Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:30][CH2:29][CH:26]1[CH2:28][CH2:27]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: NCC1CC1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NCC1CC1

Procedure:
5-(Cyclopropylmethyl-amino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and cyclopropanemethylamine. Mass spectrum (ES) MH+=391.
Reaction SMILES: CC(C)([O-:4])C.[K+].[Si:7]([O:14][C@@H:15]1[C@@:32]2([CH3:33])[C:19](=[CH:20][CH:21]=[C:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C:26]2=[O:34])[CH2:18][C@@H:17]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>O1CCCC1>[Si:7]([O:14][C@@H:15]1[C@@:32]2([CH3:33])[C:19](=[CH:20][CH:21]=[C:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][C@@H:25]([OH:4])[C:26]2=[O:34])[CH2:18][C@@H:17]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(=O)[C@H](O)C[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h
Yield: 23.1 %

Procedure:
Under an argon atmosphere, a solution of potassium t-butoxide (4.13 g, 36.8 mmol) in dry tetrahydrofuran (500 ml) was cooled to -78° C., and a solution of 1α,3β-bis(t-butyldimethylsilyloxy)-17-oxoandrosta-5,7-diene (13.0 g, 24.5 mmol) in tetrahydrofuran (40 ml) was added dropwise. After the mixture was stirred at the same temperature for 1 hour, a solution of 2-(phenylsulfonyl)-3-phenyloxazyldine (9.62 g, 36.8 mmol) in tetrahydrofuran (40 ml) was added dropwise and the mixture was further stirred at -78° C. for 1.5 hour. The reaction mixture was quenched with an aqueous saturated ammonium chloride solution, poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure and the deposited solids were filtered, then the filtrate was concentrated again and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate:chloroform=7:1:2) to give the title compound as a white solid (3.10 g, 23%).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[NH2:19][N:20]1[C:24]([N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][C:27]([CH3:36])=[N:26]2)=[N:23][N:22]=[C:21]1[SH:37].C(=O)(O)[O-].[Na+].P([O-])([O-])([O-])=O>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[CH:9]1[S:14][CH2:15][C:6]([CH2:5][S:37][C:21]1[N:20]([NH2:19])[C:24]([N:25]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:28][C:27]([CH3:36])=[N:26]3)=[N:23][N:22]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1cc(-c2ccccc2)n(-c2nnc(S)n2N)n1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-c2ccccc2)n(-c2nnc(SCC3=C(C(=O)O)N4C(=O)C(N)C4SC3)n2N)n1
Temperature: 60 °C

Procedure:
A mixture of 1.36 g. of 7-aminocephalosporanic acid, 1.50 g. of 4-amino-5-(3-methyl-5-phenyl-1-pyrazolyl)-4H-1,2,4-triazole-3-thiol and 0.84 g. of sodium bicarbonate in 40 ml. of pH 6.4 phosphate buffer is stirred and heated at 60° C. for 8 hours. The mixture is cooled to room temperature, filtered and the filtrate is extracted with ethyl acetate. The aqueous portion is acidified to pH 2.5 with 4 N hydrochloric acid. The precipitate is collected by filtration and dried, giving 0.8 g. of the desired product, I.R. 5.60μ (β-lactam carbonyl).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[OH:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][NH:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CC(C)(CO)CNS(=O)(=O)c1ccc(N)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: CC(C)(CO)CNS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1

