Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=[O:24])[NH:19][CH2:20][CH:21]([CH2:22][NH2:23])[C:11]([C:12]=23)=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:2]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=[O:24])[NH:19][CH2:20][CH:21]([CH2:22][NH:23][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:11]([C:12]=23)=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCC1CNC(=O)c2cccc3c2c1cn3Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Product: O=C1NCC(CNCc2ccccc2)c2cn(Cc3ccccc3)c3cccc1c23

Procedure:
4 g of oily i-benzyl-3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino(5,4,3-cd]indole (see Example 10 for preparation) were reacted with benzaldehyde by the method described in Example 2, and the resulting Schiff's base was reduced by the method described in Example 2. The reaction mixture was worked up as described in Example 2. 4.3 g of 1-benzyl-3-benzylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole were obtained.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 174.1) and pyrimidin-5-ylboronic acid to afford a white solid. HPLC (Condition 4) tR=4.93 min, UPLC-MS (Condition 3) tR=0.97 min, m/z=476.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.57 (m, J=12.10, 7.80 Hz, 1H) 1.84 (m, J=11.90, 6.10 Hz, 1H) 2.12-2.31 (m, 1H) 2.95 (dd, J=10.56, 7.04 Hz, 1H) 3.08-3.44 (m, 5H) 4.60 (t, J=5.08 Hz, 1H) 7.33 (d, J=8.21 Hz, 2H) 7.84 (d, J=9.38 Hz, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.17 (s, 1H) 10.16 (s, 1H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)CCC.I[C:24]1[C:25]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]2)=[N:26][C:27]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:28][C:29]=1[O:30][CH3:31].CCN(CC)CC>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.O1CCOCC1>[S:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[C:24]1[C:25]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]2)=[N:26][C:27]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[N:28][C:29]=1[O:30][CH3:31]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I
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: C1COCCO1
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Tributylstannylbenzothiazole (221 mg, 0.520 mmol), Compound 21 (150 mg, 0.289 mmol), Tetrakis(triphenylphosphine)palladium (67 mg, 0.0578 mmol), and CuI (11 mg, 0.0578 mmol) were combined. Dioxane (4 mL) was added followed by Et3N (161 μL, 1.16 mmol) and the mixture was degassed and heated to reflux for 2 h. The solution was cooled to room temperature and an aqueous 10% KF solution was added and the mixture was stirred for 30 min. The mixture was diluted with EtOAc and washed with water, brine, dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane to give the title compound as a yellow solid. 1H NMR (CDCl3) δ 10.74 (br s, 1H), 7.86-7.82 (m, 2H), 7.41 (t, J=7.2 Hz, 1H), 7.27 (t, J=7.2 Hz, 1H), 4.25 (br s, 1H), 4.09 (s, 3H), 3.87 (br s, 4H), 3.78-3.76 (m, 4H), 3.52 (br s, 4H), 2.03 (br s, 1H), 1.90 (br s, 1H), 1.76-1.73 (m, 1H), 1.66-1.64 (m, 1H), 1.33 (s, 9H); LCMS 3.28 min, 527 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH2:11](OC=C(C#N)C#N)C>C(O)(C)C>[N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[NH:1][CH:11]=1
Reactant: CCOC=C(C#N)C#N
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: CC(C)O
Product: N#Cc1ccc2nc[nH]c2c1

