Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCCNC2)ccc1O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(C2CCCNC2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added to the obtained tert-butyl 2-(2-hydroxy-5-(piperidin-3-yl)benzamido)-4-phenylbenzoate (0.10 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and methanol and water were added the residue. After adjusting the pH to 6.0 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected from the reaction mixture by filtration to obtain 0.088 g of 2-(2-hydroxy-5-(piperidin-3-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:15](O)[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCO[CH2:31][CH3:32]>ClCCl.CCOCC>[CH2:1]([N:8]1[C@@H:15]([C:1]#[C:2][CH2:3][CH2:4][CH2:31][CH3:32])[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: O=C1N(Cc2ccccc2)C(O)[C@@H]2CS[C@@H](c3ccccc3)N12
Agent: FB(F)F
Solvent: ClCCl
Product: CCCCC#C[C@H]1[C@@H]2CS[C@@H](c3ccccc3)N2C(=O)N1Cc1ccccc1
Temperature: 0 °C
Yield: 98 %

Procedure:
To a solution of compound 6-benzyl-7-hydroxy-3-phenyl-(3S, 7aR)-perhydroimidazo[1,5-C][1,3]thiazol-5-one of formula (6) (0.326 parts, 1 mmol) in dichloromethane (10 parts) was added 1-(tri n-butyltin)hexyne(0.742 parts, 2 mmol). Then the solution was cooled to 0° C., and Lewis acid for example BF3.Et2O (0.142 parts, 1 mmol) was added drop wise. The reaction mixture was stirred at 0° C. for 10 mints, and the reaction mixture was quenched with saturated ammonium chloride (10 parts). Then the organic layer was separated, concentrated and column purification with ethylacetate:pet.ether (15:85) as eluent provided compound 6-benzyl-7-(1-hexynyl)-3-phenyl-(3S, 7S, 7aR)-perhydroimidazo[1,5-c][1.3]thiazol-5-one of formula (7g) (viscous liquid, 0.382 parts, 0.98 mmol) in 98% yield.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[C@H:9]([CH:10]([CH3:12])[CH3:11])[CH2:8][CH2:7][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1.I[CH2:21][CH3:22].O>CN(C=O)C>[CH2:21]([O:3][C@H:4]1[C@H:9]([CH:10]([CH3:11])[CH3:12])[CH2:8][CH2:7][N:6]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:5]1)[CH3:22]
Reactant: CCI
Reactant: CC(C)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(C)C
Reaction time: 0.42 h

Procedure:
Add sodium hydride (69 mg, 1.73 mmol) to a solution of trans-tert-butyl 3-hydroxy-4-isopropyl-piperidine-1-carboxylate (300 mg, 1.23 mmol) in anhydrous DMF (2.5 mL) at ambient temperature. Stir the mixture for 25 minutes and then add iodoethane (112 μL, 1.48 mmol). Stir the mixture overnight. Add additional iodoethane (59.3 μL, 0.74 μmol) and stir the mixture for 3 h, then add water. Extract the aqueous layer with EtOAc, combine the organic layers. Sequentially wash the combined organic layers with water then brine; dry over anhydrous sodium sulphate; filter; collect the filtrate; and then remove the solvent under vacuum. Purify the compound by silica gel chromatography eluting with hexane:ethyl acetate (0%, 2%, 4% and 6% ethyl acetate) to obtain the title compound as a waxy solid (260 mg, 78%). MS (m/z): 216 (M-tBu+1)
Reaction SMILES: [Cl-].[NH4+:2].[Al](C)(C)C.[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:2])=[NH:13])=[CH:10][N:9]=1
Reactant: [NH4+]
Reactant: N#Cc1ccc(Cl)nc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(N)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
Suspend ammonium chloride (1.16 g, 21.6 mmol) in toluene (10 mL). Cool to 0° C. and slowly add 2.0 M Al(CH3)3 in toluene (10.8 mL, 21.6 mmol) (see Tetrahedron Lett. 1990, 31(14), 1969-1972). After the gas stops evolving, add a solution of 6-chloronicotinonitrile (1.00 g, 7.22 mmol) in toluene (52 mL). Heat to 80° C. overnight. Cool the reaction mixture, then slowly pour into slurry of silica gel (40 g) in CHCl3 (200 mL). Stir for 10 minutes before filtering. Filter and wash the silica plug with methanol (2× 100 mL). Concentrate the filtrate and purify by 10 g SCX column washing with methanol and then eluting with 2.0 M NH3 in methanol to give the title compound (0.458 g, 40.8%): MS ES+ 155.9 (M+H)+: HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.2 min, 97.2% purity.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([O:16][CH:17]([O:19][C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1)[CH3:18])[CH3:15].CN(C)[CH:31]=[O:32]>CCCCCC.C1COCC1>[CH2:14]([O:16][CH:17]([O:19][C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[C:21]=1[CH:31]=[O:32])[CH3:18])[CH3:15]
Reactant: CCOC(C)Oc1ccc2c(c1)OCO2
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(C)Oc1ccc2c(c1C=O)OCO2
Temperature: -78 °C
Yield: 96 %

