Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])SC)#[N:5]>C(O)C>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])#[N:5]
Reactant: CCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CCO
Product: CCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
Anhydrous ethylamine (9.0 g.) was added to a solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (Example 3(c), 5.0 g.) in ethanol. The solution was heated under reflux for 8 hours and concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol, filtered, and diluted with water. The white solid obtained was recrystallised from isopropyl alcohol-ether to yield N-cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 118°-120°. (Found: C, 49.6; H, 6.8; N, 31.2; S, 11.7. C11H18N6S requires: C, 49.6; H, 6.8; N, 31.6; S, 12.0).
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:15]=[CH:14][C:8]2[NH:9][C:10](=[O:13])[CH2:11][S:12][C:7]=2[CH:6]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17]1>CN(C=O)C>[OH:4][C:5]1[CH:15]=[CH:14][C:8]2[NH:9][C:10](=[O:13])[C:11](=[CH:25][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][CH:17]=3)[S:12][C:7]=2[CH:6]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=C1CSc2cc(O)ccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(O)cc2SC1=Cc1c[nH]c2ccccc12
Temperature: 140 °C

Procedure:
Sodium methoxide (0.54 g, 10 mmol) was added in one portion to a solution of 7-hydroxy-2H-1,4-benzothiazin-3(4H)-one (0.91 g, 5 mmol) and indole-3-carboxaldehyde (1.09 g, 7.5 mmol) in dry DMF (5 ml). The mixture was heated at 140° C. for 48 h, allowed to cool and poured into ice water (60 ml). The solid was collected by filtration. The filtrate was acidified to pH=2 with 10% hydrochloric acid and the precipitated solid was collected by filtration. Both precipitates were put together, boiled with toluene and filtered hot to give a solid which was purified by silica gel chromatography using a gradient of (9:1) to (8:2) n-hexane/ethanol as the mobile phase.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13]([CH3:16])([CH3:15])[CH:12]=[CH:11][C:10]=2[CH:17]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[C:1](=[O:4])([OH:2])[NH2:5].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13]([CH3:15])([CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]=1
Reactant: O=C([O-])[O-]
Agent: CC1(C)C=Cc2cc(N)ccc2O1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After a carbonate resin (0.80 mmol/g, 10 g, 8.0 mmol) of formula 2 was mixed with dimethylacetamide (DMA, 50 mL) by shaking at room temperature for 10 min, 6-amino-2,2-dimethyl-2H-1-benzopyran (2.80 g, 16.0 mmol) and N,N-diisopropylethylamine (DIPEA; 5.17 mg, 40.0 mmol) were successively added thereto and shaked at 25° C. for 15 hrs. After the reaction was completed, the reaction mixture was subjected to filtration and repeatedly washed with DMF, DCM, DCM/MeOH and MeOH, to obtain a solid resin (Formula 4-1; 11.5 g). (ATR-FTIR; carbamate: 1725 cm−1)
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH2:9]1[O:11][CH2:10]1.[Na+].[Cl-].C[OH:15]>>[OH:6][CH2:1][CH2:2][CH:3]1[CH2:5][CH2:10][O:11][C:9]1=[O:15]
Reactant: C1CO1
Reactant: COC(=O)CC(C)=O
Reactant: CO
Agent: [Cl-]
Agent: [Na+]
Product: O=C1OCCC1CCO
Temperature: 80 °C
Yield: 81 %

Procedure:
A mixture of 58 g of methyl acetoacetate, 44 g of ethylene oxide, 3 g of NaCl and 70 ml of methanol was heated in an autoclave under autogenous pressure for 12 hours at 80° C. Thereafter, the methanol was distilled off, the residue was taken up with water, and the solution was washed with a little chloroform and distilled. 52.6 g of 2-(2-hydroxyethyl)-γ-butyrolactone were obtained, corresponding to a yield of 81% of theory.
Reaction SMILES: [N:1]([C:8](C)(C)C#N)=NC(C)(C)C#N.[C:13](OO[C:23](=O)[C:24]1[CH:29]=[CH:28]C=[CH:26][CH:25]=1)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:1]=1)=[CH2:13].[CH2:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[CH:29]([C:24]1[CH:23]=[CH:8][N:1]=[CH:26][CH:25]=1)=[CH2:28].[CH2:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C=Cc1ccccc1
Product: C=Cc1ccccn1
Product: C=Cc1ccncc1

