Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:19].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH3:19])[C:9]1=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCC(NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of tert-butyl(2-oxopiperidin-3-yl)carbamate (1714 mg) in DMF (20 mL) was added 60% sodium hydride (480 mg, containing mineral oil) under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, and iodomethane (1703 mg) was added. The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (530 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].[CH:19]([C:22]1[S:23][CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=1)([CH3:21])[CH3:20].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:16]([C:3]1[C:2]([NH:1][C:27]([C:25]2[N:26]=[C:22]([CH:19]([CH3:21])[CH3:20])[S:23][CH:24]=2)=[O:28])=[C:7]([Cl:8])[C:6]([O:9][CH2:10][CH:11]([O:12][CH3:13])[O:14][CH3:15])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(C)c1nc(C(=O)O)cs1
Reactant: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(COc1ccc(C(C)=O)c(NC(=O)c2csc(C(C)C)n2)c1Cl)OC
Temperature: -10 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
1-[2-amino-3-chloro-4-(2,2-dimethoxy-ethoxy)phenyl]-ethanone (3.98 g, 14.6 mmol) and 2-isopropyl-thiazole-4-carboxylic acid (2.5 g, 14.6 mmol) was dissolved in pyridine (40 mL) and was cooled to −10° C. POCl3 (1.74 mL, 19.0 mmol) was added dropwise. The reaction was stirred at −10° C. for 2 hours. The reaction was quenched with CH3OH (5 mL). After 15 minutes, the reaction was taken up in EtOAc and extracted with 2N HCl(aq). The organic layer was dried with Na2SO4, filtered and was concentrated. 2-Isopropyl-thiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)-phenyl]-amide (5.58 g, 89%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCSc1ccccc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCSc1ccccc1
Yield: 55.7 %

Procedure:
4-(Phenylthio)-1-butanol (5.25 g), 1,6-dibromohexane (21.08 g), TAB (1 g) and 40% sodium hydroxide solution (45 ml) were stirred together at room temperature for 18 h. The mixture was diluted with water (150 ml), extracted with diethyl ether (2×150 ml), the organic layer washed with brine (100 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System A (0:20→1:19) gave the title compound (5.54 g) as a colourless oil. T.l.c. (System A 1:9) Rf 0.12.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:19]2[CH:20]=[CH:21][C:22]([C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][C:5]3[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=3)=[CH:23][C:18]=2[F:17])=[CH:34][N:35]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: N#Cc1cc(Oc2ccccc2Br)ccn1
Product: N#Cc1cc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)ccn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)picolinonitrile and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H14FN5O, 383.12; m/z found, 384.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.50 (d, J=5.7, 1H), 8.40 (d, J=1.3, 2H), 7.61 (dd, J=7.9, 2.0, 2H), 7.53 (dd, J=11.1, 5.0, 2H), 7.48-7.42 (m, 1H), 7.36 (dd, J=12.1, 1.5, 1H), 7.31 (dd, J=11.5, 5.0, 2H), 7.11 (dd, J=5.7, 2.5, 1H), 6.86 (s, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46](Cl)(=[O:48])=[O:47]>O1CCCC1.O>[F:25][C:11]1[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13][N:14]([S:46]([C:42]2[S:41][CH:45]=[CH:44][CH:43]=2)(=[O:48])=[O:47])[C:10]=1[C:9]1[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccs2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of sodium hydride (60% in oil, 37 mg) in tetrahydrofuran (2 mL) were added dropwise a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (1 mL), 15-crown-5 (205 mg) and 2-thiophenesulfonyl chloride (136 mg) at room temperature and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a colorless oil (yield 276 mg, 95%).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:8]([I:19])=[C:9]([C:13]([I:18])=[C:14]([NH2:17])[C:15]=1[I:16])[C:10]([Cl:12])=[O:11])=[O:6])[CH:2]=[CH2:3].[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21]>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([NH:4][C:5]([C:7]1[C:15]([I:16])=[C:14]([NH:17][C:25]([CH2:24][O:23][C:20](=[O:22])[CH3:21])=[O:26])[C:13]([I:18])=[C:9]([C:10]([Cl:12])=[O:11])[C:8]=1[I:19])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=CCNC(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Allylcarbamoyl-5-amino-2,4,6-triiodo-benzoyl chloride (6) (5 g, 8.11 mmol) was dissolved in dry DMA (5 mL) and acetoxyacetylchloride (1.73 mL, 16.2 mmol) was added. The reaction was stirred overnight at room temperature with nitrogen bubbling through. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with ice-water (5×20 mL). The organics were collected, dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The residue was washed with acetonitrile, filtered and dried under vacuum to give acetic acid (3-allylcarbamoyl-5-chlorocarbonyl-2,4,6-triiodo-phenylcarbamoyl)-methyl ester as a white solid. (4.47 g, 77%). The structure was confirmed by 1H and 13C NMR, and purity by LCMS.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[C:14]([C:25](=[O:28])[NH:26][CH3:27])=[N:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17]=2[OH:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br.[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37]>N1C(C)=CC=CC=1C.C(N(C(C)C)CC)(C)C>[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[C:14]([C:25](=[O:28])[NH:26][CH3:27])=[N:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17]=2[OH:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NCCCCCCBr
Reactant: CNC(=O)c1nn(-c2ccccc2)c(O)c1N=Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Product: CNC(=O)c1nn(-c2ccccc2)c(O)c1N=Nc1ccc(S(=O)(=O)NCCCCCCBr)cc1

