Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].[O:9]=[C:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][C:12]([C:20]2[N:25]=[C:24]([CH2:26]S([O-])(=O)=O)[CH:23]=[CH:22][CH:21]=2)=[N:11]1.C(OCC)(=O)C>CN(C=O)C.O>[O:9]=[C:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][C:12]([C:20]2[N:25]=[C:24]([CH2:26][S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:23]=[CH:22][CH:21]=2)=[N:11]1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
Methyl thioglycolate (0.35 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystallized from ethanol to give the titled compound (0.55 g, 51%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:3]([NH:5][C@@H:6]([CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:7]([OH:17])[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])=[O:4].[CH:31]1[CH:36]=[C:35]2[C:37]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45](O)=[O:46])[C:38]=3[C:39](=[O:40])[C:34]2=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH2:20]([O:19][CH2:18][CH:6]([NH:5][C:3](=[O:4])[C@H:2]([NH:1][C:45]([C:41]1[C:38]2[C:39](=[O:40])[C:34]3[C:35](=[CH:36][CH:31]=[CH:32][CH:33]=3)[C:37]=2[CH:44]=[CH:43][CH:42]=1)=[O:46])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH:7]([OH:17])[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cccc2c1C(=O)c1ccccc1-2
Reactant: CCOC(=O)CNC(=O)C(O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)C(O)C(COCc1ccccc1)NC(=O)[C@@H](CC(C)C)NC(=O)c1cccc2c1C(=O)c1ccccc1-2
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Ethyl 2-[(3S)-3-[(2S)-2-amino-4-methylpentanoyl]amino-4-(benzyloxy)-2-hydroxyl butanoyl]aminoacetate (500 mg, 1.2 mmole), 9-Fluorenone-1-Carboxylic acid (266 mg, 1.2 mmole), and HBTU (587 mg, 1.6 mmole) were dissolved in DMF (10 mL). Et3N (330 ul, 2.4 mmole) was added and stirring was continued overnight. DMF was removed under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, EtOAc, Rf=0.3) afforded ethyl 2-(4-(benzyloxy)-2-hydroxy-3-[((2R)-4-methyl-2-[(9-oxo-9H-1-fluorenyl)carbonyl]aminopentanoyl)amino]butanoylamino)acetate as a white solid (641 mg, 85%).
Reaction SMILES: [CH2:1]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:11]N1C(=O)CCC1=O.C(O)(=O)C.C(Cl)(Cl)Cl>O>[Br:11][C:8]1[S:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:10][CH:9]=1
Reactant: CCCCCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCCCc1ccc(Br)s1
Yield: 97.6 %

Procedure:
A solution of 2-pentylthiophene, (25.2 g) N-bromosuccinimide (25.5 g) and a 1:1 chloroform acetic acid mixture (100 cm3) was heated under reflux for 1 h. Water (10 cm3) was added and the resultant solution stirred for 10 min under an atmosphere of nitrogen. The organic layer was separated off and the aqueous layer extracted with diethyl ether (2×50 cm3). The combined organic layers were washed with brine (2×100 cm3), dried (MgSO4), filtered and then evaporated down. The residue was purified by distillation (Bp 132-134° C. at 15-20 mm Hg.) to yield 32.6 g of 2-bromo-5-pentylthiophene.
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].S(Cl)([Cl:14])(=O)=O>C(O)(=O)C>[Cl:14][C:7]1[CH:6]=[C:5]([F:10])[C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[CH3:9]
Reactant: Cc1ccc(F)c(N)c1F
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1c(Cl)cc(F)c(N)c1F
Yield: 65.7 %

Procedure:
A solution of 2,6-difluoro-3-methylaniline (15 g, 105 mmol) in acetic acid (80 mL) was heated to 70° C. and a solution of sulfuryl chloride (16.0 g, 115 mmol) in acetic acid (40 mL) was added dropwise over 20 minutes. The temperature was maintained for 3 hours, then cooled and concentrated. The residue taken into water (100 mL) and the pH was adjusted to 9 with 2N sodium hydroxide and then extracted with methylene chloride (2×75 mL) and the combined extracts washed with brine, dried (sodium sulfate) and concentrated. The residue was distilled to give 4-chloro-2,6-difluoro-3-methylaniline (12.2 g, 69 mmol): bp 55°-65° C./55 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[N:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.Cl.C(O)(C)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[N:5]=[N:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nnc(C(F)(F)F)cc2Cl)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: FC(F)(F)c1cc(Cl)c(NC2CCNCC2)nn1
Yield: 8.6 %

