Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH:15]=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH:15]=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C=O)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C=O)C1

Procedure:
The title compound is prepared from a mixture of 3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indole-2(5H)-carbaldehyde, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: CN.C[CH2:4][N:5](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:36]([O:43][C:44]1[CH:45]=[C:46]2[C:52]([C:53]([OH:55])=O)=[C:51]([C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=3)[O:50][C:47]2=[CH:48][N:49]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:36]([O:43][C:44]1[CH:45]=[C:46]2[C:52]([C:53]([NH:5][CH3:4])=[O:55])=[C:51]([C:56]3[CH:57]=[CH:58][C:59]([F:62])=[CH:60][CH:61]=3)[O:50][C:47]2=[CH:48][N:49]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2cnc(OCc3ccccc3)cc12
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cnc(OCc3ccccc3)cc12
Yield: 38.9 %

Procedure:
Methanamine (3.1 mL, 6.2 mmol, 2M in THF) was added to a stirring solution of DIEA (646 μL, 3.70 mmol), HATU (563 mg, 1.48 mmol), 5-(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine-3-carboxylic acid (448 mg, 1.23 mmol) in DMF (12 mL) at room temperature. The mixture concentrated then diluted with EtOAc and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give 5-(benzyloxy)-2-(4-fluorophenyl)-N-methylfuro[2,3-c]pyridine-3-carboxamide (180 mg, 39% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1H, s), 8.37-8.45 (1H, m), 7.98-8.08 (2H, m), 7.29-7.50 (7H, m), 7.06 (1H, s), 5.42 (2H, s), 2.83 (3H, d, J=4.52 Hz). LC-MS retention time: 2.00 min; m/z (MH+): 377. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C=O)C>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:11]2[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)(=[O:7])=[O:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)n[nH]c12
Yield: 32.1 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-Chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide (Example 38a) (0.222 mmol) in DMF (4 mL) was reacted with K2CO3 (61 mg, 0.444 mmol) and morpholine (97 uL, 1.11 mmol) to afford the title compound (37.73 mg, 32% for 2 steps).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>ClCCl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)[S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(c1ccc(NCc2ccccc2)cc1)N1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)cc1)N1CCCCC1
Temperature: 40 °C
Yield: 62.5 %

Procedure:
To a stirred solution of (4-benzylamino-phenyl)-piperidin-1-yl-methanone (39 mg, 0.14 mmol) in dichloromethane (1 ml) was added benzene sulfonylchloride (57 μl, 0.46 mmol) followed by pyridine (42 μl, 0.5 mmol) and the reaction was heated to 40° C. for 20 hours. The reaction was allowed to cool to room temperature and partitioned between water (5 ml) and dichloromethane (5 ml). The organics were collected, concentrated in vacuo and purified by preparative TLC to afford the title compound as a white solid (38 mg, 62% yield). HPLC retention time 5.8 min. Mass spectrum (ES+) m/z 435 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C[CH2:11][N:12](C(C)C)[CH:13](C)C.CNC.O>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([N:12]([CH3:13])[CH3:11])[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: CNC
Solvent: CC#N
Solvent: O
Product: CN(C)c1cc(Cl)nc(N)n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 104.5 %

Procedure:
To a solution of 4,6-dichloropyrimidinamine (2.0 g, 12.2 mmol) in acetonitrile were added Hunig's base (2.34 mL, 13.4 mmol) and dimethylamine (6.7 mL, 13.4 mmol), and the reaction mixture was stirred for 1.5 hours at 50° C. The mixture was poured onto CH2Cl2 and water. The organic layer was separated, washed with brine, and concentrated to afford the title compound (2.2 g, 94%) as an off-white solid. LC-MS (ES) m/z=173, 175 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][N:9]=[C:10]([CH3:12])[CH3:11])=[O:7])=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18]>CN(C)C.CC(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([C:17](=[O:18])[NH:16][CH3:15])[N:9]=[C:10]([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)=NNC(=O)c1ccc(Cl)cc1
Reactant: CN=C=O
Agent: CN(C)C
Solvent: CC(C)=O
Product: CNC(=O)N(N=C(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
10.5 g of 1-p-chlorobenzoyl-2-isopropylidene hydrazine, 2.9 g of methyl isocyanate and 100 ml of acetone were placed in a 200 ml round-bottom flask, and 3 drops of trimethylamine were added thereto. The mixture was stirred at room temperature for one hour. The separated crystalline mass was recovered to obtain 12.7 g (95%) of 1-p-chlorobenzoyl-1-methylcarbamoyl-2-isopropylidene hydrazine as white crystals having a melting point of 119°-123° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.O>CN(C=O)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:6]([C:4]2[N:3]=[CH:2][S:1][CH:5]=2)[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:23][CH:24]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cscn2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 72.1 %