Procedure:
A series of 2-vinylpyridine/styrene and 4-vinylpyridine/styrene copolymers was prepared by radical polymerization using azobisisobutyronitrile or benzoyl peroxide as initiator. The styrene content of the copolymer ranged from 15% to 50% by weight. Larger or smaller amounts of styrene may be used.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][C:26]=1[F:34].Cl.[CH3:36][O:37][C:38](=[O:43])[C@H:39]([CH2:41][OH:42])[NH2:40].C(N(CC)CC)C>O.CN(C)C=O>[CH3:36][O:37][C:38](=[O:43])[C@H:39]([CH2:41][OH:42])[NH:40][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([Br:24])=[C:26]([F:34])[CH:27]=1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)c1ccc(Br)c(F)c1
Reaction time: 0.5 h
Yield: 111.4 %

Procedure:
1-Hydroxybenzotriazole monohydrate (839 mg, 5.48 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.05 g, 5.48 mmol) were added to an N,N-dimethylformamide (34 mL) solution of 4-bromo-3-fluorobenzoic acid (1.00 g, 4.57 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes, and then L-serine methyl ester hydrochloride (1.42 g, 9.13 mmol) and triethylamine (1.27 mL, 9.13 mmol) were added to the mixture. The resulting mixture was further stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the resulting mixture was extracted twice with ethyl acetate. The organic layer thus obtained was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the crude title compound (1.63 g).
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:33])[N:12]([CH2:14]/[CH:15]=[CH:16]/[C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4C(OC(C)(C)C)=O)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.CCOC(C)=O>[C:1]1([CH:7]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:33])[N:12]([CH2:14]/[CH:15]=[CH:16]/[C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)n1ccc2c(/C=C/Cn3cc(C(c4ccccc4)c4ccccc4)ccc3=O)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1C/C=C/c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl 4-{(1E)-3-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]-1-propen-1-yl}-1H-indole-1-carboxylate (247 mg) in MeOH (5 mL) was added 1M NaOH aqueous solution (1.5 mL) at ambient temperature. The reaction mixture was stirred for 17 hours at ambient temperature. The resulting mixture was diluted with EtOAc (15 mL) and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20-50:50) to give 5-(diphenylmethyl)-1-[(2E)-3-(1H-indol-4-yl)-2-propen-1-yl]-2(1H)-pyridinone.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(OCC)(=O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([O-:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH:22]([NH3+:25])([CH3:24])[CH3:23]
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: CC(C)N
Solvent: CCOC(C)=O
Product: CC(C(=O)[O-])c1ccc2c(=O)c3ccccc3ccc2c1
Product: CC(C)[NH3+]

Procedure:
0.45 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid was dissolved in ethyl acetate and isopropylamine is added dropwise until no more precipitate is formed. The precipitate is filtered off and recrystallized from acetone to afford isopropylammonium 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate (m.p. 176°-180° C).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][CH:5]([C:19](=[O:44])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([N:28]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([F:43])[CH:37]=1)(=[O:35])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:26][OH:27])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:46][CH2:47][O:48][P:49](Cl)([O:51][CH2:52][CH3:53])=[O:50]>>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:19](=[O:44])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]([N:28]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([F:43])[CH:37]=1)(=[O:34])=[O:35])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:26][O:27][P:49]([O:51][CH2:52][CH3:53])([O:48][CH2:47][CH3:46])=[O:50])[CH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: COC(=O)NC(C(=O)NCCCCC(CO)N(CC(C)C)S(=O)(=O)c1ccc(N)c(F)c1)C(c1ccccc1)c1ccccc1
Product: CCOP(=O)(OCC)OC[C@H](CCCCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(CC(C)C)S(=O)(=O)c1ccc(N)c(F)c1

Procedure:
The product of step A was phosphorylated with chlorodiethylphosphate following the procedure described in example 1A, step G. Yields 157 mg, 68%.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH:20]1[C:25]([OH:27])=[O:26].[OH-:28].[Na+].Cl>C(#N)C>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:19]2[CH2:24][CH2:23][N:22]([C:8](=[O:28])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:21][CH:20]2[C:25]([OH:27])=[O:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1CNCCN1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)C1CN(C(=O)N(c2ccccc2)c2ccccc2)CCN1C(=O)N(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 26 %

Procedure:
A solution of 946 mg (4 mmole) of 98% diphenylcarbamoyl chloride in 4 ml of acetonitrile was added dropwise to a stirring solution of 406.2 mg (2 mmole) of piperazine-2-carboxylic acid dihydrochloride [E. Felder, S. Maffei, S. Pietra and D. Pitre, Helv. Chim., Acta. 43, 888 (1960)] in 4 ml of 2.5N-sodium hydroxide at a temperature between 0° and 5° C. After the addition was completed, the stirring was continued for 4 hours and the solution was acidified with 2N-hydrochloric acid while cooling in an ice bath. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform. After washing with water, the chloroform solution was dried over MgSO4 and concentrated in vacuo. The only product which solidified on cooling was triturated with isopropyl ether to give 270 mg (26%) of (±)-1,4-bis(diphenylcarbamoyl)piperazine2-carboxylic acid, m.p. 244°-246° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH:16]=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.S(=O)(=O)(O)[OH:20].[C:24]1([CH3:30])C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH:16]3[O:20][CH2:24][CH2:30][O:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: Cc1ccccc1
Reactant: O=S(=O)(O)O
Product: COC(=O)c1ccc([C@H]2CC[C@H](C3OCCO3)CC2)cc1