Procedure:
n-Butyllithium (18.6 ml of a 2.5M solution in hexane, 46.5 mmol) and N,N,N',N'-tetramethylethylenediamine (5.38 g, 46.3 mmol), respectively, were added (using a syringe) to a stirred solution of 5-(1-ethoxyethoxy)-1,3-benzodioxole (8.9 g, 42.4 mmol) in dry THF (100 ml) in a nitrogen atmosphere at -78° C. The resulting solution was allowed to attain room temperature and then cooled to -78° C. A solution of N,N-dimethylformamide (3.70 g, 50.6 mmol) in dry THF (20 ml) was added using a syringe, and the reaction mixture was allowed to attain room temperature. The resulting mixture was quenched with water and extracted with diethyl ether (3times). The combined ether layers were washed with water (2 times), dried over Na2SO4, filtered and evaporated in vacuo to to yield 5-(1-ethoxyethoxy)-4-formyl-1,3-benzodioxole (9.7 g, 96% yield; compound No. 2) as a pale yellow solid, m.p. 48°- 50° C.
Reaction SMILES: [CH:1]12[CH:7]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][N:13]=[CH:12]4)[CH:4]([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:2]2[CH2:3][CH:4]3[CH:7]([NH:8][C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][N:13]=[CH:12]5)[CH:1]2[CH2:6][CH2:5]3)=[CH:21][CH:20]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: c1cc2[nH]ncc2cc1NC1C2CCC1NC2
Product: Cc1ccc(CN2CC3CCC2C3Nc2ccc3[nH]ncc3c2)cc1

Procedure:
Reaction of Intermediate 23 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH:17]([CH:22](O)[CH3:23])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CS(Cl)(=O)=O>C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=[O:21])[C:17](=[CH:22][CH3:23])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
0.77 g (7.6 mmol) of triethylamine were added to a 20 ml methylene chloride solution of 1.86 g (7.6 mmol) of the 1-(t-butoxycarbonyl)-3-(1-hydroxyethyl)-4-piperidone obtained above. Under ice cooling, 0.88 g (7.6 mmol) of methanesulfonyl chloride were added and the resulting mxiture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue. The solid thus precipitated was filled out, followed by concentration under reduced pressure again. The concentrate was then dissolved in 20 ml of chloroform, followed by the addition of 1.16 g (7.6 mmol) of 1,8-diazabicyclo[5.4.0]under-7-ene (DBU) at room temperature. The mixture was stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=19/1), whereby 1.32 g (yield: 77.2%) of the title compound were obtained as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:31][C:32]2([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]2)=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Reactant: COCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(-c3ccc4c(c3)COC4=O)ccc(OC)c2OC(F)F)COC1
Temperature: 70 °C
Yield: 18.6 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (144 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 18%).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[C:7]2[CH:8]=[C:9]([CH2:12][O:13][C:14]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[N:17]=[C:16]([CH2:24][CH3:25])[CH:15]=3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[N:33]=[N:34][N:35](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:36]=1>CO.C(O)C>[ClH:1].[Br:2][C:3]1[C:7]2[CH:8]=[C:9]([CH2:12][O:13][C:14]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[N:17]=[C:16]([CH2:24][CH3:25])[CH:15]=3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[NH:36][N:35]=[N:34][N:33]=1
Reactant: CCc1cc(OCc2ccc3oc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c(Br)c3c2)c2c(n1)CCCC2
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCc1cc(OCc2ccc3oc(-c4ccccc4-c4nnn[nH]4)c(Br)c3c2)c2c(n1)CCCC2
Reaction time: 2 h

Procedure:
Concentrated hydrochloric acid (1 ml) was added to a suspension of 4-[(3-bromo-2-(2-(2-triphenylmethyl-2H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methoxy]-2-ethyl-5,6,7,8-tetrahydroquinoline (A) (650 mg) in methanol (2 ml) and ethanol (4 ml). The mixture was warmed gently until the solid dissolved and then left to stand for 2 hours. The precipitated solid was filtered off, slurried with ether (10 ml) and recrystallised from methanol to give 4-[(3-bromo-2-(2-(1H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methoxy]-2-ethyl-5,6,7,8-tetrahydroquinoline hydrochloride, m.p. 210°-212° C.; NMR (d6 -DMSO): 1.3(t, 3H), 1.65-1.9(m, 4H), 2.5-2.7(m, 2H), 2.9-3.1(m, 4H), 5.6(s, 2H), 7.55(s, 1H), 7.6(s, 2H), 7.7(s, 1H), 7.75-7.85(m, 2H), 7.9-8.0(m, H); mass spectrum (+ve fast atom bombardment (+FAB), DMSO/Methanol/nitrobenzyl alcohol(NBA)): 532 (M+H)+ ; microanalysis, found: C, 57.0; H, 4.6; N, 12.4%; C27H24BrN5O2.HCl requires: C, 57.2; H, 4.45; N, 12.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N+:17]([O-])=O.[H][H]>CO.[Ni]>[NH2:17][C:3]1[CH:4]=[CH:5][C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)c2ccccc2)cc1N