Procedure:
A solution of D8 (1.1 g, 2.9 mmol) and hydrochloric acid/isopropanol (6N, 20 ml) in methanol (100 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was evaporated in vacuo, the residue re-dissolved in methanol and the solution made alkaline with methanolic ammonia. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (silica gel; 5%-15% methanolic ammonia in dichloromethane) to give D9 (70 mg, 9%). C10H12ClF3N4 requires 280; Found 281 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:13][CH:12]=1.OS(O)(=O)=O>C1(C)C=CC=CC=1>[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)=[CH:13][CH:12]=2)[CH3:2])=[CH:5][CH:6]=1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CC(=O)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(C2=NNC(=O)CC2)cc1)c1ccncc1

Procedure:
A solution containing 0.36 g (0.003 mol) of 4-acetylpyridine and 0.57 g (0.003 mol) of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one in a mixture of 40 ml of toluene and 40 ml of DMT was refluxed over night with a Dean-Stark separator in the presence of catalytic amount of conc. H2SO4. The solvents were evaporated in vacuo and the residue treated with NaHCO3 -solution. The product was filtered and crystallized from ethanol. Yield 0.53 g (60%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]3[CH2:16][CH2:17][CH2:18][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=1.ClC1C(OC2N=CC=CN=2)=CC(N2C(=O)N3CCCCN3C2=S)=C(F)C=1>>[Cl:1][C:2]1[C:7]([O:8][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]3[CH2:16][CH2:17][CH2:18][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: O=c1cc2n(c(=O)n1-c1cc(O)c(Cl)cc1F)CCC2
Agent: O=c1n(-c2cc(Oc3ncccn3)c(Cl)cc2F)c(=S)n2n1CCCC2
Product: O=c1cc2n(c(=O)n1-c1cc(Oc3ncccc3C(F)(F)F)c(Cl)cc1F)CCC2
Yield: 90 %

Procedure:
This was synthesized from 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-6,7-dihydro-pyrrolo-[1,2-c]pyrimidine-1,3(2H,5H)-dione and 2-chloro-3-trifluoromethylpyridine in 90% yield under similar conditions described below for the preparation of 2-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]hexahydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (Example 10.3) (compound (8-29).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C1COCC1.CSC.B>O>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)O)cc(OC)c1Br
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: COc1cc(CO)cc(OC)c1Br
Yield: 99.5 %

Procedure:
To a mixture of 4-bromo-3,5-dimethoxybenzoic acid (50.0 g, 192 mmol) and THF (1 L) was added borane methyl sulfide (27.1 mL, 286 mmol) while cooling on ice, and the mixture was heated to reflux for one hour. Water was gradually added to the mixture while cooling on ice, and the solvent in the mixture was then distilled off under reduced pressure. To the residue, water and ethyl acetate were added. After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (47.3 g, 191 mmol).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](Br)=[C:22]([CH3:28])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:23]2[C:24]([CH3:26])=[CH:25][C:20]([O:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:21][C:22]=2[CH3:28])=[CH:34][CH:33]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2cc(C)c(Br)c(C)c2)cc1
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1cc(OC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(F)cc1

Procedure:
This compound is made in a manner substantially similar to Example 117 using isomer 1 of 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-fluorophenylboronic acid as starting materials in step D. MS (ES): 476.2 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]#[C:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]>C1COCC1.N1C=CC=CC=1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:1]([O:3][C:4](=[O:11])/[CH:5]=[CH:6]\[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C#CCC(C)C
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)/C=C\CC(C)C
Yield: 56.5 %

