Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[C:10]([C:12]1[CH:13]=[C:14]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:15]2[C:19]=1[CH2:18][S:17][CH2:16]2)=[O:11].[OH-].[Na+].C>C(Cl)Cl.C(#N)C>[C:2]1([NH:1][C:10]([C:12]2[CH:13]=[C:14]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[N:15]3[C:19]=2[CH2:18][S:17][CH2:16]3)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cc(-c2cccnc2)n2c1CSC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cc(-c2cccnc2)n2c1CSC2
Temperature: 20 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
A solution of aniline (11.2 g) in methylene chloride (50 cc) is added over 15 minutes at a temperature of about 24° C. and 29° C. to a suspension of 7-chloroformyl-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (12 g) in methylene chloride (200 cc). The suspension obtained is stirred at a temperature of about 20° C. for 16 hours. Methylene chloride (300 cc) and distilled water (200 cc) are then added to the suspension. The insoluble material is separated off by filtration, washed 3 times with methylene chloride (75 cc in total) and 3 times with distilled water (75 cc in total). The mother-liquors from filtration and washing are combined; the organic phase is separated off, washed twice with distilled water (400 cc in total), once with a 2 N aqueous solution of sodium hydroxide (200 cc), then twice with distilled water (400 cc in total), dried over anhydrous magnesium sulphate, treated with decolourising charcoal (0.5 g) and filtered. A crude solution (625 cc) of product in methylene chloride is thus obtained. The insoluble material obtained earlier is taken up with a 5 N aqueous solution of sodium hydroxide (200 cc). The oil obtained is extracted 3 times with methylene chloride (750 cc in total). The organic extracts are combined, washed 3 times with distilled water (450 cc in total), dried over anhydrous magnesium sulphate, treated with decolourising charcoal (0.5 g) and filtered. The methylene chloride solution obtained is combined with the methylene chloride solution obtained earlier (625 cc) and the solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. A crude product (15.4 g) is thus obtained. This product is dissolved in boiling acetonitrile (210 cc). The solution obtained is treated with decolourising charcoal (0.5 g) and filtered hot. The filtrate is cooled at a temperature of about 4° C. for 2 hours. The crystals which have appeared are separated off by filtration, washed 3 times with acetonitrile (30 cc in total) cooled to a temperature of about 4° C. and 3 times with isopropyl ether (75 cc in total) and are then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. N-phenyl-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (7.4 g) is thus obtained in the form of cream crystals melting at 188° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=12.[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH3:20][N:17]1[C:18](=[O:19])[N:13]2[CH:12]=[N:11][C:10]([C:2]3[N:1]([CH3:23])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[C:14]2[N:15]=[N:16]1
Reactant: Cn1nnc2c(-c3nc4ccccc4[nH]3)ncn2c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnc2c(-c3nc4ccccc4n3C)ncn2c1=O
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a 0° C. solution of 8-(1H-benzo[d]imidazol-2-yl)-3-methylimidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (0.54 mmol, 0.144 grams, 1 eq.) in anhydrous DMF (2.5 mL) was added sodium hydride 60% in mineral oil (0.59 mmol, 24 mg, 1.1 eq.) portion-wise. The formed suspension was stirred at low temperature for 10 minutes and methyl iodide (1.07 mmol, 67 μL, 2 eq.) was added into it in one portion. The suspension was stirred over night at room temperature. The reaction mixture was filtered and the obtained solid was washed with water, acetonitrile and ethyl acetate, and dried under vacuum to give the title compound. Yield: 55%. δH (DMSO-d6) 9.02 (1H, s), 7.77 (1H, d, J: 8.09), 7.68 (1H, d, J: 8.12), 7.36 (1H, m), 7.32 (1H, m), 4.14 (3H, s), 3.90 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=O)[CH:10]([CH2:11][O:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(O)C>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=[N:18][OH:19])[CH:10]([CH2:11][O:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1C2COC1CN(Cc1ccccc1)C2
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1C2COC1CN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 41.2 %