Procedure:
To a solution of tert-butyl thiazol-4-ylcarbamate (13.0 g, 64.9 mmol) in DMF (150 mL) was added Cs2CO3 (42.3 g, 130 mmol) and 1-(chloromethyl)-4-methoxybenzene (12.1 g, 78.0 mmol, Spectrochem). The reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was allowed to cool to room temperature and water (500 mL) was added. The aqueous layer was extracted with diethyl ether (2×500 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was further purified by column chromatography (silica gel 100-200 mesh and 0-20% ethyl acetate in hexanes) to obtain tert-butyl 4-methoxybenzyl(thiazol-4-yl)carbamate (15.0 g, 80%) as an off-white solid. MS (ESI, positive ion) m/z=321 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([I:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.I[CH3:11]>>[I:9][C:3]1[C:2]([O:1][CH3:11])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: CI
Reactant: Cc1ccc(O)c(I)n1
Product: COc1ccc(C)nc1I

Procedure:
Under the conditions of example 1 D, 10 g of 3-hydroxy-2-iodo-6-methylpyridine is reacted with 2.7 ml of iodomethane and worked up. 10.5 g of 2-iodo-3-methoxy-6-methylpyridine of melting point 45°-50° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[C:10]([Cl:14])[C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])[CH:19]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)COc1cc(Cl)c(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)COc2cc(Cl)c(Cl)cc2Cl)c1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
The mixture of (2,4,5-trichloro-phenoxyacetic acid (127.8 mg, 0.5 mmol), 3-aminobenzoic acid methyl ester (151.2 mg, 1.0 mmol), 4-dimethylaminopyridine (122.2 mg, 1.0 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (pybop) (520.3 g, 1.0 mmol) in DMF (5.0 mL) was stirred overnight and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 3-[2-(2,4,5-trichloro-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (166.4 mg, 85.6% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C)C=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)[C:62]3[CH2:68][CH2:67][NH:66][CH2:65][C:63]=3[N:64]=2)=[CH:55][CH:54]=1)=[O:51])[CH3:48]>>[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:70][CH2:71][O:72][CH2:73][CH2:74]3)[C:62]3[CH2:68][CH2:67][N:66]([C:8]([C:3]4[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=4)=[O:10])[CH2:65][C:63]=3[N:64]=2)=[CH:57][CH:58]=1)=[O:51])[CH3:48]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Cc1nccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2nccnc2C)C3)cc1
Reaction time: 8 h

Procedure:
3-Methylpyrazine-2-carboxylic acid (0.0501 g, 0.000363 mol) in dry N,N-Dimethylformamide (1.80 mL, 0.0232 mol) was added 1-Hydroxybenzotriazole (0.0580 g, 0.000429 mol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0765 g, 0.000399 mol) then followed by N,N-Diisopropylethylamine (0.1150 mL, 0.0006602 mol) and then 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.1021 g, 0.0002670 mol). The reaction mixture was stirred overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.73-8.60 (m, 2H), 8.55 (s, 1H), 8.17 (dd, J=43.9, 8.8, 2H), 7.47 (dd, J=25.7, 8.8, 2H), 6.22-6.10 (m, 1H), 4.79 (s, 1H), 4.37 (s, 1H), 3.90 (t, J=5.3, 1H), 3.78-3.66 (m, 4H), 3.56-3.37 (m, 6H), 3.21-3.03 (m, 2H), 2.81 (s, 1H), 2.68 (s, 1H), 2.53 (s, 2H), 1.06 (q, J=7.3, 3H). LC/MS-m/z+503.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:25]=1)=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:19][CH2:21][CH:22]([C:24]2[CH:25]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[OH:23])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(N)Cc2ccccc2)cc1OC
Reactant: CS(=O)(=O)Nc1cccc(C(=O)CBr)c1
Product: COc1ccc(C(Cc2ccccc2)NCC(O)c2cccc(NS(C)(=O)=O)c2)cc1OC