Procedure:
A mixture of 3,4-diaminobenzonitrile (2) (1.0 g) and (ethoxymethylene)malononitrile (1.4 g) was refluxed in 50 mL of isopropyl alcohol for 16 h. The mixture was concentrated in vacuo to provide the title compound, 3H-benzo[d]imidazole-5-carbonitrile (3).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:18][C:19](=[O:21])[OH:20])[CH:10]=[CH:11][C:12]=2[O:13][C:14]([F:17])([F:16])[F:15])=[CH:5][CH:4]=[N:3]1.CN(C=O)C>C(OCC)(=O)C>[C:7]([O:21][C:19](=[O:20])[NH:18][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]([F:16])([F:17])[F:15])=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)([CH3:8])([CH3:12])[CH3:6]
Reactant: Cn1nccc1-c1cc(NC(=O)O)ccc1OC(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nccc1-c1cc(NC(=O)OC(C)(C)C)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a solution of [3-(2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-carbamic acid tart-butyl ester (65 mg, 0.18 mmol) in DMF (1.5 mL) N-bromosuccinimide (35.6 mg, 0.2 mmol) was added at 0° C. then reaction mixture stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate, washed with brine and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oily residue that was subjected to a purification by flash chromatography (SiO2, Hexanes/EtOAc gradient elution) to afford [3-(2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-carbamic acid tert-butyl ester as a white solid in 89.2% yield. LCMS m/z (%)=436 (M+H 79Br, 100), 438 (M+H 81Br, 98). 1H NMR (400 MHz, CD3OD) δ: 7.79 (d, J=8.90 Hz, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.43 (d, J=8.94 Hz, 1H), 3.73 (s, 3H), 1.55 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7].[CH3:35]I>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([CH3:35])[CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1C1=CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: CI
Product: Cc1ccccc1C1=CN(C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=497.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]dec-3-en-1-one and methyl iodide.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6](O)[C:5]([NH:10][C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[C:4]([C:18]#[N:19])[C:3]=1[CH3:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([F:8])=[C:6]2[O:17][C:11]([C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[N:10][C:5]2=[C:4]([C:18]#[N:19])[C:3]=1[CH3:20]
Reactant: Cc1c(Br)c(F)c(O)c(NC(=O)C(C)(C)CO)c1C#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(F)c2oc(C(C)(C)CO)nc2c1C#N
Temperature: 25 °C
Yield: 53.5 %

Procedure:
N-(4-Bromo-2-cyano-5-fluoro-6-hydroxy-3-methylphenyl)-3-hydroxy-2,2-dimethyl-1-propanamide (I-107) (1.80 g, 5.21 mmol) was dissolved in toluene (36 ml), pyridinium p-toluenesulfonate (262 mg, 1.04 mmol) was added, followed by heating under reflux for 28 hours. After cooling to room temperature, this was diluted with ethyl acetate, and washed with aqueous sodium hydrogencarbonate solution and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (912.6 mg, 54%) as a white solid. The filtrate was concentrated under reduced pressure to obtain a crude form (514.3 mg, 30%) as a pale yellow oily substance.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([NH:19][C:20](=[O:27])[CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:29]/[C:30]2[NH:31][CH:32]=[CH:33][C:34]=2[O:35][CH3:36])/[C:13](=[O:28])[NH:14]3)=[CH:6][CH:5]=1.O[Li].O>C1COCC1.O>[CH3:36][O:35][C:34]1[CH:33]=[CH:32][NH:31][C:30]=1/[CH:29]=[C:12]1\[C:13](=[O:28])[NH:14][C:15]2[C:11]\1=[C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=1)[C:18]([NH:19][C:20](=[O:27])[CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[CH:17][CH:16]=2
Reactant: COC(=O)c1ccc(-c2c(NC(=O)Cc3cccs3)ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(-c3ccc(C(=O)O)cc3)c21
Yield: 28.6 %