Procedure:
1.9 g. of 2-amino-1-nitro-4-phenylsulfonylbenzene is treated in methanol with hydrogen at 4 atmospheres in the presence of Raney nickel catalyst for 2 hours. The catalyst if filtered off and the filtrate stripped under vacuum. Recrystallization of the residue gives 1,2-diamino-4-phenylsulfonylbenzene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[C@H:11]([OH:26])[C@H:12]2[O:17][CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=3)[C:13]2=[O:25])=[CH:5][CH:4]=1)#[N:2].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[C@H:11]([OH:26])[C@H:12]2[O:17][CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:29]4[S:28][CH:32]=[CH:31][CH:30]=4)=[CH:20][CH:19]=3)[C:13]2=[O:25])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(I)cc3)C2=O)cc1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(-c4cccs4)cc3)C2=O)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a suspension of compound 14-4 (80 mg) in THF—H2O (2 mL-0.67 mL), were added 2-thiopheneboronic acid (43 mgl), Cs2CO3 (0.44 g), and Pd(Ph3P)4 (19.4 mg). The mixture was stirred at 80° C. for 15 hours. The reaction mixture was filtered with Celite® pad and rinsed with the mixed solvent (EtOAc-MeOH=1-1). The filtrate was concentrated in vacuo and the resulting residue was washed with H2O and Et2O. The precipitate was collected by filtration to obtain compound 22-1 (35 mg) as a pale brown amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH3:19].BrC[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:25]([O:24][C:22](=[O:23])[CH2:19][O:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Br:1])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(-c3ccccc3F)noc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Br
Temperature: 65 °C

Procedure:
A mixture of 11.6 g of 7-bromo-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, 17.5 g of ethyl bromoacetate, 13.3 g of potassium carbonate and 100 ml of dimethylformamide is heated at 65° C. for 5 hr. The reaction mixture is poured into water and the mixture is extracted with ether. The ether extracts are washed, dried and evaporated to afford ethyl{[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6yl]oxy}acetate, mp 130°-131° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>C1(C)C=CC=CC=1.CN1C(=O)CCC1>[O:14]=[C:6]1[CH:5]([CH2:4][CH2:3][N:2]2[C:18](=[O:19])[C:17]3[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]2=[O:20])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCC1C(=O)Nc2ccccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C1Nc2ccccc2C1CCN1C(=O)c2ccccc2C1=O
Yield: 56.4 %

Procedure:
A mixture of 3-(2-aminoethyl)indolin-2-one hydrochloride (3.20 g, 15.06 mmol), phthalic anhydride (3.34 g, 22.59 mmol) and TEA (4.56 g, 45.18 mmol) in toluene/NMP (20 mL/10 mL). The mixture was heated under reflux for 3 h. The reaction mixture was concentrated and the resulting mixture was washed with saturated aqueous ammonium chloride and brine. The separated organic layer was dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product, which was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to afford the title compound (2.60 g, 8.50 mmol, 56% yield) as a brown solid. MS (ESI) m/z 307.2 [M+H]+.
Reaction SMILES: CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C.[CH2:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1)[CH:23]=[CH2:24].[CH2:40]([O:48][C:49]1[CH:72]=[CH:71][C:52]([C:53]([O:55][C:56]2[CH:68]=[CH:67][C:66]3[C:65]4[C:60](=[CH:61][C:62](O)=[CH:63][CH:64]=4)[CH:59]([CH3:70])[C:58]=3[CH:57]=2)=[O:54])=[CH:51][CH:50]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>O.C(Cl)Cl>[CH2:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([O:37][C:62]2[CH:63]=[CH:64][C:65]3[C:66]4[C:58](=[CH:57][C:56]([O:55][C:53](=[O:54])[C:52]5[CH:51]=[CH:50][C:49]([O:48][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:72][CH:71]=5)=[CH:68][CH:67]=4)[CH:59]([CH3:70])[C:60]=3[CH:61]=2)=[O:36])=[CH:33][CH:32]=1)[CH:23]=[CH2:24]
Reactant: C=CCOCCCCOc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)Oc2ccc3c(c2)C(C)c2cc(O)ccc2-3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C=CCOCCCCOc1ccc(C(=O)Oc2ccc3c(c2)C(C)c2cc(OC(=O)c4ccc(OCCCCCCCC)cc4)ccc2-3)cc1
Temperature: 5 °C
Reaction time: 12 h
Yield: 22 %

