Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[C:4]([OH:15])(=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]>>[C:4]([O:15][CH2:1][CH2:2][OH:3])(=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)CCCCCC(=O)O
Reactant: C1CO1
Product: CC(C)(C)CCCCCC(=O)OCCO
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a one liter stainless steel autoclave, equipped with a mechanical stirrer, heater, cooling coils, automatic temperature controller, and a tared ethylene oxide cylinder, in a series of runs is added 500 grams neodecanoic acid and 2.0 g of the selected catalyst. The reactor is heated to approximately 100° C. and a gaseous N2 purge of the reactor is introduced to remove both oxygen and water. With continued N2 purging its temperature of the neo acid/catalyst solution is gradually raised to 150° C. Upon reaching temperature, the N2 purge is stopped and the reactor vents are sealed. Ethylene oxide is then slowly added to the reactor to maintain a reactor pressure of about 30 psig. The flow of ethylene oxide is then stopped. The reaction mixture is stirred for an additional 20 minutes, until the reactor pressure decreases to 15 psig. Total reaction time, from the start of ethylene oxide addition is about 55 minutes. The reactor is then vented, a gaseous nitrogen purge is introduced, and the reaction product is cooled to room temperature. The crude ethylene glycol mononeodecanoate product mixture thereby obtained was analyzed by gas chromatography. The data obtained are set forth in Table II below.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([NH2:43])=[O:42])=[C:39]([F:46])[CH:38]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:41]([C:40]1[CH:44]=[CH:45][C:37]([NH:36][C:11](=[O:13])[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:24])[CH3:25])=[CH:16][CH:15]=2)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:38][C:39]=1[F:46])(=[O:42])[NH2:43]
Reactant: NC(=O)c1ccc(N)cc1F
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc(C(N)=O)c(F)c2)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(tert-butoxycarbonylamino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid in pyridine was added EDC, DMAP, and 4-amino-2-fluorobenzamide (E336), and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The extracts were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-6% MeOH/CH2Cl2 gradient) gave pure tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propylcarbamate (E337).
Reaction SMILES: [Br:1][C:2]1[C:6]([CH2:7]Cl)=[C:5]([CH2:9]Cl)[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[S-2:15].[Na+].[Na+]>CO>[Br:1][C:2]1[C:6]2[CH2:7][S:15][CH2:9][C:5]=2[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1sc(CCl)c(CCl)c1Br
Reactant: [S-2]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc2c(c1Br)CSC2
Yield: 75 %

Procedure:
Compound (3) from the previous step was dissolved into 500 ml slightly boiling methanol, and a solution of sodium sulfide in 500 ml methanol was added drop-wise over about 1 hour at boiling temperature. The reactant was then kept at boiling temperature for about 1 hour. Methanol was removed by rotary evaporation and the sticky residue was absorbed by silica gel. The purification of product was performed by column chromatography using petroleum ether/ethyl acetate (30:1) as the eluent. Methyl 3-bromo-4,6-dihydrothieno[3,4-b]thiophene-2-carboxylate was obtained as colorless oil. The yield was about 75%.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([NH2:11])=[CH:3][CH:2]=1.Br[N:13]1[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15](Br)[C:14]1=[O:22].CC1(C)NC(=O)NC1=O>[Cu]=O.CC(N(C)C)=O>[NH2:11][C:4]1[CH:3]=[CH:2][C:1]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]2=[O:22])=[CH:6][C:5]=1[C:7]([F:9])([F:10])[F:8]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=[Cu]
Agent: CC1(C)NC(=O)NC1=O
Solvent: CC(=O)N(C)C
Product: CC1(C)NC(=O)N(c2ccc(N)c(C(F)(F)F)c2)C1=O
Reaction time: 0.5 h
Yield: 174.6 %

