Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][CH:12]=[O:13].[F:14][C:15]([F:21])([F:20])[Si](C)(C)C.Cl>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:13][CH:12]([C:15]([F:21])([F:20])[F:14])[CH2:11][CH:2]1[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CCC1CCc2ccccc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(CC1CCc2ccccc2O1)C(F)(F)F
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of 7.6 g (43 mmol) of 3,4-dihydro-2H-1-benzopyran-2-acetaldehyde in 110 ml of tetrahydrofuran are added dropwise, at -10° C., 7.1 ml (52 mmol) of trifluorotrimethylsilylmethane and a solution of 90 mg (2 mg/mmol) of tetrabutylammonium fluoride in 5 ml of tetrahydrofuran. The mixture is allowed to react for 2 hours at 0° C., then it is hydrolyzed for 2 hours using a 1M solution of hydrochloric acid and the product is extracted with diethyl ether. The organic phase is then washed with water, dried over sodium sulfate and then concentrated under reduced pressure. By chromatography of the residue on a silica column using a 50/50 mixture of dichloromethane and of cyclohexane, 8.6 g of product are obtained in oil form.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20]>>[Br:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: CCC1C(=O)Nc2cc(F)ccc21
Reactant: BrCCCCCBr
Product: CCC1(CCCCCBr)C(=O)Nc2cc(F)ccc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1,5-dibromopentane.
Reaction SMILES: [CH:1]12[CH2:10][C:5]3(O)[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[NH:2]1)[CH2:8]2.[CH:12]([OH:14])=[O:13].OS(O)(=O)=O.O=S(=O)=O.[CH3:24]O>>[CH:1]12[CH2:10][C:5]3([C:12]([O:14][CH3:24])=[O:13])[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[NH:2]1)[CH2:8]2
Reactant: OC12CC3CC(C1)NC(C3)C2
Reactant: CO
Reactant: O=CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: COC(=O)C12CC3CC(C1)NC(C3)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To 2-azatricyclo[3.3.1.13,7]decan-5-ol (Intermediate-7) (1.5 g, 5.9 mmol, 1 eq), 98% formic acid (9 ml) was added drop wise with vigorous gas evolution for over 30 minutes to a rapidly stirred 30% oleum (36 ml) heated to 60° C. Upon completion of this addition, 99% formic acid (9 ml) was slowly added for the next 30 minutes. The reaction mixture was stirred for another 1 hr at 60° C. (monitored by LCMS). The reaction mixture thus formed was then slowly poured into vigorously stirred methanol (75 ml) cooled to 00° C. The mixture was allowed to slowly warm to room temperature while stirring the reaction mixture for 4-5 hrs. The mixture was then concentrated under vacuum. The residue was poured into ice (30 g) and basified with saturated Na2CO3 solution. The aqueous layer was extracted with 5% methanol in DCM (3×100 ml). Combined organic layer was washed with brine and dried over Na2SO4. The organic layer was finally concentrated to get intermediate-8, (550 mg, 50% yield) as an oily mass.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)=[C:2]=[S:3].[OH:14][CH2:15][C@@H:16]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][NH:17]1>C(O)C>[OH:14][CH2:15][C@@H:16]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][N:17]1[C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: S=C=Nc1cccc2cnccc12
Solvent: CCO
Product: OC[C@@H]1Cc2ccccc2CN1C(=S)Nc1cccc2cnccc12
Reaction time: 15 h
Yield: 74.5 %

