Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>[Cu].CN(C=O)C>[N:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: N#Cc1cccc(F)c1
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A mixture of 3-fluorobenzonitrile (18 ml, 168.38 mmol), imidazole (11.46 g), K2CO3 (25.59 g), copper (1.75 g), potassium iodide (1.75 g) and DMF (125 ml) was refluxed overnight. The reaction mixture was cooled to room temperature and poured into ice/water (600 ml). A precipitate formed, which was collected by filtration, washed with water, dissolved in ethanol (25 ml)/CHCl3 (500 ml) and filtered. The filtrates were partitioned in water, the organic layer was separated, dried over MgSO4 and stripped. The residue was combined with the product from another experimental run and was recrystallized from CHCl3 /hexanes to afford 13.4 g of 3-(1-imidazolyl)benzonitrile.
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:14][CH:13]=1.CC#N.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(-n2cccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccc(-c2ccc(-n3cccn3)cc2)cc1
Temperature: 130 °C
Yield: 56 %

Procedure:
Prepared using General Procedure 16. A stirring mixture of p-tolylboronic acid (391 mg, 2.88 mmol) and 1-(4-bromophenyl)-1H-pyrazole (535 mg, 2.40 mmol) INT-84 in THF (4 mL), MeCN (4 mL) and sodium carbonate (1 M aqueous) (4.8 mL, 4.80 mmol) was de-gassed by bubbling through N2 gas. PdCl2dppf (88 mg, 0.120 mmol) was added and the reaction mixture further de-gassed. The reaction was heated at 130° C. for 30 min in a microwave. The mixture was cooled to room temperature, poured onto water (100 mL) and extracted with EA/THF (2×50/10 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (EA/hexanes) to afford 315 mg (56%) of 1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole INT-85. LCMS-ESI (m/z) calculated for C16H14N2: 234; found 235 [M+H]+, tR=2.60 min (Method 10).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10](C([Sn])=C(CCCC)CCCC)[CH2:11]CC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>C1(C)C=CC=CC=1.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>[F:1][C:2]1[CH:8]=[C:7]([CH:10]=[CH2:11])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Nc1ccc(I)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(N)c(F)c1
Temperature: 100 °C
Yield: 93 %

Procedure:
A solution of 2-fluoro-4-iodoaniline (2.37 g, 10 mmol) in toluene (50 mL) was treated with tetrakis(triphenylphosphine)palladium (0.578 g, 0.5 mmol), tributylvinyltin (3.5 mL, 12 mmol) and a catalytic amount of 2,6-di-tert-butyl-4-methylphenol. After being heated at 100° C. for 1 h, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:5) as eluant to afford 2-Fluoro-4-vinylaniline (20-1, LJO-324, 1.275 g, 93%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]#[N:24])[CH:17]=1.[OH-].[K+]>CO>[CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[C:22]([C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[C:23]#[N:24])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: N#CCc1cccnc1
Reactant: CCCCCCOc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCOc1ccc(C=C(C#N)c2cccnc2)cc1