Procedure:
100 g of O-trifluoromethylaniline is introduced at 20°±2° C. then 100 ml of dimethylacetamide is added while maintaining the same temperature. After cooling down under agitation at 0° C.±2° C. a solution of 88.8 g of dibromodimethylhydantoin and 100 ml of dimethylacetamide is then added over about 30 minutes while maintaining the temperature at 0° C.±2° C. The reaction medium is maintained under agitation for 30 minutes, then taken to 20° C.±2° C. and 40 g of dimethylhydantoin then 50 g copper oxide are added. The whole is heated under reflux for approximately 18 hours then cooled down to 20° C.±2° C., agitation is carried out for 30 minutes followed by filtering, separating and washing with 4×25 ml of dimethylacetamide. The resultant product is then poured into 300 ml of pure 22°Be ammonium hydroxide and 300 ml of demineralized water under agitation over 1 hour at 20° C.±2° C., agitation is continued for 1 hour at 20° C.±2° C. then the whole is cooled down to 0° C.±5° C. and is maintained under agitation for another hour, followed by separating, washing at 20° C.±2° C., with 100 ml of pure 22°Be ammonium hydroxide then with 4×100 ml of demineralized water and drying. In this way 155.8 g of expected product is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>CCN(CC)CC.C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:7][N:6]=1
Reactant: Cc1ncc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ncc(C#C[Si](C)(C)C)cn1
Yield: 72.5 %

Procedure:
5-Bromo-2-methyl-pyrimidine (prepared according to UK patent application GB 2 157 288) (0.2 g, 1.16 mmol), (trimethylsilyl)acetylene (164 μL, 1.3 mmol), CuI (0.022 g, 0.116 mmol) and PdCl2(PPh3)2 (0.082 g, 0.116 mmol) in Et3N (2 mL) and THF (2 mL) were stirred at 80° C. for 4 h. After cooling, the solvents were removed under vacuum and the residue chromatographed to give the subtitle compound (0.16 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[N:18]O)[CH2:10][CH2:9]1.[OH2:20]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[NH:18][C:11](=[O:20])[CH2:10][CH2:9]1
Reactant: O
Reactant: ON=C1CCC(c2ccccc2F)c2ccccc21
Product: O=C1CCC(c2ccccc2F)c2ccccc2N1
Reaction time: 0.5 h

