Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(OC)(OC)OC.[F:8][C:9]1[C:17]([I:18])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12]>O1CCCC1>[F:8][C:9]1[C:17]([I:18])=[CH:16][CH:15]=[CH:14][C:10]=1[CH2:11][OH:12]
Reactant: O=C(O)c1cccc(I)c1F
Agent: COB(OC)OC
Solvent: C1CCOC1
Product: OCc1cccc(I)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
Trimethyl borate (1.92 mL, 17.2 mmol) was added dropwise to a stirred solution of 2-fluoro-3-iodobenzoic acid (preparation 22b, 4.39 g, 16.5 mmol) in tetrahydrofuran (25 mL) at 0° C. and the mixture was stirred for a further 15 minutes at this temperature. Then borane-methyl sulfide complex (10 M, 4.4 mL, 44 mmol) in tetrahydrofuran (3 mL) was added dropwise to the mixture at 0° C. and the mixture was then allowed to warm to room temperature. After 1 hour, the mixture was carefully quenched by dropwise addition of methanol (10 mL). After stirring overnight, the mixture was concentrated in vacuo and ethyl acetate was added to the residue. The organic layer was washed with saturated aqueous potassium carbonate solution, brine, dried (MgSO4) and evaporated to give the title compound (4.03 g, 97%) as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:4]=1.[H-].[Na+].[CH3:39]I.Cl>CN(C=O)C.O>[CH3:39][O:1][CH2:2][C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:4]=1
Reactant: CCOC(=O)CCCCCCn1cc(CO)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cn(CCCCCCC(=O)O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 7-(7-(hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (Example 3)(50 mg, 0.103 mmol) in dry DMF (1 ml) under nitrogen was treated with NaH (60% in mineral oil) (4.53 mg, 0.113 mmol) and the resulting mixture was stirred at RT for 15 minutes. Methyl iodide (7.08 μl, 0.113 mmol) was added and stirring continued at RT overnight. The mixture was added to water (30 ml) and the pH was adjusted to pH1 by addition of 2M HCl. The aqueous was extracted with DCM (×3) and the combined organic portions were passed through a phase separating column and concentrated under reduced pressure. The crude product was purified by chromatography on silica eluting with 0-50% EtOAc/iso-hexane. Further purification was carried out by dissolving the product in DCM (minimal) and loading onto a 20 cm×20 cm preparative TLC plate. The plate was run using a solvent system of 67% EtOAc in iso-hexane (300 ml) and the appropriate strip of silica was scrapped off the plate. The Si was suspended in 10% MeOH/DCM and sonicated. The suspension was filtered, rinsing the solid with 10% MeOH/DCM. The filtrate was concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][CH2:34][NH2:35]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:35][CH2:34][CH2:33][C:29]4[N:28]([CH3:27])[CH:32]=[CH:31][CH:30]=4)=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: Cn1cccc1CCN
Product: Cn1cccc1CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Yield: 82 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (13 mg, 0.0365 mmol) described in example 92 and [2-(1-methyl-1H-pyrrol-2-yl)ethyl]amine (45 mg, 0.364 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (13 mg, 86% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.31 (br s, 1 H), 8.56 (s, 1 H), 7.38 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 6.56 (m, 1 H), 6.06 (m, 1 H), 5.99 (s, 1 H), 4.12 (s, 2 H), 3.68 (m, 2 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 2.90 (m, 2 H); MS m/z 435 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29](O)=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:45])[CH3:44])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1.O.C(OCC)(=O)C>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH:43]([CH3:45])[CH3:44])[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:30])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1
Temperature: 65 °C
Yield: 34 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid (256) (0.5 g, 1.19 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) (0.78 g, 3.58 mmol) in dry tetrahydrofuran (20.0 mL) were added propylphosphonic anhydride (0.76 g, 2.39 mmol, 50% in ethyl acetate) and diisopropyl ethylamine (0.8 mL, 4.78 mmol) at room temperature and the reaction mixture was heated at 65° C. for 4 h. After completion of the reaction, the mixture was portioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to get a crude product which was purified by normal silica gel column chromatography (using 30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (257) (0.25 g, 34.0%) as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:14]([O:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)c1cc(O)ccc1N
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cc(OCc2ccccc2)ccc1N

Procedure:
A mixture of 5-hydroxyanthranilamide (15.2 g), 250 ml water, 5.1 ml 50% NaOH, and 11.7 ml benzyl chloride was heated 1/2 hour at 95°, filtered and the solid recrystallized from 200 ml butanol to give 16.6 g product, m.163-5.
Reaction SMILES: [CH2:1]([S:7][CH:8]=[CH:9][CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:11][CH2:10][CH:9]=[CH:8][S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCSC=CCO
Solvent: c1ccncc1
Product: CCCCCCSC=CCOC(C)=O
Temperature: 25 °C

