Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)([Cl:8])=O.[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][C:15](=O)[CH:14]=[CH:13]1>ClCCl>[Cl:8][C:15]1[CH:14]=[CH:13][C:12]([CH3:19])([CH3:11])[CH2:17][C:16]=1[CH:3]=[O:4]
Reactant: CC1(C)C=CC(=O)CC1
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)C=CC(Cl)=C(C=O)C1
Temperature: -10 °C

Procedure:
In a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL), and the mixture was cooled to −10° C. Phosphoryl trichloride (4 mL) was added dropwise, and the solution was warmed up to room temperature. 4,4-Dimethylcyclohex-2-enone (5.5 mL) was then added slowly, and the mixture was heated to reflux overnight. The reaction mixture was cooled and quenched with a 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with diethyl ether (200 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cu][C:22]#[N:23]>CN1CCCC1=O>[C:22]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:23]
Reactant: N#C[Cu]
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Solvent: CN1CCCC1=O
Product: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)OC)c1

Procedure:
Methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (Preparation 3) (0.15 g), copper (I) cyanide, and N-methylpyrrolidinone (1 mL) was heated at 150° C. overnight, at which time the mixture was cooled and partitioned between ethyl acetate and aq. HCl (1N). The organic layer was dried (magnesium sulfate), concentrated under reduced pressure, and the residue was chromatographed on silica gel using ethyl acetate-hexane (20/80) to give 0.066 g of the desired product. ms (m+H) 289.2. See also preparation 7 for the preparation of the acid.
Reaction SMILES: [F:1][C:2]([F:8])([S:5]([O-:7])=[O:6])[CH2:3][OH:4].[CH2:9]([NH+:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH3:10].[OH:16]O>O>[F:1][C:2]([F:8])([S:5]([O-:16])(=[O:7])=[O:6])[CH2:3][OH:4].[CH2:9]([NH+:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH3:10]
Reactant: OO
Reactant: O=S([O-])C(F)(F)CO
Agent: CC[NH+](CC)CC
Solvent: O
Product: O=S(=O)([O-])C(F)(F)CO
Temperature: 40 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A 100 mL reactor was charged with 11.5 g (26% purity, 0.012 mole/1.0 equivalent) of triethylammonium 1,1-difluoro-2-hydroxy-ethane-1-sulfinate, 20 g of water and 4.2 g (0.036 mole/3.0 equivalents) of 30% hydrogen peroxide at room temperature, followed by one day of stirring at 40° C. Upon confirming the termination of the reaction, the reaction liquid underwent cooling. Thereafter, the reaction liquid was subjected to distillation of the solvent and brought into dryness, thereby obtaining 10.5 g of a target triethylammonium 1,1-difluoro-2-hydroxy-ethane-1-sulfonate. It exhibited a purity of 26% and a yield of 85% at this time.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(P(CCCC)(CCCC)=CC#N)CCC.[CH2:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH2:29]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([C:11]#[N:12])=[CH:7]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1c[nH]c2cc(Br)ccc12
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: N#Cc1cn(Cc2ccccc2)c2cc(Br)ccc12

Procedure:
A solution of 6-bromo-1H-indole-3-carbonitrile (400 mg, 1.81 mmol), 2-(tributylphosphoranylidene)acetonitrile (655 mg, 2.71 mmol) and benzyl alcohol (282 μL, 2.71 mmol) in toluene (5 mL) was heated at 75° C. overnight and concentrated. The residue was purified by flash chromatography on silica (IntelliFlash Varian 971-FP), eluting with 30% heptanes in ethyl acetate to provide the title compound. LCMS: 312.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]([N-:14]C(C)C)(C)C.[Li+].S(C#N)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]#[N:14])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2ccsc12
