Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][Cl:21])=[CH:10][CH:9]=1)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[ClH:21].[Cl:21][CH2:20][CH2:19][O:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH2:7])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCCCl)c2ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1ccc(OCCCl)c2ccccc12

Procedure:
To a stirred solution of [4-(2-chloro-ethoxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester (1.387 g, 4.3 mmol) in anhydrous dioxane (10 ml) at room temperature is added a solution of 4M HCl in dioxane (15 ml). After 18 hours diethyl ether (150 ml) is added and 4-(2-chloroethoxy)-naphthalen-1-ylamine hydrochloride salt filtered off as a pink solid (1.081 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:34])[C:26]4[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=4[F:33])[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:35][C:36]([F:45])([F:44])[C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40]>C(O)(C)C>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[C:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]4[CH:41]=[CH:42][CH:43]=[C:37]([C:36]([F:35])([F:44])[F:45])[CH:38]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[N:11]3[N:10]=2)[CH:19]=1)=[O:34]
Reactant: Cc1cccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn12
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(C)O
Product: Cc1cccc2c(-c3ccnc(Nc4cccc(C(F)(F)F)c4)n3)c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn12

Procedure:
The title compound was prepared through standard displacement conditions by microwaving N-{3-[3-(2-chloropyrimidin-4-yl)-7-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-trifluoromethylaniline in isopropanol at 150° C. for 15 min. LCMS (ESI): [M+H]+=601.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[N:19]3[C:20]([CH2:23][OH:24])=[CH:21][N:22]=[C:18]3[CH2:17][CH2:16]2)=[CH:11][C:10]=1[F:25])#[N:8].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CS(C)=O>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[N:19]3[C:20]([CH:23]=[O:24])=[CH:21][N:22]=[C:18]3[CH2:17][CH2:16]2)=[CH:11][C:10]=1[F:25])#[N:8]
Reactant: N#Cc1ccc(C2CCc3ncc(CO)n32)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1ccc(C2CCc3ncc(C=O)n32)cc1F
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (3.24 mL, 6.472 mmol) in methylene chloride (10 mL) at −78° C. was added DMSO (0.919 mL, 12.9 mmol). The solution was stirred for 15 minutes and a solution of the alcohol from Step K (1.11 g, 4.32 mmol) in methylene chloride (5 mL)/DMSO (1 mL) was added. The solution was stirred for an additional 15 minutes and then triethylamine (3.01 mL, 21.6 mmol) was added. The resulting solution was stirred for 5 minutes at −78° C. and 4 hours at 25° C. The reaction was poured onto sat. aq. NaHCO3 and extracted with methylene chloride (3×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide the title product as a brown oil which was sufficiently pure for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1Cl.[SH-:10].[Na+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[SH:10]
Reactant: Clc1ccc(Cl)c(Cl)c1
Reactant: [SH-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Product: Sc1cc(Cl)ccc1Cl

Procedure:
the method in which 1,2,4-trichlorobenzene and sodium hydrosulfide are reacted in the presence of copper acetate catalyst in liquid ammonia solvent under increased pressure to yield 2,5-dichlorothiophenol, followed by reaction with monochloroacetic acid to yield 2,5-dichlorophenylthioglycolic acid [Kogyo Kagaku, 70, 1384 (1967)].
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[N+:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].C(O)CCO>C(COC)OC.O.C(OCC)(=O)C.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>[N+:9]([C:12]1[CH:17]=[C:16]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:15]=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Brc1ccncc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: OCCCO
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromopyridine, hydrochloride (8.03; 41.3 mmol), 3-nitrophenylboronic acid (6.85 g; 41.0 mmol), potassium carbonate (34.2 g; 0.25 mol), 1,3-propandiol (14.9 ml; 0.21 mol) and tetrakis(triphenylphosphine)palladium (0.2 g) in a mixture of dimethoxyethane (80 ml) and water (40 ml) was stirred at 80° C. in a nitrogen atmosphere overnight. The cooled mixture was diluted with ethyl acetate and filtered through celite. The filtrate was evaporated to dryness and water was added to the residue. Vigorously stirring caused the product to precipitate. The product was filtered off, washed with water, dried and subsequently washed with petroleum ether. Yield: 8.15 g (99%).
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4]Cl.C(=O)([O-])[O-].[K+].[K+].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>CC(C)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:2]2([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)[CH2:4][CH2:3]2)=[O:7])=[CH:9][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Yield: 82.9 %

