Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9]Cl)[CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: ClCc1cc(Br)ccc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc(Br)cc1COc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of 4-bromo-1-chloro-2-(chloromethyl)benzene (12.2 g, 50.85 mmol) and phenol (4.79 g, 50.85 mmol) in DMF (102 mL) under nitrogen atmosphere, K2CO3 was added (35.14 g, 254.25 mmol). The resulting mixture was stirred at r.t. for 18 h. After completion of the reaction as confirmed by TLC, the reaction mixture was passed through celite plug and the filterate was evaporated. The residue obtained was dissolved in ethyl acetate (100 mL) and washed with water (2×100 mL) and brine (2×100 mL) successively. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:9 Ethyl acetate:Pet. Ether) to afford the title compound (14.7 g, 97.3%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([C:26](=C)C(OCC)=O)[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]([O:36][CH2:37][CH3:38])(=[O:35])[CH3:34]>[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH2:26][CH2:34][C:33]([O:36][CH2:37][CH3:38])=[O:35])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: C=C(C(=O)OCC)c1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Pd]
Product: CCOC(=O)CCc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 27 h
Yield: 90 %

Procedure:
A solution of ethyl 3-[2-(4,5-diphenyl-2oxazolyl)-ethyl]phenyl-2-propenoate (1.02 g, 2.4 mmol) in ethyl acetate (50 mL) was hydrogenated over 10% palladium on charcoal (0.06 g) at 35 psi. After 27 hours, the mixture was filtered, concentrated and the residue subjected to chromatography on a column of silica gel using a mixture of ethyl acetate and hexanes (9:1) as eluent. Elution gave ethyl 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]benzene propanoate (0.92 g, 90%) as an oil.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:16]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17]1>CN(C=O)C>[C:1]([Si:5]([CH3:8])([CH3:7])[O:22][CH2:21][C:18]1[CH:19]=[CH:20][S:16][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccsc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1ccsc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyldimethylchlorosilane (1.58 g), triethylamine (2.44 ml), 3-thiophenemethanol (0.822 ml) and DMF (20 ml) was stirred at 60° C. for 1 h. Additional DMF (20 ml) was added to the reaction mixture, and the mixture was stirred at 60° C. for 2 h. The mixture was quenched with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane) to give the title compound (1.6 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:27])[N:4]([CH3:26])[CH:5]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:7]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:34][OH:35].ClCCl>C(O)C.O>[Br:1][C:2]1[C:3](=[O:27])[N:4]([CH3:26])[CH:5]=[C:6](/[C:8](=[N:34]/[OH:35])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:7]=1
Reactant: Cc1ccccc1[C@H](CC(=O)c1cc(Br)c(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1[C@H](C/C(=N\O)c1cc(Br)c(=O)n(C)c1)c1ccc(Br)cc1
Temperature: 100 °C

Procedure:
To a suspension of (R)-3-bromo-5-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-1-methylpyridin-2(1H)-one in ethanol (2.5 mL) and water (0.1 mL) were added sodium bicarbonate (30.9 mg) and hydroxylamine hydrochloride (32.0 mg) and the reaction mixture was stirred at reflux (100° C. oil bath temperature) for 2 hours. The reaction mixture was poured on water and dichloromethane and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane/ethyl acetate (100:0 to 50:50) to give the title compound as a white solid, MS (ESI+): m/z=504.99 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[C:27]12[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:32]C(=O)O[C:28]2=[O:29].CCCCCC>C1(C)C(C)=CC=CC=1>[NH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=1[C:28]([NH:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4])=[O:29]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: Nc1ccccc1C(=O)NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of (3aR*,l0aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta [e][1,4]diazepin-10(1H)-one (420 mg, 1.2 mmol) and isatoic anhydride (196 mg, 1.2 mmol) was stirred for 30 minutes in xylene at 140° C. The reaction mixture was left standing for cooling at room temperature, to which was added hexane (5 mL). The resulting solid was collected by filtration, which was recrystallized from ethanol-hexane to give 345 mg (yield 58%) of the titled compound. This compound was in good agreement in
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:9]=3[C:8]([CH2:16][CH3:17])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.[CH2:23]([O+](CC)CC)[CH3:24]>C(Cl)Cl>[CH:1]1([N:6]2[C:10]3[C:11]([O:15][CH2:23][CH3:24])=[N:12][CH2:13][CH2:14][C:9]=3[C:8]([CH2:16][CH3:17])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[O+](CC)CC
Reactant: CCc1nn(C2CCCC2)c2c1CCNC2=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1=NCCc2c(CC)nn(C3CCCC3)c21
Reaction time: 21 h

