Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:18]([O-:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[CH3:22][CH:23]([CH3:47])[CH2:24][NH:25][C@H:26]1[CH2:31][C@@H:30]([C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[CH2:29][N:28]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:27]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>C(#N)C>[CH3:22][CH:23]([CH3:47])[CH2:24][N:25]([C:18]([C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])[C@H:26]1[CH2:31][C@@H:30]([C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[CH2:29][N:28]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:27]1
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])c1nc2ccccn2c1COc1ccccc1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)CN(C(=O)c1nc2ccccn2c1COc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
Ethyl 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (889 mg) was dissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The precipitated crystals were collected by filtration, and washed with ethanol to give sodium 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (680 g). The obtained sodium 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (290 mg), tert-butyl(3S, 5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (370 mg) and N,N-diisopropylethylamine (862 μ) were dissolved in acetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (561 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object product (563 mg).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:25]([N:32]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:25]([N:32]1[CH2:36][CH2:35][C@H:34]([NH:37][C:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3ccccc23)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCN(Cc4ccccc4)C3)nc3ccccc23)CC1
Yield: 62.5 %

Procedure:
A mixture of t-butyl 4-(2-chloroquinazolin-4-yl)piperazine-1-carboxylate (30 g) synthesized in the same manner as in Example 1, (S)-1-benzyl-3-aminopyrrolidine (15 g), triethylamine (8.7 g), and isopropyl alcohol (43 mL) was heated to reflux for 40 h. The reaction mixture was concentrated under reduced pressure, then water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, concentrated, and then purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=4:1) to obtain t-butyl 4-(2-((S)-1-benzylpyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (26 g).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](O)=[O:17])=[O:13])=[C:4]1[CH3:23])[CH3:2].[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=2)=[CH:34][CH:33]=1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([N:38]([C:39]3[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:43][CH:44]=3)[C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[CH:37][CH:36]=3)[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:17])[O:13]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3ccccc32)cc1

Procedure:
Following a procedure similar to that described in Example 2B but employing 10.0 g of 2-(1-ethyl-2-methyl-3-indolylcarbonyl)benzoic acid and 13.0 g of 4,4'-dioctyldiphenylamine there was obtained a quantitative yield of 3-(1-ethyl-2-methyl-3-indolyl)-3-[N,N-bis-(4-octylphenyl)amino]phthalide, m.p. 106°-108° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a yellow-colored image.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[ClH:51]>>[ClH:51].[ClH:51].[C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:41][CH:42]([CH3:43])[CH3:44])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH2:23][NH:22][CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl (3S,5R)-3-{[(2-tert-butyl-4-hexylpyrimidin-5-yl) carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (88.4 mg) was dissolved in 1M hydrogen chloride-ethyl acetate (3 ml), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated to give the object product (62.7 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[I:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl>[I:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:2][CH:3]2[C:11]3[C:6](=[CH:7][C:8]([S:12](=[O:13])(=[O:14])[NH2:15])=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:29])=[CH:26][CH:25]=1
Reactant: NC1CCc2cc(S(N)(=O)=O)ccc21
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc2c(c1)CCC2NC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask containing 1-amino-2,3-dihydro-1H-indene-5-sulfonamide hydrochloride salt (93 mg, 0.38 mmol) suspended in dichloromethane (3 mL) was added triethylamine (61 μL) followed by 4-iodobenzoylchloride (100 mg, 0.38 mmol) and the reaction was stirred overnight at room temperature. The reaction was diluted with dischloromethane (25 mL) and washed with 10% aqueous hydrochloric acid (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate and concentrated to afford the crude material as an off-white solid. Recrystallization from ethanol/water afforded MIP-1146 (19 mg, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (m, 2H), 7.85-7.35 (m, 8H), 5.60 (m, 1H), 3.15-2.75 (m, 2H), 2.15-1.90 (m, 2H); (M+H)+ (443).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10](COCC[Si](C)(C)C)[C:9]2=O)=[CH:4][CH:3]=1.[OH-:23].[NH4+:24]>CO.C1(C)C=CC=CC=1>[NH2:24][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:9][NH:10][C:11](=[O:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: [OH-]
Reactant: C[Si](C)(C)CCOCN1CCCC(c2ccc(F)nc2)C1=O
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1ccc(C2CCC(=O)NC2)cn1

