Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])=[CH:30][CH:29]=1.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:43](=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=[CH:34][C:31]1[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][CH:32]=1
Reactant: O=C(O)CCCCCCCC=Cc1ccc(Cl)cc1
Reactant: O=C1COC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCCCCCC=Cc1ccc(Cl)cc1)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a stirring solution of 189 mg (1.89 mmol) of tetronic acid in 15 mL of dimethylformamide is added 290 μL (2.08 mmol) of triethylamine and 8 mg (66 μmol) of 4-dimethylaminopyridine at 0° C. Next, 427 mg (2.22 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 690 mg (2.20 mmol) of 10-(4-chlorophenyl)dec-9-enoic acid as a mixture of E and Z isomers are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified via flash chromatography on a 40 mm×150 mm silica gel column eluting with 5% methanol/ethyl acetate to give 400 mg (58%) of pure 4-hydroxy-3-[10-(4-chlorophenyl)-1-oxodec-9-enyl] -2(5H)-furanone as a mixture of E and Z isomers.
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[OH:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:22]=1>C(OCC)(=O)C>[F:7][CH:2]([F:6])[O:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:22]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)n1nc(OC(F)F)c2cc([N+](=O)[O-])ccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Sodium chlorodifluoroacetate (4.75 g) and potassium carbonate (8.58 g) were added to a DMF (3 ml) solution containing ethyl 3-hydroxy-5-nitro-1H-indazol-1-carboxylate (1.56 g), followed by stirring at 80° C. for 1 hour. The reaction solution was adjusted to room temperature and ethyl acetate was added to remove an insoluble precipitate. The organic layers were washed with a saturated ammonium chloride aqueous solution, water, and saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A yellow solid of ethyl 3-(difluoromethoxy)-5-nitro-1H-indazol-1-carboxylate (1.14 g) was thus obtained.
Reaction SMILES: C=O.[C:3]([O:6][C:7](=[O:9])[CH3:8])(=O)[CH3:4].[C:10]1(O)[CH:15]=CC=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:7]([O:6][C:3]1[CH:12]=[CH:11][CH:10]=[CH:15][CH:4]=1)(=[O:9])[CH3:8]
Reactant: Oc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: C=O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccccc1

Procedure:
In order to fully achieve the objects of this invention and optimize the formation of paraformaldehyde, it is essential that acetic anhydride be metered into the reaction mixture at a rate such that there is sufficient acetic anhydride present to selectively react with one of the toluene oxidation products, (phenol) to give phenyl acetate but not enough acetic anhydride to convert the other oxidation product (formaldehyde) to methylene diacetate, under reaction conditions. This may conveniently be accomplished by careful control of the amount of acetic anhydride introduced into the reaction as the oxidation process is monitored, e.g., by conventional chromatographic techniques.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:15])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
To a solution of tert-butyldimethyl(m-tolyloxy)silane (1.31 g, 5.9 mmol) in CCl4 (30 mL) was added N-bromosuccinimide (1.13 g, 6.5 mmol), followed by benzoyl peroxide (55 mg, 0.2 mmol). The reaction was refluxed for 1 h, then cooled to room temperature. It was filtered and filtrate was concentrated and purified by column chromatography on ISCO with 10% ethyl acetate in hexanes to yield (3-(bromomethyl)phenoxy)(tert-butyl)dimethylsilane as a colorless oil (1.1 g, 62%). HPLC retention time (Method C)=4.44 min. LC/MS (ESI) (M+H)+=301.