Procedure:
esterifying said lactam compound of Formula (9.0.0) using triethyloxonium tetrafluoroborate, (CH3CH2)2OBF4; wherein a reaction mixture is established by slowly adding a solution of triethyloxonium tetrafluoroborate, (CH3CH2)3OBF4 in methylene chloride to a suspension of said lactam compound of Formula (9.0.0) in methylene chloride over a period of 40 minutes; and thereafter, maintaining said reaction mixture at a temperature of from 18° to 22° C., for a period of 21 hours; whereby there is produced a corresponding imino ester (imidate) compound of Formula (10.0.0):
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][C@@H:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=1.C([O-])([O-])=O.[K+].[K+].F[C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[N:31][CH:32]=1>CN(C=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][C@@H:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[N:31][CH:32]=2)[CH:8]=1
Reactant: Fc1ccc(O[C@@H]2CCOC2)c(C2CCCN2)c1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCC2c2cc(F)ccc2O[C@@H]2CCOC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.3 %

Procedure:
To a solution of 2-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidine hydrochloride (3.15 g, 10.98 mmol) in dry DMF (10 ml) was added K2CO3 (3.15 g, 22.88 mmol) and stirred for 5 min at room temperature then added 5-fluoro-2-nitropyridine (1.3 g, 91.54 mmol) under N2 atmosphere and stirred for 16 h at 80° C. After completion of reaction, reaction mixture was poured in to ice and stirred for 10 min then solid was collected by filtration. Solid was dried under high vacuum to afford 5-(2-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)-2-nitropyridine as yellow solid (2.8 g, Yield: 82.11%) MS (ESI): 374.3 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10][N:9]=[CH:8][CH:7]=2)=[CH:2]1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH3:16][N:14]([CH:13]=[C:7]([C:6](=[O:10])[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:8]#[N:9])[CH3:15]
Reactant: c1cc(-c2ccsc2)on1
Reactant: COC(OC)N(C)C
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Product: CN(C)C=C(C#N)C(=O)c1ccsc1
Yield: 56.5 %

Procedure:
A mixture of 41.2 g of 5-(3-thienyl)isoxazole and 36.0 g of dimethylformamide dimethylacetal, under nitrogen, is heated on a steam bath for 4 hours. The reaction is concentrated in vacuo to give a viscous oil which solidified. The residue is dissolved in methylene chloride and passed thru a short column of hydrous magnesium silicate. On cooling, 31.76 g of the desired product is obtained, mp 118°-119°, CI-MS:m/z 206(M+). Concentrating in vacuo the methylene chloride gives an additional 20.2 g of product. (Total recovered 51.96 g, 92%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C1(C)C=CC=CC=1>[C:8]1([N:7]2[C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:22][C:23]2=[O:24])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[Cl:21][CH2:22][C:23]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:24]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCl)N(c1ccccc1)c1ccccc1
Product: O=C1Cc2ccccc2N1c1ccccc1
Temperature: 60 °C
Yield: 83.8 %