Procedure:
A suspension of 4-(4-chlorosulfonylphenylazo)-5-hydroxy-3-methylcarbamoyl-1-phenyl-1H-pyrazole (12 g) and 6-bromohexylamine hydrobromide (12 g) in 2,6-lutidine (300 ml) and di-isopropylethylamine (3 ml) was allowed to react for 18 hours at room temperature. The reaction mixture was filtered; the filtrate was concentrated to yield an oily material which was washed with hot water to yield the above-identified pyrazole derivative; yield 7.4 g (44%), m.p. 234°-236° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:25][C:26](OC(C)=O)=[O:27]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:26](=[O:27])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To a suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (46.6 mg, 0.20 mmol), Et3N (26.0 mg, 0.26 mmol) and DMAP (2.5 mg, 0.02 mmol) in CH2Cl2 (4 mL) was added dropwise Ac2O (24.5 mg, 0.24 mmol), and the reaction mixture was then heated to reflux under argon for 1 hr. Cooled to r.t., the reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give 2-acetylamino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as an oil (54.0 mg, 98.2%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: Fc1cccc(F)c1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2,6-difluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 161. 1H NMR(CDCl3) δ 7.23-7.15 (m, 1H), 6.88-6.80 (m, 2H), 6.42 (s, 1H), 6.28 (s, 1H), 4.31 (broad s, 2H), 3.64 (s, 2H), 3.55-3.45 (m, 1H), 3.37-3.23 (m, 2H), 3.15-2.80 (m, 6H), 2.60-2.50 (m, 1H), 2.05-1.82 (m, 2H). LRMS (ES)+: 388.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[C:20]1([S:26]([NH2:29])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:16]([NH:15][S:12]([C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([S:26]([NH:29][C:6]([CH3:10])([CH3:7])[CH3:5])(=[O:28])=[O:27])[CH:21]=2)[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[O:11])[CH:5]=1)(=[O:14])=[O:13])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNS(=O)(=O)c1cc(Br)c(OC)c(C=O)c1
Reactant: NS(=O)(=O)c1ccccc1
Product: CCCCNS(=O)(=O)c1cc(C=O)c(OC)c(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)c1
Yield: 178.3 %

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-N-butyl-5-formyl-4-methoxy-benzenesulfonamide (0.65 g, 1.72 mmol) and N-tert-butyl-3-4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide (0.64 g, 1.90 mmol, 1.1 eq.), gave N-butyl-N′-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide (0.74 g) as on orange oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]=[CH:7][C:6]2=[O:14].Br[CH:18]1[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]1Br.BrC1C2=CC=CC=C2C1I.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[C:8]3[C:7](=[CH:19][C:20]4[C:21]([CH:18]=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:6](=[O:14])[C:5]=2[CH:4]=1
Reactant: BrC1c2ccccc2C1Br
Reactant: O=C1C=CC(=O)c2cc(C(F)(F)F)ccc21
Agent: BrC1c2ccccc2C1I
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1c2ccc(C(F)(F)F)cc2C(=O)c2cc3ccccc3cc21

