Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>C1COCC1.O>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH3:32])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3n2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) was added to a suspension of sodium hydride (12.78 mg, 0.320 mmol) in THF (Volume: 1.5 mL) at 0° C. The reaction was stirred for 10 minutes before iodomethane (0.200 mL, 3.20 mmol) was added. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution. It was dried over magnesium sulfate, filtered and concentrated. The crude material was purified using 50%-100% ethyl acetate in hexanes. (Yield: 41.5 mg, white solid) To obtain white solid as a product. 1H-NMR (400 MHz, DMSO-d6) 7.63-7.57, 7.53-7.47, 7.43-7.16, 7.13-7.05, 6.63, 4.67, 4.58-4.00, 3.78-3.71, 3.21-2.91, 2.79, 1.87-1.52
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH2:9]([N:16]1[C:21](=[O:22])[C:20]2=[C:23]([Cl:26])[CH:24]=[CH:25][N:19]2[N:18]=[C:17]1[CH3:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]S([O-])(=O)=O.[Mg+2]>CN(C=O)C>[CH2:9]([N:16]1[C:21](=[O:22])[C:20]2=[C:23]([Cl:26])[CH:24]=[CH:25][N:19]2[N:18]=[C:17]1[CH:27]=[CH:3][N:4]([CH3:6])[CH3:5])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Reactant: COC(OC)N(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Temperature: 140 °C
Yield: 49.8 %

Procedure:
Dimethylformamide dimethylacetal (20 ml, 152 mmol) was added to a solution of 3-benzyl-5-chloro-2-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (9.0 g, 33 mmol) in DMF (100 mL) with MgSO4 (5 g) and the reaction mixture was heated to 140° C. in a sealed tube for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved with EtOAc (50 mL) and a solid was precipitated by addition of petroleum ether (300 mL). The solid was filtered, washed with petroleum ether and dried in vacuo to afford title compound (5.4 g, 50%) as a solid: 1H NMR (CDCl3) δ 7.22 (d, 1H, J=12.43 Hz), 7.08–7.19 (m, 5H), 6.97 (m, 1H), 6.23 (m, 1H), 5.08 (s, 2H), 4.40 (d, 1H, J=12.49 Hz), 2.67 (s, 6H); MS (ESI+) 329 (M++H).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[N:18]([CH:26]4[CH2:29][NH:28][CH2:27]4)[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[N:18]([CH:26]4[CH2:27][NH:28][CH2:29]4)[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CNC4)c4cc(F)ccc34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C4CNC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.3 %

