Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.CCN(CC)CC>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: Cc1cc(N)n[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (1.27 g, 5.8 mmol) in MeCN (20 ml) was added 5-methyl-1H-pyrazol-3-ylamine (568 mg, 5.8 mmol) and Et3N (1.6 mL). The mixture was stirred at ambient temperature overnight. LC/MS showed the completion of the reaction. Evaporation of the solvent afforded yellow oil that was purified by Gilson (5-95% MeCN/H2O, 15 minutes) to give the titled compound as solid (300 mg). m/z 278.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[O:8][CH2:7][CH2:6][O:5]1.[BH4-].[Na+].O>CO>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][CH:16]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cccc(C=O)c2)OCCO1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(c2cccc(CO)c2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a ice-cold solution of 3-(2-methyl-[1,3]dioxolan-2-yl)benzaldehyde (1.84 g, 9.59 mmol) in MeOH (20 mL) was added NaBH4 (456 mg, 12.05 mmol in four portions). The reaction mixture was then stirred for 1 h at 0° C. Water was added and the mixture was extracted twice with EA. The combined org. extracts were washed with brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow oil. TLC:rf (4:1 hept-EA)=0.12. LC-MS-conditions 02: tR=0.74 min.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[CH3:19])([CH3:6])([CH3:5])[CH3:4].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25]Br>CN(C=O)C.O>[C:3]([O:7][C:8](=[O:20])[N:9]([CH2:25][C:24]1[CH:27]=[CH:28][C:29]([F:30])=[C:22]([F:21])[CH:23]=1)[C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[CH3:19])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1c(NC(=O)OC(C)(C)C)sc2ccccc12
Reactant: Fc1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(N(Cc2ccc(F)c(F)c2)C(=O)OC(C)(C)C)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
Sodium hydride (60%, 0.37 g, 9.19 mmol) was added to a solution of compound 125-B (2.2 g, 8.35 mmol) in DMF (30 mL), at 0° C. and the resultant mixture was stirred for 15 minutes. 3,4-Difluorobenzylbromide (1.18 mL, 9.2 mmol) was added, and the solution was stirred at ambient temperature for 2 h. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic extract washed with water (3×), brine, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The crude residue was purified by flash column chromatography, eluting with an ethyl acetate-heptane gradient, to afford compound 125-C as an oil (2.73 g, 84%). 1H-NMR (CDCl3): δ 1.40 (s, 9H), 1.97 (s, 3H), 4.72 (s, 2H), 6.93-7.19 (m, 3H), 7.28-7.39 (m, 2H), 7.61 (d, 1H), 7.70 (d, 1H).
Reaction SMILES: C(OC(=O)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:23][C:20]3([CH2:22][CH2:21]3)[N:19]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[N:7]=1)C.[CH:32]([NH2:34])=[O:33].C[O-].[Na+].O>CN(C=O)C.CO.CCOC(C)=O>[CH2:24]([N:19]1[CH2:18][CH2:17][N:16]([C:8]2[N:7]=[C:6]([CH2:5][C:32]([NH2:34])=[O:33])[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:23][C:20]21[CH2:22][CH2:21]2)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)Cc1nc(N2CCN(Cc3ccccc3)C3(CC3)C2)cc2ccccc12
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)Cc1nc(N2CCN(Cc3ccccc3)C3(CC3)C2)cc2ccccc12
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