Procedure:
Using Method F above, (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-5-[(2-thienylacetyl)amino]-1H-indol-4-yl]-benzoic acid methyl ester (70 mg, 0.14 mmol) (from Example 50 supra) was hydrolyzed with LiOH.H2O (20 mg, 0.48 mmol) in THF (3 mL) and water (2 mL) at room temperature for 3 days to yield (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-5-[(2-thienylacetyl)amino]-1H-indol-4-yl]-benzoic acid (yield: 20 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[NH2:16].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>CC(N(C)C)=O>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:3]1[C:2]([Cl:1])=[N:7][C:6]([CH3:8])=[N:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1nc(Cl)c(N)c(NC2CCOCC2)n1
Solvent: CC(=O)N(C)C
Product: Cc1nc(Cl)c(NC(=O)c2ccccc2Cl)c(NC2CCOCC2)n1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Dissolve 6-chloro-2-methyl-N*4*-(tetrahydro-2H-pyran-4-yl)-pyrimidine-4,5-diamine (24.4 g, 100.4 mmol) in dimethylacetamide (175 mL) in a 500 mL 3-necked flask under a nitrogen atmosphere. Cool the resulting solution to 0-5° C. Via addition funnel, add 2-chlorobenzoyl chloride (15.5 mL, 122.4 mmol) over 20 minutes, maintaining the internal temperature below 10° C. Rinse the addition funnel with dimethylacetamide (1.0 mL). Allow the resulting mixture to stir overnight while self-warming to ambient temperature. Charge ice cold de-ionized water (250 mL) to a second 500 mL flask and then transfer the reaction mixture into the cold water over 20 minutes. Stir the resulting slurry for 2 hours. Filter the solids, wash with cold water (120 mL)) and vacuum dry overnight at 50° C. to afford 2-chloro-N-(4-chloro-2-methyl-6-(tetrahydro-2H-pyran-4-ylamino)-pyrimidin-5-yl) benzamide as an off-white solid (33.1 g). MS (m/z): 381/382 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:7]2[C:6]3[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:28][CH:27]=1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Reactant: ClCc1ccc(Cl)cc1
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3ccc(Cl)cc3)c12
Yield: 92 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 4-chlorobenzyl chloride as starting materials, the title compound was obtained in a yield of 92% as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N+:24]([O-])=O)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:5].O>CN(C=O)C.[Pd]>[NH2:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:15][CH:16]=1
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)Nc1cc(Oc2ccc(N)c3ccccc23)ccn1

Procedure:
To a solution of 2-methoxy-N-(4-(4-nitronaphthalen-1-yloxy)pyridin-2-yl)acetamide (50.0 g, 142 mmol) in DMF (500 mL) under nitrogen was added palladium on carbon (10% w/w Pd/C, 5.0 g, 14.15 mmol) and the mixture was purged with hydrogen and maintained under a slight positive hydrogen atmosphere for 48 hr. The catalyst was removed by filtration through celite and the pad washed with DMF (2×100 mL) and then DCM (100 mL). The solvents were removed in vacuo to afford a dark brown residue which was treated with water (150 mL) and the mixture evaporated. Toluene (100 mL) was added and evaporated to remove residual water. After drying overnight under vacuum, the material was triturated from diethyl ether (250 mL) to give the title compound, Intermediate B1, as a green solid (43.3 g, 85%): m/z 324 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]5[NH:25][C:24]([C:26]6[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=6)=[N:23][C:21]=5[CH:22]=4)=[N:14][C:12]=3[CH:13]=2)[CH2:4][CH2:3]1.[OH-].[NH4+]>C(O)(C)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]5[NH:25][C:24]([NH:23][C:21]=5[CH:22]=4)=[C:26]4[CH:27]=[CH:28][C:29](=[O:32])[CH:30]=[CH:31]4)[NH:14][C:12]=3[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc3[nH]c(-c4ccc5[nH]c(-c6ccc(O)cc6)nc5c4)nc3c2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(c2ccc3nc(-c4ccc5c(c4)NC(=C4C=CC(=O)C=C4)N5)[nH]c3c2)CC1

Procedure:
Hoechst 33258 (3.0 g, 5 mmol) was dissolved in a hot mixture of isopropanol-water (24 mL/12 mL) and neutralized with ammonium hydroxide (3 mL). The precipitate was filtered, triturated with Et2O and dried in vacuo to obtain the free base of bisbenzimidazole. A 1.0 M solution of Bu4NOH in MeOH (0.6 mL, 0.6 mmol) was added to the solution of bisbenzimidazole (1.635 g, 3.85 mmol) in MeOH (30 mL), stirred for 15 min and concentrated to dryness in vacuo. Iodonaphthoquinone 5 (1.485 g, 3.87 mmol) in DMF (30 mL) was added to the tetrabutyl ammonium salt and the mixture was stirred for 48 h. The reaction mixture was suspended in H2O, the crude product was filtered, washed with H2O, dried and purified by flash chromatography (MeOH/CHCl3 1:9, 1:5) to afford 14 as a yellow solid (790 mg, 30%). 1H NMR (CDCl3/MeOH-d4) 8.21 (s, 1H), 8.09 (d, J=7.6 Hz, 1H), 8.05 (d, J=8.7 Hz, 2H), 7.85-7.95 (m, 2H), 7.48-7.75 (m, 4H), 7.14 (bs, 1H), 7.10-6.98 (m 3H), 4.21 (t, J=6.3 Hz, 2H), 4.08 (t, J=6.2 Hz, 2H), 2.65-2.75 (m, 4H), 2.40 (s, 3H), 1.80-2.15 (m, 4H), 1.60-1.75 (m, 4H). MS (LSIMS, 3-NBA) 725.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:7][CH2:8][NH2:9])=[CH:4][S:5][CH:6]=1.[CH2:10]1[O:18][CH:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:18][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][NH:9][CH2:8][CH2:7][C:3]1[C:2]([Br:1])=[CH:6][S:5][CH:4]=1
Reactant: NCCc1cscc1Br
Reactant: c1ccc(C2CO2)cc1
Product: OC(CNCCc1cscc1Br)c1ccccc1