Procedure:
A solution of 150 g of 4-chlorophenyl 1-bromo-3-chloropropyl ketone in 200 ml of acetone is added dropwise to a boiling solution of 100 g of potassium carbonate and 110 g of 1,2,4-triazole in 400 ml of acetone, and the mixture is then stirred under reflux for 8 hours. It is then evaporated in vacuo, and the residue is stirred in 500 ml of water. The precipitate which separates out is filtered off with suction, washed several times with water and dried. 104 g (82% of theory) of 1-(4-chlorobenzoyl)-1-(1,2,4-triazol-1-yl)cyclopropane, of melting point 78° C., are obtained.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])=[O:10])[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][CH:4]=[C:3]1[NH:28][C:29]([NH:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:30].CO>ClCCl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[C:14]([F:15])([F:17])[F:16])=[O:10])[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][CH:4]=[C:3]1[NH:28][C:29]([NH:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:30]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2cccnc2)c1=O)C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2cccnc2)c1=O)C(=O)C(F)(F)F

Procedure:
2-[6-Oxo-2-phenyl-5-[3-(3-pyridylmethyl)ureido]-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was subjected to conditions similar to those described in Example 1. Chromatography, with methanol:dichloromethane (5.95) as the eluent, gave 2-[6-oxo-2-phenyl-5-[3-(3-pyridylmethyl)ureido]-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a white solid; NMR (DMSO/D2O): 8.60 (s,1), 8.42 (m,3), 7.71 (m,1), 7.47 (m,5), 4.58 (d,1), 4.39 (d,1), 4.31 (s,2), 2.20 (m,1), 0.83 (d,3), 0.77 (d,3).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:8]([O:15][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Succinic anhydride (30 g, 300 mmole) was dissolved in methylene chloride (300 ml). To the solution were added benzyl alcohol (10.2 ml, 100 mmole), 4-dimethylaminopyridine (1.22 g, 10 mmole) and pyridine (48 ml). After 3 hours the reaction mixture was poured in to citric acid aqueous solution. The organic phase was concentrated to small volume and sodium hydrogen carbonate and water were added. Then mixture was stirred for 30 min. The aqueous phase was collected, and to it was added citric acid aqueous solution. The product precipitated out, was collected and dried. 15.3 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:13]12([NH2:23])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:23][C:13]23[CH2:14][CH:15]4[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]4)[CH2:22]2)[CH2:20]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1S(=O)(=O)Cl
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(Br)cccc1S(=O)(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Bromo-2-methylbenzene-1-sulfonyl chloride (300 mg) and 1-adamantanamine (185 mg) were dissolved in dichloromethane (4 mL). Diisopropylethylamine (432 mg) was added, and the solution was stirred at room temperature for 16 hours. The solution was diluted with 70% ethyl acetate (hexanes), washed three times with 1 M aqueous HCl, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed to yield the product.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CO.O>C1COCC1.[OH-].[Li+]>[N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([OH:17])=[O:16])=[CH:30][CH:31]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(C(=O)O)c2)C1=O
Yield: 99.5 %

Procedure:
Methyl 3-[4-(azetidine-1-carbonyl)phenoxy]-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 16) (309 mg, 0.73 mmol) was dissolved in THF (6 mL) and methanol (2 mL) and IN lithium hydroxide (0.88 mL) was added followed by water (8 mL). The resultant solution was stirred for 1 hr at room temperature. The majority of the organic solvent was removed by distillation under reduced pressure. The remaining aqueous solution was filtered and acidified with 2N hydrochloric acid and extracted with ethyl acetate (2×40 mL), the combined organics were washed with water (10 mL) and brine (20 mL) and dried (MgSO4) to afford the product (298 mg, 100%). m/z 411 (M+H)+
Reaction SMILES: C(NCCO[C:8]1[C:14]([CH3:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[CH3:16])(C)C.[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])(=[O:20])=[O:19]>>[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:12][C:11]1[CH:10]=[C:9]([CH3:16])[CH:8]=[C:14]([CH3:15])[CH:13]=1)=[O:25])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Nc1ccccc1C(=O)Cl
Reactant: Cc1cc(N)cc(C)c1OCCNC(C)C
Product: Cc1cc(C)cc(NC(=O)c2ccccc2NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
4-[2-(Isopropylamino)ethoxy]3,5-dimethylaniline (2.6 g) solution in dimethylformamido (15 ml) was added with 2-(methanesulfonamido)benzoyl chloride (3.0 g) and the mixture was stirred for 2 hours at room temperature. After being concentrated under vacuum, the reaction mixture was dissolved into chloroform (50 ml) and extracted with 1N sodium hydroxide (100 ml). Resultant aqueous layer was neutralized with 1N HCl (100 ml) and extracted with chloroform (150 ml). Chloroform layer obtained was concentrated and purified by silica-gel column chromatography (chloroform:methanol=10:1) to obtain 4′-[2-isopropylamino) ethoxy]-2-methanesulfonamido-3′,5′-dimethylbenzanilide (2.15 g) as white solid.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:4]=1.C(=O)([O-])[O-:19].[Ca+2]>C(O)C.O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:2]=[O:19])=[CH:11][CH:12]=1
Reactant: Fc1ccc(Oc2cccc(C(Br)Br)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: O=Cc1cccc(Oc2ccc(F)cc2)c1
Yield: 92.4 %