Procedure:
A solution of 88.5 g of 4-(trans-4-formylcyclohexyl)benzoic acid methyl ester in 700 ml of toluene was treated while stirring with 1.5 ml of 10% (v/v) sulfuric acid and heated to boiling for 1 hour, with damp toluene being distilled off and being replaced by the addition of fresh toluene. Subsequently, the reaction solution was treated with 1 ml of triethylamine. The mixture was washed three times with 150 ml of water each time, dried over sodium sulfate, filtered and concentrated. Twofold recrystallization of the residue from tert. butyl methyl ether at -25° C. gave 75.4 g of pure 4-[trans-4-(1,3-dioxolan-2-yl) cyclohexyl]benzoic acid methyl ester with m.p. 110°-111° C.
Reaction SMILES: [C:1](O)(=O)C.[N:5]1[C:12]([NH2:13])=[N:11][C:9]([NH2:10])=[N:8][C:6]=1[NH2:7]>[NH4+].[O-][Mo]([O-])(=O)=O.[O-][Mo]([O-])(=O)=O.O>[CH4:1].[C:6]1([NH2:7])[N:8]=[C:9]([NH2:10])[N:11]=[C:12]([NH2:13])[N:5]=1.[C:6]1([NH2:7])[N:8]=[C:9]([NH2:10])[N:11]=[C:12]([NH2:13])[N:5]=1
Reactant: CC(=O)O
Agent: O=[Mo](=O)([O-])[O-]
Agent: Nc1nc(N)nc(N)n1
Agent: [NH4+]
Solvent: O
Product: C

Procedure:
Melamine molybdate was prepared in the presence of acetic acid as follows. 10 grams of melamine, 9.52 grams of acetic acid, and 250 ml water were dissolved together by refluxing in a 500 ml round-bottomed flask equipped with a stirrer and water-cooled condenser. 26.95 grams of ammonium dimolybdate was dissolved in 50 ml. hot water and then added to the first solution. A white precipitate formed immediately.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C@H:8]([OH:17])[CH2:7]1)=[O:4].[Li][CH2:21][CH2:22][CH2:23]C.C(Br)C=C>C1COCC1>[CH2:23]([O:17][C@H:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:6]([NH:5][C:3](=[O:4])[C:2]([F:18])([F:19])[F:1])[CH2:7]1)[CH:22]=[CH2:21]
Reactant: [Li]CCCC
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)C[C@H]2O
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCO[C@@H]1C[C@H](NC(=O)C(F)(F)F)c2cc(OC)ccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Step U (1): A solution of 2,2,2-trifluoro-N-((1S,3R)-3-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl)acetamide (enantiomer A, 2.65 g, 9.63 mmol) from step T (1) was cooled to −78° C. in THF. Added n-BuLi (7.7 mL, 19.3 mmol, 2.5M in Hex, Aldrich). Allowed the precipitous mixture to stir at −78° C. for 30 min. Added allyl bromide (4.6 mL, 48.2 mmol, Aldrich), warmed to rt and the reaction became homogeneous. The mixture was stirred for 18 h. Quenched with 1M HCl. Extracted with EtOAc. Washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford 1.38 g (46% yield) of N-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide as white solid. LC-MS (M+Na)+=337.9; [α]D −115.43 (c=6.79 mg/mL, dioxane); Anal. Calcd for C15H16F3NO3: C, 57.14; H, 5.11; N, 4.44. Found: C, 57.19; H, 4.88; N, 4.31. 1H NMR (500 MHz, CDCl3) δ ppm 1.55 (s, 2H) 2.09 (d, J=14.04 Hz, 1H) 2.61-2.73 (m, 1H) 3.80 (s, 2H) 4.06 (dd, J=3.05, 1.53 Hz, 2H) 4.79 (dd, J=5.49, 1.83 Hz, 1H) 5.19 (dd, J=10.53, 1.37 Hz, 1H) 5.28 (dd, J=17.24, 1.68 Hz, 1H) 5.39 (s, 1H) 5.83-5.97 (m, 1H) 6.85-6.98 (m, 2H) 7.32 (d, J=8.24 Hz, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(Cc2ccc(Cl)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(Cl)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.81 g), sodium hydrogen carbonate (2.92 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(4-chlorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.84 g) was added, and the mixture was stirred at 90° C. for 16 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 dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution 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 colorless crystals (0.42 g, 45%).
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[Cl:21])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[CH3:22][OH:23]>C1(C)C=CC=CC=1>[CH3:22][O:23][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[Cl:21])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)c1ccc(C(Br)c2cnoc2C2CC2)c(Cl)c1
Reactant: CO
Solvent: Cc1ccccc1
Product: COC(c1ccc(S(C)(=O)=O)cc1Cl)c1cnoc1C1CC1