Procedure:
The title compound was prepared from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(3-hydroxy-2,2-dimethyl-propyl)benzenesulfonamide according to Procedure J: mp>250° C.; 1H NMR (DMSO-d6): δ0.74 (s, 6H), 2.52 (d, J=6.7 Hz, 2H), 3.06 (bs, 2H), 4.43 (bs, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.32 (t, J=6.7 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.3 Hz, 1H), 8.07 (d, J=12.2 Hz, 1H), 9.26 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.3 Hz, 1H); APCI−MS: m/z 457 (M−H)−. Anal. Calcd for C21H22N4O4S2: C, 55.01; H, 4.84; N, 12.22; S, 13.98. Found: C, 54.90; H, 4.86; N, 12.25; S, 13.94.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[C:19]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:18]2=[N:17][C:16]=3[NH2:27])=[CH:6][CH:5]=1)[CH3:2].C(O)C>[Pd].C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[C:19]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:18]2=[N:17][C:16]=3[NH2:27])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added 2-((4-ethoxyphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1 eq.) with a stirring bar. Ethanol and methylene chloride (1:2, 0.2 M) were added, followed by palladium in carbon (activated powder, wet, 10% on carbon, 0.1 eq.). The contents were degassed under vacuum followed by hydrogen flush (three times). The reaction mixture was stirred vigorously under hydrogen balloon at room temperature overnight. Afterwards the reaction mixture was filtered through a celite pad, and the celite pad was washed subsequently with methylene chloride and EtOAc until the filtrate had no UV absorption. Combined organic washes were concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded the product as a yellow solid. Further recrystallization using toluene afforded product 2-(4-ethoxyphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine as a white fine crystal. 1H NMR (CDCl3): δ 8.52 (d, 1H), 8.30 (d, 1H), 8.10 (d, 1H), 7.46 (s, 1H), 7.12 (dd, 1H), 7.06 (d, 2H), 6.75 (d, 2H), 5.95 (bs, 2H), 3.93 (q, 2H), 3.11-3.05 (dd, 2H), 2.95-2.90 (dd, 2H), 2.44 (s, 3H), 1.33 (t, 3H). LRMS [M+H]=358.2
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:25][NH:26][CH3:27].C(N(CC)CC)C.O1CCOCC1>C(Cl)(Cl)Cl>[CH3:25][N:26]([CH3:27])[C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccc(-c2nc(-c3ccnc(F)c3)c3sccc3n2)c1
Reactant: CNC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)c1cc(-c2nc(-c3cccc(O)c3)nc3ccsc23)ccn1
Temperature: 130 °C
Yield: 61.9 %

Procedure:
A mixture of 3-[4-(2-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-2-yl]-phenol, (60 mg), dimethylamine hydrochloride (151 mg), triethylamine (0.31 mL) and 1,4-dioxane (3 mL) was heated to 130° C. in a sealed tube. After heating for 24 hours the reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield the title compound (40 mg).
Reaction SMILES: P(Cl)(Cl)Cl.[C:5]([OH:9])(=O)[CH2:6][CH3:7].C(Cl)(=O)CC.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21].Cl>C(Cl)Cl>[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:5](=[O:9])[CH2:6][CH3:7])=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CCC(=O)O
Reactant: CC(C)Cc1ccccc1
Agent: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CCC(=O)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
In a 500 ml. 3-necked, round bottomed flask there was placed 25.50 ml. (40.14 g., 0.29 mmole) of phosphorus trichloride and 43.65 ml. (43.34 g., 0.58 mmole) of propionic acid. This mixture was stirred for 2.25 hours under nitrogen atmosphere at room temperature to prepare the propionyl chloride. By NMR propionyl chloride formation was complete in about 1.5 hours. Then 80 ml. of anhydrous methylene chloride was added and the resulting solution was cooled to about -5° C. (an ice-methanol bath). While stirring the cooled mixture 87.50 g. (0.66 mmole) of aluminum chloride (technical grade) was added. After 10 minutes of stirring 67.11 g. (0.50 mmole) of isobutylbenzene was added dropwise from an additional funnel over 55 minutes while maintaining the temperature of the mixture at about 0° to 5° C. The mixture was stirred for an additional 1.25 hours to insure as complete a reaction as possible and then poured into a solution of 250 ml. of ice water and 150 ml. of concentrated hydrochloric acid with vigorous stirring. The Friedal-Crafts reaction was complete in about 45 minutes under these conditions (by GLC analyses). The resulting mixture was extracted three times with 300 ml. portions of methylene chloride. The combined methylene chloride extracts were washed with 250 ml. of water and three times with 250 ml. of molar concentration aqueous sodium carbonate solution. The aqueous sodium carbonate extracts were back extracted with 100 ml. of methylene chloride and the combined methylene chloride layers were dried over sodium sulfate. The dried methylene chloride solution was concentrated under vacuum to give crude p-isobutylpropiophenone as a pale yellow oil weighing 97.85 g. By GLC analyses 3% methylene chloride was present. The chemical yield was about 95 g. or about 100% of theory.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10]1[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)[CH3:9])(C)(C)C.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>ClCCl>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[NH2:7][C@@H:8]([C:10]1[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)[CH3:9]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc(CO)co1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)c1nc(CO)co1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, [(R)-1-(4-hydroxymethyl-oxazol-2-yl)-ethyl]-carbamic acid tert-butyl ester (137 mg, 0.51 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1.2 ml, 15.6 mmol) was slowly added. The reaction was stirred at room temperature for 1.5 h then concentrated to afford [2-((R)-1-amino-ethyl)-oxazol-4-yl]-methanol trifluoroacetate as a brown oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[NH:4][C:3]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[NH:4][C:3]1=[S:26]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=S
Yield: 82.3 %