Procedure:
The title compound is prepared in accordance with the procedures described in Latrell, Bartmann, Granzier DE 2 707 268 (1978) as follows. A solution of diphenylamine (40 g, 237 mmol) and triethylamine (66.1 mL, 474 mmol) in toluene (65 mL) is added dropwise to a solution of chloroacetyl chloride (20.7 mL, 260 mmol) in toluene (40 mL) while cooling in an ice-water bath. The cold bath is removed and the reaction mixture is heated at 55-65° C. for 3 hr. The cooled reaction mixture is diluted with toluene (100 mL), filtered and the filtrate concentrated to give 2-chloro-N,N-diphenylacetamide (24.4 g, 42% yield) as a light brown solid. NMR (CDCl3) 7.56-7.19 (10H, m), 4.01 (2H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([N:11]2[CH2:14][CH:13]([S:15][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]CC3C=CC([N+]([O-])=O)=CC=3)=[O:22])[CH2:12]2)=[N:7]1>O1CCCC1.P([O-])([O-])([O-])=O.[Zn]>[CH3:1][O:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([N:11]2[CH2:12][CH:13]([S:15][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]([OH:23])=[O:22])[CH2:14]2)=[N:7]1
Reactant: COCOC[C@@H]1CSC(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)=N1
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: COCOC[C@@H]1CSC(N2CC(SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of 756 mg of Compound (30) obtained in Example 3 in 10 ml of tetrahydrofuran and 30 ml of 0.35M phosphate buffer (pH 6.0) solution was added 6.0 g of zinc powder, and the reaction mixture was stirred for 2 hours at room temperature. After removal of the zinc powder by filtration, the filtrate was washed with ethyl acetate and the pH of the filtrate was adjusted to 5.5, then the filtrate was concentrated. The resulting residue was purified by using Diaion HP-40R column (10% isopropanol-water) to give 415 mg (71%) of (1R,5S,6S)-2-[1-((4R)-methoxymethyloxymethyl-1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylic acid [Compound (31)].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:19]3[S:13][C:14](=[S:15])[NH:16][C:17]3=[O:18])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc2nccnc2c1
Product: O=C1NC(=S)SC1=Cc1ccc2nccnc2c1

Procedure:
Following the general method as outlined in Example 1, starting from quinoxaline-6-carbaldehyde (intermediate 55) and rhodanine, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10])=[O:24]
Reactant: Nc1ccccc1CCO
Reactant: O=C(Cl)CCCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCBr)Nc1ccccc1CCO
Yield: 100 %

Procedure:
A solution of 2-(2-aminophenyl)ethanol a2-0 (450 g, 3.28 mol, 1 eq) and triethylamine (332 g, 3.28 mol, 1 eq) in dichloromethane (2 l) is cooled at −5° C. and bromovalerylchloride (654 g, 3.28 mol, 1 eq) in dichloromethane (2 l) is added dropwise without exceeding 0° C. The organic phase is washed with HCl 1N (4×2 l) and brine (1×2 l). The aqueous layer is extracted with dichloromethane (1×2 l). The combined organic layers are dried over MgSO4, filtered and evaporated under vacuum to afford 1008 g of 5-bromo-N-[2-(2-hydroxyethyl)phenyl]pentanamide a2-1.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=O.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C(N)CN>C(#N)C>[CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([S:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:6])[CH2:20][N+:17]([O-:19])=[O:18]
Reactant: SCc1ccccc1
Reactant: COC(OC)C(C)=O
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: NCCN
Product: COC(OC)C(C)(C[N+](=O)[O-])SCc1ccccc1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 1,1-dimethoxyacetone (5.00 ml), benzylmercaptan (5.50 ml), nitromethane (23 ml), ethylenediamine (3.00 ml) and acetonitrile (15 ml) was stirred at room temperature, and then overnight at 80° C. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound (5.81 g, yield 48%) as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:6, volume ratio).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([CH3:29])=[C:10]([CH:26]=[CH:27][CH:28]=2)[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])[CH:5]=[CH:4][N:3]=1.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH3:29][C:9]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:25])=[CH:26][CH:27]=[CH:28][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[N:7]=1
Reactant: Cc1c(CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cccc1-c1ccnc(Cl)n1
Reactant: NCCc1ccc(O)cc1
Product: Cc1c(CN2CCNC[C@@H]2C)cccc1-c1ccnc(NCCc2ccc(O)cc2)n1

Procedure:
Intermediate 164 from above was coupled with tyramine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.0 (d, 1H) 7.7 (d, 1H) 7.5 (d, 1H), 7.3 (t, 1H), 7.0 (d, 2H) 6.6 (d, 2H), 3.9 (t, 2H) 3.8-3.7 (m, 3H) 3.6-3.4 (m, 6H) 2.8 (t, 2H), 2.5 (s, 3H), 1.7 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=1)[CH:17]([OH:23])[C:18]([O:20]CC)=[O:19].[OH-].[K+].O.S([O-])(O)(=O)=O.[K+]>C(O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=1)[CH:17]([OH:23])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(O)C(Sc1cc(Oc2ccccc2)ccc1N)c1ccc(OC)c(F)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(Sc2cc(Oc3ccccc3)ccc2N)C(O)C(=O)O)cc1F
Yield: 53.1 %

