Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][C:16](C(OC)=O)([C:17]([O:19]C)=[O:18])[C:12]2=[C:11](Br)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(C(=O)OC)CCn2c(C(=O)c3ccccc3)cc(Br)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(c1ccccc1)c1ccc2n1CCC2C(=O)O
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Dimethyl 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (2.04 g 5.0 mmoles) was dissolved in methanol (100 ml) and water (10 ml), and sodium hydroxide (0.40 g, 10 mmoles) was added. This solution was heated at reflux temperature in an argon atmosphere for 2 hours. The reaction mixture was evaporated to dryness in vacuo, the residue was dissolved in 50% aqueous methanol (125 ml), magnesium oxide (1.0 g) and 5% palladium on charcoal (0.400 g) were added and the mixture was hydrogenated at room temperature and atmospheric pressure for 2 hours. A sample withdrawn at this time, after workup, was analyzed by NMR and shown to contain 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylic acid as the sodium salt. (This material is, of course, extremely unstable in acid and decarboxylates immediately to the corresponding monocarboxylic acid if acid is added during the analytical process.) The rest of the solution was filtered through celite, the solid filter cake was washed well with methanol and water. Evaporation of most of the methanol was carried out at reduced pressure. The resulting aqueous material was made acidic with 1N, hydrochloric acid and the product was extracted into ethyl acetate (200 ml). The aqueous phase was further acidified with a few ml of concentrated hydrochloric acid and extracted with an additional quantity (150 ml) of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness to give a colorless solid (1.19 g, 93%) which was homogeneous by TLC. Recrystallization of this material from dichloromethane-hexane gave a first crop (0.699 g) melting point (154°-154.5°) corrected and a second crop (0.170 g) melting point (149°-151.5°) corrected. A third crop of the product was obtained by treatment of the residue obtained by evaporation of the mother liquors with activated charcoal in ethyl-acetate. Recrystallization from methanol-water of the material isolated from the ethyl-acetate gave the third crop (0.038 g) melting point (148°-150°) corrected. An authentic sample prepared by a well established alternative route had melting point (154.5°) corrected. The total crystallized yield of 5-benzoyl,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid was (0.907 g, 71%) based on starting material.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:19]>>[CH2:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1)[CH3:19]
Reactant: CCN1CCNCC1
Reactant: Clc1nccnc1OCCOc1ccccc1
Product: CCN1CCN(c2nccnc2OCCOc2ccccc2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) and N-ethylpiperazine (250 mg, 2.19 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 127 mg (64%) of the title product. Anal. (C18H24N4O2) C, H, N.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[C:31](=[O:34])([O-])O.[Na+]>COCCOC.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:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:31]=[O:34])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCNC(=O)OC(C)(C)C)c2c1
Reactant: O=C([O-])O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 171.5 %

Procedure:
To a suspension of methyl 2-bromo-1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-1H-indole-6-carboxylate (500 mg, 1.04 mmol), 2-formylphenylbononic acid (187 mg, 1.24 mmol) and sodium hydrogen carbonate (345 mg, 4.15 mmol) in 1,2-dimethoxyethane (5 ml) and water (2.5 ml) was added tetrakis(triphenylphosphine)palladium (60.0 mg, 0.05 mmol), and the mixture was stirred at 90° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1-3:1) to give methyl 1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-formylphenyl)-1H-indole-6-carboxylate (450 mg, yield 85%).
Reaction SMILES: [OH:1][N:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]1=[S:8].C(=O)(O)[O-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15]>O>[C:14]([O:1][N:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]1=[S:8])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1csc(=S)n1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)On1c(C)csc1=S

