Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCC(O)=O.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[N+:16]([CH:20]2[O:24][CH:23]([CH2:25][O:26][P:27]([O:30][P:31]([O:34][CH2:35][CH:36]3[O:40][CH:39]([N:41]4[C:45]5[N:46]=[CH:47][N:48]=[C:49]([NH2:50])[C:44]=5[N:43]=[CH:42]4)[CH:38]([OH:51])[CH:37]3[OH:52])([OH:33])=[O:32])([OH:29])=[O:28])[CH:22]([OH:53])[CH:21]2[OH:54])[CH:15]=1)=[O:13].N[C@H](C([O-])=O)CCC([O-])=O>>[C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])[CH3:11].[CH:47]1[N:48]=[C:49]([NH2:50])[C:44]2[N:43]=[CH:42][N:41]([C@@H:39]3[O:40][C@H:36]([CH2:35][O:34][P:31]([O:30][P:27]([O:26][CH2:25][C@H:23]4[O:24][C@@H:20]([N:16]5[CH:15]=[C:14]([C:12]([NH2:1])=[O:13])[CH2:19][CH:18]=[CH:17]5)[C@H:21]([OH:54])[C@@H:22]4[OH:53])([OH:29])=[O:28])([OH:33])=[O:32])[C@@H:37]([OH:52])[C@H:38]3[OH:51])[C:45]=2[N:46]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(=O)c1ccc[n+](C2OC(COP(=O)(O)OP(=O)(O)OCC3OC(n4cnc5c(N)ncnc54)C(O)C3O)C(O)C2O)c1
Agent: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Product: CC(=O)c1cccnc1
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
Glutamic acid was determined in the same manner as in Example 3 except that enzyme reaction was carried at 50° C. for 20 minutes in the presence of 3-acetylpyridine NAD (produced by Sigma Co. Ltd.) as coenzyme for glutamate, dehydrogenase (i.e., 3-acetylpyridine NADH formed by enzyme reaction was used as an indicator). The results had a good linear relationship to the real concentrations of glutamic acid. The measurements could be effected in a very short time (about 30 seconds).
Reaction SMILES: [Rh:1](Cl)(Cl)[Cl:2].[C:5]1([P:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:24]1[CH:29]=[CH:28][C:27]([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1.[CH:43]1[CH:48]=[CH:47][C:46]([P:49]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:45][CH:44]=1.[CH:62]1[CH:67]=[CH:66][C:65](P([C:75]2[CH:80]=[CH:79]C=CC=2)C2C=CC=CC=2)=[CH:64][CH:63]=1.[Cl-].[Rh].[CH3:83]CCC=C.[CH2:88]([OH:90])[CH3:89]>C1C=CC=CC=1>[CH:21]1[CH:20]=[CH:19][C:18]([P:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:23][CH:22]=1.[CH:40]1[CH:39]=[CH:38][C:37]([P:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)=[CH:42][CH:41]=1.[CH:59]1[CH:58]=[CH:57][C:56]([P:49]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:46]2[CH:47]=[CH:48][CH:43]=[CH:44][CH:45]=2)=[CH:61][CH:60]=1.[Cl-:2].[Rh:1].[CH2:88]([OH:90])[CH2:89][CH2:83][CH:80]([CH3:79])[CH3:75].[CH2:62]([OH:90])[CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]
Reactant: C=CCCC
Reactant: CCO
Reactant: Cl[Rh](Cl)Cl
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)CCCO
Product: CCCCCCO