Procedure:
5-Methyl-hex-2-ynoic acid ethyl ester 7 (20.97 g) in THF (540 mL), pyridine (60 mL), and 5% Pd/BaSO4 (1.10 g) was hydrogenated in 3.25 hours. The solvent was evaporated, and the light oil was chromatographed on a silica gel coulmn. After recovering some unreacted acetylene, the olefin was eluted with 5% ether in pet ether to give pure fractions of (Z)-5-methyl-hex-2-enoic acid ethyl ester 8 (12.0 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CC([O-])(C)C.[Na+]>O1CCOCC1>[NH:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:12]1
Reactant: Clc1ccccc1
Reactant: NCC1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(NCC2CCNCC2)cc1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
Following general procedure F, a mixture of chlorobenzene (102 μL, 1.0 mmol), 4-(aminomethyl)piperidine (137 mg, 1.2 mmol), NaOt-Bu (192 mg, 2.0 mmol), 10 (8 mg, 1 mol %), 1 (5 mg, 1 mol %), and dioxane (1 mL) was heated to 80° C. for 15 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g snap; 7-9% MeOH/CH2Cl2) to provide the title compound as a white solid (159 mg, 84%), mp 60-61° C. 1H NMR (300 MHz, DMSO) δ: 7.02 (t, J=7.5 Hz, 2H), 6.52 (d, J=8.0 Hz, 2H), 6.46 (t, J=8.0 Hz, 1H), 5.58 (s, 1H), 3.11 (s, 1H), 2.92 (d, J=11.5 Hz, 2H), 2.82 (t, J=6.0 Hz, 2H), 2.41 (t, J=10 Hz, 2H), 1.64 (m, 3H), 1.02 (m 2H) ppm. 13C NMR (75 MHz, DMSO) δ: 149.8, 129.5, 115.8, 112.5, 50.0, 46.5, 36.2, 31.7 ppm. IR (neat, cm−1): 3326, 2919, 1602, 1509, 1427, 1325, 1263, 749, 694.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([OH:28])=O)=[C:22]([CH3:31])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:34][N:35](C)[O:36][CH3:37]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([N:35]([O:36][CH3:37])[CH3:34])=[O:28])=[C:22]([CH3:31])[CH:21]=2)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=1[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)(c1ccc(OCC(=O)O)c(C)c1)c1ccc(OCc2ccccc2)c(C)c1
Reactant: CON(C)C
Agent: Cl
Product: CCC(CC)(c1ccc(OCC(=O)N(C)OC)c(C)c1)c1ccc(OCc2ccccc2)c(C)c1
Yield: 77.2 %

Procedure:
Using an analogous procedure to Example 1J, {4-[1-(4-benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-acetic acid (1.46 g, 3.38 mmol) and N,O-dimethylmethylhydroxyamine hydrochloride (363 mg, 3.72 mmol) give the title compound (1.24 g, 2.61 mmol, 77%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])=[C:10]([O:24][CH3:25])[C:9]([Cl:26])=[C:8]([CH3:27])[C:7]=1[C:28](=[O:30])[CH3:29].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:26][C:9]1[C:8]([CH3:27])=[C:7]([C:28](=[O:30])[CH3:29])[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[C:11]([O:12][CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])[C:10]=1[O:24][CH3:25]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: C1COCCN1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCCN2CCOCC2)c1OCCC(C)c1ccc(F)cc1
Yield: 88.6 %