Procedure:
N-(2-hydroxy-2-phenylethyl) 4-bromo-thiophene-3-ethylamine was prepared from 4-bromothiophene-3-ethylamine and styrene oxide by the method described in Example 1(b) and recrystallised from cyclohexane (m.p. 75°).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][N:14]([C@@H:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH3:17])[C:13](=[O:26])[CH2:12]2)[CH3:10])[C:5]2[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:28]([CH3:30])=[N:29][C:4]=2[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[O:47][CH3:48].C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOC1>O>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([C:2]2[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][N:14]([C@@H:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[CH3:17])[C:13](=[O:26])[CH2:12]3)[CH3:10])[C:5]3[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:28]([CH3:30])=[N:29][C:4]=3[CH:3]=2)[CH:44]=[CH:45][C:46]=1[O:47][CH3:48]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4nc(C)n(COCC[Si](C)(C)C)c34)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(OC)c(OC)c4)cc4nc(C)n(COCC[Si](C)(C)C)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
To a (R)-4-((R)-1-(6-chloro-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.65B (1 eq), 3,4-dimethoxy phenyl boronic acid (1.3 eq), Cs2CO3 (3.0 eq) and PEPPSI″-IPr catalyst (0.1 eq) was added 1-4 Dioxane and water (2:1) and the reaction was heated to 100° C. for 1 hr. The reaction mixture was concentrated and purified by normal phase chromatography (Hexanes:Acetone 1:1) to afford (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one.[M+H]+ calcd C36H48N4O6Si: 661.33; found 661.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([NH:8][C:9]2[S:10][C:11]([CH3:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[N:13]=2)[CH:7]=1.O.O.Cl[Sn]Cl>CO>[NH2:20][C:16]1[CH:15]=[C:14]([C:12]2[N:13]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:24][CH3:25])[S:10][C:11]=2[CH3:23])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(Cl)cc1Nc1nc(-c2cccc([N+](=O)[O-])c2)c(C)s1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1ccc(Cl)cc1Nc1nc(-c2cccc(N)c2)c(C)s1

Procedure:
A mixture of 12z (0.25 g, 0.66 mmol) and SnCl2.2H2O (1.35 g, 6.0 mmol) in methanol was refluxed for 48 h. Evaporation of the solvent under reduced pressure afforded 4-(3aminophenyl)-N-(5-chloro-2-methoxyphenyl)-5-methylthiazol-2-amine as a solid which was dissolved in chloroform and cooled in an ice bath to 0° C. Triethylamine (93 μL, 0.66 mmol) was added and the mixture was stirred for 15 min at the same temperature. Pivaloyl chloride (0.08 g, 0.66 mmol) was then added dropwise at 0° C. and the mixture was stirred overnight at which point the mixture was poured onto ice-cold water and the aqueous layer was extracted with DCM. The collected organic extract was washed with sat. aq. NaHCO3 and brine, dried over anhydrous MgSO4, and filtered. Evaporation of the solvent under reduced pressure afforded 13z as a yellowish white solid (0.21 g, 75%). Mp decomposition at 195° C. 1H NMR (300 MHz, CDCl3): δ 7.83 (s, 1H), 7.76 (s, 1H), 7.45 (m, 1H), 7.38 (d, J=2.40 Hz, 1H), 7.33 (s, 1H), 7.27 (m, 1H), 6.93 (d, J=9.0 Hz, 1H), 3.89 (s, 3H), 2.42 (s, 3H), 1.33 (s, 9H). 13C NMR (150 MHz, CDCl3): δ 177.4, 168.4, 151.5, 139.1, 129.9, 127.8, 125.9, 124.3, 123.6, 121.3, 120.3, 118.5, 114.5, 113.3, 111.4, 111.0, 56.4, 39.9, 27.7, 12.5. HRMS m/z (ESI) calcd. for C22H24ClN3O2S (M+H)+ 430.1351. Found 430.1345.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:24][SH:25])[C:4]([N:6]([CH:11]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[CH2:13][CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5].II.O>C(O)C>[CH3:23][O:22][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][C:17]=1[O:20][CH3:21])[CH:11]([N:6]([C:4]([CH:3]1[CH2:24][S:25][S:1][CH2:2]1)=[O:5])[CH2:7][C:8]([OH:10])=[O:9])[CH2:12][CH2:13]2
Reactant: COc1cc2c(cc1OC)C(N(CC(=O)O)C(=O)C(CS)CS)CC2
Agent: II
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OC)C(N(CC(=O)O)C(=O)C1CSSC1)CC2
Yield: 30.2 %