Procedure:
To the above alcohol (0.64 g) is added 2 ml of pyridine, followed by 1 ml of acetic anhydride and the mixture is stirred at RT to give 3-hexylthio-2-propenyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][O:14][CH2:15][C:16]([OH:18])=O)[CH2:7][CH:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:5][C:4]=2[N:3]=1.S(Cl)(Cl)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)CC)C>C(Cl)Cl>[N:35]1([C:16](=[O:18])[CH2:15][O:14][N:13]=[C:8]2[CH2:7][CH:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:5][C:4]3[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]2=3)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: C1COCCN1
Reactant: Cc1nc(N)nc2c1C(=NOCC(=O)O)CC(c1ccccc1-c1ccccc1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1nc(N)nc2c1C(=NOCC(=O)N1CCOCC1)CC(c1ccccc1-c1ccccc1)C2

Procedure:
The title compound was prepared from (2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-ylideneaminooxy)-acetic acid (compound 69) by treating with thionyl chloride followed by amidation using morpholine and triethylamine in DCM.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]2[CH2:10][CH:6]([CH2:7][CH:8]2[C:11](Cl)=[O:12])[C:5]=1[CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)([CH3:26])[CH3:25])=[CH:20][CH:19]=1.C1C[O:37]CC1>N1C=CC=CC=1>[CH2:1]([C:4]1[CH:9]2[CH2:10][CH:6]([CH2:7][CH:8]2[C:11]([OH:17])=[O:12])[C:5]=1[CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].[CH2:1]([C:4]1[CH:9]2[CH2:10][CH:6]([CH2:7][CH:8]2[C:11]([OH:37])=[O:12])[C:5]=1[CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].[OH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)([CH3:26])[CH3:25])=[CH:22][CH:23]=1
Reactant: C1CCOC1
Reactant: C=CCC1=C(CC=C)C2CC1CC2C(=O)Cl
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: C=CCC1=C(CC=C)C2CC1CC2C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
130 g of diallyl-bicyclo[2.2.1]hept-5-ene-2-carbonyl chloride are added dropwise at 20° C. within 30 minutes to a solution of 62.7 g of bisphenol A in 200 ml of pyridine. The mixture is then stirred for 1 hour at 80° C. and then worked up as described in Example 2. This gives 162 g (95% of theory) of a brown, liquid resin with η25 =3,165 mPas. By gel permeation chromatography (THF), the molecular weight is found to be 610 (Mn) or 691 (Mw).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([O:11]C)[O:9]C)=[C:4]([F:13])[C:3]=1[O:14][CH3:15].[OH-:16].[K+:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B-:8]([OH:16])([OH:11])[OH:9])=[C:4]([F:13])[C:3]=1[O:14][CH3:15].[K+:17]
Reactant: [OH-]
Reactant: COB(OC)c1ccc(Cl)c(OC)c1F
Agent: [K+]
Product: COc1c(Cl)ccc([B-](O)(O)O)c1F

Procedure:
Another embodiment of the present disclosure includes a method of forming 2-(4-chloro-2-fluro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane that comprises contacting 2-chloro-6-fluoroanisole with n-butyl lithium to form 6-chloro-2-fluoro-3-lithioanisole. The 6-chloro-2-fluoro-3-lithioanisole may be contacted with trimethyl borate to form dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate. The dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate may be reacted with aqueous potassium hydroxide to form potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate. The potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate then may be reacted with aqueous hydrochloric acid to form 4-chloro-2-fluoro-3-methoxyphenylboronic acid. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid may be reacted with 2,3-dimethyl-2,3-butanediol.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11].CCCCCC>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH:20]=[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:24])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1)#[N:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N#Cc1ccc(N)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(C#N)cc1)C(=O)OCC
Yield: 87.5 %

