Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]1[O:19][C:18]([CH3:20])=[N:17][N:16]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.ClCCl>[C:21]([O:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]1[O:19][C:18]([CH3:20])=[N:17][N:16]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nnc(C2=C(O)c3ccccc3S(=O)(=O)N2C)o1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nnc(C2=C(OC(=O)c3ccccc3)c3ccccc3S(=O)(=O)N2C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 4-hydroxy-2-methyl-3-(2-methyl-1,3,4-oxadiazol-5-yl)-1,2-benzothiazine 1,1-dioxide, (0.155 g) in pyridine (0.5 ml) was added benzoyl chloride (0.63 ml) at 5°-10° C. After being stirred at room temperature for 1 hour, the mixture was diluted with dichloromethane, washed successively with dilute HCl, water and dilute sodium bicarbonate solution and dried over sodium sulfate to give, on concentration, crude solids 0.213 g. Recrystallization from toluene gave the title compound 0.156 g (74%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:15][S:16]([O:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])=[O:17]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1OS(C)(=O)=O
Temperature: 50 °C

Procedure:
Methyl 2-hydroxy-4-nitrobenzoate (19.7 g) was dissolved in 100 ml of chloroform and triethylamine (15 ml). The solution was kept at a temperature below 15° C., and methanesulfonylchloride (8.6 ml) was added dropwise. The solution was maintained at 50° C. for 1 hr, whereupon it was poured onto ice-hydrochloric acid and extracted with a total of 600 ml chloroform. The solution was dried with magnesium sulfate, treated with active carbon and evaporated. The product was recrystallized from methanol. Yield: 20 g.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[CH3:34][N:35]([CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)[C:36]([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42])=[O:37].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:17][C:16]=2[NH:27][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[C:38]([C:36]([N:35]([CH3:34])[CH2:47][CH2:48][N:49]3[CH2:50][CH2:51][O:52][CH2:53][CH2:54]3)=[O:37])[CH:39]=2)[CH:10]=1)=[O:28]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: CCCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(ethyl(propyl)amino)phenyl)isonicotinamide (150 mg, 0.30 mmol, 1.00 equiv, 90%) in dichloromethane (8 mL), 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (144 mg, 0.44 mmol, 1.50 equiv, 90%), EDC.HCl (126 mg, 0.66 mmol, 2.00 equiv), 4-dimethylaminopyridine (80 mg, 0.66 mmol, 2.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of NH4Cl aq. and 1×20 mL of sodium bicarbonate (10%). The resulting mixture was washed with 1×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (250 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (25% CH3CN up to 39% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 183.7 mg product was obtained. This resulted in 183.7 mg (56%) of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(ethyl(propyl)amino)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide as a yellow solid. LC-MS (ES, m/z) 731 [M+H]+; H-NMR (300 MHz, DMSO, ppm): 9.83 (s, 1H), 9.52 (t, J=18 Hz, 1H), 8.89 (d, J=3 Hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.99 (m, 2H), 7.82 (d, 1H), 7.54-7.69 (m, 6H), 6.95-7.54 (m, 2H), 4.60 (s, 2H), 3.85-4.02 (m, 4H), 3.64 (m, 4H), 3.36-3.47 (m, 6H), 3.18 (m, 2H), 2.95 (s, 3H), 1.60 (m, 2H), 1.09-1.13 (m, 3H), 0.87-0.92 (m, 3H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([CH2:13][O:14][CH3:15])=[N:9][O:10][C:11]=1[CH3:12].C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl>C1COCC1.O>[CH3:15][O:14][CH2:13][C:8]1[C:7]([B:20]([OH:21])[OH:19])=[C:11]([CH3:12])[O:10][N:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCc1noc(C)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCc1noc(C)c1B(O)O
Temperature: -78 °C
Reaction time: 15 h
Yield: 26 %