Procedure:
Example 22a (40 mg, 0.08 mmol) was reacted with morpholine (0.2 mL, 2.29 mmol) as described under General Procedure G and the crude mixture was purified by flash chromatography (silica-gel, DCM/EtOAc/MeOH 1:0:0, 9:8:2) to afford the title compound (36 mg, 88%) as yellow/brown oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.00 (t, J=6.4 Hz, 2H), 3.94 (t, J=6.7 Hz, 2H), 3.83 (s, 3H), 3.72-3.69 (m, 4H), 3.07-2.95 (m, 1H), 2.46 (s, 3H), 2.45-2.40 (m, 6H), 2.18 (s, 3H), 2.02-1.99 (m, 2H), 1.88-1.79 (m, 2H), 1.30 (d, J=6.9 Hz, 3H). MS (ES+) m/z 508.3 (M+H+)
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH3:34][C:33]1[CH:32]=[CH:31][O:30][C:29]=1[C:27]([NH:26][C:22]1[CH:21]=[C:20]([C:19]#[C:18][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([CH:17]=2)[C:10]([N:9]=[S@:7](=[O:8])([CH2:3][C:4](=[O:5])[N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:11])[CH:25]=[CH:24][CH:23]=1)=[O:28]
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Reactant: C1CCNC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CC(=O)N3CCCC3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate and pyrrolidine were reacted to give the title compound.
Reaction SMILES: [C:1]([C:6]1[CH:39]=[C:38]([C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:37]=[CH:36][C:7]=1[O:8][CH:9]([CH2:34][CH3:35])[C:10]([N:12]1[C:17]2[CH:18]=[C:19]([O:25]CC3C=CC=CC=3)[C:20]([N+:22]([O-])=O)=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:33])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([C:6]1[CH:39]=[C:38]([C:40]([CH2:43][CH3:44])([CH3:41])[CH3:42])[CH:37]=[CH:36][C:7]=1[O:8][CH:9]([CH2:34][CH3:35])[C:10]([N:12]1[C:17]2[CH:18]=[C:19]([OH:25])[C:20]([NH2:22])=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:33])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)N1C(=O)COc2cc([N+](=O)[O-])c(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)N1C(=O)COc2cc(N)c(O)cc21

Procedure:
The nitro compound ((f), 8.19 g, 0.0136 mole) in THF (ml 100) was reduced and debenzylated under 25 PSI hydrogen pressure at room temperature in the presence of 10% Pd on charcoal. The resulting amine (g) was not isolated.
Reaction SMILES: CN(C)CCO.[Li]CCCC.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH:19]1[CH2:21][CH2:20]1.[C:22](=[O:24])=[O:23].Cl>CCCCCC.C1(C)C=CC=CC=1.C(OCC)C>[Cl:12][C:13]1[C:14]([CH:19]2[CH2:21][CH2:20]2)=[CH:15][N:16]=[C:17]([C:22]([OH:24])=[O:23])[CH:18]=1
Reactant: O=C=O
Reactant: Clc1ccncc1C1CC1
Agent: CN(C)CCO
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(O)c1cc(Cl)c(C2CC2)cn1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of N,N-Dimethylethanolamine (CAN 108-01-0, 1.89 g, 2.13 ml, 21.2 mmol) in dry Hexane (40 ml) under an argon atmosphere at −15° C. was slowly added BuLi 1.6M in Hexane (26.4 ml, 42.3 mmol). The reaction mixture was stirred at −15° C. for 15 minutes, then reaction mixture was cooled down to −78° C. followed by addition of a solution of 4-chloro-3-cyclopropylpyridine (Example 48a, 1.3 g, 8.46 mmol) in dry toluene (9 ml). The resulting reaction mixture was stirred at −78° C. for 1 hour. Addition of carbon dioxide (3.72 g, 84.6 mmol) (pellets from a dry ice dispenser) into the mixture. The reaction mixture was let to warm up to −15° C. and kept at −15° C. for 1 hour. The reaction was quenched by addition of water and stirred at r.t for 15 min. The reaction mixture was diluted with ethyl acetate, poured into a separatory funnel and extracted with 4.0M aqueous solution hydrochloric acid (21.2 ml, 84.6 mmol). The organic phase was collected and the aqueous was back-extracted twice with ethylacetate. All organic phases were combined, dried over sodium sulfate and evaporated down to dryness to give a yellow oil. The former oil was dissolved in diethylether which gave a white suspension. The suspension was kept at 0° C. for few hours. The precipitate was collected by filtration, dried under high vacuum to yield the title compound (886 mg, 53%) as a white solid. MS (ESI, m/z): 196.0 (M−H+).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([S:13][CH3:12])=[CH:15][CH:16]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: CSc1ccc(C(=O)O)cc1
Agent: N
Product: CSc1ccc(C(=O)NC2C3CC4CC2CN(C4)C3)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-(methylthio)benzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.92-1.98 (m, 2H), 2.11 (s, 1H), 2.31 (d, J=14 Hz, 2H), 2.38 (s, 2H), 2.52 (s, 3H), 3.49 (s, 2H), 3.59 (s, 4H), 4.37 (s, 1H), 7.31-7.35 (m, 2H), 7.74-7.80 (m, 2H); MS (APCI/NH3) m/z 287 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[C:7]([O:9][CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)=[O:8])(=[O:3])[CH3:2]>[Pd].CO>[C:1]([O:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[C:7]([O:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)OCCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1ccccc1C(=O)OCCCN
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g, 5.4 mmol), 10% Pd/C (0.2 g) and CH3OH (50 mL) was stirred under a H2 atmosphere (RT, 16 h). The mixture was filtered and concentrated under reduced pressure to afford a colorless oil. Purification by silica chromatography afforded 3-aminopropyl 2-acetoxybenzoate as a colorless oil. Mass calculated for C12H15NO4=237.25. found: [M+H]+=238.3.
Reaction SMILES: [H-].[Na+].[C:3]([O:13]C)(=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=[O:9].[C:15]1(C=O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[C:23]1(=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][CH2:22]1
Reactant: COC(=O)CCCCC(=O)OC
Reactant: O=Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCC(C(=O)O)=C1CC=Cc2ccccc21
Yield: 34766.1 %