Procedure:
To -(6-fluoropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one (290 mg, 0.894 mmol) in a steel bomb, ammonium hydroxide (34.8 μl, 0.894 mmol) solution was added (40% head volume remained). The steel bomb reactor was heated at 150° C. for 44 h (250 psi on pressure gauge). LCMS—0.23 min, MH+192.1 (without SEM); 0.66 min, MH+322.1 (with SEM). After diluted with MeOH and toluene, volatile materials were completely removed in vacuo. 5-(6-aminopyridin-3-yl)piperidin-2-one was used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 79.3 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([CH:8]([NH:11]C(=O)OC(C)(C)C)[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.ClS([N:24]=[C:25]=[O:26])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[ClH:1].[C:25](=[O:26])([O:10][CH2:9][CH:8]([NH2:11])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:19])[NH2:24]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(Cl)c1F
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cl
Product: NC(=O)OCC(N)c1cccc(Cl)c1F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Of the compound from Example 160A, 243 mg (0.84 mmol) were introduced in 10 ml of acetonitrile under argon. Then at −15° C. 102 μl (1.17 mmol) of chlorosulphonyl isocyanate were added dropwise. After 30 min, the reaction solution was admixed with 20 ml of water and heated at 60° C. overnight. The reaction mixture was cooled and introduced into saturated aqueous sodium hydrogen carbonate solution. It was then extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. The residue was taken up in 4 ml of dichloromethane and admixed with 4 ml of a 4M solution of hydrogen chloride in dioxane. A precipitate formed immediately. After a subsequent stirring time of 10 min, the batch was freed from the solvent on a rotary evaporator. Drying in an HV gave 219 mg (77% of theory) of the title compound in 79% purity.
Reaction SMILES: [CH:1]([O-:5])([O-])[O:2][CH3:3].[CH3:6]N1CCN(C)C1=O.S(=O)(=O)(O)O.[N+:19]([N:22]=[C:23]1[NH:28][CH2:27][CH2:26][CH2:25][NH:24]1)([O-:21])=[O:20]>>[CH3:6][O:5][CH:1]([O:2][CH3:3])[N:24]1[CH2:25][CH2:26][CH2:27][NH:28][C:23]1=[N:22][N+:19]([O-:21])=[O:20]
Reactant: CN1CCN(C)C1=O
Reactant: O=[N+]([O-])N=C1NCCCN1
Reactant: COC([O-])[O-]
Agent: O=S(=O)(O)O
Product: COC(OC)N1CCCNC1=N[N+](=O)[O-]
Temperature: 25 °C

Procedure:
20.0 g of methyl orthoformate was dropped in about 1.5 hours in a mixture of 10 g of 2-nitroiminohexahydropyrimidine, 20 ml of 1,3-dimethyl-2-imidazolidinone and 0.05 g of sulfuric acid at 150° C., followed by heating under reflux for further 1 hour while removing the resultant distillate by means of the Dean-Stark trap. After cooling to room temperature, the mixture was poured into water, and extracted with ethyl acetate. After washing with water, the extract was dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resultant oily substance was purified by column chromatography [silica gel, eluant: hexane/ethyl acetate (1:2)] to give 1.5 g of 1-dimethoxymethyl-2-nitroiminohexahydropyrimidine.
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:12][CH:3]([C:2]([Cl:13])([Cl:14])[Cl:1])[C:4]2[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Reactant: COc1ccc(O)cc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(OC(c2ccc(OC)cc2)C(Cl)(Cl)Cl)cc1
Reaction time: 8 h