Procedure:
5-Isothiocyanatoisoquinoline (0.93 g.) is added to a solution of (S)-3-hydroxymethyl-1,2,3,4-tetrahydro isoquinoline (0.82 g.) in ethanol (10 cc.). After 15 hours at a temperature of about 20° C., the crystals formed are filtered off, washed with ethanol and then dried at 60° C. under reduced pressure (0.1 mm. Hg). (S)-3-Hydroxymethyl-N-(isoquinol-5-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (1.3 g. ), melting at 190° C., is thus obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]([C:67]1[S:71][C:70]2[CH:72]=[CH:73][C:74]([NH2:76])=[CH:75][C:69]=2[CH:68]=1)=[O:66]>>[CH3:63][O:64][C:65]([C:67]1[S:71][C:70]2[CH:72]=[CH:73][C:74]([NH:76][C:30]([C@@H:20]3[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]4([C:12]5[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=5)[NH:15][C:16]4=[O:38])[C@H:21]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])=[O:32])=[CH:75][C:69]=2[CH:68]=1)=[O:66]
Reactant: COC(=O)c1cc2cc(N)ccc2s1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@@]4(C(=O)Nc5cc(Cl)ccc54)[C@H]3c3cccc(Cl)c3F)ccc2s1
Yield: 43.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (100 mg, 0.173 mmol), was reacted with diisopropylethylamine (111 mg, 0.86 mmol), diphenylphosphinic chloride (106 mg, 0.446 mmol), then reacted with 5-Amino-benzo[b]thiophene-2-carboxylic acid methyl ester (Maybridge, 41 mg, 0.190 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzo[b]thiophene-2-carboxylic acid methyl ester (49 mg, 43%). MS (ES+) m/z [(M+H)+]: 654
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH:37]C=O)[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8].Cl.CO>O1CCCC1>[CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCSC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCSC)c3csc(N)n3)[C@H]2SC1
Yield: 86 %

Procedure:
A mixture of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.95 g), conc.hydrochloric acid (0.324 g), methanol (9.5 ml) and tetrahydrofuran (2 ml) was stirred for 2 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.78 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[C:40](Br)[CH:39]=1>>[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:39]=[C:40]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N+:32]([O-:46])([O:34][CH2:35][C@@H:36]([O:42][N+:43]([O-:45])=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40]O)=[O:33].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([O:13][CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]([O:42][N+:43]([O-:45])=[O:44])[CH2:35][O:34][N+:32]([O-:46])=[O:33])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: O=[N+]([O-])OC[C@H](CCCCO)O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCc1nc(Cl)c(C(=O)OCCCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 12 h