Procedure:
7.96 g (0.18 mmole) of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 26.4 g (0.15 mmole) of dimethyl adipate and 23.7 g (0.15 mmole) of 1-naphthaldehyde dissolved in 200 ml of anhydrous methanol, and the mixture was heated under reflux for 30 minutes. At the end of this time, 150 ml (0.15 mole) of a 1N aqueous solution of sodium hydroxide were added to the solution, and the mixture was heated under reflux for 1 hour. The solvent was then removed by distillation under reduced pressure, and the residue was mixed with water and then washed with diethyl ether. The aqueous layer was acidified and extracted with diethyl ether. The ethereal extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and residue was triturated with diisopropyl ether to precipitate crystals, which were collected by filtration to afford 14.2 g of 2-(1-naphthylidene)adipic acid.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12]C3CCCCO3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:19][S:20]([O:23][CH3:24])(=[O:22])=[O:21])[O:3]1.Cl>C1COCC1>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:19][S:20]([O:23][CH3:24])(=[O:22])=[O:21])[O:3]1
Reactant: COS(=O)(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(C)c21
Agent: Cl
Solvent: C1CCOC1
Product: COS(=O)(=O)CC1OB(O)c2cc(O)cc(C)c21
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl (1-hydroxy-4-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methanesulfonate (1.64 g) in THF cooled at −20° C. was added 6N HCl until pH=1. After the mixture was stirred at −20° C. for 20 minutes, concentrate. The residue was purified by flash chromatography to give desired product as an off-white solid.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].BrC[CH2:7][C:8]1([CH3:34])[CH:12]([C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14])[N:11]2[C:21](=[O:33])[CH:22]([NH:23][C:24](=[O:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:10]2[S:9]1>O.CC(C)=O>[S:1]([CH2:7][C:8]1([CH3:34])[CH:12]([C:13]([O:15][CH2:16][C:17]([Cl:18])([Cl:19])[Cl:20])=[O:14])[N:11]2[C:21](=[O:33])[CH:22]([NH:23][C:24](=[O:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:10]2[S:9]1)[C:2]#[N:3]
Reactant: CC1(CCBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(CSC#N)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 80.4 %

Procedure:
Potassium thiocyanate (1.17 g) was dissolved in a mixture of water (20 ml) and acetone (100 ml). To this solution was added 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-(2-phenyl-acetamido)penam-3-carboxylate (5.45 g) at room temperature and the mixture was stirred for 5.5 hours at room temperature. After removing acetone under reduced pressure at room temperature, precipitates were collected by filtration, washed with ether and further washed with ethanol to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (4.10 g). This substance was recrystallized from isopropylether containing 5% acetone to give pure compound, mp 133° to 135° C.