Procedure:
n-Butyl lithium (2.5 M in hexanes, 2.20 mmol) was added dropwise to 4-bromo-3-methoxymethyl-5-methyl isoxazole (412 mg, 2.00 mmol) in THF (8 mL) at −78° C. under nitrogen. After stirring at −78° C. for 30 min triisopropylborate (564 mg, 3.00 mmol) was added dropwise. The temperature was maintained at −78° C. for 2 h then the reaction was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was poured into a mixture of 1N hydrochloric acid and water (1:1, 100 mL) and stirred rapidly for 1 h. The organic layer was separated and the aqueous layer was extracted with ether (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered and evaporated to dryness. The residue was triturated with hexanes (30 mL) then dried under high vacuum to provide 89 mg (29% yield) of 3-methoxymethyl-5-methyl isoxazole-4-boronic acid as a waxy tan solid which was immediately carried forward to the next reaction: 1H NMR (300 MHz, CDCl3) δ ppm 4.74 (s, 2H), 3.37 (s, 3H), 2.74 (s, 3H), 2.60 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:17][C:18](=O)[CH3:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:18]([CH3:19])[CH2:17][C:16]([CH3:21])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CC(C)(C)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CC(C)(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-methyl-4-phenyl-pentan-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].Br[C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:24]4[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4cccc(S(N)(=O)=O)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (159 mg, 0.5 mmol) and commercially available 3-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (140 mg, 59%). MS (ISP) 473.2 [(M+H)+]; mp 215° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:10]1[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15])[CH2:25]2
Reactant: COc1ccc2c(c1)CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccc(OC)cc4C3)c(F)c21
Yield: 31.6 %

Procedure:
135 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 104 mg of 5-methoxyisoindoline, 121 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 63 mg of the target compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][O:30][CH3:31]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:28][CH2:29][O:30][CH3:31])[CH2:26][CH2:25][O:24][CH3:23])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: COCCNCCOC
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Product: COCCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1)CCOC

Procedure:
According to the method in example 29, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and bis(2-methoxyethyl)amine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-bis-(2-methoxy-ethyl)-amine as light brown oil, MS: 492 (MH+,1Br).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][OH:23].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[CH2:22][OH:23])[CH:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Nc1ccccc1CO
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1Nc1ccccc1CO
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Methyl 1-Boc-4-oxo-3-piperidinecarboxylate from Step 1 above (3.86 g, 15 mmol) was combined with 2-aminobenzyl alcohol (1.5 g, 12.2 mmol) and acetic acid (1.29 mL, 1.35 g, 22.5 mmol) in methanol (10 mL). Sodium cyanoborohydride (0.94 g, 15 mmol) was added and the mixture was stirred at ambient temperature for 3.5 h. The solvent was removed in vacuo and the residue treated with ethyl acetate (100 mL). The solution was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1:4, 1:2, and 3:5 EtOAc:hexane. The combined product fractions were evaporated to dryness in vacuo to give methyl 1-Boc-4-(2-hydroxymethylphenylamino)-3-piperidine carboxylate.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].C(=O)(O)[O-].[Na+].[NH:15]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:16]([C:21](ON1C(=O)CCC1=O)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19].Cl>CN(C=O)C.O>[NH:15]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:16]([C:21]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CSCC[C@@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCC[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
D-Met-OH (1.4 g, 10 mM) and sodium bicarbonate (1.68 g, 20 mM) were added to a mixture of water (15 ml) and DMF (5 ml). Boc-Leu-OSu (3.28 g, 10 mM) in DMF (30 ml) was added thereto and the mixture was stirred overnight at room temperature. After cooling to 0° C., the pH was adjusted to pH 6.5 with 1 N-HCl and the solution was concentrated in vacuo. The residue was dissolved in ethyl acetate-1 N-HCl (50 ml-50 ml). The ethyl acetate layer was washed with water, dried by adding sodium sulfate and ethyl acetate was distilled off. The residue was charged on a column of silica gel (100 g) and eluted with benzene-ethyl acetate (1:1) to obtain Boc-Leu-D-Met-OH (1.6 g).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:39]([O:41][CH3:42])=[O:40]>C(#N)C>[CH3:47][O:46][C:45]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=1[CH2:35][N:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])=[CH:12][CH:13]=2)[CH2:20][CH2:21]1
Reactant: O=C(Nc1ccccc1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: COC(=O)c1ccc(OC)c(CCl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OC)c(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccc4)cc3)CC2)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
1-Phenyl-3-(4-(piperazin-1-carbonyl)phenyl)urea (439 mg, 1.0 mmol) was stirred in acetonitrile (8 mL) at room temperature for 1 hour, N-Ethyl-N-isopropylpropan-2-amine (697 μl, 4 mmol) was added, followed by a solution of methyl 3-(chloromethyl)4-methoxy-benzoate (215 mg, 1.0 mmol) in acetonitrile (5 mL). The mixture was heated to 45° C. and stirred overnight. The mixture was concentrated under vacuum, diluted with dichloromethane (40 mL) and washed with saturated aqueous ammonium chloride (25 mL) and saturated aqueous sodium chloride (25 mL). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum. The residue was submitted to silica chromatography (0-10% methanol in dichloromethane as eluant) to give the title compound (216 mg). MS (ESI) m/z 503.1 [M+H]+
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[C:11]([O:19][CH2:20][CH3:21])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:24]>>[CH2:20]([O:19][C:11]1[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:23][CH3:24])[CH2:37][CH2:36]2)=[O:22])=[CH:15][C:14]([CH2:16][CH3:17])=[C:13]([CH3:18])[N:12]=1)[CH3:21]
Reactant: CCOc1nc(C)c(CC)cc1NC(=O)Oc1ccccc1
Reactant: CCOc1ccccc1N1CCNCC1
Product: CCOc1ccccc1N1CCN(C(=O)Nc2cc(CC)c(C)nc2OCC)CC1
Yield: 79 %