Procedure:
0.74 parts of 3-hydroxy-4-methylthiazol-2-(3H)-thione, 0.84 parts of sodium bicarbonate and 30 parts of water were stirred at 0°-5° C. while 0.52 parts of acetic anhydride were added dropwise and the reaction mixture was stirred at 0°-5° C. for a further hour. A precipitate was formed which was separated by filtration and recrystallised from aqueous methanol. 0.33 parts of 3-acetoxy-4-methylthiazol-2(3H)-thione, of melting points 100°-101° C., was obtained.
Reaction SMILES: [CH2:1]1[O:13][C:4]2[CH:5]=[C:6]([CH2:9][CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][C:3]=2[O:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]1[O:13][C:4]2[CH:5]=[C:6]([CH2:9][CH2:10][CH2:11][O:12][S:15]([CH3:14])(=[O:17])=[O:16])[CH:7]=[CH:8][C:3]=2[O:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc2c(c1)OCO2

Procedure:
A solution of 1,2-methylenedioxy-4-[3-hydorxypropyl]benzene, (10.0 g), methanesulfonyl chloride (6.33 g, 4.28 ml) and triethylamine (5.6 g) in methylene chloride (100 ml) is stirred at 0° for 2 hr. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is dissolved in acetonitrile (100 ml).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[N:40][CH:39]=[C:38]([CH3:42])[N:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[N:40][CH:39]=[C:38]([CH3:42])[N:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) (290 mg, 1.0 mmol) and 3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K16) (312 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (400 mg, 76%).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10](O)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(Cl)(Cl)(Cl)[Cl:45]>C(Cl)Cl>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10]([Cl:45])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1C=CC(c2ccccc2)(c2ccccc2)C1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: ClC1C=CC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4,4-diphenyl-2-cyclopenten-1-ol (0.30 g), and triphenylphosphine (0.43 g) in carbon tetrachloride (3 ml) was refluxed for 8 hours and cooled. To the mixture was added n-hexane (5 ml), and the mixture was stirred for 10 minutes at room temperature. The insoluble material was filtered off and the filtrate was condensed under reduced pressure. The residue was dissolved in methylene chloride, and to the solution was added silica gel (1 g). After being stirred for 10 minutes, silica gel was filtered off and the filtrate was evaporated in vacuo to give 4,4-diphenyl-2-cyclopentenyl chloride (0.30 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[I-:14].[K+]>C(#N)C>[I:14][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: [I-]
Reactant: COC(=O)c1ccc(CCCl)cc1
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCI)cc1

Procedure:
70 g (352.4 mmol) of methyl 4-(2-chloroethyl)benzoate [CAS Reg. No. 65787-72-6] and 146.2 g (880.9 mmol) of potassium iodide are suspended in 800 ml of acetonitrile and stirred under reflux for three days. After the reaction has gone to completion, the reaction solution is cooled and filtered and the filtrate is evaporated to dryness under reduced pressure. The resulting residue is purified by flash chromatography on silica gel (mobile phase:petroleum ether/ethyl acetate 30:1→20:1). This gives 101 g (348.3 mmol, 98.8% of theory) of a yellowish oil.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH:23]C(C)(C)C)[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][C:10]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[CH:2]=[CH2:3].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH2:23])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][C:10]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sc(-c2ncnc3sc(NC(C)(C)C)nc23)cc1-c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCn1ccnc1-c1sc(-c2ncnc3sc(N)nc23)cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture of 7-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]-N-(tert-butyl)[1,3]thiazolo[5,4-d]pyrimidin-2-amine (480 mg, 0.886 mmol), trifluoroacetic Acid (2.0 mL) and DCM (6.0 mL) was stirred at rt. After being stirred for 30 min, trifluoromethanesulfonic acid (0.118 mL, 1.33 mmol) was added to the mixture. The mixture was stirred at rt for 49 hours and then the solvent was removed in vacuo. To the residue, sat. NaHCO3 and EtOAc were added. After being stirred for 30 min, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was crystallized from EtOAc and Hexane to yield the title compound (352.9 mg, 82%) as a pale yellow solid. LCMS: (AA) ES+ 485, 487. NMR (400 MHz, d6-DMSO) δ: 8.66 (s, 1H), 8.55 (s, 1H), 8.43 (bs, 2H), 7.74 (d, J=2.0 Hz, 1H), 7.41 (dd, J=8.3, 2.3 Hz, 1H), 7.23-7.20 (m, 2H), 7.02 (d, J=1.3 Hz, 1H), 5.68-5.59 (m, 1H), 5.08-5.05 (m, 1H), 4.85-4.80 (m, 1H), 4.35 (d, J=5.5 Hz, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>O1CCCC1>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(C(=O)O)cc1
Yield: 97.4 %