Procedure:
Chlorotris(triphenylphosphine)rhodium(I), [(03P)3RhCl], was prepared by refluxing an ethanol solution of rhodium(III) chloride in the presence of an excess amount of triphenylphosphine. Chlorotris(triphenylphosphine)rhodium(I) was dissolved in benzene, and the microspheres of Example III were added to the resulting red solution in an autoclave, equipped with a magnetic driven stirrer. Pentene-1 was introduced to the reactor along with benzene. The reaction was performed under conditions similar to Example IV. About 82% of the feed was reacted to give predominantly isohexanol and n-hexanol. The solid catalyst left inside of the reactor from this run was rinsed with fresh portions of benzene, and saved for another run.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C4CCCCO4)=[CH:20][CH:19]=3)[C:16]([C:32]([F:35])([F:34])[F:33])(O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:36]C4CCCCO4)[CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]2[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=3)[O:9][C:10]3[C:15]([C:16]=2[C:32]([F:35])([F:33])[F:34])=[CH:14][C:13]([OH:36])=[CH:12][CH:11]=3)=[CH:23][CH:22]=1
Reactant: OC1(C(F)(F)F)c2cc(OC3CCCCO3)ccc2OC(c2ccc(I)cc2)C1c1ccc(OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc(C2=C(C(F)(F)F)c3cc(O)ccc3OC2c2ccc(I)cc2)cc1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A mixture of 2-(4-iodo-phenyl)-6-(tetrahydro-pyran-2-yloxy)-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-4-trifluoromethyl-chroman-4-ol (3.0 g, 5.7 mmol) and TsOH (0.6 g, 3.18 mmol) in toluene (60 mL) was refluxed for 18 h, removing water with a Dean Stark trap. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE/EA=10/˜14/1) to afford a white solid (1.5 g). 1H NMR (DMSO-d6): δ 9.17 (s, 1H), 9.07 (s, 1H), 7.56-7.54 (m, 2H), 7.35-6.95 (m, 5H), 6.67-6.50 (m, 4H), 5.73 (s, 1H). LCMS: 509 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH3:23])[C:13]([O:19][C:20](=[O:22])[CH3:21])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH3:23])[C:13]([O:19][C:20](=[O:22])[CH3:21])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1C
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1C)OCC(c1ccc(O)cc1)C2=O
Reaction time: 62 h

Procedure:
Acetic acid 3-(4-hydroxy-phenyl)-8-methyl-4-oxo-4H-chromen-7-yl ester (26.32 g), 10% Pd/Al2O3 (12.93 g, 50%) and ethyl acetate (EtOAc) (1.5 L) were added to a hydrogenation round bottom flask (2 L). The flask was placed on the hydrogenator, evacuated, purged with nitrogen gas (×5) and hydrogen gas (×5). The reaction was monitored by HPLC. 10% Pd/Al2O3(9 g, 35%) was added to the round bottom flask at 40 hours, indicated there was no product peak present, only starting material was present. HPLC at 62 hours indicated that the major peak was product peak with starting material peak being half height of product peak. 10% Pd/Al2O3(5.69 g, 20%) was added to the round bottom flask to speed up reaction rate. Reaction was completed at 64 hours. The reaction mixture was filtered through celite to remove the Pd/Al2O3 catalyst, the celite was rinsed with EtOAc (1 L) to ensure majority of product was collected. The EtOAc was evaporated off on a rotary evaporator to give a yellow solid. The solid was re-crystallised in 95% EtOH (650 ml) and left in the freezer overnight. Off-white crystals were collected by suction filtration. 1HNMR in d-CDCl3 indicated the off-white crystals were 8Acetic acid 3-(4-hydroxy-phenyl)-8-methyl-4-oxo-chroman-7-yl ester with >95% purity. The crystals were stored in a desiccator for 24 hours, and weighed (18.37 g, 69%).
Reaction SMILES: O[CH:2]1[NH:7][C:6](=[O:8])[C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1.[H][H].[CH:23]([NH2:26])([CH3:25])[CH3:24]>[Pd]>[C:6]([C:5]1([CH2:4][CH2:3][CH2:2][NH:26][CH:23]([CH3:25])[CH3:24])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:8])[NH2:7]
Reactant: CC(C)N
Reactant: [H][H]
Reactant: O=C1NC(O)CCC12c1ccccc1-c1ccccc12
Agent: [Pd]
Product: CC(C)NCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
The general procedure described above was followed when 6'-Hydroxyspiro-(9H-fluorene-9,3'-piperidine)-2'-one (2.7 g) was dissolved in isopropylamine (350 ml) and 10% palladium on charcoal (0.3 g) was added and the vessel pressurized to 90 p.s.i. with hydrogen. The reaction mixture was then heated at 40° for 16 hours and then allowed to cool to room temperature. The catalyst was removed by filtration and the isopropylamine evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (20 ml) washed with water (2×50 ml), dried with anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue was triturated with hexane to give 9-carbamoyl-9-(3-isopropylaminopropyl)fluorene crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:6]=1[NH2:7]>ClCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:6]=1[NH:7][C:6](=[NH:7])[CH2:5][CH2:11][CH2:10][CH3:9]
Reactant: COCOc1cc(OC)ccc1N
Solvent: ClCCl
Product: CCCCC(=N)Nc1ccc(OC)cc1OCOC
Yield: 159.7 %