Procedure:
5.65 g (25 mmol) of 6-(trifluoromethyl)-1,4-naphthoquinone, 9.82 g (approx. 37 mmol) of 1,2-dibromobenzocyclobutene (containing a little 2-bromo-1-iodobenzocyclobutene as an impurity) and 100 ml of xylene are kept under reflux for 16 hours, using a water separator. The mixture is cooled and the precipitate is filtered off and washed with xylene. Yield 5.82 g (71%); melting point 253°-254° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=3[F:28])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:7][CH3:8].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CC1N(C(N(C)C)=O)C1>CCCCCC.C1COCC1>[CH2:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:23]([F:27])[C:22]=3[F:28])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH2:7][CH3:8]
Reactant: CCCc1ccc(-c2ccc(-c3cccc(F)c3F)cc2)cc1
Reactant: CCCCCBr
Agent: CC1CN1C(=O)N(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(-c3ccc(CCC)cc3)cc2)c(F)c1F
Temperature: -100 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium (0.1 mol) in 65 ml of hexane is added to a mixture of 4"-propyl-2,3-difluoro-p-terphenyl (0.1 mol), potassium t-butylate (0.1 mol) and 200 ml of THF at -100° C. After stirring 5 minutes at -100° C. a mixture of brompentane (0.1 mol) and N,N-dimethylpropylene urea (0.1 mol, DMPU) is added. After warming-up to -30° C. and usual work-up 4"-propyl-4-pentyl-2,3-difluoro-p-terphenyl is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].COC1C=C([N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)C=C([N+]([O-])=O)C=1>CO>[N+:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)[CH:10]=1)[C:5]([OH:7])=[O:6])([O-:13])=[O:12]
Reactant: COc1cc(-n2cncn2)cc([N+](=O)[O-])c1
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Solvent: CO
Product: O=C(O)c1cc(-n2cncn2)cc([N+](=O)[O-])c1

Procedure:
3-Nitro-5-(1H-1,2,4-triazol-1-yl)benzoic acid was prepared from 3-bromo-5-nitrobenzoic acid following the procedure in Intermediate 2A. HPLC: Rt=1.12 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=235.07 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.[NH:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1.CC([O-])(C)C.[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C1(C)C=CC=CC=1>[O:77]1[CH2:78][CH2:79][N:74]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=2)[CH2:75][CH2:76]1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(N3CCOCC3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 5 mL microwave vial were added ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate (50 mg, 0.08 mmol), RuPhos (4.0 mg, 0.008 mmol), RuPhos pre-catalyst (6.2 mg, 0.008 mmol), morpholine (10.3 μL, 0.12 mmol), NaOt-Bu (11 mg, 0.12 mmol) and toluene (0.85 mL). The vial was flushed with N2 then capped and placed in a heating block at 85° C. After 1.5 h, the mixture was cooled to RT. The mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). The organic layer was dried with Na2SO4, filtered and concentrated to dryness. The residue was purified by reverse phase HPLC to afford the title compound. MS (ESI): mass calcd. for C37H40N4O4, 604.3; m/z found 605.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30]([O:32][C:33]([C:35]1[C:36]2[S:43][C:42](Cl)=[CH:41][C:37]=2[CH:38]=[N:39][CH:40]=1)=[O:34])[CH3:31].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:30]([O:32][C:33]([C:35]1[C:36]2[S:43][CH:42]=[CH:41][C:37]=2[C:38]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:39][CH:40]=1)=[O:34])[CH3:31]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1cncc2cc(Cl)sc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c2ccsc12
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To the solution of 0.2 g (0.51 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 3 mL N,N-dimethylformamide, 27 mg (0.61 mmol) sodium hydride was added. After 15 min. 148 mg (0.61 mmol) chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was added and stirring was continued for another 2 h at room temperature. The reaction was poured on 20 mL 1N aqueous hydrochloric acid and 20 mL ethyl acetate. The phases were separated, the aqueous layers extracted with 20 mL ethyl acetate and the combined organic layers washed with 20 mL water and 20 mL brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 75:25) to give the desired compound as a white solid (71%). MS (Turbo Spray): m/z=596.3 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH3:7][S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O>>[CH3:7][S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: COC(=O)CN
Reactant: CSc1ccccc1C=O
Product: COC(=O)CNCc1ccccc1SC
Yield: 50 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 2-(methylthio)benzaldehyde. Yield 50%. MS M+H calculated 226.1; found 226.1
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C([Mg]Br)(C)C.[C:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([C:20]([OH:27])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:3][CH:4]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(I)cc1
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
To a stirred solution of tert-butyl 4-iodobenzoate (0.304 g, 1.0 mmol) in 10 mL THF at −40° C. was added a solution of isopropylmagnesium bromide (1.05 ml, 1.05 mmol, 1M in THF) dropwise under argon. After stirring for 1 hour at −40° C., ethyl benzoylformate (0.175 ml, 1.1 mmol) was added dropwise and the cold bath allowed to warm to room temperature over a 40 min. period. The reaction was quenched by the addition of an aqueous solution of 20% ammonium chloride. The reaction mixture was extracted twice with ether, the combined organic layers washed with brine, dried over Na2SO4 and was evaporated to give an oil that was chromatographed on 10 g silica gel using a gradient elution from 0-40% EtOAc in Hexanes. Product containing fractions were combined and concentrated to give (0.078 g, 22%) ethyl (4-tert-butyloxycarbonylphenyl)(hydroxy)phenylacetate as a colorless oil. NMR, 400 MHz (CDCl3) 7.95 ppm (d, J=8.55 Hz, 2H), 7.52 ppm (d, J=8.55 Hz, 2H), 7.30-7.40 ppm (m, 5H), 4.33 ppm (q, J=7.08 Hz, 2H), 4.29 ppm (s, OH, 1H), 1.59 ppm (s, 9H), 1.28 ppm (t, J=7.08 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:40])([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35]C(C)C)=[CH:31][CH:30]=2)([CH3:28])[C:25]([OH:27])=[O:26])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)C(C)C.C(OC(=O)C(C)(C1C=CC(C)=CC=1)CCCCC(=O)CCCCC(C)(C1C=CC(C)=CC=1)C(OCC)=O)C.[OH-].[K+]>O.C(O)C>[CH3:28][C:24]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)([CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:39])[CH2:18][CH2:17][CH2:16][CH2:15][C:11]([CH3:40])([C:8]1[CH:7]=[CH:6][C:5]([CH3:1])=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13])[C:25]([OH:27])=[O:26]
Reactant: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)c1ccc(C)cc1)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(C)cc2)C(=O)O)cc1
Yield: 39 %