Reactant: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cc2ncnc(Cl)c2s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a suspension of compound 6.2 (5.0 mmol) in dry THF (25.0 mL) was added lithium diisopropylamide (“LDA”; 6.0 mmol; 2.0 M in heptane/THF/ethylbenzene) at −78° C. under an atmosphere of N2. After stirring at −78° C. for 30 minutes, the mixture was transferred to a pre-cooled solution of TsCN (8.0 mmol) in dry THF (10 mL) at −78° C. The resulting mixture was slowly warmed to room temperature and stirred for several hours. The reaction was quenched by the addition of several drops of saturated ammonium chloride and then concentrated. The residue was diluted with saturated sodium bicarbonate and extracted with EtOAc. The organic layers was dried, concentrated and purified by flash column chromatography on silica gel to provide 4-chloro-thieno[3,2-d]pyrimidine-6-carbonitrile c (compound 47.1) in 20% yield. EIMS (m/z): calcd. for C7H2CN3S (M+)+H 195.97. found 196.00.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[N:14][OH:15])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc2C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCc2cc(F)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of 6-fluoro-3,4-dihydronaphthalen-2(1H)-one (W. Adcock, P. D. Bettess, S. Q. A. Rizvi, Aust. J. Chem. 1970, 23, 1921-1937; 1.50 g, 9.13 mmol) in ethanol (10 mL) was treated with hydroxylamine hydrochloride (775 mg, 11.14 mmol), sodium acetate (2.01 g, 14.79 mmol) and water (6 mL) and the mixture was stirred at room temperature for 30 min, during which time a dense precipitate formed. The mixture was diluted with water and extracted with ether. The organic phases were dried and concentrated to provide a yellowish solid (1.58 g, 97%) used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[C:61]([Cl:62])=[CH:60][CH:59]=[CH:58][C:57]=2[Cl:63])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[C:57]([Cl:63])=[CH:58][CH:59]=[CH:60][C:61]=2[Cl:62])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2c(Cl)cccc2Cl)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 106 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(2,6-dichloro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 2 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was crystallized from diethylether, leading to 123 mg white solid (85%). MS (ISP) 479.5 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[F:18])=[C:4]2[CH:3]=[CH:2]1.[Cl:19][C:20]1[C:25]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[O:27])=[CH:24][N:23]=[CH:22][CH:21]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CN1C(=O)CCC1>[ClH:19].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:20]4[C:25]([C:26]([NH:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=5[F:36])=[O:27])=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:13][C:12]=3[F:18])=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Cl
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
A homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.039 g, 0.16 mmol), 4-chloro-N-(2,4-difluorophenyl)nicotinamide (0.043 g, 0.16 mmol) and p-toluenesulfonic acid monohydrate (Aldrich, 0.024 g, 0.13 mmol), in anhydrous NMP (1 mL), was microwaved in a CEM Explorer PLS microwave system (300 W). The temperature was measured with an IR temperature sensor and maintained at 160° C. After one hour, the reaction mixture was partitioned between chloroform and brine. The aqueous layer was extracted twice with chloroform, and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and lyophilized to an off-white solid that was dissolved in anhydrous THF (1 mL), cooled to 0° C. and treated with HCl (4 N in dioxane, 1.0 mL, 4.0 mmol). The reaction mixture was stirred for ten minutes, before being lyophilized to afford the title compound (0.015 g, 18%) as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[CH:4]=1.[CH2:28]([C:30]1[S:31][CH:32]=[C:33](/[CH:35]=[CH:36]/[C:37]2[C:38](O)=[N:39][N:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)[N:34]=1)[CH3:29].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:28]([C:30]1[S:31][CH:32]=[C:33](/[CH:35]=[CH:36]/[C:37]2[C:38]([O:1][CH2:2][C:3]3[O:7][N:6]=[C:5]([O:8][CH2:9][C:10]4[N:11]=[C:12]([C:16]5[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=5)[O:13][C:14]=4[CH3:15])[CH:4]=3)=[N:39][N:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)[N:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3cc(CO)on3)c(C)o2)cc1
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(-c2nc(COc3cc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)on3)c(C)o2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