Procedure:
To a stirring solution of 20.6 g of 4-hexyloxybenzaldehyde and 11.8 g of 3-pyridylacetonitrile in methanol was added 25 ml of aqueous potassium hydroxide (25 percent). A precipitate formed and the resultant mixture was stirred at room temperature for an additional two hours. The resultant precipitate was collected by filtration, washed with water and recrystallized from ethanol to yield the intermediate, α-[[4-(hexyloxy)phenyl]methylene]-3-pyridylacetonitrile (m.p. 67°-68° C). 46 g of said nitrile, 10 g of Raney nickel, 150 ml of anhydrous ammonia and 300 ml of tetrahydrofuran were stirred at 100° C. for ten hours at a pressure of 1500 psi. The catalyst and solvent were removed and the residue was taken up in diethyl ether and fitered through magnesia-silica gel. The hydrochloride salt was made in the filtrate by the addition of anhydrous hydrochloric acid. Recrystallization from ethanol yielded β-[[4-(hexyloxy)phenyl]methyl]-3-pyridineethanamine dihydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.COC1C=C([F:30])C(F)=CC=1C=O>>[C:11]1([C:10]#[C:9][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[C:3]([F:30])=[CH:4][C:5]=2[O:18][CH3:19])[OH:17])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1cc(F)c(F)cc1C=O
Product: COc1cc(F)c(F)cc1C(O)C#Cc1ccccc1
Yield: 97 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-methoxy-4,5-difluorobenzaldehyde was reacted to give the title compound as a colourless oil (531 mg, 97%). LCMS (Method B): RT=3.90 min, [M−H2O+H]+=257.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1Br.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>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.O.C(OCC)C.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1Br
Reactant: OB(O)c1ccccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: Brc1ccccc1-c1ccccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A solution of 2-benzyloxyphenylboronic acid (4.3 g. 19.3 mmol) and 1,2-dibromobenzene (9.11 g, 4.66 ml, 38.6 mmol) in 1:1 toluene:ethanol (150 ml) was stirred under nitrogen and tetrakis(triphenylphosphine)palladium(0) (1.12 g, 0.95 mmol) and potassium carbonate (21.3 g, 154 mmol) added. The reaction was stirred at 90° C. under nitrogen for 2 hours. After cooling, diethyl ether (100 ml) and water (100 ml) were added and the organic phase separated. The aqueous phase was extracted with diethyl ether (50 ml) and the combined organic layers washed with water, dried (MgSO4) and the solvent removed in vacuo. The residue was flash chromatographed (silica gel, 5-15% CH2Cl2-isohexane) to give the title compound as a clear oil (4.53 g, 69%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[CH:29]=3)[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.IC>O1CCCC1>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:28]3[CH:32]([CH3:37])[CH2:31][C:30](=[O:33])[CH:29]=3)[CH2:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[C@@H](O[C@H]1CN(C2=CC(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CC(=O)C=C1N1C[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a round bottomed flask, 50 mg (0.0997 mmol) 3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one (Example 3, step F) was dissolved in tetrahydrofuran (5 mL) under nitrogen atmosphere and cooled to −78° C. To this solution was added by syringe, 0.090 mL (0.9 equiv, 0.0897 mmol) of a 1M solution of LiHMDS in THF. The resulting faint yellow solution was stirred for 1 hr at −78° C. then 0.0155 mL (0.249 mmol) iodomethane was added by syringe. The resulting yellow solution was stirred for 5 min at −78° C. then warmed to RT over 30 min. The reaction was quenched by the addition of 2 mL sat. aq. NH4Cl stirred 5 min then 2 mL water was added. The resulting mixture was extracted with ether (3×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum to provide a yellow oil. The resulting oil was purified by prep TLC on silica gel eluting with methylene chloride/methanol (9/1). The UV active band with Rf˜0.85 was isolated. The resulting yellow oil (48 mg) was purified by prep HPLC on Chiralcel OD eluting with heptanes/absolute alcohol (94/6) to afford the title compound as a mixture of stereoisomers. 1H-NMR (CD3OD) rotamers: δ: 1.2-1.45 (m, 6H), 2.04 (m, 1H), 2.78 (m, 1H), 3.18 (m, 1H), 3.30-4.35 (m, 6H), 4.7-4.9 (m, 2H), 4.95, 5.0 (2d, 1H), 6.95-7.02 (m, 2H), 7.10-7.22 (m, 2H), 7.62 (s, 1H), 7.80 (s, 1H), 7.83 (s, 1H)ppm. MS: 516.2 (MH+) observed.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:5]([C:9]([C:12]3[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].CO>N.[Pd]>[NH2:2][CH2:1][C:3]1[C:4]2[N:5]([C:9]([C:12]3[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:29])([F:30])[F:28])=[O:24])[CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(-c2cnc3c(C#N)cccn23)c1
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(-c2cnc3c(CN)cccn23)c1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
1-(3-(8-cyanoimidazo[1,2-a]pyridin-3-yl)-5-isopropoxyphenyl)-3-(2,2,2-trifluoroethyl)urea (0.030 g, 0.072 mmol) was taken up in 7N AMMONIA in methanol (20 mL, 140 mmol) and Pd—C (10 mg, 0.094 mmol) added. Reaction was stirred under H2 balloon for 1 hour. Mixture was then filtered through celite and solvent removed. Residue was dried under high vacuum overnight to to give title compound as a yellow solid (0.026 g, 0.062 mmol, 86% yield). MS (ES+) C20H22F3N5O2 requires: 421. found: 422 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH2:21]([NH:28][CH2:29][C:30]1[N:31]=[N:32][N:33]([CH3:35])[N:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cn1nnc(CNCc2ccccc2)n1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ccccc2)Cc2nnn(C)n2)[C@H]1O
Yield: 48 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using epoxide compound (200 mg, 0.71 mmol) obtained in step 1 of example 2 and N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (145 mg, 0.71 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (165 mg, yield: 48%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12])=[O:4].[CH2:13](O)[CH2:14][OH:15].[Na+].[Cl-]>C1(C)C(C)=CC=CC=1.O>[Cl:1][CH2:2][C:3]1([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=2[CH3:12])[O:15][CH2:14][CH2:13][O:4]1
Reactant: Cc1ccc(C)c(C(=O)CCl)c1
Reactant: OCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc(C)c(C2(CCl)OCCO2)c1
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture of 18.3 g [0.1 mol] of 2-chloro-1-(2,5-dimethylphenyl)ethanone, 12.6 g [0.2 mol] of ethylene glycol, 1.9 g [0.01 mol] of p-TsOH hydrate and 100 ml of xylene is heated to boiling with a water trap for about 3 hours. 40 ml of water and 20 ml of saturated aqueous NaCl solution are then added to the reaction mixture at room temperature. After addition of 20 ml of xylene, the organic phase is separated off and extracted with 20 ml each of water and saturated aqueous NaCl solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. 18.35 g of oil result with, according to GC, 95.3% product (77.2% of theory).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=O)(C)(C)C.[ClH:35]>ClCCl.C(OCC)(=O)C>[ClH:35].[ClH:35].[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C@H:9]3[CH2:10][NH:11][CH2:12][CH2:13][NH:8]3)=[CH:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCN3C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc([C@H]3CNCCN3)cc2)cc1
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4′-methoxybiphen-4-yl)-piperazine (1.46 g, 3.12 mmol) in dichloromethane (8 mL) was added 4 N hydrogen chloride in ethyl acetate (8 mL) at room temperature. After stirring for 1 h, the precipitate was collected and dried in vacuo to afford (S)-2-(4′-methoxybiphen-4-yl) piperazine dihydrochloride (1.00 g, 94%) as white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]#[N:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:20][OH:21].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([NH2:15])=[N:20][OH:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1CN(Cc2ccccc2)CCO1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: NC(=NO)C1CN(Cc2ccccc2)CCO1