Procedure:
To a solution of 2-(1-azetidin-3-yl-6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (36 mg, 0.69 mmol) in CH2Cl2 (1 mL) was added TFA (0.5 mL, 6.5 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (1 mL) and ethylene diamine (0.2 mL, 3.00 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and extracted with 5% MeOH/CH2Cl2 (3×). The combined organic layers were dried over MgSO4 and concentrated. The residue was triturated with EtOAc to afford 17 mg (63%) of 2-(1-azetidin-3-yl-6-fluoro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a pale yellow powder. MS: (M+H)+=394; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.14 (s, 1H), 8.40-8.50 (m, 2H), 8.04 (d, J=7.6 Hz, 1H), 7.78-7.86 (m, 1H), 7.13-7.24 (m, 1H), 5.65-5.76 (m, 1H), 4.12-4.28 (m, 3H), 3.86 (t, J=7.9 Hz, 2H), 1.30 (d, J=6.4 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([CH3:35])[CH3:34])[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([CH3:35])[CH3:34])[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Reactant: O=C(O)Cc1ncccn1
Product: COc1ccc(N2CCN(C(=O)Cc3ncccn3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using pyrimidin-2-yl-acetic acid and 3 (S)-benz yl-1-(3-(1-methylethoxy)-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil. LC/MS (Method B) 2.67 min, [M+1]+ 461. Potency class B.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].CS(O[C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1)(=O)=O.C(OCC)(=O)C>CN(C=O)C.O>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][N:10]([C@H:23]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22]3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: Clc1nccc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cc(I)c3c(Cl)nccc32)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (225 mg) obtained in Step 1 was dissolved in DMF (3.0 ml). After cooling to 0° C., 60% sodium hydride (64.5 mg) was added thereto. The (R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (322 mg) obtained in Example 2 (Step 1) was added to the reaction mixture using DMF (2.0 ml), and the mixture was stirred overnight. 60% Sodium hydride (64.5 mg) was additionally added, and the mixture was stirred at 85° C. overnight. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a crude product (192 mg). Physical properties: m/z [M+H]+ 448.3
Reaction SMILES: [OH:1][C@H:2]([C:5]1[C:6]([F:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][OH:4].O.[C:18]1(C)[CH:23]=CC(S(O)(=O)=O)=C[CH:19]=1.C(=O)(O)[O-].[Na+]>COC(OC)(C)C>[CH3:19][C:18]1([CH3:23])[O:1][C@H:2]([C:5]2[C:6]([F:16])=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][O:4]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1cccc([C@@H](O)CO)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)OC
Solvent: O
Product: CCOC(=O)c1cccc([C@@H]2COC(C)(C)O2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A 5.71 g portion of ethyl 3-[(1R)-1,2-dihydroxyethyl]-2-fluorobenzoate was dissolved in 30 ml of 2,2-dimethoxypropane, mixed with 476 mg of p-toluenesulfonic acid monohydrate and stirred at room temperature for 30 minutes. This was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried with sodium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 5.46 g (81%) of ethyl 3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluorobenzoate (Reference Example 16-1). FA: 269
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]#[N:33])=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:34]([CH3:36])[CH3:35])[O:11][N:10]=1.[Cl-].[NH4+].[N-:39]=[N+:40]=[N-:41].[Na+].Cl>CN(C)C=O.O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]3[NH:41][N:40]=[N:39][N:33]=3)=[CH:27][CH:26]=[CH:25]4)=[CH:20][CH:21]=2)=[C:12]([CH:34]([CH3:36])[CH3:35])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C#N)cccc3c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(-c4nnn[nH]4)cccc3c2)cc1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
To a solution of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarbonitrile (75 mg, 0.14 mmol) in dimethylformamide (1 mL) was added ammonium chloride (8.5 mg, 0.15 mmol) and sodium azide (10 mg, 0.15 mmol). The mixture was then heated to 100° C. for 18 hours. The reaction was diluted with water (5 mL) and acidified with 2 N HCl (2 mL). A white precipitate was formed upon acidification which was removed via filtration and dried under high vacuum for four hours. The crude residue was then dissolved in methanol (5 mL) and purified via preparative high pressure liquid chromatography (C18 Luna column eluted with a 10-100% gradient of acetonitrile in water with 0.1% formic acid modifier) to give the title compound as a white solid (62 mg, 78%) 1H NMR (CDCl3): 8.54 (d, J=9 Hz, 1H), 7.91-8.02 (m, 2H), 7.75 (d, J=9 Hz, 1H), 7.73 (d, J=9 Hz, 1H), 7.54 (dd, J=2, 8 Hz, 1H), 7.60-7.48 (m, 3H) 7.38 (d, J=9 Hz, 2H), 7.34-7.27 (m, 1H), 6.88 (d, J=9 Hz, 2H), 4.78 (s, 2H), 3.42-3.28 (m, 1H), 1.53-1.34 (m, 6H). ESI-LCMS m/z 556 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[NH:5][C:6]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.O.C(O)[CH2:26][OH:27]>>[OH:27][CH2:26][CH2:1][O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[N:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[N:12]=[C:13]1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H](C)Nc1ncccc1NC(=O)c1ccc(Cl)cc1
Reactant: OCCO
Solvent: O
Product: C[C@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 96 %