Procedure:
To a solution of 1-methoxypentaimidate (11.3 g, 0.109 mol) in dichloromethane (20 ml) was added freshly prepared 2-methoxymethoxy-4-methoxy aniline (10.0 g, 0.055 mol) of Example 1(d) and the mixture was stirred at reflux for 3 days. After removing the solvent flash chromatography of the residue (silica gel, 5% methanol/dichloromethane) afforded the title compound as a dark solid (11.7 g, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:14]=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C@@H:17]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:14][NH:16][CH:17]([C:18](=[O:19])[NH:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:31]=1)[CH2:10][CH:11]([CH3:12])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
A solution consisting of 1.00 g (4.64 mmol) N-tert-butoxycarbonyl-L-leucinal and 1.52 g (4.64 mmol) 2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (Example 2, Step C) in 20 mL methanol containing 1% acetic acid was stirred at 25° C. for 20 minutes, at which time a solution of 0.614 g (9.29 mmol) sodium cyanotrihydridoborate (Aldrich, Milwaukee, Wis.) in 12 mL methanol was added and the resulting mixture stirred for 24 hours. The reaction was quenched by the addition of 3 M HCl in 3 mL increments until the vigorous bubbling subsided. The mixture was neutralized with saturated NaHCO3 solution then extracted with three 50 mL portions of ethyl acetate. The combined extracts were washed with 100 mL brine, dried over anhydrous sodium sulphate, and evaporated at reduced pressure to give a clear, colorless oil which was chromatographed on a silica gel column using 30% to 40% ethyl acetate:hexane to give 735 mg (30%) of [S-(R*,S*)]-(1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester as a clear foam.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][C:38]=1[O:45][CH3:46]>C1COCC1.O>[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[CH:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:39][C:38]=1[O:45][CH3:46]
Reactant: COc1cc(C=O)ccc1F
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=CCC(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
To a solution of (2-carboxyethyl)triphenylphosphonium bromide (14.8 g, 35.7 mmol) in THF (40 mL) was added NaHMDS (35.8 mL, 71.5 mmol) at −20° C., and the reaction was stirred for 20 min. 4-Fluoro-3-methoxybenzaldehyde (5.0 g, 32.5 mmol) was added to the reaction at −78° C., and the reaction was stirred overnight while warming to rt. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). Organics were washed with brine (30 mL), dried (Na2SO4), and concentrated to give 6.0 g (88%) of the crude title compound as a yellow solid. [M+H] Calc'd for C11H11FO3, 211. Found, 211.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1.[CH3:22][O:23][CH:24](OC)[CH2:25]OC>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([NH:2][CH2:25][CH2:24][O:23][CH3:22])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Nc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Reactant: COCC(OC)OC
Agent: Cl
Product: COCCNc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Yield: 8 %

Procedure:
Using an analogous reductive amination procedure to that described in Example 1, 6-amino-4-(3'-chloro-4'-fluoroanilino)quinazoline hydrochloride was reacted with 2-methoxyacetaldehyde dimethyl acetal to give 4-(3'-chloro-4'-fluoroanilino)-6-(2-methoxyethylamino)quinazoline in 8% yield, m.p. 152-154° C.; NMR Spectrum: 3.32 (s, 3H), 3.4 (t, 2H), 3.62 (t, 2H), 6.25 (t, -1H), 7.2 (d, 1H), 7.3 (m, 1H), 7.43 (t, 1H), 7.55 (d, 1H), 7.82 (m, 1H), 8.13 (m, 1H), 8.41 (s, 1H), 9.5 (s, 1H); Elemental Analysis: Found C, 57.9; H, 4.8; N, 15.3; C17H16ClFN4O 0.33H2O 0.1EtOAc requires C, 57.7; H, 4.8; N, 15.5%.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8](=[O:10])[NH2:9].[CH2:11](C(CC)(CC)C([O-])([O-])[O-])[CH3:12].C(OC(=O)C)(=O)C>>[CH3:7][C:4]1[C:3]2[C:8](=[O:10])[NH:9][C:11]([CH3:12])=[N:1][C:2]=2[O:6][N:5]=1
Reactant: Cc1noc(N)c1C(N)=O
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2onc(C)c2c(=O)[nH]1