Procedure:
A solution of the product of step (b) (16.04 g) in a mixture of ethanol (100 ml) and water (25 ml) was treated with precipitated calcium carbonate (13.37 g) and the mixture refluxed for 20 hours. After cooling, the mixture was filtered, the filtrate stripped, and the residue taken up in 2 M aqu. HCl (100 ml) and extracted with ether (200 ml). The extract was washed with water (100 ml), dried over Na2SO4 and stripped to give a pale yellow oil which was distilled under reduced pressure to give the desired product (8.90 g), bp 100°-130° C./0.2 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C1(C)C=CC(S(O[CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=O)=O)=CC=1.CCCCCC[C@@H](O)C>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CCCCCC[C@H](C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(OCc2ccccc2)cc1

Procedure:
p-Benzyloxyphenol (50 g), ethanol (150 ml) and 50% NaOH aqueous solution (25 g) were mixed with stirring, followed by pouring in the mixture, optically active 1-methylheptyl p-toluenesulfonate derived from S-(+)-2-octanol, heating the mixture under reflux for 4 hours, distilling off most of ethanol, extracting with toluene, washing with acid, alkali and water, drying, concentrating and purifying the concentrate according to column chromatography with activated alumina (150 g) to obtain oily p-benzyloxy-(1-methylheptyloxy)benzene (68.6 g), which was then subjected to hydrogenolysis with 5% Pd-C catalyst in ethanol, followed by removing the catalyst, concentrating the solution and subjecting the concentrate to vacuum distillation to obtain oily p-(1-methylheptyloxy)phenol (IIIa-2) (30.7 g) having a b.p. of 129°-130.5° C./0.5 Torr.
Reaction SMILES: Br[C:2]1([CH2:17][C:18]([OH:20])=[O:19])[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCCCC=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28]>C(Cl)(Cl)Cl>[N+:27]([C:2]1([CH2:17][C:18]([OH:20])=[O:19])[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:32])=[O:28]
Reactant: O=C(O)CC1(Br)OC2=CC=CC2=CC1c1ccccc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: C1=CCCCC1
Product: O=C(O)CC1([N+](=O)[O-])OC2=CC=CC2=CC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-bromo-3-phenyl-4-benzofuranacetic acid (12.1 g., 0.0365 mole) and cyclohexene (3.3 g., 0.04 mole) in 100 ml. of chloroform is treated with 5 g. of dinitrogen tetroxide in 20 ml. of chloroform dropwise. The mixture is stirred for 16 hours at about 25° C. then at 50°-55° C. for about 20 minutes. The mixture is washed with water, and the organic layer is treated with an aqueous base. The aqueous layer is acidified, then extracted with dichloromethane. The organic layer is washed thrice with water, dried and evaporated. Two recrystallizations from benzene give light yellow solid 2-nitro-3-phenyl-4-benzofuranacetic acid, m.p. 187.5°-189.5° C.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][C:9]=1[C:20]([OH:22])=O)=[O:4].Cl.CN.[CH:27]([N:30](C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[F:23][CH:2]([F:1])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][C:9]=1[C:20]([NH:30][CH3:27])=[O:22])=[O:4]
Reactant: COc1cc2c(CCNC(=O)C(F)F)c(C(=O)O)[nH]c2cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1[nH]c2cc(F)c(OC)cc2c1CCNC(=O)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-{2-[(difluoroacetyl)amino]ethyl}-6-fluoro-5-methoxy-1H-indole-2-carboxylic acid (2.48 g), methylamine hydrochloride (2.54 g), diisopropylethylamine (9.00 mL), and N,N-dimethyl formamide (49.6 mL) was added 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (8.57 g), followed by stirring at room temperature for 1 hour. To the mixture was added ice water, followed by extraction with ethyl acetate and further extraction with chloroform/methanol (10:1). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 10:1) to obtain 3-{2-[(difluoroacetyl)amino]ethyl}-6-fluoro-5-methoxy-N-methyl-1H-indole-2-carboxamide (1.42 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][N:25]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:5])C.[OH-].[Na+]>>[C:39]([O:38][C:36]([N:25]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:24][CH2:23][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:11][C:10]=1[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(Cl)cc(Cl)c3)c(CCN(CCCCc3cccnc3)C(=O)OC(C)(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N(CCCCc1cccnc1)CCc1c(-c2cc(Cl)cc(Cl)c2)[nH]c2ccc(C(=O)O)cc12
Temperature: 75 °C
Yield: 101.6 %