Procedure:
To a dichloromethane (20 mL) solution of 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (1.76 g, 3.72 mmol), (2S)-6-hydroxyhexane-1,2-diyl dinitrate (intermediate 3, 0.83 g, 3.72 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.85 g, 4.46 mmol), and 1-hydroxybenzotriazole (0.68 g, 4.46 mmol) was added N-methylmorpholine (1.84 mL, 16.7 mmol), followed by N,N-dimethylaminopyridine (4.5 mg, 0.04 mmol). After 12 hours, the reaction mixture was washed with saturated sodium bicarbonate solution, brine, dried (magnesium sulfate), filtered, and concentrated in vacuo. Purification of the reaction mixture by reversed-phase mass-directed high-performance liquid chromatography afforded the title compound. 1H NMR (500 MHz, CD3CN) δ 7.69 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.10 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 5.63 (s, 2H), 5.34-5.41 (m, 1H), 4.83 (dd, J=2.5, 12.8 Hz, 1H), 4.58 (dd, J=6.2, 13.0 Hz, 1H), 4.25 (t, J=6.2 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H), 1.79 (q, J=7.5 Hz, 2H), 1.71 (quintet, J=6.8 Hz, 2H), 1.48-1.60 (m, 4H), 1.28 (sextet, J=7.4 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); LC-MS: m/z 643 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([OH:13])[C:11]3[S:14][CH2:15][CH2:16][S:17][C:10]=3[C:9]2=[O:18])=[N:6][CH:7]=1.[H-].[Na+].Cl[C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23].C(O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:9]([O:18][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[O:23])[C:10]3[S:17][CH2:16][CH2:15][S:14][C:11]=3[C:12]2=[O:13])=[N:6][CH:7]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc(Cl)cn2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A solution of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (15.0 g.) in anhydrous tetrahydrofuran (150 cc.) is treated for 15 minutes at about 10°-15° C with sodium hydride (1.44 g.), and a solution of 1-chlorocarbonyl-4-methylpiperazine (24.4 g.) in anhydrous tetrahydrofuran (200 cc.) is then added, at 5° C. The reaction mixture is stirred for 4 hours at 5° C. After evaporating the solvent under reduced pressure (20 mm.Hg), the residue is dissolved in diethyl ether (450 cc.). The ether solution is rapidly extracted twice with an ice-cold normal aqueous solution of methanesulphonic acid (total 500 cc.). The combined aqueous extracts are rendered alkaline by adding 10N sodium hydroxide solution (100 cc.). The oil which separates out is extracted with methylene chloride (250 cc.) and then with diethyl ether (300 cc.). The combined organic extracts are washed five times with distilled water (total 250 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.1 g.) and evaporated. The crystals obtained (18.0 g.; m.p. 170° C.) are dissolved in boiling ethanol (225 cc.). After filtering the boiling solution and then cooling it for 3 hours at 2° C., the crystals which have appeared are filtered off, washed three times with ice-cold ethanol (total 45 cc.) and dried under reduced pressure (20 mm.Hg). 6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (15.6 g.), melting at 180° C., is thus obtained.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][OH:18])=[CH:14][CH:13]=1.C(N([CH2:26][CH3:27])CC)C>ClCCl>[C:1]1([S:7]([O:18][CH2:17][CH2:16][C:15]2[CH:19]=[CH:20][C:12]([O:11][S:7]([C:27]3[CH:26]=[CH:3][CH:2]=[CH:1][CH:6]=3)(=[O:9])=[O:8])=[CH:13][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCN(CC)CC
Reactant: OCCc1ccc(O)cc1
Solvent: ClCCl
Product: O=S(=O)(OCCc1ccc(OS(=O)(=O)c2ccccc2)cc1)c1ccccc1
Yield: 72.2 %

Procedure:
42.2 g (240 mmole) benzenesulfonyl chloride in dichloromethane was slowly added to a solution of 15 g (108 mmole) 4-hydroxyphenethyl alcohol and 24.3 g (240 mmole) triethylamine in 120 ml dichloromethane at 0° C. After stirring at 0° C. to room temperature the starting material was consumed, water was added, the phases were separated and the organic phase was evaporated in vacuo. Diisopropyl ether was added, two phases were formed, the diisopropyl ether phase was decanted off and the rest of solvent was evaporated to give 32.65 g (yield 73%) of 4-[phenylsulfonyloxy]phenethyl 1-benzenesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:6].[CH3:19]COCC.C[Mg]Br>O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]([C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=1[O:2][CH3:1])([OH:6])[CH3:19]
Reactant: CCOCC
Reactant: COc1ccccc1C(=O)c1ccccc1OC
Agent: C[Mg]Br
Solvent: O
Product: COc1ccccc1C(C)(O)c1ccccc1OC
Temperature: 25 °C

Procedure:
2,2'-Dimethoxybenzophenone (24.2 g, 0.14 mole) and 400 ml of ether were placed in a 1 1 flask and stirred at ambient temperature and methyl magnesium bromide (40 ml of 3.0 M solution in ether) was added dropwise. The resulting mixture was stirred overnight and then a few ml of water were added to quench the Grignard reagent. About 300 ml of ethyl acetate and 250 ml of 10 percent hydrochloric acid were then added and the mixture was shaken. The organic layer was next recovered, extracted with 100 ml of water and 100 ml of saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 25.6 g (98 percent of theory) of the title compound as a white solid melting at 122-123° C. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1]([C:3]1[C:8](OC)=[CH:7][CH:6]=[CH:5][C:4]=1[NH:11][C:12](=[O:18])OC(C)(C)C)=O.[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:28]C(OCC)=O.N1CCCCC1.[CH2:40]([OH:42])C>>[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[C:28]1[C:12](=[O:18])[NH:11][C:4]2[C:3]([CH:1]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[O:42][CH3:40]
Reactant: CCO
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C=O
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Solvent: C1CCNCC1
Product: COc1cccc2cc(-c3nc4ccccc4[nH]3)c(=O)[nH]c12