Procedure:
A mixture of 4-[bromo-(2-chloro-4-methanesulphonylphenyl)-methyl]-5-cyclopropylisoxazole (2.5 g) and methanol (2.0 ml) in toluene was stirred at reflux for 16 hours. The resultant solution was evaporated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with water, dried (MgSO4), and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluted with ethyl acetate and petroleum ether to give 4-[methoxy-(2-chloro-4-methanesulphonyl-phenyl)methyl]-5-cyclopropylisoxazole (compound 307, 1.40 g) as a colourless oil, NMR: (CDCl3) 1.0(4H, m), 2.1 (1H, m), 3.0(3H,s), 3.3(3H, s), 5.6(1H,s), 7.9(4H,m).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](=[O:8])[CH:6]=[CH2:7].[Br-:9].[K+].[Br:11]Br>C(O)(C)C>[Br:9][CH2:7][CH:6]([Br:11])[C:5](=[O:8])[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: BrBr
Reactant: C=CC(=O)CCCCl
Reactant: [Br-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(CCCCl)C(Br)CBr
Reaction time: 1 h

Procedure:
To a solution of 6-chlorohex-1-en-3-one (from step 3) in isopropanol (80% solution in water, 30 mL) at 0° C. were added potassium bromide (4.8 g, 40 mmol) and bromine (2.0 mL, 39 mmol). After 1 hour, the reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 1,2-dibromo-6-chlorohexan-3-one, which was used without further purification.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[CH:8](=[N:15]/[C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:25])\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:26][O-:27].[Na+]>C(OCC)(=O)CC>[O:27]=[C:26]1[C:17]2[C:21]([C:20]([O:19][CH3:18])=[O:25])=[CH:22][CH:23]=[CH:24][C:16]=2[NH:15][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]1[C:5]1[S:1][CH:2]=[N:3][CH:4]=1
Reactant: C[O-]
Reactant: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Reactant: O=Cc1cncs1
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: COC(=O)c1cccc2c1C(=O)C(c1cncs1)C(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
A mixture of thiazole-5-carbaldehyde (500 mg, 4 mmol), (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (960 mg, 4 mmol), sodium methanolate (375 mg, 16.1 mmol) and ethyl propionate (30 mL) were stirred at room temperature overnight. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (4×100 mL) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 10:1 to 1:1) to give methyl 4-oxo-2-phenyl-3-(thiazol-5-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (110 mg, yield 7%). LC-MS (ESI) m/z: 379 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH3:17][C:18]1([CH3:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20](O)[CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:17][C:18]1([CH3:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]([O:16][C:13]2[CH:14]=[CH:15][C:10]([C@@H:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH3:9])=[O:7])=[CH:11][CH:12]=2)[CH2:19]1
Reactant: CCO[C@@H](CC(=O)OC)c1ccc(O)cc1
Reactant: CC1(C)CC(O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCO[C@@H](CC(=O)OC)c1ccc(OC2CC(C)(C)c3ccccc32)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
Methyl (3S)-3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.446 mmol) produced in Example 41 (41C) and 3,3-dimethylindan-1-ol (110 mg, 0.669 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (101 mg, yield: 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)(O)[O-].[Na+].CO.ClCCl.[I:19](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[I:19])[NH2:5]
Reactant: O=I(=O)Cl
Reactant: Nc1cccc(F)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(I)c(F)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a suspension of 3-fluoroaniline (1.0 mL, 1.16 g, 10.39 mmol) and solid sodium bicarbonate (1.75 g, 20.79 mmol) in 1:1 methanol-dichloromethane (20 mL) at 0° C. was added a solution of benzyl trimethylammonium dichloroiodate (3.62 g, 10.39 mmol) in dichloromethane (15 mL) over 30 minutes. The mixture was then allowed to warm to room temperature for 1 hour. The mixture was quenched by addition of water and the organic layer was extracted with water (2×). Drying (Na2SO4) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (2.20 g, 89%) as a pink solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.41 (dd, J=8.3, 7.3 Hz, 1 H), 6.42 (dd, J=9.9, 2.5 Hz, 1 H), 6.27 (dd, J=8.5, 2.5 Hz; 1 H), 3.81 (s, 2 H); MS+ESI m/z (rel abundance) 238 (100, M+H).