Procedure:
Phenyl-N-(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(2-ethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([O:19][CH2:20][CH3:21])=[CH2:18]>ClCCl>[CH2:17]([O:19][CH2:20][CH2:21][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18]
Reactant: C=COCC
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOCCOC(=O)C(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
Diphenylacetic acid 2-ethoxyethyl ester was prepared in the following manner: To a mixture of 2.0 g (9.4 mmol) of diphenylacetic acid in 10 ml of dichloromethane was added 1.1 ml (0.82 g, 11.4 mmol) of ethyl vinyl ether. The mixture was allowed to stir overnight at which point the reaction mixture was washed with aqueous sodium bicarbonate, dried with MgO-MgSO4, and concentrated in vacuo to give 1.7 g (6.0 mmol, 63% yield) of the corresponding ethoxy ethyl ester.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([OH:38])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=3[OH:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(F)ccc1O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Oc1ccc(F)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-fluoro-2-hydroxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 503; MS (ESI) m/z 501.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][CH2:36][O:37][CH2:38][CH3:39]>Cl([O-])(=O)(=O)=O.[Ag+]>[CH2:36]([O:37][C@@H:38]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)[C@H:35]([CH2:12][O:11][C:10](=[O:13])[CH3:9])[C@@H:15]([CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:25][C@@H:39]1[O:25][C@@H:15]1[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:13][C@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:16]1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:35]1[CH:31]=[CH:30][CH:29]=[CH:34][CH:33]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCOCC
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](COC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
Ethereal silver perchlorate (0.08 M, 9.58 mL, 7.67 mmol) is added with stirring at -30° C. to a solution of methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (2.592 g, 5.59 mmol), 2,3,6-tri-O-benzyl 1,4-dideoxy-4-acetyloxymethyl-D-glucopyranosyl chloride (3.661 g, 6.98 mmol) in ether (20 mL). The mixture is stirred 15 min at -30° C. and silver chloride precipitated. The mixture is filtered through a celite pad, the solids are washed with ether, the filtrate is concentrated under reduced pressure. The residue is dissolved in methylene chloride and the organic layer is washed successively with aqueous sodium thiosulfate and water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure so as to afford a foam. Flash chromatography on silica gel and elution with a graded mixture of hexane and ethyl acetate will afford methyl 4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside as a foam.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]([F:24])([F:23])[S:12]([O:15]S(C(F)(F)F)(=O)=O)(=[O:14])=[O:13].[CH2:25]([C:27]([C:45]1[CH:50]=[C:49]([CH3:51])[C:48](O)=[C:47]([CH3:53])[CH:46]=1)([C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([CH2:42][CH3:43])([OH:41])[CH2:39][CH3:40])=[C:32]([CH3:44])[CH:31]=1)[CH2:28][CH3:29])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([C:27]([C:45]1[CH:46]=[C:47]([CH3:53])[C:48]([O:15][S:12]([C:11]([F:24])([F:23])[F:10])(=[O:14])=[O:13])=[C:49]([CH3:51])[CH:50]=1)([C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([CH2:39][CH3:40])([OH:41])[CH2:42][CH3:43])=[C:32]([CH3:44])[CH:31]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(O)c(C)c2)cc1C)CC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(OS(=O)(=O)C(F)(F)F)c(C)c2)cc1C)CC
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
Diisopropylethylamine (2.2 mL, 12.92 mmol) and trifluoromethanesulfonic anhydride (1.3 mL, 7.75 mmol) were added to a solution of 4-{1-ethyl-1-[(E)-4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenol (Example 38-(4); 2.55 g, 6.46 mmol) in dichloromethane (30 mL) at −40° C., and the mixture was stirred at −40° C. for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was then heated to room temperature and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50, 40 minutes) to give the target compound as a colorless oil (2.92 g, 86%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7]2.[H-].[Na+].Cl[CH2:19][C:20]([NH2:22])=[O:21]>CN(C)C=O>[C:20]([CH2:19][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7]2)(=[O:21])[NH2:22]
Reactant: NC(=O)CCl
Reactant: COC(=O)c1cc2cccc(O)c2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cccc(OCC(N)=O)c2n1C
Temperature: 25 °C
Yield: 84.4 %