Procedure:
A solution of tert-butyl 2-formyl-3-methoxyphenylcarbamate (13-1, 0.50 g, 1.9 mmol, 1 equiv, prepared by the formylation method utilized in the examples above), ethyl 1H-benzimidazol-2-ylacetate (0.39 g, 1.9 mmol, 1.0 equiv, prepared by the method of Rahmouni, M, Derdour, A., Bazureau, J., and Hamelin Tetrahedron Lett. 1994, 35, 4563-4564), and piperidine (0.090 mL, 0.91 mmol, 0.48 equiv) in ethanol (50 mL) was heated at reflux for 20 h. The reaction mixture was cooled and the precipitate which formed was filtered and air dried to give 3-(1H-benzimidazol-2-yl)-8-methoxy-2(1H)-quinolinone (13-2). 1H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 12.43 (s, 1H), 9.25 (s, 1H), 7.71 (m, 1H), 7.66 (m, 1H), 7.55 (t, 1H, J=8.2 Hz), 7.20 (m, 2H), 7.03 (d, 1H, J=8.2 Hz), 6.85 (d, 1H, J=8.2 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:16])[C@H:5]([N:8]=CC1C=CC=CC=1)[CH2:6][OH:7].[CH2:17](Br)[CH:18]=[CH2:19].CO>C1COCC1>[CH2:19]([O:7][CH2:6][C@@H:5]([NH2:8])[CH:4]([CH3:3])[CH3:16])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CC(C)[C@@H](CO)N=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOC[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 69.5 %

Procedure:
1.25 g (60%, 31.36 mmol) of sodium hydride were added to a solution of 3.00 g (15.68 mmol) of (S)-3-methyl-2-{[1-phenylmethylidene]amino}butan-1-ol in 28 ml of dry THF, and the mixture was stirred at RT for 45 min. Then 1.43 ml (16.46 mmol) of allyl bromide were added, and the mixture was stirred further at RT overnight. 20 ml of methanol were added to quench, and the mixture was acidified (pH 1) with 1N hydrochoric acid and stirred further. After 3 h, the reaction mixture was washed twice with dichloromethane, and the combined dichloromethane phases were extracted with 1N hydrochloric acid. The combined aqueous phases were basified with 1N sodium hydroxide solution (pH 14), saturated with sodium chloride and extracted three times with ethyl acetate, readjusting the pH after each extraction step. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and taken up once in dichloromethane and again concentrated. 1.56 g of the title compound were obtained as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[Cl:19]C1C=CC(F)=C(B(O)O)C=1>>[Cl:19][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)[CH:4]=1
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2cc(Cl)ccc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (5-chloro-2-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:18][CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([C:7]1[CH:15]=[CH:14][C:10]([C:11](=[O:12])[NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:9][CH:8]=1)[CH:16]1[CH2:17][CH2:18][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:20][CH2:21]1
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1ccccc1
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)Nc3ccccc3)cc2)CC1
Yield: 70.4 %