Procedure:
Dimethylaminopyridine 0.01 g and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 0.8 g were added to a methylene chloride (50 ml) solution of 4-(4-allyloxybutyloxy)benzoic acid 0.84 g and 2-(4-octyloxybenzoyloxy)-7-hydroxy-9-methylfluorene (J1) 1.5 g while maintaining 5° C., and the mixture was further stirred at room temperature for 12 hours. Water 50 ml was added thereto, and the resulting organic layer was dried on anhydrous magnesium sulfate. A residue obtained by distilling the solvent off was refined by silica gel column chromatography to obtain 0.5 g of 2-[4-(4-allyloxybutyloxy)benzoyloxy]-7-(4-octyloxybenzoyloxy)-9-methylfluorene (J2).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C[C:11]#[N:12].NC.[OH-].[Na+]>O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:12][CH3:11])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC#N
Agent: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of cyanuric chloride (300 mg, 1.63 mmol, 1.00 equiv) in 1:1 CH3CN:H2O (2.7 mL) at 0° C. was added NH2Me (2.0 M solution in THF, 0.81 mL, 1.6 mmol). The solution was treated with 1 N NaOH to maintain a pH of 9-10 and stirred for 5 min at 0° C. The resulting suspension was used in the next step without workup or purification. MS (ES+): m/e 178.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([C:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]=3)=[CH:17][C:10]=12.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH:19]=3)=[CH:17][C:10]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4cccc(F)c4F)ccnc3[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(-c2ccnc3[nH]c(C4=CCNCC4)cc23)c1F
Reaction time: 3 h

Procedure:
A solution of Example 222B (0.255 g, 0.620 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid (0.477 mL, 6.20 mmol) and the mixture was stirred for 3 hours and concentrated. The residue was dissolved in 2 mL methanol and treated slowly with 2 mL 2M hydrogen chloride in ether. The suspension was diluted with ether and stirred for 10 minutes. The solids were filtered, washed with ether, and dried to give the title compound as a hydrochloride salt. MS (ESI+) m/z 312.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:11][OH:12])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 5-fluoro-2-formylpyridine (5.0 g, 41 mmol) and hydroxylamine hydrochloride (3.06 g, 44 mmol) in ethanol (3.2 mL) and water (9.6 mL) was added ice (18.6 g). Then a solution of NaOH (4.0 g, 100 mmol) in water (4.6 mL) was added dropwise over 10 min keeping the temperature between −5° C. and 5° C. The reaction mixture was then stirred at room temperature for 30 min. Then HCl (4 N) was added to acidify the mixture and the resulting precipitate was filtered off and washed with water to afford the title compound (4.41 g, 79%) as a light brown solid. MS: m/e=141.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccc(F)cc1F)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccc(F)cc1F)C2
Yield: 78.2 %

Procedure:
A mixture of 7-(2,4-difluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.43 g), aminoguanidine hydrochloride (0.18 g), concentrated hydrochloric acid (0.39 ml), water (0.39 ml) and ethanol (50 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and the mixture was concentrated under reduced pressure. The residue was recrystallized from water-ethanol to give 7-(2,4-difluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 60) (0.45 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[C-:15]#[C-:16].[Na+].[Na+]>C1COCC1>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([CH:6]([OH:7])[C:15]#[CH:16])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: [C-]#[C-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A solution of 3,4,5-trimethoxybenzaldehyde (1.0 g, 5.0 mmol) in THF (50 mL) was stirred at 0° C. Sodium acetylide (18% w.t. slurry in xylene, 1.63 g, 6.1 mmol) was added via syringe. The reaction mixture was stirred overnight at room temperature and quenched by water. It was then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a crude product, which was purified by flash column chromatography eluting with EtOAc/n-hexane (1:2) to afford 1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol as a white solid (815 mg, 72%).
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:10][CH:11]([CH3:15])[C:12](O)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([O:9][C:12](=[O:13])[CH:11]([SH:10])[CH3:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCCCC1
Reactant: CC(S)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OC1CCCCCCC1

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, thermometer, hot plate, spin bar and heating mantle are placed 12.8 grams of cyclooctanol; 22 grams of 2-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and maintained at reflux for a period of 10 hours. At the end of the reaction mass, the reaction product is washed with one 25 ml volume of water and dried over anhydrous sodium sulfate. The reaction mass is then distilled on a micro distillation column yielding the compound having the structure: ##STR98##