Procedure:
According to the procedure given for 210f, 209e (9.0 g, 17.2 mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in water (10 mL) and ethanol (30 mL) at reflux for 6 h. After the usual extractive workup, the crude material was purified by flash chromatography (silica gel; ethyl acetate/hexanes=1/10, 1/6, 1/2) to give 210e (3.1 g, 39%) as a white solid. Mp 48-50° C. 1H NMR (CDCl3): δ 10.8-8.8 (br., 2H), 7.22 (d, 4H, J=8.1), 7.12 (d, 4H, J=8.1), 2.36 (t, 4H, J=7.5), 2.31 (s, 6H), 1.98-1.80 (m, 4H), 1.56-1.44 (m, 4H), 1.51 (s, 6H), 1.24-1.15 (m, 4H). 13C NMR (CDCl3): δ 211.63, 183.07, 140.40, 137.00, 129.58, 126.43, 50.02, 42.82, 39.10, 24.74, 24.50, 22.82, 21.39. HRMS (LSIMS, gly): Calcd for C29H39O5 (MH+): 467.2797. found: 467.2785. HPLC: 92.4% pure. Anal. (C29H38O5) C, H.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH2:8][NH2:9])([CH3:4])[CH3:3].[C:21]1([NH:27][C:28](N)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:8][NH:9][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])([CH3:1])[CH3:3]
Reactant: NC(=O)Nc1ccccc1
Reactant: COCOc1c(C(C)(C)C)cc(CN)cc1C(C)(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COCOc1c(C(C)(C)C)cc(CNC(=O)Nc2ccccc2)cc1C(C)(C)C
Yield: 9148 %

Procedure:
The above-titled compound was prepared substantially in accordance with the procedure described in Example 6A using 5.4 g (19.2 mmol) of 3,5-Bis(1,1-dimethylethyl)-4-(methoxymethoxy) benzylamine (prepared substantially in accordance with the procedures described in Example 1), 2.61 g (19.2 mmol) of N-phenylurea, 0.96 g (16 mmol) of acetic acid and 160 ml of toluene. Such reaction provided 700 g of N-[[3,5-bis-(1,1-dimethylethyl)-4-(methoxymethoxy)phenyl]methyl]-N'-phenylurea. (m.p. 168°-170° C.). The methoxymethyl hydroxy protecting group was then removed, substantially in accordance with the procedure described in Example 6B, to provide 600 mg of the above-titled compound. m.p. 199°-202° C.