Procedure:
To a stirred solution of 4-benzylmorpholine-2-carbonitrile (intermediate 25, 5.0 g, 24.7 mmol) in the mixture of ethanol and water (2/1, 75 ml) was added hydroxylamine hydrochloride (5.2 g, 74.2 mmol) and sodium bicarbonate (13.1 g, 123.5 mmol), and the reaction mixture was stirred under reflux for 12 hours. The reaction was diluted with chloroform, and the reaction mixture was washed with water and brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The resulting 4-benzyl-N′-hydroxymorpholine-2-carboxamidine (intermediate 26) was used for next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[N:15]=[C:16]([O:49][CH3:50])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH:29]C(=O)OC(C)(C)C)=[C:25]([NH:37]C(=O)[O-])[CH:24]=3)=[CH:21][N:20]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]=2[N:19]=1.Cl.N>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[N:15]=[C:16]([O:49][CH3:50])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH2:37])[CH:24]=3)=[CH:21][N:20]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:48])[CH3:47])[C:18]=2[N:19]=1)[C:8]([N:9]([CH3:11])[CH3:10])=[O:12]
Reactant: COc1nc(Nc2ccc(C(=O)N(C)C)cc2Cl)nc2c1c(-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)[O-])c1)cn2COCC[Si](C)(C)C
Agent: Cl
Agent: N
Product: COc1nc(Nc2ccc(C(=O)N(C)C)cc2Cl)nc2c1c(-c1ccc(N)c(N)c1)cn2COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
tert-Butyl 4-(2-(2-chloro-4-(dimethylcarbamoyl)phenylamino)-4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1,2-phenylenedicarbamate (1 equiv) was dissolved in methanolic hydrochloric acid (1N, 7.8 equiv) and stirred at 0° C. overnight. After the reaction was complete, the mixture was basified at 0° C. with aqueous ammonia to pH=7-8 and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave the crude product, which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to afford the title compound (78% yield). MS (ESI) m/z 582.3 [M+1]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:26][C@@H:27]([CH2:40][NH2:41])[CH2:28][O:29][C:30]1[C:38]2[NH:37][C:36](=[O:39])[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1>>[OH:26][C@H:27]([CH2:28][O:29][C:30]1[C:38]2[NH:37][C:36](=[O:39])[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1)[CH2:40][NH:41][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from octane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 230) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.85(t, J=7.0 Hz, 3 H), 1.10–1.40 (m, 10 H), 1.50–1.70 (m, 4 H), 1.95–2.16 (m, 2 H), 2.67 (brt, J=11.1 Hz, 2 H), 2.93 (brt, J=7.9 Hz, 2 H), 2.95–3.20 (m, 3 H), 3.62–3.75 (m, 2 H), 4.00–4.12 (m, 2 H), 4.12–4.30 (m, 1 H), 6.59 (d, J=7.8 Hz, 1 H), 6.63 (d, J=8.3 Hz, 1 H), 6.80–7.00 (m, 3 H), 7.07 (d, J=9.0 Hz, 2 H), 9.33 (brs, 1 H), 10.60 (brs, 1 H), 10.75 (brs, 1 H); MS (ES) m/z: 574.1 (MH+); HRMS Calcd. for C29H44N5O5S (MH+): 574.3063. Found: 574.3084.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])(=O)C.Cl>O1CCOCC1>[NH2:4][C:5]1[S:6][C:7]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)(=[O:14])=[O:15])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11]
Reactant: CC(=O)Nc1sc(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cc(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)sc1N
Temperature: 105 °C
Reaction time: 8 h