Procedure:
To 5.00 g (42.3 mmol) 4-aminobenzonitrile (Aldrich, 98%) was added 10.1 g (9.41 mL, 46.6 mmol, 1.1 eq) diethylethoxymethylenemalonate (Aldrich, 99%), and the mixture was dissolved in 50 mL toluene (HPLC grade). The solution was refluxed for four hours with a condensor open to the air. The solution was then poured into 200 mL hexane, and the resulting white precipitate was filtered and washed well with more hexane to yield 10.62 g (37.0 mmol, 85% yield) of the title compound as a slightly off-white solid (per LC/MS and 1H NMR). LC [MH+] 289, 97% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][C:11]=2[CH3:22])=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:31](=[O:32])[CH2:30][OH:33])[CH2:18][CH2:17]3)=[N:12][C:11]=2[CH3:22])=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Cc1nc(N2CCNCC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)CO
Product: Cc1nc(N2CCN(C(=O)CO)CC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
100 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(piperazin-1-yl)nicotinamide was coupled to glycolic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2-hydroxyacetyl)piperazin-1-yl)-2-methylnicotinamide. MS (Q1) 466.3 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[N:9]1[C:29](=[O:52])[CH2:30][NH:31][C:32](=[O:51])[NH:33][C:34]1[CH:35]=[C:36]([CH2:40][C:41]([O:43]CC2C=CC=CC=2)=[O:42])[CH:37]=[CH:38][CH:39]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH:11]([S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[N:9]1[C:29](=[O:52])[CH2:30][NH:31][C:32](=[O:51])[NH:33][C:34]1[CH:35]=[C:36]([CH2:40][C:41]([OH:43])=[O:42])[CH:37]=[CH:38][CH:39]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CC(S(=O)(=O)c2ccccc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CC(S(=O)(=O)c2ccccc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 46 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 2A, but from 3.6 g of benzyl (2RS,4SR,5RS)-3-{3-[2-(2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-phenylsulphonyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetate 0.4 g of 10% palladium-on-charcoal in 200 cm3 of ethanol. After treatment, there are obtained 1.45 g of (2RS,4SR,5RS)-3-{3-[2-(2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-phenylsulphonyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetic acid [Rf =0.27; eluent: methylene chloride/methanol (80/20)].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.[ClH:17].[H][H]>CO.[Pd]>[ClH:17].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=[O:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH:2]=1
Reactant: O=C1C(=Cc2cccnc2)N2CCC1CC2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1C2CCN(CC2)C1Cc1cccnc1

Procedure:
2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (20 g, 93 mmol) was suspended in methanol (200 mL) and treated with 46 mL of 6N HCl. 10% Palladium on carbon (1.6 g) was added and the mixture was shaken under 25 psi hydrogen for 16 h. The mixture was filtered through Celite and solvent removed from the filtrate by rotary evaporation, to give crude 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one hydrochloride as a white gum (20 g). This was treated with 2N NaOH (50 mL) and chloroform (50 mL) and stirred for an hour. The chloroform layer was separated and the aqueous phase was treated with 2N NaOH, enough to raise the pH to 10 (about 5 mL), and saturated aqueous NaCl (25 mL). This was extracted with chloroform (3×10 mL), and the combined extracts were dried (MgSO4) and concentrated by rotary evaporation. The residue (18 g) was dissolved in warm ether (320 mL) and cooled to 4° C. The white solid was filtered off, washed with a small portion of cold ether and air dried. Concentration of the filtrate to ˜10% of its former volume and cooling at 4° C. produced a second crop. A combined yield 16 g (79%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14].[OH-].[Na+].C(O)=O>CO>[CH3:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:14])([F:15])[F:16]
Reactant: COC(=O)c1c[nH]c(-c2ccccc2C(F)(F)F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: Cc1c(C(=O)O)c[nH]c1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 83.4 %

Procedure:
Methyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (1.4 g, 4.9 mmol) was dissolved in methanol (12 mL), and a 5 M aqueous sodium hydroxide solution (10 mL) was added thereto, and the resulting mixture was heated under reflux for 3 hours. After the mixture was cooled to room temperature, formic acid (5 mL) was added thereto to stop the reaction. After the mixture was concentrated under reduced pressure, water (10 mL) was added thereto to suspend the resulting residue. The precipitated solid was collected by filtration and washed times with water. The obtained solid was dried under reduced pressure, whereby 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (1.1 g, 83%) was obtained as a solid. The thus obtained solid was suspended in dichloromethane (10 mL), oxalyl chloride (0.86 mL, 10 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 2 hours. After the mixture was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL), and 4-(methylsulfonyl)aniline hydrochloride (1.0 g, 4.9 mmol) and N,N-diisopropylethylamine (2.8 mL, 16 mmol) were sequentially added to the solution, and the resulting mixture was heated under reflux for 18 hours. After the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and acetonitrile (10 mL) and 3 M hydrochloric acid (100 mL) were added to the residue. A precipitated solid was triturated, collected by filtration and washed with water, and then, dried under reduced pressure, whereby 4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (1.4 g, 89%) was obtained as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]2[NH:7][C:8]([CH:10]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][NH:22]4)[CH2:11][CH:12]([CH3:17])[C:13](OC)=[O:14])=[N:9][C:5]=2[CH:4]=1)#[N:2].[BH4-].[Na+]>CO>[OH:14][CH2:13][CH:12]([CH3:17])[CH2:11][CH:10]([C:8]1[NH:7][C:6]2[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)[C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2
Reactant: COC(=O)C(C)CC(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(CC(C)CO)c1nc2cc(C#N)ccc2[nH]1
Temperature: 60 °C