[3-(4-Benzyl-4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetic acid ethyl ester (700 mg, 1.68 mmol) is dissolved in dry DMF under an atmosphere of argon. Formamide (224 μl, 254 mg, 5.64 mmol) is added, and the reaction mixture is heated to 105° C. At this temperature, NaOMe (312 μl of a 5.4 M solution in MeOH, 91 mg, 1.68 mmol) is added dropwise during 20 minutes. After 30 minutes at 105° C., TLC analysis indicates complete conversion of starting material. Cooling the reaction mixture to RT is followed by addition of water and extraction with EtOAc. The organic layers are washed with H2O (twice), dried over Na2SO4 and concentrated. The residue is purified by FCC (hexanes/EtOAc 1:1 to 1:3 to 0:100 to EtOAc/MeOH 98:2) to afford the title compound. 1H NMR (DMSO, 400 MHz) δ 0.68-0.70 (m, 2H), 0.82-0.88 (m, 2H), 3.08 (t, J=4.4, 2H), 3.45 (s, 2H), 3.58 (t, J=4.4, 2H), 3.96 (s, 2H), 4.27 (s, 2H), 5.3-5.5 (br, 1H), 6.55-6.7 (br, 1H), 6.72 (s, 1H), 7.26-7.36 (m, 6H), 7.51 (t, J=8.8, 1H), 7.60 d, J=9.9, 1H), 8.02 (d, J=9.9, 1H); ES-MS: 387 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([NH:30][C:31](=[O:50])[C:32]4[CH:37]=[C:36]([NH:38][C:39](=[O:48])[C:40]5[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=5)[CH:35]=[CH:34][C:33]=4[Cl:49])=[CH:26][N:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl>[Cl:49][C:33]1[CH:34]=[CH:35][C:36]([NH:38][C:39](=[O:48])[C:40]2[CH:41]=[CH:42][C:43]([C:46]#[N:47])=[CH:44][CH:45]=2)=[CH:37][C:32]=1[C:31]([NH:30][C:27]1[CH:26]=[N:25][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[N:29][CH:28]=1)=[O:50].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5ccc(C#N)cc5)ccc4Cl)cn3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc(Nc4ccc(S(=O)(=O)C5CCNCC5)cc4)nc3)c2)cc1
Reaction time: 18 h

Procedure:
A stirred suspension of intermediate 27 (Example 39) (0.12 g, 0.143 mmol) in DCM (8 mL) was treated with TFA (0.200 mL) and stirred for 18 h. Solvents were then removed yielding desired product as TFA salt (0.104 g, 99%). 1H NMR (DMSO-d6): δ 1.61-1.70 (m, 2H), 2.01-2.04 (m, 2H), 2.80-2.90 (m, 2H), 7.61 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.9 Hz, 2H), 7.90 (dd, J=8.7 Hz, J=2.5 Hz, 1H), 8.04-8.13 (m, 7H), 8.21-8.25 (m, 1H), 8.64-8.68 (m, 1H), 8.90 (s, 2H), 10.37 (s, 1H), 10.78 (s, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](=[CH:8][C:9]2[NH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:13]=2)[NH:6][C:5](=[O:25])[CH:4]=1.CS(O)(=O)=O.O>C(O)CCCC.O1CCOCC1>[CH2:1]([O:2][C:3]1[C:7](=[CH:8][C:9]2[NH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:13]=2)[NH:6][C:5](=[O:25])[CH:4]=1)[CH2:7][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCCCCCCCc1ccc(C=C2NC(=O)C=C2OC)[nH]1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CCCCCO
Solvent: C1COCCO1
Product: CCCCCCCCCCCc1ccc(C=C2NC(=O)C=C2OCCCCC)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
A solution of 4-methoxy-5-(5-undecyl-1H-pyrrol-2-yl-methylene)-1,5-dihydro-pyrrol-2-one (190 mg; 1 mmol) in amyl alcohol (4.75 ml) and dioxane (4.75 ml) is treated with 0.25 N methansulphonic acid in dioxane (1 ml) and stirred at room temperature under nitrogen atmosphere for 6 hours. The mixture is then poured into water (50 ml) and extracted with ethyl acetate (3×30 ml). The organic phase is shacked with brine, dried over sodium sulphate and evaporated to dryness. The crude material is purified on silica gel eluting with ethyl acetate/methanol 98/2 to give 4-amyloxy-5-(5-undecyl-1H-pyrrol-2-yl-methylene)-1,5-dihydro-pyrrol-2-one (110 mg; 0.45 mmols). Yield: 45%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[F:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:33][S:34][C:35]1[N:40]=[C:39]([NH:41][S:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)(=[O:44])=[O:43])[CH:38]=[C:37]([O:51][CH3:52])[N:36]=1.CN1CCOCC1>CN(C=O)C>[F:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:33][S:34][C:35]1[N:40]=[C:39]([NH:41][S:42]([N:45]2[CH2:46][CH2:47][N:48]([C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:49][CH2:50]2)(=[O:43])=[O:44])[CH:38]=[C:37]([O:51][CH3:52])[N:36]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1cc(NS(=O)(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)glycine (0.11 g) in DMF (10 mL) was added 1,3-Dicyclohexycarbodiimide (0.14 g) and 1-hydroxybenzotriazole hydrate (94 mg). After stirring at room temperature for 1 h, a solution of N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, hydrochloride salt (the product of step i, 0.27 g) and N-methylmorpholine (78 μL) in DMF (5 mL) was added dropwise and stirring continued at room temperature for 24 h. The mixture was filtered, rinsed with DCM and the filtrate evaporated. The crude material was purified by column chromatography on silica gel using EtOAc/isohexane (3:2) as eluent to give the subtitle compound as a foam. Yield: 0.24 g
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].[OH-:25].[Na+]>O>[CH2:2]([O:25][C:17]1[C:16]([CH3:22])=[N:15][N:14]([CH3:23])[C:13](=[O:24])[C:12]=1[C:4]1[C:3]([CH2:1][CH3:2])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=1[CH2:10][CH3:11])[CH2:1][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Agent: [Na+]
Solvent: O
Product: CCCCOc1c(C)nn(C)c(=O)c1-c1c(CC)cc(C)cc1CC
Temperature: 120 °C
Reaction time: 8 h
Yield: 717.1 %

Procedure:
To a test tube (outside diameter: 21 mm Φ×overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (0.21 g), 1-butanol1 (4 ml, water (0.1 ml), and sodium hydroxide (0.20 g) were added under a nitrogen atmosphere at room temperature, and stirred at 120° C. for 8 hours. Then, to the reaction mixture was added water at room temperature, and extracted with tert-butyl methyl ether. The resulting organic layer was concentrated under reduced pressure to give 0.74 g of 5-(n-butoxy)-4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-5)-(1)-39).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([NH:27][CH3:28])[C@@:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[F:36][C:37]([F:47])([F:46])[C:38]1[CH:45]=[CH:44][C:41]([CH2:42]O)=[CH:40][CH:39]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C.O>[F:36][C:37]([F:46])([F:47])[C:38]1[CH:45]=[CH:44][C:41]([CH2:42][O:5][C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([NH:27][CH3:28])[C@@:15]3([CH3:26])[O:19][C:18]4=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]4[CH2:16]3)[CH2:10][CH2:9]2)=[O:7])=[CH:40][CH:39]=1
Reactant: CNC(C1CCN(C(=O)OC(C)(C)C)CC1)[C@]1(C)Cn2cc([N+](=O)[O-])nc2O1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(C1CCN(C(=O)OCc2ccc(C(F)(F)F)cc2)CC1)[C@]1(C)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
(S)-2-{[1-(Tert-butoxycarbonyl)piperidin-4-yl]-N-methylaminomethyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 225 (400 mg, 1.01 mmol) was dissolved in methylene chloride (1 ml). To the solution, trifluoroacetic acid (1 ml) was added followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and added methylene (1 ml) chloride and triethylamine (2 ml). The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure, and the residue was dissolved in DMF (8 ml). To the solution, a mixture of 4-(trifluoromethyl)benzyl alcohol (267 mg, 1.51 mmol) and 1,1′-carbonyldiimidazole (246 mg, 1.51 mmol) in DMF (2 ml) stirred at room temperature for 4 hours was added followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-isopropyl ether to afford (S)-2-{[l-(4-trifluoromethylbenzyloxycarbonyl)piperidin-4-yl]-N-methylaminomethyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (341 mg, yield 68%) as a light yellow powder.