Procedure:
A mixture of (rac)-3-benzyl-6-oxa-3-aza-bicyclo[3.2.1]octan-8-one (500 mg, 2.30 mmol), hydroxylamine hydrochloride (224 mg, 3.22 mmol) and pyridine (0.32 mL) in ethanol (5 mL) was heated to 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. 2.5 N Aqueous sodium hydroxide solution (10 mL) was added to the residue. The resulting solution was extracted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 5-10% ethyl acetate/hexane mixture as eluent to afford the title compound as a brown sticky liquid (220 mg, 43%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.O.[NH2:22][NH2:23].Cl>C(O)C>[F:19][C:15]1[CH:14]=[C:13]([C:12]2[C:3]3[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=3)[NH:23][N:22]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(F)c(C(=O)c2cccc(F)c2)c1
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A total of 11.5 g of methyl 4-fluoro-3-(3-fluorobenzoyl)benzoate was dissolved in 40 ml of ethanol, and the reaction mixture was treated with 2.4 ml of hydrazine monohydrate with stirring at room temperature for 12 hours. The reaction mixture was treated with 2 N hydrochloric acid to be acidic and was extracted with two portions of ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was recrystallized from hexane-diisopropyl ether, to give 7.0 g of title compound as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1CCCC1=O.C(OCC)(=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[CH:34][C:35]([NH:38][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2.5 g, 9.76 mmol), 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.65 g, 10.34 mmol), and triethylamine (4.1 mL, 29.3 mmol) were dissolved in 50 mL of 1-methyl-2-pyrrolidinone. To this solution was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 4.51 g, 10.34 mmol) in one portion. The mixture was stirred at room temperature overnight and then diluted with 250 mL of ethyl acetate. The organic layer was washed with saturated sodium bicarbonate (2×50 mL), dried over magnesium sulfate, filtered and evaporated to dryness under vacuum. The residue was purified by chromatography over a silica gel plug (eluting with ethyl acetate/methylene chloride) to yield 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester as an amorphous solid. ES-MS calcd for C26H27F3N4O4 (m/e) 516.52, obsd 517 (M+H).
Reaction SMILES: C(N[C:10]([N:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([NH2:20])=[O:19])=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>O>[CH2:21]([N:12]1[C:13]2[N:14]=[CH:15][NH:16][C:17]=2[C:18](=[O:19])[NH:20][C:10]1=[S:11])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCN(C(=S)NC(=O)c1ccccc1)c1nc[nH]c1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Yield: 94 %

Procedure:
A mixture of 4-[[(benzoylamino)carbonothioyl](pentyl)amino]-1H-imidazole-5-carboxamide (11.8 g, 0.0263 mol) and 1 M of sodium hydroxide in water (75 mL) was heated to reflux for 3 h. Solid was formed in the reaction mixture. The reaction mixture was adjusted to pH 3-4 with concentrated HCl with cooling in an ice bath. The solid was filtered, washed with water and air-dried to give the product (9.0 g, 65% purity, 94% yield). The product was used for the next step without further purification. LCMS calculated for C10H15N4OS (M+H): 239.1; found: 239.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=3)=[O:22])=[C:16]([C:38]3[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][CH:39]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47].CO>C(Cl)Cl.CO>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[CH3:44][C:41]1([CH3:45])[CH2:42][CH2:43][C:38]([C:16]2[N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:19]=[CH:18][C:17]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])=[CH:39][CH2:40]1
Reactant: CC1(C)CC=C(c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC=C(c2nc(C3CCNCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 97 %