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:12])([C:8]([F:11])([F:10])[F:9])[C:4]([OH:7])([F:6])[F:5].C(N(CC)CC)C.F[C:21](=[CH2:25])[C:22](F)=[O:23]>C(Cl)(Cl)Cl>[C:22]([O:7][C:4]([F:5])([F:6])[C:3]([CH3:12])([CH2:2][F:1])[C:8]([F:9])([F:10])[F:11])(=[O:23])[CH:21]=[CH2:25]
Reactant: C=C(F)C(=O)F
Reactant: CC(CF)(C(O)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(F)(F)C(C)(CF)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
Into a 200-ml, four-necked glass flask provided with a thermometer, a dropping funnel, a stirrer and a reflux condenser were placed 58.83 g (0.3 mol) of hexafluoroneopentyl alcohol, 30.36 g (0.3 mol) of triethylamine and 50 g of chloroform. Subsequently, to the mixture was added dropwise 30.37 g (0.33 mol) of 2-fluoroacrylic fluoride at a temperature of up to 10° C. with ice-cooling. After addition, the mixture was stirred at room temperature for 30 minutes. The mixture was washed with an aqueous solution of sodium bicarbonate (5%) and then with pure water, followed by evaporation to remove chloroform, producing hexafluoroneopentyl acrylate. The amount of the obtained product was 67.17 g and the yield was 76.7%. To the product was further added 0.1 g of t-butyl catechol as a polymerization inhibitor and the mixture was distilled under reduced pressure for purification. The boiling point was 55° to 56° C./20 mm.Hg. The identification was performed with 1H-NMR spectrum, 19F-NMR spectrum and 13C-NMR spectrum (in every case, sovent: acetone-d6).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]=[C:11]([CH3:13])[CH3:12]>>[C:11]([C:4]1[CH:3]=[C:2]([OH:1])[C:7]([C:11]([CH3:13])([CH3:12])[CH3:10])=[CH:6][C:5]=1[O:8][CH3:9])([CH3:13])([CH3:12])[CH3:10]
Reactant: C=C(C)C
Reactant: COc1ccc(O)cc1
Product: COc1cc(C(C)(C)C)c(O)cc1C(C)(C)C
Reaction time: 20 h
Yield: 6 %

Procedure:
A suspension of 124 parts of 4-hydroxyanisole and 3 parts of exchanger resin is prepared in a stirred reactor by stirring at 500 revolutions per minute at 100° C. under 1 bar, and 28 parts of isobutene are passed in. The exchanger resin is a sulfonated styrene-divinylbenzene copolymer resin which has been dehydrated for 20 hours at 100° C. under reduced pressure before being used; it has a gel structure and a particle size for from 20 to 150 micrometers. The suspension in the reactor is now stirred steadily at 500 revolutions per minute. After one hour, 80 parts of 4-hydroxyanisole and 20 parts of isobutene are fed in hourly, and correspondingly 100 parts of suspension are filtered through a suction take-off line fitted with a metal filter (pore diameter 10 micrometers) and are fed to a fractional distillation. After 100 hours' operation, 5,486 parts (85% of theory, based on starting material II) of a mixture of 2-tert.butyl-4-hydroxyanisole and 3-tert.-butyl-4-hydroxyanisole of boiling point 140°-145° C./14 millibars are obtained in addition to 490 parts (6% of theory, based on starting material II) of 2,5-di-tert.-butyl-4-hydroxyanisole. The conversion is 51 percent, based on 4-hydroxyanisole employed. The isobutene is consumed quantitatively.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][C@@H:34]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:33]([CH2:47][C:48]#[N:49])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[C:48]([CH2:47][C@H:33]1[CH2:32][CH2:31][C@H:30]([N:29]2[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:35][C@H:34]1[NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)#[N:49]
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)C[C@H]1NC(=O)OCc1ccccc1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 61.3 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (17.1 mg, 0.192 mmol) and triethyloxonium tetrafluoroborate (34.2 mg, 0.180 mmol) in tetrahydrofuran (0.36 mL) was stirred at room temperature for 75 min and then concentrated. The residue was dissolved in ethanol (0.14 mL), and this solution was then added to a solution of benzyl [(1R,2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-2-(cyanomethyl)cyclohexyl]carbamate (26 mg, 0.060 mmol) in ethanol (0.36 mL) in a vial. The resulting mixture was stirred at 80° C. overnight. After cooling, the mixture was concentrated and purified on silica gel, eluted with 0-10% MeOH in dichloromethane to give 18 mg of the desired product. LCMS calculated for C26H28N5O3S (M+H)+: m/z=490.2. Found: 490.0.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.Cl[C:14]1[CH:24]=[C:18]2[N:19]([CH3:23])[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=1>>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=[C:14]([O:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=3)[CH:24]=[C:18]12