Procedure:
To a suspension of 3-{2-[tert-butoxycarbonyl-(4-pyridin-3-yl-butyl)amino]ethyl}-2-(3,5-dichlorophenyl)-1H-indole-5-carboxylic acid ethyl ester (65 mg in 4 mL methanol) at 0° C. was added 1.4 mL of a 1.25N sodium hydroxide solution and the mixture heated to 75° C. on an oil bath. After 2.5 hours the mixture was cooled to room temperature and the reaction quenched by the addition of saturated aqueous ammonium chloride. The mixture was extracted with the ethyl acetate, washed with saturated ammonium chloride solution and the organic portion dried over sodium sulfate. Concentration in vacuo provided the crude title compound (63 mg).
Reaction SMILES: [C:1]([OH:16])(=[O:15])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:17]1[C@@H:22]([NH2:23])[C@H:21]([O:24][C@H:25]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:28]([OH:33])[C@H:27]([NH2:34])[C@H:26]2[OH:35])[C@@H:20]([OH:36])[C@H:19]([O:37][C@H:38]2[O:43][C@H:42]([CH2:44][NH2:45])[C@@H:41]([OH:46])[CH2:40][C@H:39]2[NH2:47])[C@H:18]1[NH2:48].OS(O)(=O)=O>O>[CH2:17]1[C@@H:22]([NH2:23])[C@H:21]([O:24][C@H:25]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:28]([OH:33])[C@H:27]([NH2:34])[C@H:26]2[OH:35])[C@@H:20]([OH:36])[C@H:19]([O:37][C@H:38]2[O:43][C@H:42]([CH2:44][NH2:45])[C@@H:41]([OH:46])[CH2:40][C@H:39]2[NH2:47])[C@H:18]1[NH2:48].[C:1]([O-:16])(=[O:15])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13]
Reactant: O=C(O)/C=C/CCCCCCCCC(=O)O
Agent: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)C[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C([O-])/C=C/CCCCCCCCC(=O)[O-]
Temperature: 4 °C

Procedure:
11.4 g of trans-traumatic traumatic acid (50 mmol) are suspended in 200 ml of cool water at 4° C., A solution of 14.3 g of tobramycin sulfate (20mmol) in 200 ml of water is eluted through a column cooled to 4° C. containing 150 ml of [OH--] Dowex 1×8 resin. The eluate free from sulfate is collected into the suspension of traumatic acid kept under continuous stirring at 4° C. The resulting solution is frozen and lyophilized.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22](=[O:25])[CH:23]=[CH2:24])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>CC(O)=O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:6]=[C:5]3[CH:24]=[CH:23][C:22](=[O:25])[C:3]=1[C:4]=23
Reactant: C=CC(=O)c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(C)cc(C)c42)C(=O)C=C3)cc1
Temperature: 100 °C

Procedure:
To a mixture of 1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)prop-2-en-1-one (240 mg, 0.679 mmol), PdOAc2 (152 mg, 0.679 mmol) and P-CHLORANIL (167 mg, 0.679 mmol), AcOH (7 mL) was added and the reaction heated to 100° C. for 1.5 h. The reaction was stopped and filtered to remove precipitated salts. The AcOH was removed in vacuo and then the resulting residue was purified using FCC eluting with heptane:EtOAc 1:1 to give the title compound. MS (ESI+) m/z 352.3 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[CH3:28][C:26]1[CH:25]=[CH:24][N:23]=[C:22]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]=[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:16]=2)[CH:27]=1
Reactant: Cc1ccnc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccnc(Oc2cccc(C=C3CCNCC3)c2)c1

Procedure:
4-[3-(4-Methyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (1.15 g, 2.9 mmol) from Step 4 was dissolved in DCM (10 mL) and treated with HCl in dioxane (4.34 mL, 4.0 M, 17.3 mmol). After 16 hours the reaction was concentrated in vacuo to provide the title compound as a white solid (1.6 g).
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O)C.[OH-].[Na+:18]>CO>[C:1]12([C:11]([O-:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Na+:18]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: O=C([O-])C12CC3CC(CC(C3)C1)C2
Reaction time: 0.25 h

Procedure:
Approximately 10 g (0.06 mole) of adamantane carboxylic acid was added to 150 ml of ethanol. An equivalent number of moles (2.2 g) of sodium hydroxide also was added to the methanol and the solution was stirred for approximately 15 minutes. This resulted in the formation of sodium adamantane carboxylate. To this reaction mixture was added 7.72 g (0.05 mole) of onitrobenzyl chloride. The resulting solution was heated to reflux temperature and stirred at this temperature for 3 hours. The ester thus formed was precipitated by adding 250 ml, in 1 aliquot, of water. The mixture was cooled to ambient temperature and the precipitate was separated by vacuum filtration. The precipitate was recrystallized from 500 ml of a one-to-one by volume solution of ethanol and water to yield approximately 6.4 g of o-nitrobenzyl adamantane carboxylate.