Procedure:
A solution of (R)-N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]alanine methyl ester (27.4 g, 0.0822 mole) in ethylene glycol (150 ml) was refluxed under nitrogen for 1.75 hours and then cooled. One-third of this solution was added to water (1 liter), extracted with ethyl acetate twice and the combined organic layers were washed three times with water and once with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, treated with charcoal, filtered, and evaporated to give 8.3 g of a yellow solid (96% yield). The solid was dissolved in hot isopropyl ether (with a little isopropyl alcohol) and filtered hot. Upon cooling to room temperature, solid precipitated, which was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at room temperature to give 3.29 g of title compound, mp 110°-113° C.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][N:6]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:5]2[CH2:4][NH:3]1.O>C1COCC1>[CH2:4]1[NH:3][CH2:2][CH2:8][CH2:7][N:6]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:5]12
Reactant: O=C1CCN2c3ccccc3Cc3ccccc3C2CN1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)Cc1ccccc1N1CCCNCC21
Temperature: 0 °C

Procedure:
A solution of 7.5 g 2,3,4,5,11,15b-hexahydro-3-oxo-1H-dibenz[3,4:6,7]azepino[1,2-a](1,4)diazepine in 200 ml THF is added to a vigorously stirred suspension of 5 g LiALH4 in 400 ml dry THF. The mixture is boiled under reflux for 3 hours, after which it is cooled to about 0° C. 20 ml water is then added slowly to the mixture and the inorganic precipitate which forms is removed by filtration. The filtrate is evaporated to dryness, leaving a crystalline residue. Yield 5.3 g.
Reaction SMILES: Cl.ClC(C#N)(C1C=CC=CC=1)C1C=CC([NH:10][C:11]([CH:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:14]2)=[O:12])=CC=1>CO>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:15]2[CH2:14][CH:13]([C:11]([NH2:10])=[O:12])[O:17][N:16]=2)[CH:19]=1
Reactant: N#CC(Cl)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Agent: Cl
Solvent: CO
Product: NC(=O)C1CC(c2cccnc2)=NO1

Procedure:
) A solution of (±)-N-[4-(chlorocyanophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide monohydrochloride (0.004 mol) in methanol (50 ml) was stirred and refluxed for 30 minutes. The solvent was evaporated. The residue was purified by high-performance liquid chromatography over silica gel ((I) eluent: CH2Cl2/CH3OH 96/4; (II) eluent: CH2Cl2/CH3OH 97.5/2.5). The desired fractions were collected and the solvent was evaporated. The residue was repurified by high-performance liquid chromatography over Kromasil C18 (eluent: CH3OH/H2O 70/30). The desired fractions were collected and the solvent was evaporated. The residue was crystallized from Et2O/hexane, filtered off and dried, yielding 0.113 g (6%) of (±)-N-[4-cyanomethoxyphenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide. (compound 76)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.Cl.N>O>[CH3:15][CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]3)=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: O=c1ccocc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: Cl
Agent: N
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (1.0 g), 4H-pyran-4-one (0.52 g), water (20 ml), and concentrated hydrochloric acid (0.41 ml) was heated under reflux for 31/2 hours. The resultant solid was dissolved in the minimum of hot water and the solution was neutralised with aqueous ammonia to give the crude product, 1.16 g, m.p. 249-256° C. The product was recrystallised first from water to which a little 2N NaOH was added, and then from water alone to give the pure title compound, 0.82 g, m.p. 254-256° C. (after melting and resolidifying at about 150° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[N:9][CH:10]=[C:4]2[CH:3]=1.[NH2:11][C:12]1[C:21]2[C:16](=[C:17](Br)[C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[N:14][C:13]=1[C:24]([NH2:26])=[O:25]>>[NH2:11][C:12]1[C:21]2[C:16](=[C:17]([C:2]3[CH:7]=[CH:6][N:5]4[CH:8]=[N:9][CH:10]=[C:4]4[CH:3]=3)[C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[N:14][C:13]=1[C:24]([NH2:26])=[O:25]
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: Brc1ccn2cncc2c1
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccn2cncc2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 7-bromoimidazo[1,5-a]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.44 (s, 3 H), 6.64 (dd, J=7.07, 1.52 Hz, 1 H), 7.44 (s, 1 H), 7.50 (s, 1 H), 7.71 (d, J=8.59 Hz, 1 H), 8.23 (d, J=8.84 Hz, 1 H), 8.35 (d, J=7.07 Hz, 1 H), 8.42 (s, 1 H); ESI-MS m/z [M+H]+ 319.1.
Reaction SMILES: C1([CH2:4][N:5]2[CH2:25][CH2:24][C@@:12]34[C:13]5[C:18]6[CH2:19][C@@H:6]2[C@H:7]3[CH2:8][C@H:9]([C@:27]([OH:33])([C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:28])[C@H:10]([OH:26])[C@@H:11]4[O:23][C:14]=5[C:15]([OH:22])=[C:16]2[CH2:21][CH2:20][C:17]2=6)CC1.C[C@@](O)(C(C)(C)C)[C@@H]1[C@]2(OC)[C@@H]3OC4=C(O)C=CC5=C4[C@]43CCN(CC3CC3)[C@H](C5)[C@@]4(CC2)C1>>[CH3:30][C:29]([CH3:32])([CH3:31])[C@:27]([C@H:9]1[CH2:8][C@H:7]2[C@@:12]34[CH2:24][CH2:25][N:5]([CH3:4])[C@@H:6]2[CH2:19][C:18]2[C:13]3=[C:14]([O:23][C@H:11]4[C@H:10]1[OH:26])[C:15]([OH:22])=[C:16]1[CH2:21][CH2:20][C:17]1=2)([OH:33])[CH3:28]
Reactant: CC(C)(C)[C@@](C)(O)[C@H]1C[C@@H]2[C@H]3Cc4c5c(c(O)c6c4[C@@]2(CCN3CC2CC2)[C@@H](O6)[C@H]1O)CC5
Agent: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Product: CN1CC[C@]23c4c5c6c(c(O)c4O[C@H]2[C@@H](O)[C@@H]([C@](C)(O)C(C)(C)C)C[C@@H]3[C@H]1C5)CC6
Yield: 82.5 %