Procedure:
α-trichloromethyl-p-methoxybenzyl alcohol, 5.0g, and p-methoxyphenol, 2.48g, were added to a mixture of phosphorus pentoxide, 18g, and phosphoric acid, 12 ml, and heated for 1 hr. on the steam bath. After standing overnight, ice was added and the mixture extracted with ether. The product was purified by column chromatography on silica gel and eluted with 5% ether in petroleum ether (60°-68°C) to give α-trichloromethyl-p-methoxybenzyl p-methoxyphenyl ether, mp 90°C. This method of synthesis is referred to in Table I as method B.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([S:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])[S:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.Cl[C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1>C(#N)C>[CH2:1]([N:8]([C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1)[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([S:16][C:17]([CH3:21])([CH3:22])[C:18]([OH:20])=[O:19])[S:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)O)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.7 %

Procedure:
To a suspension of 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid resin (0.15 g) synthesized in Example 461-6 in acetonitrile (1.5 ml) were added triethylamine (0.16 ml) and 2-chloro-3-nitropyridine (0.089 g), and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the mixture, washed three times with dimethylformamide, tetrahydrofuran and methanol, and vacuum dried. Trifluoroacetic acid (2.0 mL) was added to the obtained resin, and the mixture was left standing at room temperature for 2 hr. Then the resin was removed by filtration from the reaction mixture, and the filtrate was concentrated by blowing a nitrogen gas, vacuum dried, and purified by preparative HPLC to give the title compound (1.5 mg) as a pale-brown oil.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=2)[O:2]1.[N+:13]([O-])([OH:15])=[O:14]>>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=2)[O:9]1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: -5 °C

Procedure:
0.103 mol (17.2 g) of 4,5-methylenedioxy-1-nitrobenzene is added in small portions in the course of 15 minutes to a mixture, cooled to -5° C., consisting of 125 ml of nitric acid (d=1.50) and 125 ml of nitric acid (d=1.40), the temperature being maintained at between 0° and 5° C. 1 hour after the addition is complete, the reaction mixture is poured onto 1 kg of ice. The expected product precipitates. After being dried hot in the presence of phosphorus pentoxide, it melts at 99° C. (literature 98°-100° C.). It can optionally be recrystallized from 96° strength ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31]C)=[C:25]([CH:30]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.CO>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)cc12
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(O)cc3C)cc12
Yield: 77.9 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate (350.5 mg, 0.783 mmol) in DCM (8 mL). To this solution was then added, under nitrogen, a 1M solution of boron trichloride (3.92 mL, 3.92 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was cooled in an ice bath and 10 mL of methanol was slowly added. The solvent was removed under vacuum. The flask was again cooled, 25 mL of ice cold methanol was added and the resulting solid was filtered to give 264.5 mgs (78% yield) of methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-hydroxy-4-methylbenzoate as an ivory colored solid. The LC/MS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using the following set of conditions: PHENOMENEX® Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. 1H NMR (400 MHz, DMF-d7) δ ppm 2.30 (s, 3H), 2.95 (d, J=4.77 Hz, 3H), 3.98 (s, 3H), 7.02 (s, 1H), 7.38-7.48 (m, 3H), 7.68-7.73 (m, 2H), 7.76 (d, J=8.53 Hz, 1H), 8.08-8.15 (m, 2H), 8.33 (br. s., 1H). LCMS Rt=3.636, m/z 434.3 (M+H), 100% purity.
Reaction SMILES: [O-]CC.[Na+].O[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C.C(OCC)C>[O:8]=[C:7]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[O:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1
Reactant: O=C(CO)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2ccccc2o1
Yield: 82.9 %