Procedure:
A solution of (±)-methyl 4-(5-cyano-1H-benzo[d]imidazol-2-yl)-4-(5-methoxy-7-methyl-1H-indol-4-yl)-2-methylbutanoate (Example 151-B) (95 mg, 0.228 mmol) in MeOH (3 mL) was treated with sodium borohydride (220 mg, 6.7 mmol) and heated at 60° C. for 4 hours. The reaction was cooled to room temperature and quenched with a saturated solution of ammonium chloride. The product was extracted with ethyl acetate, the organics were dried over sodium sulfate, concentrated and purified via reversed phase FCC(C18 gold column, 10-70% ACN:water) to obtain the title compound as a mixture of diastereomes. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (br. s., 1H) 7.96 (br. s., 1H) 7.55 (br. s., 1H) 7.46-7.52 (m, 1H) 7.15 (t, J=2.75 Hz, 1H) 6.79 (s, 1H) 6.14 (d, J=1.96 Hz, 1H) 5.01 (dd, J=10.39, 4.89 Hz, 1H) 3.70-3.81 (m, 3H) 3.17-3.23 (m, 1H) 3.09-3.16 (m, 1H) 2.45 (d, J=0.61 Hz, 3H) 2.38 (ddd, J=13.57, 10.39, 3.67 Hz, 1H) 2.14-2.24 (m, 1H) 1.21-1.33 (m, 2H) 0.95 (d, J=6.60 Hz, 3H). HRMS calcd. for C23H24N4O2 (M+H)+ 389.1975. found 389.1978.
Reaction SMILES: [CH:1](=[N:23][OH:24])[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][N:16]=4)[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClN1C(=O)C[CH2:28][C:27]1=O.C(Br)=C.C(N(CC)CC)C>CN(C=O)C.O>[O:24]1[CH:28]=[CH:27][C:1]([C:2]2[CH:22]=[CH:21][C:5]3[N:6]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]5[CH:20]=[CH:19][N:18]=[CH:17][N:16]=5)[CH:10]=4)[CH:7]=[N:8][C:4]=3[CH:3]=2)=[N:23]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Agent: C=CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(-c2ccncn2)cc(-n2cnc3cc(-c4ccon4)ccc32)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
A mixture of 42a (2.1 g) and N-chlorsuccinimide (1.1 g, 1.2 equivalents) in DMF (100 ml) was stirred under argon at 60° C. for 0.5 hours. Vinyl bromide (25 ml) was added to the reaction mixture under ice-cooling, and thereafter triethylamine (4.8 ml, 5 equivalents) in 15 ml DMF was added dropwise over one hour. The mixture was stirred at 0° C. for 3 hours and at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried, and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel using a mixture of CH2Cl2 and methanol (30:1) as the eluent to give 5-(3-isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (1.5 g, 64%).M.p. 214-215° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[C:2]=S.NC1C=CC=CN=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21]([C:20]1[CH:25]=[CH:26][C:27]2[NH:28][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=3)=[N:17][C:18]=2[CH:19]=1)=[O:22]
Reactant: S=C=Nc1ccccn1
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: Nc1ccccn1
Product: COC(=O)c1ccc2[nH]c(Nc3ccccn3)nc2c1

Procedure:
2-Isothiocyanatopyridine (4 mmol), prepared from 2-aminopyridine employing general procedure A, was reacted with methyl 3,4-diaminobenzoate as described in general procedure B to afford 2-(pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid methyl ester. This ester was hydrolyzed, following general procedure C, to obtain 2-(pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.CC(C)([O-])C.[K+].[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=1.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[OH:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=[C:2]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=3)[CH:7]=2)[CH2:9][CH2:10]1
Reactant: OC1CCN(c2cc(Cl)nc(-c3ccccc3)c2)CC1
Reactant: CC(=O)c1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Nc2cc(N3CCC(O)CC3)cc(-c3ccccc3)n2)cc1
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a solution of 2′-chloro-6′-phenyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ol (40 mg, 0.13 mmol) in toluene (4 mL) were added potassium tert-butoxide (31 mg, 0.26 mmol), palladium(II)acetate (3 mg, 0.156 mmol), BINAP (4 mg, 0.0065 mmol) and 1-(4-aminophenyl)-ethanone (22 mg, 0.156 mmol) in a 10 mL reaction vessel. This reaction mixture was subjected the microwave radiation, in which the microwave power was 250 W, to attain a reaction temperature of 150° C. After this reaction proceeded for 30 min, water (5 mL) was added to the reaction mixture and the reaction product was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and the filtrate concentrated under vacuum. The product was purified through column chromatography using 230-400 mesh silica gel (5% methanol in dichloromethane) to afford the desired compound as a yellow solid (29 mg, yield 55%, purity 96%).