Procedure:
Compound 21 was synthesized similar to the procedure described in Example 1 for the preparation of compound 2 using compound 20 rather than compound 1. After isolation, 3.76 g of compound 21 (82.5%) was obtained with a purity of 92.7% as an off-white solid A sample was further purified by column chromatography to afford compound 21 in >99% purity as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][N:22]([CH2:24][C:25]1[N:26]=[C:27]2[CH2:32][NH:31][CH2:30][CH2:29][N:28]2[CH:33]=1)[CH3:23]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:31]4[CH2:30][CH2:29][N:28]5[CH:33]=[C:25]([CH2:24][N:22]([CH3:23])[CH3:21])[N:26]=[C:27]5[CH2:32]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN(C)Cc1cn2c(n1)CNCC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: CN(C)Cc1cn2c(n1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)CC2

Procedure:
Using 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and (2-dimethylaminomethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, the same procedure as in Production Example 1 was followed to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:20][C:17]1[CH:18]=[CH:19][C:14]([F:13])=[C:15]([NH:21][C:22](=[O:34])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[CH:16]=1)#[N:2]
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)Nc1cc(O)ccc1F
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
To a solution of 3-cyano-4-fluoronitrobenzene (0.530 g, 3.19 mmol) and N-(2-fluoro-5-hydroxyphenyl)-2-[3-(trifluoromethyl)phenyl]acetamide (1.00 g, 3.19 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.530 g, 3.83 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off. The obtained organic layer was purified by basic silica gel column chromatography (eluate: 50% ethyl acetate/n-hexane), and the obtained solution was concentrated under reduced pressure to give the title compound (1.38 g, 94%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:16])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][OH:15])[C:9]=2[N:10]=1.[NH3:17]>CO>[OH:15][CH2:14][CH2:13][O:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:16])[NH:3][C:2]([NH2:17])=[N:10][C:9]1=2
Reactant: O=c1[nH]c(Cl)nc2c1ncn2COCCO
Reactant: N
Solvent: CO
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Temperature: 125 °C