Procedure:
A 2,68 M sodium ethoxide solution in ethanol (21,9 ml) was added slowly to a solution of 2-hydroxyacetophenone (1.76 ml, 14.7 mmol) and diethyl oxalate (3.98 ml, 29.4 mmol) in a mixture of dry ethyl ether (20 ml) and absolute ethanol (20 ml). The mixture was stirred under reflux for 3 h. Afterwards it was diluted with ethyl ether (40 ml), added with 1M HCl (25 ml) and extracted with ethyl ether (3×40 ml). The combined ether phases were dried and the solvents were removed by evaporation under reduced pressure. The obtained residue was dissolved in absolute ethanol (60 ml) and 0.380 ml of concentrated hydrochloric acid were added. The resulting mixture was left under stirring at 75° C. for 1 h. After this time, 50 ml of water were poured on the mixture which was extracted with ethyl acetate (3×50 ml). The organic phase was washed successively with a sodium bicarbonate saturated solution and a NaCl saturated solution, dried and the solvents were evaporated off under reduced pressure, to obtain a crude which was purified by crystallization in ethyl ether, thereby obtaining 2.660 g of the title product (83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([OH:11])=C([CH:10]=1)C(O)=O.[C:12](=O)([O-])[O-].[Cs+].[Cs+].CI.C[CH2:21][O:22][C:23]([CH3:25])=[O:24].O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:25]([C:23]([O:22][CH3:21])=[O:24])[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cc(Cl)cnc1O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)cn(C)c1=O
Reaction time: 12 h

Procedure:
To a suspension of 5-chloro-2-hydroxynicotinic acid (2.0 g, 12 mmol) and cesium carbonate (8.2 g, 26 mmol) in 50 mL DMF was added MeI (1.6 ml, 26 mmol). The reaction was allowed to stir for approximately 12 h. The cloudy yellow mixture was added to EtOAc/water. The organic layer was removed and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed once with water and brine, dried with Na2SO4, filtered, and concentrated to give an orange-yellow solid. The material was partitioned between 1N HCl and EtOAc. The organic layer was washed twice with 1N HCl, dried with Na2SO4, filtered, and concentrated to give the desired product as an orange solid. MS (m/z): 202.0 (M+H)+. Calc'd for C8H8ClNO3: 201.61.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11](Cl)(=O)[CH:12]([CH3:14])[CH3:13].CC1C2C(=CC=CC=2)CNC1.C1C2C(=CC=CC=2)C=CN=1.[OH-].[Na+].[Cl:40][CH:41]([Cl:45])[C:42](Cl)=[O:43]>O.C(Cl)Cl>[Cl:40][CH:41]([Cl:45])[C:42]([N:4]1[CH2:3][CH:2]([CH3:1])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]1[CH:12]([CH3:14])[CH3:13])=[O:43]
Reactant: CC(CN)c1ccccc1
Reactant: CC(C)C(=O)Cl
Reactant: O=C(Cl)C(Cl)Cl
Agent: CC1CNCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2cnccc2c1
Solvent: O
Solvent: ClCCl
Product: CC1CN(C(=O)C(Cl)Cl)C(C(C)C)c2ccccc21

Procedure:
By procedures described in Example 1 (Method A), β-methyl-phenethylamine and isobutyryl chloride were converted to -4-methyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 3.0 g of this isoquinoline compound, 10 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 2 ml dichloroacetyl chloride was added dropwise to the mixture. The mixture was stirred for 2 minutes, then water was added. The organic extract was dried with magnesium sulfate and stripped of solvent. The residue was recrystallized from aqueous ethanol to provide 4 g of a white needle-crystalline product having the elemental analysis reported in Table I.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([O:18]CC)=[O:17].[OH-].[Li+]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)[C@@H]1CCCCN1c1nc2ccccc2s1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2s1

Procedure:
The title compound was prepared by a similar method to Preparation 3 from ethyl (2S)-1-(1,3-benzothiazol-2-yl)-2-piperidinecarboxylate [see Preparation 42] and 1N aqueous lithium hydroxide solution. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 10:1, by volume, dichloromethane:methanol to afford (2S)-1-(1,3-benzothiazol-2-yl)-2-piperidinecarboxylic acid as a solid.