Procedure:
The 2-acetylamino-5-(4-trifluoromethoxy-benzenesulfonyl)-thiophene-3-carboxylic acid amide (10 g, crude) is dissolved in 1,4-dioxane (300 mL) and an aqueous solution of 2 M HCl (100 mL). This mixture is stirred at 105° C. overnight, after which the dioxane is concentrated in vacuo and the remaining aqueous basified with an aqueous solution of 5 M NaOH to pH-8-9. The resulting precipitate is collected by filtration, washed thoroughly with water and dried to afford the desired compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=[O:29])[CH:23]=1>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:28]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[OH:29])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(O)c2cccnc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 35 %

Procedure:
Dissolve 4-(tert-butyldimethylsilyloxymethyl)bromobenzene (1 g, 3.319 mmol, prepared by following the procedure described in J. Am. Chem. Soc. 1995, 117, 704-714) in anhydrous THF (20 mL). Cool the solution to −78° C., add n-BuLi (4.149 mL, 6.638 mmol, 1.6M solution in hexane) and stir at this temperature for 1.5 h. Warm to −60° C., stir for an additional 30 min and add 3-pyridine carboxaldehyde. Allow the reaction mixture to warm gradually to room temperature and stir overnight. Add brine and extract with EtOAc. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and EtOAc to give the desired intermediate (380 mg, 35%). MS (ES+) m/z: 330 (M+H)*.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C:24](=[O:35])NC2CCN(C(C)C)CC2)=[O:10])=[N:6][CH:7]=1.NCC[OH:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C:24]([OH:35])=[O:39])=[O:10])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: CC(C)N1CCC(NC(=O)c2nc3ccc(C(=O)O)cc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Product: O=C(Cn1c(C(=O)O)nc2ccc(C(=O)O)cc21)Nc1ccc(Cl)cn1

Procedure:
5-[(2-hydroxy-ethyl)-amide]2-[(1-isopropyl-piperidin-4-yl)-amide]3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-3H-benzoimidazole-2,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-amide]2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 3-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid and 6.7 mg (0.11 mmol) 2-amino-ethanol. The title compound was obtained as its formiate in form of a white amorphous solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:17][C:16]=2[Cl:34])=[N:6][C:7]([S:12][CH3:13])=[N:8][C:9]=1[NH:10][NH2:11])(=[O:3])[NH2:2].C(O[C:38](OCC)(OCC)[CH2:39][CH3:40])C>>[C:1]([C:4]1[C:9]2[N:8]([C:38]([CH2:39][CH3:40])=[N:11][N:10]=2)[C:7]([S:12][CH3:13])=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]2)=[CH:17][C:16]=1[Cl:34])(=[O:3])[NH2:2]
Reactant: CSc1nc(NN)c(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2Cl)n1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2c(C(N)=O)c(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3Cl)nc(SC)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Example 55B (250 mg, 0.49 mmol) was added 1,1,1-triethoxypropane (3 mL) and the mixture was stirred at ambient temperature for 1 hour and heated at 55° C. for 5 hours. After cooling, 90/10 petroleum ether/ethyl acetate was added and the precipitate was collected. The solid was washed with petroleum ether and dried under vacuum to give the title compound. MS: 546 (M+H+).