Procedure:
N-(3-Mercapto-2-mercaptomethylpropionyl)-N-(5,6-dimethoxy-1-indanyl)glycine (1 g) is dissolved in 20 ml of ethanol, and a 5% iodine solution in ethanol is added dropwise with ice cooling and stirring. When the color of iodine does not fade any more, the dropping is discontinued, the reaction mixture is poured into 100 ml of water and extracted with ethyl acetate, the extract is dried, and the solvent is then distilled off under reduced pressure. The residue is dissolved in ether, the insoluble substance is filtered off with a small amount of activated carbon, and ether is distilled off at room temperature under reduced pressure, to give 0.3 g of N-(5,6-dimethoxy-1-indanyl)-N-(1,2-dithiolane-4-carbonyl)glycine as a pale yellow viscous oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH3:12])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH3:12])=[CH:4][N:3]=1
Reactant: CCSc1cnc(Cl)cc1C#N
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCSc1cnc(Oc2ccc(Cl)c(Cl)c2)cc1C#N

Procedure:
2-Chloro-5-ethylthio-4-pyridinecarbonitrile (4.0 g) was reacted with 3.6 g of 3,4-dichlorophenol in the presence of 2.6 g of t-BuOK in 40 ml of THF and 4 ml of DMSO. 5.5 g (84.6%) of the desired, 2-(3,4-dichlorophenoxy)-5-ethylthio-4-pyridinecarbonitrile was recovered, m.p. 68°-69° C.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][CH:40]2[CH2:41][CH2:42][N:43]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]4[CH2:29][CH2:28][CH2:27]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:44][CH2:45]2)=[CH:35][CH:36]=1
Reactant: O=C[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Reactant: Fc1ccc(CCCC2CCNCC2)cc1
Product: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1
Yield: 85.5 %

Procedure:
The title compound was prepared from 25 mg (0.06 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, benzyl ester (from EXAMPLE 25, Step B) and 16 mg (0.06 mmol) of 4-(3-(4-fluorophenyl)propyl)piperidine.HCl (from EXAMPLE 96, Step B) using procedures analogous to those described in EXAMPLE 95, Steps F and G. 26 mg (81%) of the title compound was obtained: ESI-MS 507 (M+H); HPLC A: 2.69 min.
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([O:20]C)=[O:19])[CH:12]=[CH:11]2)([CH3:3])[CH3:2].[OH-].[K+]>CO>[CH:22]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=[CH:11]2)([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc2cc(OCCN(C(C)C)C(C)C)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(CCOc1ccc2cc(C(=O)O)ccc2c1)C(C)C
Yield: 95.7 %

Procedure:
3.6 g of methyl 6-(2-diisopropylaminoethoxy)-2-naphthoate and 1.8 g of KOH are heated under reflux for 5 h in methanol. After concentrating and taking up the residue in water, the mixture is adjusted to pH 6 using hydrochloric acid, whereupon the product precipitates. 3.3 g of 6-(2-diisopropylaminoethoxy)-2-naphthoic acid are obtained;