Reaction SMILES: [OH-].[Na+].C(O)C.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])[CH3:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH:19]1[CH:20]=[CH:21][C:16](/[CH:15]=[CH:7]/[C:6]([C:9]2[N:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: CC(=O)c1ccccn1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccccc1)c1ccccn1
Reaction time: 15 h

Procedure:
A solution of NaOH (12.8 mmol, 1.28 equiv.) in water (4.55 g) and ethanol (2.32 g) are introduced into a round bottom flask with a magnetic stirrer. Into the alkaline solution is placed 2-acetyl pyridine 1a (10 mmol, 1 equiv.) and the flask is rapidly surrounded by ice and the stirrer is started. The temperature reaches 10° C.-15° C. and benzaldehyde 1b (10 mmol, 1 equiv.) is added at once. The ice bath is removed and the reaction is stirred for 15 hours. The reaction is filtered. The filtrate is concentrated under reduced pressure and the product is purified by flash column chromatography on SiO2 (33% ethyl acetate/hexanes) to give the 3-phenyl-1-pyridin-2-yl-propenone 1c as a pale yellow solid. See Kohler, E. P. & H. M. Chadwell, H. M., Org. Synth., Coll. Vol. 1, 2nd ed., p. 78.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][CH2:8][N:9]2[C:14](=[O:15])[CH:13]=[N:12][C:11]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:10]2=3)[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[N:12][C:11]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:10]1=2
Reactant: COc1ccc2ncc(=O)n(CC[C@@H]3COC(C)(C)O3)c2n1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2ncc(=O)n(CC[C@@H](O)CO)c2n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
In tetrahydrofuran (100 ml) was dissolved 4-{2-[(4R)-2,2-dimethyl-1,3-dioxolan-4yl]ethyl}-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (2.55 g, 8.34 mmol), and 1N Hydrochloric acid aqueous solution (25 ml) was added thereto at room temperature and the mixture was stirred at 60° C. for 16 hours. After cooling in the air, the reaction solution was concentrated under reduced pressure and alkalized by adding 1N sodium hydroxide aqueous solution (30 ml) under cooling on ice. The solution was extracted with a lower layer solvent of chloroform/methanol/water (7:3:1) and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure so as to yield 1.95 g (88%) of the title compound in the form of an orange solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[C:37]([CH3:42])=[N:38][O:39][C:40]=1[CH3:41].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[C:37]([CH3:42])=[N:38][O:39][C:40]=2[CH3:41])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2c(C)noc2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.02 g), potassium carbonate (1.28 g), 4-(chloromethyl)-3,5-dimethylisoxazole (0.45 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.43 g, 33%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([O:20][CH2:21][CH2:22][NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:17]=[N:18][CH:19]=1.[H-].[Na+].[CH3:31]I>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([O:20][CH2:21][CH2:22][N:23]([CH3:31])[S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:17]=[N:18][CH:19]=1
Reactant: CCS(=O)(=O)NCCOc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCS(=O)(=O)N(C)CCOc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1

Procedure:
In analogy to the procedure described for the preparation of example 195, ethanesulfonic acid {2-[5-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-yloxy]-ethyl}-amide (example 243) has been reacted with sodium hydride and methyl iodide to give the title compound as orange amorphous solid. MS: 422.4 (M+H+).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:6]2([CH2:11][CH2:10][N:9]([C:12]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])[CH2:8][CH2:7]2)[CH2:5]1)#[N:2].[Sn]([N:31]=[N+:32]=[N-:33])(C)(C)C>C1(C)C=CC=CC=1>[NH:31]1[C:1]([CH2:3][CH:4]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6]3([CH2:11][CH2:10][N:9]([C:12]([NH:14][CH:15]4[CH:20]5[CH2:26][CH:4]6[CH2:5][CH:18]([CH2:17][CH:16]4[CH2:3]6)[CH2:19]5)=[O:13])[CH2:8][CH2:7]3)[CH2:5]2)=[N:2][N:33]=[N:32]1
Reactant: N#CCC1CC2(CCN(C(=O)NC3CCCCC3)CC2)c2ccccc21