Procedure:
Following a procedure similar to that described in Example 1(b), 1.85 g of ethyl 3-(2-amino-5-phenoxyphenyl)thio-3-(3-fluoro-4-methoxyphenyl)-2-hydroxypropionate [prepared as described in step (a) above ] was hydrolyzed in ethanol using an aqueous solution prepared from 334 mg of 85% caustic potash. After water and ethyl acetate had been added to the reaction mixture, its pH was adjusted to a value of 3 by the addition of an aqueous solution of potassium hydrogen sulfate. The mixture was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue Was triturated in diethyl ether, filtered and dried to give 922 mg of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]=1[OH:15])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1>N1C=CC=CC=1>[C:1]([C:4]1[C:5]([OH:15])=[C:6]([CH:10]=[C:11]([CH2:13][CH3:14])[CH:12]=1)[C:7]([NH:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCc1cc(C(C)=O)c(O)c(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCc1cc(C(C)=O)c(O)c(C(=O)Nc2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A mixture of 3-acetyl-5-ethylsalicylic acid (55.0 g) and N,N'-dicyclohexylcarbodiimide (60.1 g) in dry pyridine (550 ml) was stirred at 25° C. for one hour. Anhydrous 5-aminotetrazole (24.7 g) was then added to the mixture, and stirring was continued at 60° C. for 24 hours. The pyridine was removed in vacuo, and the residue was treated with aqeuous ammonia solution (2N; 500 ml). The resulting slurry was stirred at between 90° and 100° C. for 15 minutes. The insoluble N,N'-dicyclohexylurea was filtered off, and the filtrate was acidified by treatment with concentrated hydrochloric acid. The resulting green precipitate was filtered off and recrystallized twice from aqueous dimethylformamide to give 3-acetyl-5-ethyl-2-hydroxy-N-(tetrazol-5-yl)benzamide (35.4 g), in the form of a pale yellow solid, m.p. 257°-258° C.
Reaction SMILES: C1(C2C3C=CC4C(=O)NCCC=CCCNC(=O)CN(C=3C=4)C=2C2C=CC(OCC3C=C([N+]([O-])=O)C=CC=3N3CCN(S(C)(=O)=O)CC3)=CC=2)CCCCC1.[CH2:56]([NH:60][C:61]([C:63]1[CH:71]=[C:70]2[C:66]([C:67]([CH:110]3[CH2:115][CH2:114][CH2:113][CH2:112][CH2:111]3)=[C:68]([C:80]3[CH:85]=[CH:84][C:83]([O:86][CH2:87][C:88]4[CH:93]=[C:92]([N:94]5[CH2:98][CH2:97][CH2:96][C:95]5=[O:99])[CH:91]=[CH:90][C:89]=4[N:100]4[CH2:105][CH2:104][N:103]([S:106]([CH3:109])(=[O:108])=[O:107])[CH2:102][CH2:101]4)=[CH:82][CH:81]=3)[N:69]2[CH2:72][C:73](=[O:79])[NH:74][CH2:75][CH2:76]C=C)=[CH:65][CH:64]=1)=[O:62])[CH2:57][CH:58]=[CH2:59]>>[CH:110]1([C:67]2[C:66]3[CH:65]=[CH:64][C:63]4[C:61](=[O:62])[NH:60][CH2:56][CH2:57][CH:58]=[CH:59][CH2:76][CH2:75][NH:74][C:73](=[O:79])[CH2:72][N:69]([C:70]=3[CH:71]=4)[C:68]=2[C:80]2[CH:81]=[CH:82][C:83]([O:86][CH2:87][C:88]3[CH:93]=[C:92]([N:94]4[CH2:98][CH2:97][CH2:96][C:95]4=[O:99])[CH:91]=[CH:90][C:89]=3[N:100]3[CH2:101][CH2:102][N:103]([S:106]([CH3:109])(=[O:107])=[O:108])[CH2:104][CH2:105]3)=[CH:84][CH:85]=2)[CH2:111][CH2:112][CH2:113][CH2:114][CH2:115]1
Reactant: C=CCCNC(=O)Cn1c(-c2ccc(OCc3cc(N4CCCC4=O)ccc3N3CCN(S(C)(=O)=O)CC3)cc2)c(C2CCCCC2)c2ccc(C(=O)NCCC=C)cc21
Agent: CS(=O)(=O)N1CCN(c2ccc([N+](=O)[O-])cc2COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCC=CCCNC5=O)cc2)CC1
Product: CS(=O)(=O)N1CCN(c2ccc(N3CCCC3=O)cc2COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCC=CCCNC5=O)cc2)CC1
Yield: 32 %

