the magnesium sulfate was removed by filtration, and the filtrate was added with a solution of oxalic acid (1.23 g, 0.0137 mole) dissolved in acetone (7 ml). The mixture was stirred for 30 minutes under ice cooling, and the precipitated crystals were collected by filtration to obtain oxalic acid salt of N,N-dibenzylhydroxylamine (3.0 g, yield: 65.2%) having melting point of 152-153° C. Chemical structure of the product was analyzed by 1H-NMR, mass spectrometry and elemental analysis. 1H-NMR (DMSO-D6) σ (ppm) (multiplicity, integrated value): 7.45-7.12 (m, 11H), 3.85 (s, 4H). Elemental analysis, calculated for C16H17N1O5 : C, 63.36; H, 5.65; N, 4.62, found: C, 63.30; H, 5.65; N, 4.62.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([C:10]([F:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]([CH3:20])[C:4]=1[NH2:5])[CH3:2].N1C=CC=CC=1.[Cl:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>O1CCCC1.CN(C)C1C=CN=CC=1.O>[Cl:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:5][C:4]2[C:6]([CH3:20])=[CH:7][C:8]([C:10]([F:19])([C:11]([F:14])([F:13])[F:12])[C:15]([F:16])([F:17])[F:18])=[CH:9][C:3]=2[CH2:1][CH3:2])=[O:34])=[CH:31][CH:30]=1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CCl)cc1
Yield: 82.5 %

Procedure:
2-Ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylaniline (0.50 g) and pyridine (0.20 g) were dissolved in tetrahydrofuran (10 ml). To the solution, 4-(chloromethyl)benzoyl chloride (0.33 g) and 4-dimethylaminopyridine (0.02 g) were added and the mixture was refluxed under heating for 3 hours. After adjusting to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with 2N hydrochloric acid and dried over Mg(SO4). After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was washed with hexane to obtain 4-(chloro methyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoro-propan-2-yl)-6-methylphenyl]benzamide (0.62 g, yield 74%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([C:21]2[CH:25]=[C:24]([C:26](=O)[CH3:27])[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:26]([C:24]2[O:23][N:22]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:25]=2)[CH3:27])=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(-c2ccccc2)no1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1cc(-c2ccccc2)no1

Procedure:
Prepared according to the procedure described in Example 1, Step 12, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-(3-phenyl-isoxazol-5-yl)-ethanone.
Reaction SMILES: O=[C:2]1[C:15]2[C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2.O.[NH2:21][NH2:22]>CC(N(C)C)=O>[N:21]1[NH:22][C:16](=[O:18])[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=1[NH:9]3
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCCC3
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc2c3c(cccc13)NC1=C2CCCC1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
To the solution of the crude methyl 9-oxo-5,6,7,8,9,10-hexahydroacridine-1-carboxylate in DMA (4 mL) was added hydrazine hydrate (4 mL) at room temperature, and the mixture was heated at 130° C. for 4.0 h. The reaction mixture was cooled to room temperature and stirred for another 12 hours. Then the mixture was filtered and recrystallized from MeOH (twice) to give the product (20 m g, 15%) as a yellow solid.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])[NH2:3]>[Pd].C(O)C.CCO>[C:11]1([N:8]2[CH2:9][CH2:10][CH:5]([C:2]([NH2:3])=[O:4])[CH2:6][CH2:7]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC(=O)c1cc[n+](-c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC(=O)C1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
2.0 g palladium on charcoal (10%) were added to a solution of 22.7 g 4-Carbamoyl-1-phenyl-pyridinium hydrochloride in 500 ml ethanol EtOH. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen at 3 bar for one hour. The catalyst was filtered off through a pad of celite and washed with ethanol. The filtrate was evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel with the eluent ethyl acetate:methanol=9:1=>4:1 to obtain 6.9 g 1-Phenyl-piperidine-4-carboxylic acid amide as a solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>O1CCCC1>[Cl:14][CH2:15][CH2:16][CH2:17][C:18]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:19]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)CCCCl
Solvent: C1CCOC1
Product: O=C(CCCCl)N(c1ccccc1)c1ccccc1

Procedure:
A solution 22.8 g (0.14 mole) of diphenylamine in 150 ml of tetrahydrofuran was added dropwise to a solution of 9.9 g (0.07 mole) of 4-chlorobutyryl chloride in 100 ml of tetrahydrofuran. The reaction mixture was stirred mechanically and the temperature maintained between 5° C. and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates and the filtrate was concentrated under reduced pressure to give a yellow solid. The solid was purified by column chromatography using 300 g of silica gel on a 65 cm×4 cm column, eluted with 10% ethyl acetate in hexane. The fractions containing the desired product were combined and concentrated under reduced pressure to yield 16.8 g (88%) of white, crystalline solid, mp 78°-79° C.