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CC(Cc1nnn[nH]1)c1ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of (±)-3-(cyanomethyl)-N-cyclohexyl-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (30 mg, 0.075 mmol) in toluene (2 mL), Me3SnN3 (80 mg, 0.375 mmol) was added. The reaction mixture was stirred at 80° C. overnight. The mixture was concentrated. The crude product was purified by preparative HPLC to afford (±)-3-((1H-tetrazol-5-yl)methyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (15 mg, 45%). LC-MS Method 5 tR=1.28 min, m/z=447.3; 1H NMR (CD3OD): δ=1.62-1.69 (m, 2H), 1.71-1.86 (m, 4H), 1.89-2.24 (m, 13H), 2.56-2.68 (m, 1H), 3.09-3.29 (m, 3H), 3.49 (s, 1H), 3.66-3.74 (m, 1H), 3.1-3.90 (m, 1H), 3.99 (s, 1H), 4.09-4.21 (m, 2H), 7.27 (d, 1H), 7.30-7.49 (m, 3H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4]O.[CH2:7]=CC=C.[H-].C([Al+]CC(C)C)C(C)C.C(O)(O)CCC.[Nd].C(Br)C=C.C(O)(O)CCC.[H-].C([Al+]CC(C)C)C(C)C.C(Br)C=C.C=CC=C>[Nd].CCCCCC>[CH2:1]=[CH:2][C:3](=[CH2:4])[CH3:7].[CH2:1]=[CH:2][CH:3]=[CH2:4]
Reactant: OCCCCO
Agent: C=CC=C
Agent: CC(C)C[Al+]CC(C)C
Agent: CCCC(O)O
Solvent: CCCCCC
Solvent: C=CCBr
Product: C=CC(=C)C
Temperature: 20 °C
Yield: 87 %

Procedure:
In this experiment, an isoprene-butadiene copolymer was synthesized using an alcohol modified neodymium catalyst system modified with 1,4-butanediol. In this procedure, a one gallon (3.78 liter) reactor was charged with 1,093 grams of hexane containing 81.9 grams of butadiene and 663 grams of 1.2 molar diisobutylaluminum hydride (DIBAH) in hexane (i.e., 25% weight percent DIBAH). To this solution was then added 6.78 grams of 1,4-butanediol with stirring and with temperatures maintained at 20° C. The suspension of the butanediol gradually dissolved upon reacting with the DIBAH. After one hour of stirring, 105.4 grams of a 10.3% neodymium solution (neodymium neodecanoate), diluted with 165 grams of hexane, was added to the reactor. The solution was stirred for another thirty minutes after which time. 19.1 grams of allyl bromide was added. The cooling was stopped and the mixture allowed to warmup to ambient (and above) temperature. After the exotherm subsided, the catalyst solution was aged by heating at 65° C. for ninety minutes. The catalyst prepared had a butanediol-DIBAH!-ND-allyl bromide-butadiene molar component ratio of 1-16!-1-2-20, respectively, and a concentration of 0.025 molarity with respect to the neodymium. The aged catalyst was then cooled and stored in a dry container under nitrogen.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:18]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=3)[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: Nc1cnc(Cl)cc1I
Reactant: COC(=O)CCC#Cc1ccc(Cl)cc1
Product: COC(=O)CCc1c(-c2ccc(Cl)cc2)[nH]c2cnc(Cl)cc12

Procedure:
Prepared from 6-chloro-4-iodo-3-pyridinamine (Description 8) and methyl 5-(4-chlorophenyl)-4-pentynoate (Description 2) according to the method of Description 4. 1H NMR (360 MHz, CDCl3) δ 8.56 (1H, br s), 8.50 (1H, s), 7.50 (5H, m), 3.63 (3H, s), 3.15 (2H, t, J 7.9 Hz), and 2.62 (2H, t, J 7.9 Hz). m/z (ES+) 349, 351 (M+1).
Reaction SMILES: Cl[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:3]([C:9]([O:11]CC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH:29][CH3:30])=[CH:24][CH:23]=1)#[N:21]>C1(C)C=CC=CC=1>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:9](=[O:11])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:29]2[CH3:30])=[CH:26][CH:27]=1)#[N:21]
Reactant: CCOC(=O)C(C(=O)OCC)=C(Cl)c1ccccc1
Reactant: CNNc1ccc(C#N)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Yield: 26.2 %

Procedure:
4.7 g of the title compound was prepared as colorless crystals from 14.6 g of ethyl 3-chloro-2-ethoxycarbonyl-3-phenyl-acrylate, 11.0 g of 1-(4-cyanophenyl)-2-methyl-hydrazine and toluene in the same manner as in Reference Example 5.
Reaction SMILES: C([N:4]1[C:8]2=[CH:9][C:10]3[N:14]=[N:13][NH:12][C:11]=3[CH:15]=[C:7]2[C:6]([CH3:17])([CH3:16])[CH2:5]1)(=O)C.[ClH:18]>>[ClH:18].[ClH:18].[CH3:16][C:6]1([CH3:17])[C:7]2[C:8](=[CH:9][C:10]3[N:14]=[N:13][NH:12][C:11]=3[CH:15]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2cc3[nH]nnc3cc21
Agent: Cl
Product: CC1(C)CNc2cc3nn[nH]c3cc21

Procedure:
0.5 g. of the product of Example 7 is heated under reflux for 2.5 hours with 20 ml. ethanolic hydrogen chloride solution, then allowed to cool and filtered. There is obtained 0.4 g. (70% of theory) of the title compound; m.p. 243°-245° C.