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(C(F)(F)F)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(trifluoromethyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[N:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:20]=[CH:19][N:18]=[CH:23][CH:22]=3)=[CH:29][CH:28]=2)(=[O:31])=[O:32])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccncc2)cc1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccncc4)cc3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.2 g, 0.79 mmol) as in EXAMPLE 24, Part B using 4-pyridin-4-ylbenzene sulfonyl chloride (0.50 g, 1.98 mmol) in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by chromatography (2.5 to 5% MeOH/CH2Cl2) to obtain a white solid (0.25 g, 0.58 mmol).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][C:6]#[C:7][OH:8])([CH3:4])[CH3:3].CCN(CC)CC.[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>CCOCC>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH2:7][O:8][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C[Si](C)(C)CC#CO
Reactant: C=C(C)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trimethylsilyl propyn-1-ol (1 g, 7.8 mmol) and Et3N (1.4 mL, 10 mmol) in Et2O (10 mL) is cooled to −20° C. and a solution of methacryloyl chloride (0.9 mL, 9.3 mmol) in Et2O (5 mL) is added dropwise over 1 h. The mixture is stirred at this temperature for 30 min, and then allowed to warm to ambient temperature overnight. Any precipitated ammonium salts can be removed by filtration, and volatile components can be removed under reduced pressure. The crude product is then purified by flash chromatography.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)=[N:6][CH:7]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc(NCCN2CCCCC2)nc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(NCCN4CCCCC4)nc3)nc2)cc1

Procedure:
Prepared according to general working method I from (5-iodo-pyridin-2-yl)-(2-piperidin-1-yl-ethyl)-amine (397 mg, 1.20 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (256 mg, 1.20 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14]O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:35][CH2:14][CH2:13][CH2:12][C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=1
Reactant: OCCCc1ccc(C(F)(F)F)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1cc(CCCBr)ccc1C(F)(F)F
Yield: 79 %

Procedure:
Compound 68-2 (2.83 g) was dissolved in methylene chloride (42 ml), triphenylphosphine (3.67 g) and N-bromosuccinimide (2.56 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.87 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][C:14](=O)[C:13]3([CH3:20])C)=[CH:8][C:6]=2[N:7]=1.[N:27]1[N:28]=CN2CCNCC=12>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]4[CH:14]=[N:27][N:28]=[C:20]4[CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: c1nnc2n1CCNC2
Reactant: CC1(C)C(=O)NCCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCn4cnnc4C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3,3-dimethyl-piperazin-2-one using 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in place of 3,3-dimethyl-piperazin-2-one. The title compound was obtained as a white solid (115 mg, 84%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH:8]([CH3:12])[C:9](Br)=[O:10]>C1(C)C=CC=CC=1>[Br:7][CH:8]([CH3:12])[C:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:10]
Reactant: C1CCNCC1
Reactant: CC(Br)C(=O)Br
Solvent: Cc1ccccc1
Product: CC(Br)C(=O)N1CCCCC1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
Piperidine (73.3 grams; 0.91 moles) is dissolved in 400 cc of toluene and the solution is cooled to -10° C. There is added dropwise, (45.3 cc; 0.45 moles) of 2-bromopropionyl bromide while the temperature is not allowed to exceed -5° C. over a period of three hours. The mixture is stirred again for four hours, while the temperature is allowed to rise, then the mixture is filtered and the filtrate is evaporated under reduced pressure. The product boils at 102° C. (0.3 mm); IR (neat) νmax: 2940, 2860, 1650, 1450, 1380, 1260, 1140, 1020 cm-1. The product is a liquid very irritating to the skin and mucosae.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].N[C@H:7]([C:9]([OH:11])=[O:10])[CH3:8]>>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:8][CH2:7][C:9](=[O:10])[OH:11]
Reactant: NCC(=O)O
Reactant: C[C@H](N)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Gly 471.4; Ala 576.9;
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([C:46](=[O:54])[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[C:19]([CH2:55][CH3:56])[CH:18]=1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])=[O:7])(=[O:3])[CH3:2].[CH3:57][C:58]([O:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C@H:69]([NH2:77])[C:70]([O:72]C(C)(C)C)=[O:71])=[CH:64][CH:63]=1)([CH3:60])[CH3:59].