Procedure:
26 g of 4-(2-fluorophenyl)-1-tetralone oxime are added to 130 g of polyphosphoric acid pre-heated to 125°. The solution obtained is stirred at 125° for 30 minutes, cooled, mixed with ice and water and extracted with chloroform. After evaporation of the organic phase, the residue is crystallized from ethanol. There is obtained 5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one of melting point 210°-212°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][C:42]([CH2:46][N:47]2[CH:51]=[CH:50][C:49]([NH2:52])=[N:48]2)([OH:45])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:40][CH2:41][C:42]([CH2:46][N:47]2[CH:51]=[CH:50][C:49]([NH:52][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]3)=[O:30])=[N:48]2)([OH:45])[CH2:43][CH2:44]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cn2ccc(N)n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (500 mg, 1.0 mmol), 4-(3-amino-pyrazol-1-ylmethyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (592 mg, 2.0 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 593 mg, 1.5 mmol) and iPr2NEt (0.718 mL, 4 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-4-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-ylmethyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a white powder (480 mg, 64.4%).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[N+:12]([O-])=O)#[N:2].[N:15]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl>Cl.O>[NH2:2][C:1]1[C:3]2[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=2[NH:12][N:15]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C#N)s1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc2[nH]nc(N)c2s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To an ice-cooled suspension of methyl 5-cyano-4-nitro-thiophene-2-carboxylate (0.10 mol, 21.0 g) in 120 mL of hydrochloric acid 37% was added, dropwise, a solution of sodium nitrite (0.12 mol, 8.3 g) in 12 mL of water. After 1.5 hours, the cold suspension was added dropwise to a preformed solution of tin chloride (0.80 mol, 151.7 g) in 120 mL of hydrochloric acid 37%, at 5° C. After 3 hours, the cold suspension was filtered and the moist solid was treated with 350 mL of boiling water, for 30 min. The hot cloudy solution was clarified by filtration through a cloth filter. The liquors were ice-cooled and treated, dropwise, with 180 mL of sodium hydroxide 17%. The obtained solid was filtered off and dried, under vacuum, at 50° C., to give 7.3 g of the title compound as a yellow solid (37% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:10].[O:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:20]=[CH:19]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[CH:24][CH:25]=2)(=[O:30])=[O:31])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3cnco3)cc2)n1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride 1H-NMR (400 MHz, CDCl3): δ 2.67 (s, 3H), 7.46-7.50 (m, 4H), 7.61-7.70 (m, 4H), 7.65 (m, 2H), 7.94-8.00 (m, 1H), 8.15 (s, 1H). MS: m/z454.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37].[CH3:38][N:39](C=O)[CH3:40]>C(Cl)Cl.CNC.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:39]([CH3:40])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37]
Reactant: CN(C)C=O
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Agent: CNC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(N(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide, (0.054 g, 0.1 mmol) was dissolved in a mixture of DMF (0.5 mL) and CH2Cl2 (10 mL), and 40% dimethylamine in water (1 mL) was added. The mixture was stirred under argon at room temperature for 3 h. The solvents were pumped off in vacuo. The residue was flash chromatographed on silica gel (10 g) eluted with 10-60% EtOAc/CH2Cl2 to give the title compound as a white amorphous solid. The solid was crystallized from CH2Cl2/hexane to give the title compound as a white crystalline solid. mp 214-215° C.; LC-MS m/z 521 (M+H)+, 2.0 min (ret. time).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:23][C:24]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])=[O:27]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:14](=[O:16])[NH:23][C:24]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:25]=1[C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
82 g of carbobenzoxy-L-alanine are dissolved in 100 ml of absolute tetrahydrofuran, the solution is cooled to -40° C and treated with 80 g of phosphorus pentachloride. The mixture is stirred at -30° C for 20 minutes and subsequently added to a shaken solution of 80 g of 2-amino-5-nitro-2'-chlorobenzophenone in 100 ml of absolute tetrahydrofuran. The solution is concentrated on a rotary evaporator at 50°-60° C, treated twice with toluene and evaporated each time. By crystallisation of the residue from ether, there is obtained (-)-benzyl-[1-[{2-(o-chlorobenzoyl)4-nitrophenyl}carbamoyl]-ethyl]carbamate which melts at 147° C and exhibits a rotation of [α]25D =-18.2° (in methylene chloride, 1%).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][C:13]1[C:17](=[O:18])[O:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(O)(=O)C>[C:15]([NH:14][CH:13]([CH2:12][CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:17](=[O:18])[CH3:25])(=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1OC(c2ccccc2)N=C1CCCNC(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)C(CCCNC(=O)c1ccccc1)NC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 4-(3-benzamidopropyl)-2-phenyl-5-oxazolone (1.0 g, 3.1 m.mol), 4-dimethylaminopyridine (0.016 g), acetic anhydride (0.62 ml) and triethylamine (0.62 ml) was stirred for one hour. Acetic acid (4.7 ml) was added and the solution was set aside overnight and evaporated to dryness. The residue was dissolved in chloroform and washed with dilute NaOH, dilute HCl and then dried over MgSO4. Concentration gave the crude product which could be purified by dry-column chromatography on alumina with ethyl acetate as solvent to give 3,6-dibenzamidohexan-2-one.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1.O>CN1CCCC1=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:24]3[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CSCCN1
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1nc2cc(N3CCSCC3)c([N+](=O)[O-])cc2s1

Procedure:
A mixture of 2 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole, described in Example 5, 2 g of anhydrous potassium carbonate and 1.5 ml of thiomorpholine in 7 ml of 1-methyl-2-pyrrolidinone is heated in a sealed glass tube at 120° for 12 hours, poured into water, the solid filtered, washed with water and isopropyl alcohol to give 2-tert-butyl-6-nitro-5-[thiomorpholin-4-yl]benzothiazole, melting at 117°-120°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:39])[C@H:22]([CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:40]1[CH2:42][C@@H:41]1[CH2:43][O:44][C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[N:50]2>C(O)C>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21](=[O:39])[C@H:22]([CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:42][C@@H:41]([OH:40])[CH2:43][O:44][C:45]3[CH:54]=[CH:53][CH:52]=[C:51]4[C:46]=3[CH:47]=[CH:48][CH:49]=[N:50]4)[CH2:28][CH2:27]2)=[O:25])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
N-(Piperidine-4-carbonyl)-3-(3-pyridyl)-alanine [4-phenyl- 1-(3-phenyl-propyl)-butyl]-amide (87) (261.8 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 25 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (190 mg) as a white solid. ESMS:MH+ 728.6
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].OS(C(F)(F)F)(=O)=O.[Br:21]N1C(=O)CCC1=O>CC#N>[Br:21][C:9]1[C:10]([OH:12])=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1cc(Br)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.5 %