Procedure:
A mixture of 2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid ethyl ester of Step A (3.7 g, 14.4 mmol) in tetrahydrofuran (40 mL) and 1 N sodium hydroxide (30 mL, 30 mmol) was heated at reflux overnight. After cooling, the reaction mixture was concentrated in vacuo, and the residue was acidified with 2N hydrochloric acid to give a white solid which was collected by filtration and dried under vacuum to provide the title compound (3.2 g, 97.4%) as a white solid, m.p. 250-253° C.
Reaction SMILES: [OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH2:7][C@@H:6]1[C:22]([O:24]C)=[O:23].[OH-].[Na+]>O1CCOCC1.ClCCl>[OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH2:7][C@@H:6]1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4cc(F)cc(F)c4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
A mixture of 0.89 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 9 cm3 of dioxane to which had been added 1.41 cm3 of 5N aqueous sodium hydroxide solution was stirred for 18 hours at a temperature in the region of 60° C. After cooling to approximately 20° C., the reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3.3 cm; mass 56 g), elution first was carried out with a dichloromethane/methanol (95/5 by volume) mixture. A fraction of 100 cm3 was first collected and then 16-cm3 fractions. Fractions 1 to 36 were separated. Elution was subsequently carried out with a dichloromethane/methanol (75/25 by volume) mixture. A first fraction of 200 cm3 a second of 150 cm3, and then a third of 100 cm3 were obtained. The latter two were combined and concentrated as above. The residue obtained was taken up in dichloromethane and filtered. The filtrate was evaporated as above and then the new residue obtained was triturated in 25 cm3 of a diisopropyl ether/pentane (50/50 by volume) mixture. The product which crystallized was filtered off and washed with 2 times 10 cm3 of the same mixture and then 3 times 10 cm3 of pentane. 0.53 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of solid with a cream color melting at 106° C.
Reaction SMILES: [Br:1][C:2]1[C:12]([OH:13])=[C:11]([Br:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>CN(C)C=O>[Br:1][C:2]1[C:12]([O:13][CH2:22][CH3:23])=[C:11]([Br:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC)c1Br
Temperature: 85 °C
Yield: 95.9 %

Procedure:
Ethyl 2,4-dibromo-3-hydroxybenzoate (50 g) was added to a stirred suspension of potassium carbonate (106.4 g) in dry N,N-dimethylformamide (DMF). A solution of iodoethane (25.7 g) in DMF was added over 18 minutes, and the resulting mixture was heated at 85° C. for 1.3 hours. The cooled mixture was poured onto water and extracted with ether. The extract was washed (brine solution), dried (anhydrous magnesium sulphate) and the solvent evaporated in vacuo to give ethyl 2,4-dibromo-3-ethoxybenzoate (52.08 g), NMR 1.4(t,3H), 1.5(t,3H), 4.1(q,2H), 4.4(q,2H), 7.35(d,1H), 7.55(d,1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[C:17]=3[CH:22]=2)[C:3]1=[O:23].S(Cl)([Cl:27])(=O)=O.ClCCCl>C(Cl)Cl>[Cl:27][C:6]1[C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[C:17]=3[CH:22]=2)[C:3](=[O:23])[N:2]([CH3:1])[C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nsc2ccc(-n3c(=O)c(Cl)c(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.8 %