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]([NH:4][CH:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([C:46](=[O:54])[C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([O:32][CH:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:31])=[C:19]([CH2:55][CH3:56])[CH:18]=1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:77][C@@H:69]([CH2:68][C:65]1[CH:64]=[CH:63][C:62]([O:61][C:58]([CH3:57])([CH3:59])[CH3:60])=[CH:67][CH:66]=1)[C:70]([OH:72])=[O:71])=[O:14])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A mixture 5-{[2-(acetylamino)-3-(4-{2-[(benzhydryloxy)carbonyl][tert-butoxy(oxo)acetyl]anilino}-3-ethylphenyl)propanoyl]amino}pentanoic acid (30 mg, 0.04 mmol), H-TYR(TBU)-OTBU HCL(26 mg, 0.08 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (16 mg, 0.048 mmol) and diisopropylethylamine (26 μL) in N,N-dimethylformamide (250 μL) was stirred at ambient temperature overnight, concentrated under reduced pressure and the residue purified by reverse-phase HPLC eluting with 5-100% acetonitrile/aqueous 0.1% trifluoroacetic acid to provide the titled compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH:26]([NH2:29])([CH3:28])[CH3:27]>CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:29][CH:26]([CH3:28])[CH3:27])[S:8]1(=[O:25])=[O:24]
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NCCOCCN1c2ccccc2N(c2c(F)cccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with isopropylamine (0.8 mL, 9.2 mmol) in methanol to give N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}ethyl)propan-2-amine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.32 g, 31%). HRMS: calcd for C19H23F2N3O3S+H+, 412.15009; found (ESI, [M+H]+Obs'd), 412.1497.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=O)([CH3:3])[CH3:2].P(Br)(Br)([Br:22])=O>>[Br:22][C:13]1[C:12]2[C:11]([N:10]=[C:5]3[C:6]=1[CH:7]=[CH:8][CH:9]=[C:4]3[CH:1]([CH3:3])[CH3:2])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)c1ccccc1Nc1ccccc1C(=O)O
Product: CC(C)c1cccc2c(Br)c3ccccc3nc12
Temperature: 120 °C
Yield: 102.5 %

Procedure:
2-(2′-Isopropylphenylamino)benzoic acid 8 (1.0 g, 3.9 mmol) was suspended in 11.0 g (38 mmol) of phosphorus oxybromide, and the mixture was heated to 120° C. for 2 hours. Excess phosphorus oxybromide was removed by distillation and the residual solution was poured into a 1:1 mixture of aqueous ammonium hydroxide:CH2Cl2. The CH2Cl2 solution was separated, dried, filtered, and the combined organic layers was dried in vacuum to give 10 (1.2 g, 79%) as yellow powder. 1H-NMR δ=1.45 (d, J=6.9 Hz, 6H), 4.56 (sept, J=6.9 Hz, 1H), 7.56-7.70 (m, 3H), 7.78 (ddd, J=1.5 Hz, J=6.6 Hz, J=6.6 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.29 (dd, J=1.5 Hz, J=8.5 Hz, 1H), 8.41 (d, J=8.8 Hz, 1H). 13C-NMR δ=24.00, 28.21, 125.20, 125.62, 125.86, 126.49, 127.38, 127.64, 129.90, 130.58, 130.83, 135.69, 147.44, 148.01, 148.14. Anal. calcd. for C16H14NBr: C, 64.02; H, 4.70; N, 4.67. Found: C, 64.23; H, 4.78; N, 4.59.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[N+:15]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O)([O-:17])=[O:16]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][CH:28]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc([N+](=O)[O-])c3)nc2n(CC)c1=O
Yield: 44.9 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.68 g (13.9 mmol) of 3-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.01 g (yield 30%) of Compound 152 as a yellow powder.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.O=S(Cl)[Cl:14]>>[C:1]([Cl:14])(=[O:11])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add p-anisic acid (77 g, 0.55 mol) to 100 mL SOCl2 and stir overnight at room temperature. Evaporate the excess SOCl2 to give p-anisoyl chloride. Add (2R,3R)-(+)-tartaric acid (25 g, 166 mmol) and stir the mixture and heat at 170° C. for an hour. Allow the mixture to cool to 100° C. and add 200 mL toluene. Cool the mixture to room temperature and add another 100 mL toluene. Collect the precipitate, rinse with toluene and dry. Reflux the crude product in a mixture of 300 mL acetone and 20 mL water for two hours. Then add 200 mL water and evaporate the acetone. Add another 200 mL water and collect the precipitate, rinse with water and dry. Reflux the product in 200 mL toluene for 15 minutes and collect the precipitate while the mixture is hot. Rinse the precipitate with 50 mL warm toluene and dry to give (2R,3R)-(−)-di-(p-anisoyl)tartaric acid.
Reaction SMILES: [CH2:1]([C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]#[N:16])[CH2:5]1)[CH:2]=C.[O:17]=[O+][O-]>ClCCl>[O:17]=[CH:2][CH2:1][C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]#[N:16])[CH2:5]1
Reactant: C=CC[C@@H]1C[C@H](CC#N)OC2(CCCC2)O1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: N#CC[C@H]1C[C@@H](CC=O)OC2(CCCC2)O1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-9-(2-propenyl)-6,10-dioxa-spiro[4.5]decane-7-acetonitrile, 3.4 g (15.36 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage=90V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 4.2 g (16 mmol), as added and the colorless solution is allowed to warm to room temperature. Fash chromatography provides after concentration in vacuo 2.5 g of pure (±)-cis-9-(2-oxo-ethyl)-6,10-dioxaspiro[4.5]decane-7-acetonitrile.