Procedure:
After 0.50 g (2.44 mmol) of methyl 7-hydroxy-1-methyl-2-indolecarboxylate was added to a suspension of 0.01 g (2.44 mmol) of 60% sodium hydride in 25 ml of dimethyl-formamide, the mixture was stirred at room temperature until the mixture became a transparent solution. Then 0.25 g (2.68 mmols) of 2-chloroacetamide was added dropwise to the transparent solution at room temperature followed by stirring at 50° C. for an hour. The reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 0.54 g (84.4%) of methyl 7-carbamoylmethoxy-1-methyl-2-indolecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH:15]([CH2:21][CH2:22][CH3:23])[C:16]([O:18]CC)=[O:17])=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:12]2[C:11]3[CH2:10][CH2:9][N:8]([CH3:31])[CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[C:14]([CH:15]([CH2:21][CH2:22][CH3:23])[C:16]([OH:18])=[O:17])=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:12]2[C:11]3[CH2:10][CH2:9][N:8]([CH3:31])[CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: CCCC(C(=O)OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(C)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(C)C3
Yield: 5.9 %

Procedure:
To a suspension of ethyl [2,7-dimethyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate (0.438 g; 1 mmol) in a mixture methanol-ethanol (2:1) (15 mL) was added a 5% sodium hydroxide solution (15 mmol; 12 mL) and the reaction mixture was heated at reflux for 18 h. After cooling, the organic volatiles were removed under reduced pressure and the remaining basic solution was acidified with HCl (1N) until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulphate and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 2) furnished 0.024 g (5.8%) of the title compound as a yellow oil.