A mixture of ethyl {4-[4-({[5-(hydroxymethyl)isoxazol-3-yl]oxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (500 mg), 4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol (389 mg), 1,1′-(azodicarbonyl)dipiperidine (440 mg), tributylphosphine (0.501 mL) and tetrahydrofuran (20 mL) was stirred at 50° C. for 1 hr. After cooling, the resulting precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4-1:3, v/v). The obtained eluate was subjected to reversed phase HPLC and eluted with acetonitrile-water (10:90-100:0, v/v). The obtained fraction was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (4-{4-[({5-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]isoxazol-3-yl}oxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (257 mg, yield 30%) as pale-yellow amorphous form.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13]
Reactant: CCOC(=O)CN1CCC(O)C1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCCCN
Product: C[C@@H]1CCC[C@H](C)N1CCCCNC(=O)CN1CCC(O)C1=O

Procedure:
3.0 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate and 5.9 g of cis-4-(2,6-dimethyl-1-piperidinyl)butylamine are heated to 95°-100° for 3.5 hours under nitrogen. The mixture is chromatographed on 70 g of aluminum oxide (activity grade III, neutral). The (R/S)-cis-N-[4-(2,6-dimethyl-1-piperidinyl)butyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with ethanol has a melting point of 90°-92° after crystallization from diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29]>>[O:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:11]3[N:10]=[C:9]([S:8][C:4]4[CH:3]=[C:2]([NH:1][C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH:7]=[CH:6][CH:5]=4)[CH:14]=[CH:13][N:12]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: N#CCC(=O)O
Reactant: Nc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Product: N#CCC(=O)Nc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Yield: 65.5 %

Procedure:
In a procedure analogous to Example 15, reaction of 4-(3-aminophenylthio)-N-(4-morpholinophenyl)pyrimidin-2-amine (50 mg, 0.13 mmol) and cyanoacetic acid (23 mg, 0.26 mmol) furnished the product (38 mg, 64%).
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([CH2:60][C:61]([N:63]2[CH2:67][CH2:66][C@H:65]([NH:68][C:69]([O:71][CH2:72][C:73]3[CH:78]=[CH:77][C:76]([N+:79]([O-:81])=[O:80])=[CH:75][CH:74]=3)=[O:70])[CH2:64]2)=[O:62])[CH2:43]1>C(#N)C.C(N(C(C)C)CC)(C)C>[N+:57]([C:54]1[CH:55]=[CH:56][C:51]([CH2:50][O:49][C:47]([N:45]2[CH2:46][C@@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])[CH2:43][C@H:44]2[CH2:60][C:61]([N:63]2[CH2:67][CH2:66][C@H:65]([NH:68][C:69]([O:71][CH2:72][C:73]3[CH:74]=[CH:75][C:76]([N+:79]([O-:81])=[O:80])=[CH:77][CH:78]=3)=[O:70])[CH2:64]2)=[O:62])=[O:48])=[CH:52][CH:53]=1)([O-:59])=[O:58]
Reactant: O=C(N[C@H]1CCN(C(=O)C[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CC(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@@H]12
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (478 mg) in anhydrous acetonitrile (5.5 ml), a solution of (2R,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonylmethyl]pyrrolidine (450 mg) in anhydrous acetonitrile (5.5 ml) and diisopropylethylamine (0.140 ml) were added under ice cooling. The resulting mixture was allowed to stand for one day at the same temperature. The reaction mixture was concentrated by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with water and saline, dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to chromatography on a silica gel column. From the fraction eluted with ethyl acetate-methanol (20:1), 4-nitrobenzyl (1R,5R,6S)-2-[(2R,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonylmethyl]pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (675 mg) was obtained as a powder.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:29]=2[NH:28][CH:27]=[C:26]3[S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[NH4+]>ClCCl.O>[C:31]1([S:30][C:26]2[C:25]3[C:29](=[C:21]([N:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)[CH:22]=[CH:23][CH:24]=3)[NH:28][CH:27]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Sc4ccccc4)c[nH]c23)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Sc2c[nH]c3c(N4CCNCC4)cccc23)cc1