Procedure:
A solution of 215 mg (0.339 mmol) 5-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL of CH2Cl2 was treated with three drops MeOH and 3 mL TFA at room temperature for 4 h. MeOH (10 mL) was added and the solvents evaporated in vacuo. Chromatography of the residue on a 50-g silica Varian MegaBond Elut column with 10% MeOH—CH2Cl2 afforded 210 mg (97%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.59 (d, 1H, J=8.4 Hz), 8.04 (s, 1H), 7.28 (d, 1H, J=8.4 Hz), 6.02-5.93 (m, 1H), 3.58-3.48 (m, 2H), 3.32-3.03 (m, 3H), 2.54-2.42 (m, 2H), 2.23-2.02 (m, 6H), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C23H28N6O, 405.2 (M+H). found 405.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([P:30]([O:34]C)([O:32]C)=[O:31])[CH2:5][C:6]([CH3:29])=[CH:7][CH2:8][C:9]1[C:10]([O:22]CC[Si](C)(C)C)=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[CH3:1][O:2][C:3](=[O:36])[CH:4]([P:30]([OH:34])([OH:32])=[O:31])[CH2:5][C:6]([CH3:29])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: COC(=O)C(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)P(=O)(OC)OC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)P(=O)(O)O
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 2-(dimethoxy-phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid methyl ester (30 mg, 0.055 mmol) in acetonitrile (2 mL) was added trimethylsilyl bromide (0.18 mL). After 10 minutes, 2,6-lutidine (0.16 mL) was added to the reaction at ambient temperature. The reaction was allowed to proceed for 16 hours before it was concentrated to dryness. The residue was resuspended in a solution of DMF:H2O (8:2, 1 mL) and purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 18 mg of the product as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.81 (s, 3H), 2.16 (s, 3H), 2.40-2.49 (m, 1H), 2.63 (dt, 1H, J=6, 17 Hz), 3.07 (ddd, 1H, J=4,12,23 Hz), 3.38(3, 2H, J=7 Hz), 3.52 (s, 3H), 3.77 (s, 3H), 5.25 (s, 2H), 5.28 (t, 1H, J=7 Hz) ppm; 31P (121.4 MHz, CDCl3) δ 19.5 ppm; MS (m/z) 415.2 [M+H]+, 437.2 [M+Na]+.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[N:13]1([C:22]2[N:27]=[C:26]([NH:28][C@H:29]3[C:38]4[C:33](=[C:34]([F:39])[CH:35]=[CH:36][CH:37]=4)[O:32][CH2:31][CH2:30]3)[C:25]([NH2:40])=[CH:24][N:23]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1>C1COCC1>[N:13]1([C:22]2[N:27]=[C:26]3[C:25]([NH:40][C:1](=[O:2])[N:28]3[C@H:29]3[C:38]4[C:33](=[C:34]([F:39])[CH:35]=[CH:36][CH:37]=4)[O:32][CH2:31][CH2:30]3)=[CH:24][N:23]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnc(-n2cnc3ccccc32)nc1N[C@@H]1CCOc2c(F)cccc21
Solvent: C1CCOC1
Product: O=c1[nH]c2cnc(-n3cnc4ccccc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbonyldiimidazole (0.2 g) was added to a solution of the above amine in THF (10 mL). The resulting mixture was stirred at RT overnight, silica gel was added, then the solvents were removed under reduced pressure and purified via column chromatography, elution with 5% MeOH/DCM, to yield the titled product (28 mg), MH+=403, 1H NMR (CDCl3) δ 10.6 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.8 (m, 2H), 7.3 (m, 2H), 7.0 (m, 1H), 6.7 (m, 1H), 5.9 (dd, 1H), 4.7 (m, 1H), 4.4 (t, 1H), 2.7 (m, 1H), 2.3 (m, 1H) ppm, 19F NMR δ −135.7 (m). Chiral HPLC—no evidence of other enantiomer, Method; Chiralcel™ OD-H (0.46×25 cm analytical column, Daicel Chemical Industries) isocratic 15% (0.05% TFA/EtOH) 85% (0.05% TFA/Hex), Rt=19.5 min (R)-enantiomer, Rt=22.4 min (S)-enantiomer.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([S:12]([NH2:15])(=[O:14])=[O:13])[C:8]([OH:11])([CH3:10])[CH3:9])=[CH:3][CH:2]=1.[CH2:22]([O:24][C:25](OCC)(OCC)OCC)[CH3:23]>C(O)(=O)C>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:2]=[CH:3][C:4]([CH:7]2[C:8]([CH3:9])([CH3:10])[O:11][C:25]([O:24][CH2:22][CH3:23])=[N:15][S:12]2(=[O:13])=[O:14])=[CH:5][CH:6]=1
Reactant: CCOC(OCC)(OCC)OCC
Reactant: CC(C)(O)C(c1ccc(-c2ccccc2)cc1)S(N)(=O)=O
Solvent: CC(=O)O
Product: CCOC1=NS(=O)(=O)C(c2ccc(-c3ccccc3)cc2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 3.14 g of 1-biphenyl-4-yl-2-hydroxy-2-methylpropane-1-sulfonamide in 75 ml of tetraethoxymethane and 15 ml of acetic acid was stirred at 100° C. for 24 hours. The conversion was checked by LCMS. Since it was incomplete, the reaction mixture was admixed with a further 15 ml of acetic acid and stirred at 120° C. for 4 hours. Subsequently, a further 20 ml of tetraethoxymethane were added and the reaction mixture was stirred at 120° C. for 5 hours. Since, by checking with LCMS, no further conversion had been achieved, the solvent was removed under reduced pressure and the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (1.04 g) with a molecular weight of 359.5 g/mol (C19H21NO4S).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:18]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Oc2ccccc2)cc1
Yield: 39.8 %