Procedure:
2,2-Dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (3.4 g) and Lawesson's reagent (6.19 g, 1.0 eq.) were suspended in toluene (100 ml). The reaction mixture was refluxed for one hour. The mixture was then evaporated. The residue was purified by Combiflash chromatography (EtOAc in hexanes=0-100%) to give 2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazine-3(4H)-thione (3 g, 82% yield).
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.B1([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[N:27][CH:26]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(#N)C>[N:14]1[C:6]2[C:5]3[S:15][C:2]([C:25]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[N:27][CH:26]=4)=[CH:3][C:4]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Brc1cc2c(s1)-c1ncccc1OCC2
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1

Procedure:
A mixture of 80 mg (0.3 mmol) of 9-bromo-6,7-dihydro-pyrido[3,2-b]thieno[2,3-d]oxepine, 78.3 (0.34 mmol), 2-cyanopyridine-5-boronic acid pinacole ester, and 10 mg (0.014 mmol) of bis(triphenylphosphine)palladium (II) chloride in 0.35 ml (0.35 mmol) of aqueous 1 M solution of sodium carbonate and 4 ml of acetonitrile was degassed and microwaved on 200 Wt at 140° C. for 30 min. the reaction mixture was filtered through celite and partitioned between ethyl acetate and water. The organic layer was washed with water, brine dried over sodium sulfate and concentrated in vacuum. The residue was purified on a 4 g silica column eluting with 10% of methanol in dichloromethane to give 5-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)pyridin-2-nitrile. Yield 27 mg (30%). MS: (ESI+) 306.1
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]/[C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]/[C:60]([CH3:70])([O:62][Si:63]([CH2:66][CH3:67])([CH2:68][CH3:69])[CH2:64][CH3:65])[CH3:61])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C/CBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C/CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 88.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (E)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (116 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) to give the title compound as a colorless oil (73.4 mg, 89%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[NH:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:33]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:26])[NH:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:8]=1)(=[S:33])[NH2:2]
Reactant: COC(=O)COc1ccc(C(=O)NC(=O)Nc2ccc(C#N)cc2)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)COc1ccc(C(=O)NC(=O)Nc2ccc(C(N)=S)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of step (a) (600 mg), pyridine (56 ml) and triethylamine (8 ml) was covered with a blanket of H2S gas and stirred at ambient temperature overnight. The dark green reaction mixture was evaporated to dryness and the residue was stirred with dry ether for 1 hour. The resultant solid was collected and washed thoroughly with ether to give methyl 4-[4-(4-thiocarbamoylphenyl)allophanoyl]phenoxyacetate (593 mg) as a yellow solid; m.p. 215°-218° C. (decomposes); NHR Spectrum (DMSO-d6 +CD3CO2D) 3.73 (3H, s), 4.90 (2H, s), 7.08 (2H, d), 7.64 (2H, d), 7.98 (2H, d), 8.06 (2H, d); Mass Spectrum m/Z 388 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](O)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[Br:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]([CH3:41])[CH:32]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:36]2[C:35]3[C:40](=[C:31]([Br:30])[CH:32]=[C:33]([CH3:41])[CH:34]=3)[CH:39]=[CH:38][CH:37]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)c2ccccc2c1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)[C@@H](O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1cccc2c(Br)cc(C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (50 mL) was added to ethyl N-(4-{(1R)-1-[(R)-(4-chlorophenyl)(hydroxy)methyl]butyl}benzoyl)-β-alaninate (EXAMPLE 1, Step A, 2.00 g, 4.79 mmol) and 1-bromo-3-methylnaphthalene (1.16 g, 5.26 mmol). The solution was stirred overnight at RT, then the solvent was evaporated and the residue was purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to afford the title compound. LC3 4.49 min. [M+H]+ 622.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[C:4]([F:14])[C:3]=1[CH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]1=[O:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:15][CH:16]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[C:17]2=[O:27])=[C:4]([F:14])[C:5]([CH2:8][CH2:9][CH2:10][C:11]([N:60]2[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]2)=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1F
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C(=O)CCCc2ccc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c2F)CC1
Temperature: 80 °C