Procedure:
A mixture of 5-amino-4-carbamoyl-3-methylisoxazole (14.9 g), triethylorthoacetate (112 ml) and acetic anhydride (112 ml) was refluxed for seven hours then evaporated in vacuo. The residue was dissolved in 0.880 ammonia solution (250 ml) and the solution treated with charcoal and filtered. The filtrate was acidified to pH 6 with acetic acid and the precipitate filtered and dried to give 3,6-dimethylisoxazolo [5,4-d] pyrimidin-4(5H)-one (9.8 g, m.p. 275°-280°, decomp.). A mixture of this material (3.2 g), thionyl chloride (30 ml) and N,N-dimethylformamide (1 ml) was refluxed for ten minutes, evaporated in vacuo at ca 50°. The residue was dissolved in dichloromethane, washed well with ice-cold water, dried and evaporated to give crude chloro derivative. A solution of this material in acetonitrile (50 ml) was treated with α-methylbenzylamine (4.84 g, two equivalents) keeping the temperature below 15°. The mixture was stirred for twenty hours at room temperature*, evaporated in vacuo, and distributed between ether and water. The extracts were washed, dried, evaporated and distilled in a bulb-tube apparatus (200°-210°/0.05 mm). The distillate crystallised on trituration with petroleum (b.p. 40°-60°). Recrystallisation from cyclohexane gave Compound no 26 of Table I (0.70 g, m.p. 99°-101°).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[CH3:9][C:4]1[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Cc1cc(N)nc(C)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1cc(C)nc(C)n1

Procedure:
To a suspension of 1.2 g of 4-amino-2,6-dimethylpyrimidine in 30 ml of dry acetonitrile with stirring was added 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. The mixture was stirred for two hours at ambient temperature, allowed to stand for sixteen hours and the desired product, which had precipitated, was removed by filtration and washed with butyl chloride to yield 2.4 g, m.p. 125°-127°. The product showed absorption peaks of Nuclear Magnetic Resource at 4.0, 2.62 and 2.9 ppm; consistent for the product.
Reaction SMILES: [CH:1]1([N:7]=[C:8]([CH3:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:18](Cl)([Cl:20])=[O:19]>C(Cl)(Cl)(Cl)Cl>[C:8]([N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:18]([Cl:20])=[O:19])([CH3:10])=[CH2:9]
Reactant: O=C(Cl)Cl
Reactant: CC(C)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)N(C(=O)Cl)C1CCCCC1

Procedure:
139 parts of acetone cyclohexylimine and 111 parts of triethylamine are dissolved in 500 parts of carbon tetrachloride, and the whole reacted with 110 parts of phosgene as described in Example 1. 123 parts (61% of the theory) of N-isopropenyl-N-cyclohexylcarbamyl chloride is obtained having a boiling point of 85° C. at 0.01 mm.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.N1CCCCC1>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:27]([C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)[C:28](=[O:30])[CH3:29])=[CH:15][CH:14]=1
Reactant: CC(=O)Cc1ccncc1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=O)C(=Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccncc1