Procedure:
Using general procedure E, 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (40 mg, 0.074) and aniline (8 μL, 0.08 mmol) afforded COMPOUND 89 as a white solid (32 mg, 71%). 1H NMR (CDCl3) δ 0.93-1.25 (m, 2H), 1.01 (d, 3H, J=6.3 Hz), 1.51-1.55 (m, 1H), 1.72-1.76 (m, 3H), 2.19 (t, 1H, J=11.1 Hz), 2.31 (s, 6H), 2.58 (t, 1H, J=11.1 Hz), 2.76-2.92 (m, 3H), 3.25-3.32 (m, 1H), 3.67-3.75 (m, 1H), 3.87 (s, 2H), 3.87-3.93 (m, 1H), 6.57 (d, 2H, J=8.7 Hz), 6.95-7.12 (m, 6H), 7.23-7.32 (m, 4H), 7.60 (d, 2H, J=7.8 Hz), 7.68 (d, 2H, J=8.4 Hz), 7.76 (s, 1H), 8.35 (br s, 1H). 13C NMR (CDCl3) δ 13.85, 19.55, 29.42, 30.70, 31.35, 40.22, 43.96, 48.59, 52.47, 56.25, 60.92, 112.50, 120.35, 122.88, 124.35, 124.61, 126.60, 127.47, 127.78, 128.89, 129.13, 129.37, 130.27, 134.44, 134.95, 138.80, 138.97, 142.01, 151.51, 165.65, 170.31. ES-MS m/z 623 (M+H). Anal. Calcd. for C38H43N4ClO2.0.2CH2Cl2: C, 71.65; H, 6.83; N, 8.75. Found. C, 71.64; H, 6.81; N, 8.84.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[I:10]N1C(=O)CCC1=O>C(#N)C.O>[I:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: c1cnc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O
Product: Ic1n[nH]c2ncccc12
Temperature: 75 °C
Reaction time: 17 h

Procedure:
A solution of the intermediate from Step A above (14.3 g, 120 mmol) and N-iodosuccinimide (28.4 g, 126 mmol) in acetonitrile (210 mL) was heated at 75° C. After 17 hours, N-iodosuccinimide (5.4 g, 24 mmol) was added and the reaction solution stirred at 75° C. for an additional 1.5 hours. The reaction solution was cooled to room temperature and diluted with water. The slurry was concentrated in vacuo to remove most of the acetonitrile. The solid was collected, washed with water, and dried under a vacuum with a nitrogen sweep for 17 hours to give the title compound. 1H NMR (400 MHz, CH3CN-d3): δ 11.85 (s, 1H); 8.55 (dd, J=4.53, 1.53 Hz, 1H); 7.87 (dd, J=8.11, 1.53 Hz, 1H); 7.24 (dd, J=8.11, 4.51 Hz, 1H). m/z=246.1 (M+H).
Reaction SMILES: C(Cl)Cl.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][C:6]=1[O:15][CH3:16].[C:17](Cl)(=O)[C:18](Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>CN(C=O)C>[Br:4][C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][C:6]=1[O:15][CH3:16])[CH2:11][C:12](=[O:14])[CH2:18][CH2:17]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(CC(=O)O)ccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CCC(=O)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a DCM solution of (4-Bromo-3-methoxyphenyl)acetic acid (900 mg, 3.67 mmol) was added oxalyl chloride (0.64 ml, 7.3 mmol) and a drop of DMF. The solution was allowed to stir at RT for 3 hours, at which point bubbling stopped. The volatiles were removed under vacuum, and the residue was redissolved in DCM. The solution was cooled to 0° C. To this solution was added aluminum trichloride (1.2 g, 9.2 mmol). After stirring the mixture for 15 minutes, ethylene was bubbled into the reaction. The reaction was poured into ice, extracted with DCM, washed with brine, and purified by MPLC. LC-MS (IE, m/z): 255 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:12][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: NC1CC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCO
Product: Brc1cnc(NC2CC2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
In a pressure tube with one end sealed, add 193 mg 5-bromo-2-chloropyrimidine (1.0 mmol) and 285 mg cyclopropylamine (5.0 mmol) in 3.0 mL ethanol, and the mixture is heated to 80° C. and stirred for 3 h. The reaction mixture was cooled to room temperature, and 203 mg solid product was collected by filtration for direct use yield: 95%).