Procedure:
The title compound was prepared in a similar manner to Preparation 18 from (±) N-tert-butoxycarbonyl-1,2-iminoindane (3 g, 13 mmol), 4-phenoxyphenol (2.42 g, 13 mmol), pyridinium p-toluenesulfonate (50 mg) and chloroform (100 ml). After a reaction time of 3 h, the reaction was diluted with chloroform (100 ml) then washed sequentially with saturated aq. sodium bicarbonate, water and brine. After drying over Na2 SO4, volatiles were removed in vacuo and the residue subjected to column chromatography on neutral alumina eluting with 10% diethyl ether in hexanes to afford the title compound (2.16 g) as a foam.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:21]=3[N:32]([CH3:34])[CH3:33])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][C:6]([O:37][CH3:38])=[C:7]([O:35][CH3:36])[CH:8]=2)[N:3]=1>C(N(CC)CCCN)C>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][CH2:13][NH:12][C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:21]=3[N:32]([CH3:34])[CH3:33])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][C:6]([O:37][CH3:38])=[C:7]([O:35][CH3:36])[CH:8]=2)[N:3]=1)[CH3:18]
Reactant: COc1cc2nc(Cl)nc(NC3CCN(Cc4c(OCCN(C)C)cccc4N(C)C)CC3)c2cc1OC
Agent: CCN(CC)CCCN
Product: CCN(CC)CCCNc1nc(NC2CCN(Cc3c(OCCN(C)C)cccc3N(C)C)CC2)c2cc(OC)c(OC)cc2n1

Procedure:
Following General Procedure E, Compound 75 (35 mg 0.065 mmol) and 3-(diethylamino)propylamine (30 μL, 019 mmol) were converted into Compound 166.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[O:1]([C:8]1[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(Oc2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of ethyl 2-phenoxypyrimidine-5-carboxylate (400 mg, 1.6 mmol) in mixed solution of tetrahydrofuran/methanol/water=3:1:1 (4 mL) was added lithium hydroxide monohydrate (200 mg, 8.4 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo. To the residue, was added water (50 mL) and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried by sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1) to give the product 2-phenoxypyrimidine-5-carboxylic acid (300 mg, 79%) as pale solid.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)#[CH:42].C(N(CC)CC)C>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:42]#[C:41][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc2nc(C#Cc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reaction time: 12 h

Procedure:
The solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (35 mg, 0.06 mmol), ethynylbenzene (8 μL, 0.08 mmol), and triethylamine (1 mL) in ethyl acetate (0.5 mL) was degassed with nitrogen. Copper(I) iodide (1 mg) and bis(triphenylphosphine)palladium (II) dichloride (7 mg) were added, and the mixture was stirred for 12 hours. The mixture was diluted with ethyl acetate, washed with water and brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (silica gel, ethyl acetate/hexanes) gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H37ClNO3: 554.2. Found: 554.3.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][CH:33]([CH3:36])[CH2:34][NH2:35].[BH4-].[Na+]>C(Cl)Cl.CO.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:35][CH2:34][CH:33]([CH3:36])[CH3:32])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CC(C)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCC(C)C)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL), MeOH (1.5 mL), and acetic acid (4 drops) was added 2-methyl-1-propanamine (137 μL, 1.37 mmol) and stirred at room temperature. After 2 h, sodium borohydride (23 mg, 0.684 mmol) was added and the reaction mixture was purified by SCX cartridge to give 47.8 mg of the title compound (85%).
Reaction SMILES: N([N:3]([CH2:6][CH3:7])CC)=O.[CH2:8]1[CH:12]2C3C=C[CH:15]([CH:11]2[CH:10]=[CH:9]1)C3.C(#N)C=C>>[C:6]([C:7]12[CH2:15][CH:11]([CH2:12][CH2:8]1)[CH:10]=[CH:9]2)#[N:3]
Reactant: CCN(CC)N=O
Reactant: C1=CC2C3C=CC(C3)C2C1
Solvent: C=CC#N
Product: N#CC12C=CC(CC1)C2
Yield: 93 %

Procedure:
Example 1 was repeated except that N-nitrosodiethylamine was used in place of N-nitrosodiphenylamine. N-nitrosodiethylamine was added to a mixed solution of dicyclopentadiene and acrylonitrile in an amount of 0.005% by weight. As a result, cyanonorbornene was continuously obtained with an average yield of 93% by mole. In this example, the amount of the soluble polymer produced was 0.01% by weight at the beginning of the reaction, which did not change significantly in 60 days after the initiation of the reaction. In addition , the operation was stopped after 80 days from the initiation to inspect in detail the inlet for the raw material, the inner wall, the outlet for the reaction solution and the-stirrer of the autoclave. No insoluble polymer was found to adhere to those surfaces.