Procedure:
A mixture of 2-chloro-9-(2-hydroxyethoxymethyl) hypoxanthine (0.375 g) and methanol (80 ml) saturated with anhydrous ammonia was heated in a bomb at 125° C. for 5 hours. The bomb was cooled in an ice bath and the reaction mixture removed. Solvent and excess ammonia were removed under reduced pressure at 50° C. After the residue was triturated with cold water to remove the ammonium chloride formed, the remaining solid was dried and then recrystallized from methanol to give pure 9-(2-hydroxyethoxymethyl)guanine (0.24 g), m.p. 256.5°-257° C.
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.FC(F)(F)S(O[C:18]1[C@:19]2([CH2:36][CH2:35][C@H:34]3[C@@H:24]([CH2:25][CH2:26][C@@H:27]4[C@:32]3([CH3:33])[CH2:31][CH2:30][C@@H:29]([O:37][C:38](=[O:40])[CH3:39])[CH2:28]4)[C@@H:21]2[CH2:22][CH:23]=1)[CH3:20])(=O)=O.C(O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)C1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.C1COCC1>[C:38]([O:37][C@@H:29]1[CH2:30][CH2:31][C@@:32]2([CH3:33])[C@@H:27]([CH2:26][CH2:25][C@@H:24]3[C@@H:34]2[CH2:35][CH2:36][C@@:19]2([CH3:20])[C@H:21]3[CH2:22][CH:23]=[C:18]2[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:28]1)(=[O:40])[CH3:39]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]32)C1
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Yield: 82.1 %

Procedure:
The method followed that described in Example 1, using in step (b) diethyl(3-pyridyl)borane (1.41 g, 9.6 mmol), 3α-acetoxy-5α-androst-16-en-17-yl trifluoromethanesulphonate (3.44 g, 7.4 mmol), prepared from the 3α-acetoxy-5α-androstan-17-one by the method of step (a), THF (40 ml), bis(triphenylphosphine)palladium(II) chloride (52 mg, 0.07 mmol), and aqueous sodium carbonate (2M, 15 mmol). Chromatography, on elution with light petroleum-diethyl ether (2:1), afforded the title compound (2.39 g, 82%), 1H-NMR (CDCl3) inter alia δ0.85(3H,s, 19-CH3), 1.01(3H,s,18-CH3), 2.06(3H,s,CH3CO2), 5.02(1H,m,3β-H), 6.00(1H,m,16-H), 7.24(1H,m,Py 5-H), 7.68(1H,m,Py 4-H), 8.47(1H,m,Py 6-H), 8.63(1H,m,Py 2-H); MS m/z 393 (M+).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCO>[C:5]1([CH:11]2[CH2:12][CH2:13][N:14]([CH2:3][CH2:2][C:1]#[N:4])[CH2:15][CH2:16]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CC#N
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCO
Product: N#CCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
Acrylonitrile (3.1 mL, 44 mmol, 2.5 eq) was added to a solution of 4-phenylpiperidine (3.00 g, 18.0 mmol) in EtOH (40 mL) and the mixture was stirred at room temperature for 1.5 h. The volatiles were removed, giving 3.80 g of the desired product (brown oil, 99%).
Reaction SMILES: Cl[C:2]1C(CN)=CC=C(Cl)N=1.[CH2:11]([N:13]([CH2:18][C:19]1[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:14]([NH:16][CH3:17])=[S:15])[CH3:12].CNC(N(CC)CC1C=NC=CC=1)=S>>[CH3:2][S:15][C:14](=[N:16][CH3:17])[N:13]([CH2:11][CH3:12])[CH2:18][C:19]1[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=1
Reactant: CCN(Cc1ccc(F)nc1)C(=S)NC
Reactant: NCc1ccc(Cl)nc1Cl
Agent: CCN(Cc1cccnc1)C(=S)NC
Product: CCN(Cc1ccc(F)nc1)C(=NC)SC

Procedure:
The reaction procedure of Example 13 (2) was repeated except that N-ethyl-N-(6-fluoro-3-pyridylmethyl)-N'-methylthiourea was used in lieu of N-methyl-N'-ethyl-N'-(3-pyridylmethyl)thiourea to give S-methyl-N-ethyl-N-(6-fluoro-3-pyridylmethyl)-N'-methylisothiourea as a pale brown oil.