Procedure:
The target product 17-cyclohexyl-18-[4-[2-(4-methanesulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1,4,11-triaza-tricyclo[11.5.2.016,19]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione 12 was synthesized in 32% yield, following the procedure reported for the synthesis of compound 3 and using intermediate 11-7 instead of intermediate 3-11; m/z=808 (M+H)+. NMR (DMSO-d6): δ (ppm) 1.21-1.27 (m, 4H, cyclohexyl), 1.66-1.94 (m, 6H, cyclohexyl), 2.06 (qt, J=7.6 Hz, 2H, CH2 pyrrolidinone), 2.30 (m, 4H, 2×CH2CH═CH), 2.48 (m, 2H, CH2 pyrrolidinone), 2.60 (m, 1H, CH cyclohexyl), 2.92 (s, 3H, SO2CH3), 2.99 (m, 4H, piperidine), 3.28 (m, 4H, piperidine), 3.36 (m, 2H, CH2NHCO), 3.43 (m, 2H, CH2NHCO), 3.82 (t, J=7.1 Hz, 2H, CH2 pyrrolidinone), 4.39 (s, 2H, CH2CONH), 5.23 (s, 2H, CH2O), 5.37 (m, 1H, CH═CH), 5.46 (m, 1H, CH═CH), 7.21 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.7 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.58 (dd, J=2.6 Hz, 8.7 Hz, 1H), 7.67 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.86 (d, J=2.6 Hz, 1H), 8.27 (m, 1H, NH), 8.46 (broad t, J=5.9 Hz, NH).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[CH3:40][C:41]([O:44][C:45]([N:47]1[CH2:54][CH2:53][CH2:52][C@H:48]1[C:49](O)=[O:50])=[O:46])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:49]([C@@H:48]2[CH2:52][CH2:53][CH2:54][N:47]2[C:45]([O:44][C:41]([CH3:43])([CH3:42])[CH3:40])=[O:46])=[O:50])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Yield: 51 %

Procedure:
5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol) was treated with 1-{[(1,1-dimethylethyl)oxy]carbonyl}-L-proline (0.022 g, 0.103 mmol), DIPEA (0.090 mL, 0.514 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.079 g, 0.309 mmol) as in the general procedure described herein. The crude product was purified by silica gel chromatography (hexanes/ethyl acetate) to afford the title compound (0.035 g, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.51 (s, 1H), 9.77 (s, 1H), 8.95 (s, 1H), 7.88-7.98 (m, 1H), 7.77 (s, 1H), 7.44 (s, 3H), 7.33-7.40 (m, 1H), 7.27-7.33 (m, 1H), 7.19-7.26 (m, 1H), 7.07 (s, 1H), 4.52 (s, 2H), 4.15 (m, 1H), 3.24-3.45 (m, 2H), 2.14 (m, 1H), 1.62-1.92 (m, 3H), 1.36 (s, 3H), 1.23 (s, 6 H). MS: m/z 666 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH3:5].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Br-:1].[CH2:2]([N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: c1ccncc1
Reactant: CCCCBr
Product: CCCC[n+]1ccccc1
Product: [Br-]

Procedure:
Butylpyridinium bromide is prepared by a Menshutkin reaction of 27.5 g of 1-bromobutane with 15.8 g of pyridine at 40° C. in 24 hours, without solvent. The solid obtained is dried under low vacuum at 50° C.