Procedure:
A solution of methyl 2-chloro-4-hydroxybenzoate (5.0 g, 26.8 mmol) in MeCN (100 mL) was cooled to −30° C. Triflic acid (2.60 mL, 29.48 mmol) was added followed by N-bromosuccinimide (5.25 g, 29.48 mmol) and the reaction was warmed to room temperature and stirred for 1.5 hours. The reaction was quenched by the addition of saturated aqueous Na2CO3 solution (50 mL). The solution was extracted with EtOAc (2×100 mL), the combined organic layers were combined, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20-40% EtOAc in heptanes to afford the title compound as a white solid (2.60 g, 37%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:18])[CH2:14][CH:15]([OH:17])[CH3:16].[CH3:19]I>CCOC(C)=O.[Ag]=O>[CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:18])[CH2:14][CH:15]([O:17][CH3:19])[CH3:16]
Reactant: CI
Reactant: COCC1C(=O)OC1CCCCC(C)CC(C)O
Agent: O=[Ag]
Solvent: CCOC(C)=O
Product: COCC1C(=O)OC1CCCCC(C)CC(C)OC
Temperature: 60 °C

Procedure:
10 mg of 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanol in 1 ml of EtOAc was added a small amount of activated silver oxide and 0.5 ml of methyl iodide. The mixture was heated for 5.5 hours at 60° C. The solution was filtered and the filtrate was concentrated to dryness. The product was purified by flash chromatography to yield 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-methoxyoctane. ##STR13##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][S:23](=[O:30])(=[O:29])[NH:24][CH:25]3[CH2:28][O:27][CH2:26]3)[C:11](=[O:33])[C@:10]([CH2:35][C:36]([O:38]C)=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][S:23](=[O:29])(=[O:30])[NH:24][CH:25]3[CH2:26][O:27][CH2:28]3)[C:11](=[O:33])[C@:10]([CH2:35][C:36]([OH:38])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CS(=O)(=O)NC1COC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@H](CS(=O)(=O)NC1COC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetate (41.1 mg, 0.069 mmol; Example 372, Step C) in THF (2.0 ml) and MeOH (1.0 ml) was added 1 N lithium hydroxide (3.0 ml, 3.0 mmol). The suspension was stirred at room temperature for 15 hours, then acidified to pH 4 using 1 N HCl, and then concentrated in vacuo. Purification of the residue by chromatography on silica gel (4 g SiO2, 5 to 25% gradient of a 1:6.5 MeOH/acetone mixture in hexanes) provided the title compound. The material was purified further by reversed phase preparatory HPLC (Eclipse Plus C1s, 30×250 mm, 5 μm column; Agilent, Santa Clara, Calif.) (eluent: 0.1% TFA in acetonitrile/water, gradient 30% to 60% over 25 min) to provide the title compound, as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:27]([NH:34][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:26])=[CH:19][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CCc1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCc1ccc(CNCc2ccccc2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 24 h

Procedure:
A reaction mixture of 70 mg (0.18 mmol) of N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)propionamide, 16 mg (0.15 mmol) of benzylamine, and 41 mg (0.3 mmol) of potassium carbonate in 5 mL of acetone is agitated for 24 hours at reflux temperature. The reaction mixture is evaporated down. The residue is triturated with water and diisopropyl ether, suction filtered, and dried in the air. The residue is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia (30:1:0.1)). Yield: 23 mg (40% of theory); melting point: 176° C.; C29H27ClN2O (M=454.99); calc.: molecular ion peak (M+H)+: 455/57 (Cl); found: molecular ion peak (M+H)+: 455/57 (Cl).