Procedure:
A mixture of 4-((quinolin-2-yl)methoxy)benzaldehyde (2.5 g, 9.5 mmol), 1-(pyridin-4-yl)propan-2-one (1.3 g, 9.5 mmol) and piperidine (162 mg, 1.9 mmol) in toluene (50 mL) was heated at reflux for 18 h, concentrated, and the residue chromatographed on silica eluting with a gradient of ethyl acetate in hexanes giving impure title substance (2.4 g) as a yellow solid which was chromatographed again on silica eluted with 1% and 2% methanol in dichloromethane containing 0.5% concentrated ammonium hydroxide giving a 3:1 mixture of the title substance contaminated with the pyridyl starting material. Yield 2.0 g, 55%. The title substance appeared to be a 10:1 mixture of two isomers by NMR. 1H NMR (CDCl3, 400 mHz, partial) δ 2.35 (s, 3H, major isomer), 2.23 (s, 3H, minor isomer). HPLC-MS 6.09 min, m/e 381 (MH+).
Reaction SMILES: Cl[C:2]1([CH2:7][Cl:8])[O:5][C:4](=[O:6])[CH2:3]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:8][CH2:7][C:2](=[O:5])[CH2:3][C:4]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]
Reactant: O=C1CC(Cl)(CCl)O1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)CC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
7.8 Parts of 4-chloro-4-chloromethyloxetan-2-one are dissolved in 150 parts of methylenechloride containing 4.2 parts of anhydrous sodium bicarbonate and the solution is cooled to 0° C. 4.7 Parts of aniline are then added over 30 minutes and the reaction mixture is finally stirred for 48 hours at room temperature. The solids are then filtered off and the filtrate evaporated. The residue is crystallised twice from chloroform to give γ-chloroacetoacetanilide, m.p. 142°-143° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH:13]=[CH2:14])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:18])C=C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][OH:10])[CH2:11][CH2:12][CH:13]=[CH:14][C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:6][CH:7]=1
Reactant: C=CCCC(CO)c1ccc(Br)cc1
Reactant: C=CC(=O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(C=CCCC(CO)c1ccc(Br)cc1)OCc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a degassed solution of 2-(4-bromophenyl)hex-5-en-1-ol (108 mg, 0.423 mmol) in DCM (5 ml) at room temperature was added benzyl acrylate (0.191 ml, 1.270 mmol) and Grubbsll (35.9 mg, 0.042 mmol) and the mixture was stirred at 40° C. for 30 min. The mixture was concentrated and the residue was purified by flash chromatography (5 to 40% Acetone/Heptane) to give the title compound 130 mg (yield 79%). MS (ESI) m/z 490.4 (M+1). Retention time 1.49 min (condition A).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([CH:12]=O)[N:11]=1)=[O:5].[N+](=[C:31](P(=O)(OC)OC)C(=O)C)=[N-].C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[C:12]([C:10]1[N:11]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:27][CH:26]=[CH:25][C:24]=2[F:28])[S:8][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)#[CH:31]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: O=Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
Into a solution of Compound 67 (50.0 mg, 0.12 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (46.0 mg, 0.24 mmol) in MeOH (1.00 mL) was added K2CO3 (50.0 mg, 0.36 mmol) was added. The mixture was stirred at room temperature overnight, diluted with CH2Cl2, washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified on silica to give Compound 104 (10.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:30](=[O:42])[C:31]([NH:34]C(=O)OC(C)(C)C)([CH3:33])[CH3:32])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[NH2:34][C:31]([CH3:33])([CH3:32])[C:30]([N:15]1[CH2:16][CH:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:23][CH:24]=2)[CH2:18][CH:13]([C:11]2[O:10][N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:12]=2)[CH2:14]1)=[O:42]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(N)C(=O)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
110 mg (0.186 mmol) of the compound from Example 188A were initially charged in 1.4 ml of dichloromethane, and 143 μl (212 mg, 1.87 mmol) of trifluoroacetic acid were added. The reaction mixture was stirred at RT for 12 h, and then taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC. Yield: 48 mg (53% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:5]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: NCc1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: S=C=NCc1ccccc1Cl
Yield: 46.7 %

Procedure:
The title compound was prepared following the procedure described for Intermediate-2 using 2-chloro benzyl amine (5.0 g, 35 mmol), thiophosgene (4.38 g, 38.5 mmol) and N-ethyl di-isopropyl amine (13.5 g, 105 mmol) to afford 3.0 g of the desired product. 1HNMR (DMSO-d6): δ 5.00 (s, 2H), 7.41 (m, 2H), 7.54 (m, 2H).