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of 4-(3-phenylsulfanyl-1H-indol-7-yl)piperazine-1-carboxylic acid tert-butyl ester (700 mg, 1.7 mmol), prepared as described in Example 1 Step 1, in 4 mL of dichloromethane. After 15 min the solution was diluted with water, basified with ammonium hydroxide, and extracted with dichloromethane. The dichloromethane was washed with brine and evaporated to afford 3-phenylsulfanyl-7-piperazin-1-yl-1H-indole (701) as a solid. The hydrochloride salt crystallized from ethanol-HCl to afford 500 mg of white solid, m.p. 300° C. Similarly replacing 4-(3-phenylsulfanyl-1H-indol-7-yl)piperazine-1-carboxylic acid tert-butyl ester with the appropriate sulfanyl derivatives, prepared as described in other examples herein, the following compounds were prepared:
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([C:8]1[N:12]([CH:13]([CH3:15])[CH3:14])[N:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:13]([N:12]1[C:8]([CH:6]=[CH2:1])=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11]1)([CH3:15])[CH3:14]
Reactant: [Li]CCCC
Reactant: COC(=O)c1cc(C=O)n(C(C)C)n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(C(=O)OC)nn1C(C)C
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 262.7 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (2.69 g, 7.52 mmol) in dry THF (40 mL) was cooled to −78° C. and n-butyllithium (1.6 M solution in hexane, 3.7 mL, 5.91 mmol) was added dropwise. The yellow-orange suspension was stirred at −78° C. for 50 min and then a solution of methyl 5-formyl-1-isopropyl-1H-pyrazole-3-carboxylate (prepared as described in WO 2011/020615, 1.05 g, 5.37 mmol) in dry THF (10 mL) was added dropwise. The mixture was stirred at −78° C. for 1.75 h, the cooling bath was removed and the mixture (off-white suspension) was stirred at rt for 1 h. The mixture was then partitioned between diluted aq. NaHCO3 solution (150 mL) and EA (150 mL). The aq. layer was extracted twice with EA (50 mL each) and the combined organic layer was washed twice with water (50 mL each) and concentrated without drying to give 2.74 g of a yellow oil which slowly crystallized. The crude product was purified by CC (preadsorption with CH2Cl2, hexane/EA 4:1) to give alkene 7a (590 mg, 57%) as a colorless oil. 1H NMR (DMSO-d6) δ: 7.02 (s, 1H), 6.87 (dd, J=17.3, 11.2 Hz, 1H), 5.94 (dd, J=17.3, 1.3 Hz, 1H), 5.45 (dd, J=11.2, 1.3 Hz, 1H), 4.80 (sept, J=6.6 Hz, 1H), 3.79 (s, 3H), 1.38 (d, J=6.6 Hz, 6H). C10H14N2O2 (194.23). LC-MS (ESI): 195 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:11]1[C:28](O)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[CH:42]([O:55][NH2:56])([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH:42]([O:55][NH:56][C:28]([CH:11]1[CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)(=[O:19])=[O:18])=[O:29])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NOC(c1ccccc1)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COCc3ccccc3)C2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2CCCCC(COCc3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-Benzyloxymethyl-1-(4-methoxybenzene sulfonyl)-azepane-2-carboxylic acid (19 mg, 0.044 mmoL) in 0.63 mL of dimethylformamide was added 1-Hydroxy-benzotriazole hydrate (7.1 mg, 0.0525 mmoL) and O-Benzhydryl-hydroxylamine (10.4 mg, 0.0525 mmoL). This solution was cooled to 0° C. and 1-(3-Dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (10 mg, 0.0525 mmoL) was added in. The reaction was warmed to ambient temperature after 20 minutes, and the reaction was stopped after 3 hours by diluting with ethyl acetate. This solution was washed sequentially with saturated sodium bicarbonate, 0.5N HCl, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by column chromatography (silica: 20% to 30% ethyl acetate in hexanes) to yield 3-Benzyloxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid benzhydryloxy-amide; MS: (M+H)+ =615, (M+NH4)+ =632.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>>[CH3:25][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=2)=[CH:24][C:6]=1[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Agent: Cl
Product: Cc1ccc(NC(=O)c2cccnc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (20 mg, 0.058 mmol) and nicotinoyl chloride hydrochloride (10 mg, 0.058 mmol) similar to Example 139 and isolated as a tan solid (13 mg, 47%). 1H NMR (DMSO-d6): 10.50 (s, 1H), 9.85 (s, 1H), 9.12 (d, J=1.5 Hz, 1H), 8.77 (dd, J=1.5, 4.5 Hz, 1H), 8.72 (d, J=5.7 Hz, 2H), 8.34–8.28 (m, 1H), 8.21 (bs, 1H), 8.16 (d, J=6.0 Hz, 2H), 7.60–7.53 (m, 2H), 7.34 (d, J=8.1 Hz, 1H), 7.14 (s, 1H), 2.25 (s, 3H).