Procedure:
A mixture of 1-methyl-3-(3-methyl-1,2-benzisothiazol-5-yl)-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 0.00293 mol), sulfuryl chloride (2.00 g 0.0148 mol) and 1,2-dichloroethane is stirred for five hours at reflux, cooled to room temperature, and diluted with methylene chloride. The resultant mixture is washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a residue. The residue is chromatographed on silica gel with ethyl acetate/hexanes to afford the title product as a white solid (0.350 g, 31.8%, mp 252-254° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([N:20]1[C:25]2([CH3:29])[CH2:26][CH2:27][CH2:28][C:21]1([CH3:31])[CH2:22][C:23](=O)[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[C:13]([O:17][C:18]([N:20]1[C:21]2([CH3:31])[CH2:28][CH2:27][CH2:26][C:25]1([CH3:29])[CH2:24][C:23](=[N:11][NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH2:22]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C2(C)CCCC1(C)CC(=O)C2
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NN=C2CC3(C)CCCC(C)(C2)N3C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 61.8 %

Procedure:
p-Toluenesulfonyl hydrazine (6.37 g, 34.2 mmol) was added to a benzene solution (115 ml) of N-tert-butoxycarbonyl-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (3.04 g, 11.4 mmol), and the mixture was heated under reflux for 6 h with a Dean-Stark device. After adding saturated sodium bicarbonate water under ice-cooled condition, the ice-cooled reaction liquid was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give N-tert-butoxycarbonyl-1,5-dimethyl-3-(tosylhydrazono)-9-azabicyclo[3.3.1]nonane (3.07 g, 62%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[C:10]([O:15][CH3:16])[N:9]=1.[N+:17]([O-])([OH:19])=[O:18]>>[CH3:6][O:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[N:9]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(N)nc(OC)n1
Agent: O=S(=O)(O)O
Product: COc1nc(N)c([N+](=O)[O-])c(OC)n1
Temperature: 25 °C

Procedure:
To a solution of 20 ml of concentrated nitric acid and 16 ml of concentrated sulfuric acid was added 3.9 g (0.025 mmol) of 2,6-dimethoxy-4-pyrimidinamine. The resulting solution was stirred at ambient temperature and pressure for thirty minutes and was then stirred at 50° for fifteen minutes. The solution was then cooled in an ice bath to ~0° C. The solid was collected by filtration, washed with water and dried in an oven at 60° C. to afford 3.6 g of the title compound, m.p. 178°-179° C.
Reaction SMILES: [Cl:1][CH:2]([O:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:5])=[O:4].[CH3:12][O-].[K+].CI>CO>[CH3:12][O:4][C:3](=[O:5])[CH:2]([O:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[Cl:1]
Reactant: C[O-]
Reactant: O=C(O)C(Cl)Oc1cccs1
Agent: [K+]
Solvent: CO
Solvent: CI
Product: COC(=O)C(Cl)Oc1cccs1
Yield: 86.5 %

Procedure:
A mixture of 1.93 g of the product of Step A, 25 ml of methanol, 0.75 g of potassium methylate and 25 ml of methyl iodide was refluxed for 24 hours and was then evaporated to dryness. The residue was taken up in ether and the ether phase was washed with dilute sodium bicarbonate, dried, treated with activated carbon and was filtered. The filtrate was evaporated to dryness to obtain 1.79 g of methyl-2-chloro-thienyloxy-acetate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)([N:15]1C=CN=C1)=O>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:15])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NC(=O)c1cc2ccccc2[nH]1
Reaction time: 1 h

Procedure:
Add to the 2-indole carboxylic acid (12.4 mmol) in anhydrous THF (30 ml), carbonyldiimidazole (1.5 equiv, 18.6 mmol) and stir for 1 h. Add the desired amine [for example, methylamine, ethylamine, dimethylamine, pyrrolidine, piperidine, piperazine, or morpholine, (3.0 equiv, 37.2 mmol)] in one portion and stir the reaction at rt. After 16 hours, quench the reaction with H2O, collect the resulting precipitate by filtration and dry under vacuum to afford the desired 2-indole carboxamide.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[C:16]1([CH:4]([NH:3][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (140 mg, 0.42 mmol) in DCM (5 ml), were sequentially added triethylamine (175 μl, 1.26 mmol) and pivaloyl chloride (62.1 μl, 0.50 mmol). The reaction was stirred at RT for 2 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with Na2CO3, water and brine, dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-phenyl-2-pivalamidoacetate (95 mg; 66% yield).