Procedure:
Add 4-[4-chloro-3-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-2-fluoro-phenyl]-butyric acid (Preparation 80) (200 mg, 0.22 mmol), EDAC (63 mg, 0.33 mmol), HOBT (45, mg, 0.33 mmol), triethylamine (0.1 mL, 0.7 mmol) and 1-methylpiperazine (0.1 mL, 0.9 mmol) in THF (5 mL). Heat the mixture at 80° C. for 3 hours. Evaporate solvent and purify the residue by column chromatography to give the title product as white solid: Mass spectrum (ion spray): m/z=478.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:18])[C:16]#[CH:17])=[O:8].C(N(CC)C(C)C)(C)C.[CH2:28]([O:30][C:31](=[O:35])[CH:32]=[CH:33]I)[CH3:29].CCCCCC>C1COCC1.CCOC(C)=O.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.[Cu]I.CC(C)=O>[CH2:28]([O:30][C:31](=[O:35])[CH:32]=[CH:33][C:17]#[C:16][CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]([C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:8])[CH3:18])[CH3:29]
Reactant: C#CC(C)c1ccccc1C(=O)c1ocnc1C
Reactant: CCOC(=O)C=CI
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C=CC#CC(C)c1ccccc1C(=O)c1ocnc1C
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A solution of 300 mg (1.25 mmol, 1.0 eq) of alkyne 11b in 3.0 mL of dry THF was stirred in a 10 mL round bottom flask at room temperature under argon. To this solution was added 650 μL (3.75 mmol, 5.0 eq) of N,N-diisopropylethylamine followed by 340 mg (1.50 mmol, 1.2 eq) of 3-Iodo-acrylic acid ethyl ester. This solution was then sparged with argon for 10 minutes, at which point 44 mg (0.063 mmol, 0.05 eq) of PdCl2(PPh3)2 and 12 mg (0.063 mmol, 0.05 eq) of CuI were added at once and the solution was stirred at room temperature until the reaction was complete by TLC (3:1 hexane:acetone, Rf=0.30). Upon completion (˜4 hours) the reaction was diluted with EtOAc and washed with 1.0 M HCl. The aqueous layer was then extracted twice with EtOAc. The combined organic fractions were then washed with saturated NaHCO3 and brine and then dried over MgSO4. Purification via silica gel flash chromatography (hexane/EtOAc) yielded 252 mg (63%) of 11c as a pale brown oil, Rf 0.47 (1:1 hexane:EtOAc). 1H-NMR (500 MHz, CDCl3): 7.92 (1H, s), 7.87 (1H, d, J=7.9 Hz), 7.56 (1H, dt, J=7.8 Hz, 1.2 Hz), 7.41 (1H, d, J=7.6 Hz), 7.35 (1H, t, J=7.6 Hz), 6.11 (1H, dd, J=11.5 Hz, 2.4 Hz), 6.04 (1H, d, J=11.5 Hz), 4.35 (1H, dq, J=7.1 Hz, 2.2 Hz), 4.21 (2H, q, J=7.1 Hz), 2.39 (3H, s), 1.57 (3H, d, J=7.1 Hz), 1.27 (3H, t, J=7.1 Hz). 13C-NMR (500 MHz, CDCl3): 185.43, 164.92, 152.18, 147.04, 145.37, 142.09, 136.11, 131.86, 129.00, 128.44, 128.35, 126.69, 123.28, 105.40, 79.35, 60.52, 29.88, 24.64, 14.42, 14.18. IR (cm−1): 2976 (m), 2213 (w), 1719 (s), 1653 (s), 1603 (m), 1579 (s), 1384 (m), 1355 (m), 1291 (m), 1183 (vs), 905 (s). HRMS (EI) calcd. for C20H19NO4: 337.1314. found: 337.1322.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](C2C=CC=C(C)C=2)([CH2:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([N:30]1[CH:34]=[CH:33]N=C1)(N1C=CN=C1)=[O:24]>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([N:30]([C:34]3[CH:33]=[CH:4][CH:3]=[C:2]([CH3:7])[CH:1]=3)[C:23](=[O:24])[NH:15][CH2:14]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C2(CN)CCN(Cc3ccccc3)CC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1cccc(N2C(=O)NCC23CCN(Cc2ccccc2)CC3)c1
Reaction time: 72 h

Procedure:
A mixture of 1-benzyl-4-(3-methylphenyl)-4-aminomethyl-piperidine (0.52 g, 1.67 mmol) and 1,1′-carbonyldiimidazole (0.41 g, 2.5 mmol) in dichloromethane (2 mL) was stirred at room temp. for 3 days. The resultant solution was concentrated and the residue subjected to column chromatography on silica gel eluting with a 1:1 mixture of chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provide the title compound. FAB MS m/e 336 (M+1)