Procedure:
The title compound was prepared by coupling α-(3,4-dimethoxyphenyl)benzeneethanamine, prepared as described in step C of Example 1, with 2-bromo-1-[3-[(methylsulfonyl)amino]phenyl]ethanone via the procedure described in step D of Example 1. The title compound, after silica gel chromatography, was purified by preparative HPLC using 49% solvent B to elute the desired material from a YMC S10 C18 column.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2[S:8][C:9]3[C:10](=[O:17])[N:11]([CH3:16])[C:12](=[O:15])[C:13]=3[S:14][C:4]=2[C:3]1=[O:18].[N+]([O-])(O)=[O:20]>>[CH3:1][N:2]1[C:3](=[O:18])[C:4]2[S:14][C:13]3[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[O:17])[C:9]=3[S:8](=[O:20])[C:5]=2[C:6]1=[O:7]
Reactant: O=[N+]([O-])O
Reactant: Cn1c(=O)c2sc3c(=O)n(C)c(=O)c3sc2c1=O
Product: CN1C(=O)C2=C(C1=O)S(=O)C1=C(S2)C(=O)N(C)C1=O
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
With stirring, 3 g (10.63 mmol) of 2,6-dimethyl-1H,5H-[1,4]dithiino[2,3-c:5,6-c′]dipyrrole-1,3,5,7(2H,6H)-tetrone [compound No. (1)] were added to 20 ml of ice-cooled (5° C.) fuming nitric acid. After dissolution was complete, stirring was continued for 5 min, the mixture was subsequently poured into ice-water and the yellow crystals were filtered off with suction. This gave 2.56 g (80.8% of theory) of the desired compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Cc1c2n(c3c(-c4cc(F)cc(F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (76 mg, 88%), MS (ISP) m/z=347.5 [(M+H)+], mp 241° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3,5-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1)#[CH:2].Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>C(N(CC)CC)C.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:13][O:12][C:11]1[C:4]2[C:3]([C:1]#[C:2][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[CH:7][S:6][C:5]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(Br)cc1
Reactant: C#Cc1csc2cccc(OC)c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cccc2scc(C#Cc3ccc(C)cc3)c12

Procedure:
3-Ethynyl-4-methoxybenzo[b]thiophene (0.15 g) was dissolved in triethylamine (10 mL). To the solution were added 4-bromotoluene (0.11 mL), tetrakis(triphenylphosphine)palladium (0) (92 mg) and copper (I) iodide (30 mg), and the mixture was heated for ref lux under an argon atmosphere for 10 hours. The reaction mixture was diluted with diethyl ether, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=50/1) to give 4-methoxy-3-[2-(4-methylphenyl)ethynyl]benzo[b]thiophene (27 mg). This material was dissolved in ethanol (1.5 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-methoxy-3-[2-(4-methylphenyl)ethyl]-benzo[b]thiophene (27 mg). This material was dissolved in dichloromethane (1.5 mL). To the solution was added boron tribromide (0.011 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hour. Then the mixture was stirred under ice-cooling for 1 hour. The reaction mixture poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=15/1) to give the title compound (10 mg).
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH3:15][N:16]([CH3:67])[C:17]([C@H:19]1[N:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[CH2:22][C@@H:21]([S:37][C:38]2[C@H:39]([CH3:66])[C@@H:40]3[C@@H:57]([C@H:58]([O:60][Si](C)(C)C)[CH3:59])[C:56](=[O:65])[N:41]3[C:42]=2[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])[CH2:20]1)=[O:18]>CO>[CH3:67][N:16]([CH3:15])[C:17]([C@H:19]1[N:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[CH2:22][C@@H:21]([S:37][C:38]2[C@H:39]([CH3:66])[C@@H:40]3[C@@H:57]([C@H:58]([OH:60])[CH3:59])[C:56](=[O:65])[N:41]3[C:42]=2[C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=2)=[O:44])[CH2:20]1)=[O:18]
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 84.3 %

Procedure:
8 mg (0.039 mmol) of citric acid hydrate were added to 2 ml of a solution containing 55 mg of 4-nitrobenzyl (1R,5S,6S)-2-[(3S,5S)-5-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-3-pyrrolidinylthio]-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 18)in methanol, and the resulting mixture was stirred at room temperature for 35 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through 5 g of silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 42 mg (yield 84%) of the title compound as a vitreous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:42][N:43]([C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:42][N:43]([C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:27])([F:28])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(c1ccccc1)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccc(F)cc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (458 mg, 1.00 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 1 h then was concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-methyl-N-(4-fluorophenyl)aniline (0.50 mL, 3.5 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS) then quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-(4-fluorophenyl)amide. MS m/z 570.1(M+Na); 526.0 (M+H-MeOH).
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+].[CH3:24][OH:25]>>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:14]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[CH:13][C:12]=2[O:25][CH3:24]
Reactant: CO
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (200 mg, 0.5 mmol) in methanol (20 mL) was added NaH (Aldrich, 60%, 0.6 g, 15 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated under reflux for 1.5 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 25% ethyl acetate in hexanes) to give 6-fluoro-5-methoxy-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 73.2 mg, 51.9%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:22]=O)[C:8]([OH:21])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([OH:21])=[C:7]([CH2:22][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2cccc(C(F)(F)F)c2)c1O

Procedure:
5-(tert-Butyl)-3-((tert-butylamino)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-ol was prepared as a white solid using the procedure described in Example 27, Step 2 5-(tert-butyl)-2-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine. HPLC/MS Rt=6.64 min, m/z 380.2 (M+H+).