Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:13]1[Se:14][CH:15]=[CH:16][CH:17]=1)(=O)[CH3:11]>>[C:2]1([NH:8][N:9]=[C:10]([C:13]2[Se:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc[se]1
Reactant: NNc1ccccc1
Agent: Cl
Product: CC(=NNc1ccccc1)c1ccc[se]1

Procedure:
This compound is prepared from commercial phenylhydrazine hydrochloride (Aldrich) and 2-acetylselenophene, which is itself obtained according to the procedure described by S. Umezawa (reference 18).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=3)=[O:21])=[C:15]([C:29]3[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31][CH:30]=3)[CH:14]=2)([N:10]=[N+]=[N-])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:37]([OH:40])(=[O:39])[CH3:38]>C1COCC1.[Zn]>[C:37]([OH:40])(=[O:39])[CH3:38].[C:1]([N:4]1[CH2:5][CH2:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=3)=[O:21])=[C:15]([C:29]3[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31][CH:30]=3)[CH:14]=2)([NH2:10])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N=[N+]=[N-])(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(N)(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-acetyl-4-azido-piperidin-4-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step, 40.0 mg, 0.0822 mmol) and zinc (54.0 mg, 0.822 mmol) in 1.6 mL of THF was added acetic acid (0.40 mL). The resulting mixture was stirred at RT for 16 h under Ar. The solid was removed by filtration on Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10% MeOH/DCM) to give 13 mg (30%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.33 (d, 1H, J=8.6 Hz), 7.91 (s, 1H), 7.52 (dd, 1H, J=8.6, 2.3 Hz), 7.40 (s, 1H), 5.77 (m, 1H), 3.76-3.98 (m, 2H), 3.42 (m, 2H), 2.46 (m, 2H), 2.32 (m, 2H), 2.13 (s, 3H), 2.07 (m, 2H), 1.86-2.03 (m, 2H), 1.93 (s, 6H), 1.59 (t, 2H, J=6.1 Hz). Mass spectrum (ESI-neg, m/z): Calcd. for C26H32N6O2, 459.3 (M−H). found 459.5.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:14]=[C:15]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=[C:17]([N+:18]([O-])=O)[C:4]=2[N:3]=1>CCO.[Pd]>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:14]=[C:15]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=[C:17]([NH2:18])[C:4]=2[N:3]=1
Reactant: Cc1nc2c([N+](=O)[O-])cc(N3CCOCC3)cc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2c(N)cc(N3CCOCC3)cc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 50 h
Yield: 47.6 %

Procedure:
To a solution of 2-methyl-6-(4-morpholinyl)-4-nitro-1-(phenylmethyl)-1H-benzimidazole (17 g) in EtOH (300 mL) was added watery Pd/C (8.7 g) and the mixture was stirred at 60° C. for 50 h under H2 atmosphere (4 atm). The mixture was cooled to room temperature and filtered; the filtrate was concentrated in-vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to afford the desired product as a white solid (7.4 g, 66%). 1H NMR (300 MHz, DMSO-d6): δ ppm 2.37 (s, 3H), 2.96 (t, 4H, J=4.8 Hz), 3.72 (t, 4H, J=4.8 Hz), 4.94 (br s, 2H), 6.04-6.11 (m, 2H), 11.57 (br s, 1H); LC-MS: m/e=233 [M+1]+
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH:41]6[CH:42]([O:43]C(=O)C)[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:56]([CH3:58])[CH3:57])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O>CO>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:56]([CH3:58])[CH3:57])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Yield: 77.3 %

Procedure:
90 mg of compound (5) was dissolved in 2.2 ml of methanol and stirred together with 121 μl of 1N NaOH for 2 hours under cooling with ice. After addition of water, the reaction solution was extracted with ethyl acetate, and the ethyl acetate extract was dried over anhydrous sodium sulfate and concentrated in vacuo to dryness to give 66 mg of compound (6) as a colorless powder.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[Cl:21][C:22]1[C:27]([CH3:28])=[C:26](Cl)[N:25]=[CH:24][N:23]=1>C1COCC1>[Cl:21][C:22]1[N:23]=[CH:24][N:25]=[C:26]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[C:27]=1[CH3:28]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 30 °C
Reaction time: 17.5 h

Procedure:
Potassium tert-butoxide (3.4 gm, 0.0306 moles) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (6.8 gm, 0.0368 moles) and 4,6-dichloro-5-methylpyrimidine (5.0 gm, 0.0368 moles) in dry THF at 0° C. and the reaction mixture was stirred for 15-20 hours at 30° C. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The organic extract was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to collect 5.1 gm off-white solid product.
Reaction SMILES: [Cu]C#N.[Br-].[Li+].[I-].[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Zn+])#[N:8].[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].[NH4+].[Cl-]>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[C:7]#[N:8])=[O:22]
Reactant: COc1ccc(C(=O)Cl)cc1Br
Reactant: N#Cc1c(F)cccc1[Zn+]
Agent: N#C[Cu]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cccc(F)c2C#N)cc1Br
Yield: 53.7 %

Procedure:
To a solution of copper(I) cyanide (1.746 g, 19.50 mmol) and lithium bromide (0.98 mL, 39 mmol) in anhydrous THF (40 mL), (2-cyano-3-fluorophenyl)zinc(II) iodide (0.5M in THF, 39 mL, 19.50 mmol) was added at −78° C. followed by addition of 3-bromo-4-methoxybenzoyl chloride (5.35 g, 21.45 mmol) in THF (40 mL). The reaction mixture was allowed to reach room temperature and stirred over night. Saturated aqueous NH4Cl (40 mL) was added and the resulting mixture was concentrated under reduced pressure. The residue was diluted with water (30 ml) and extracted with DCM (3×50 mL). The combined organic extracts were passed though a phase separator (Sorbent) and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-60% ethyl acetate in heptane) to afford the title compound (3.5 g, 54%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[CH:19]1([N:25]=[C:26]=[S:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[S:27])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: S=C=NC1CCCCC1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: S=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)NC1CCCCC1
Yield: 36.4 %

Procedure:
1-(3-Aminopropyl)-4-(4-chlorobenzyl)piperazine (5.36 g; 20 mmole) was reacted with cyclohexyl isothiocyanate (2.82 g; 20 mmole) in methylene chloride (35 ml) for two hours in the manner described in Example 17. The crude product was isolated and chromatographed on silica gel in analogous manner. The product, on recrystallization from ethanol, yielded the title compound (2.98 g; 36% yield) as colorless crystals, m.p. 127°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[NH:26][C:25](/[CH:27]=[CH:28]/[CH2:29][NH:30]C(=O)OC(C)(C)C)=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.[OH-].[Na+]>O1CCCC1>[NH2:30][CH2:29]/[CH:28]=[CH:27]/[C:25]1[NH:26][C:19]2[C:18]([NH:17][C:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:23][CH:22]=[N:21][C:20]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC/C=C/c1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of tert-butyl (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]prop-2-enylcarbamate (150 mg) in tetrahydrofuran (6.0 mL) was added 2N hydrochloric acid (3.0 mL) at room temperature and the mixture was stirred at 60° C. for 2 hrs. 1N Aqueous sodium hydroxide solution was added to alkalize the reaction system. After extraction with chloroform, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resultant crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (104 mg) as pale-brown powder crystals.
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[CH3:18][C@H:19]1[S:23][C:22](=[O:24])[NH:21][C@@H:20]1[C:25]([OH:27])=O.[N+]([O-])(O)=O.[N+:32]([O:35][CH2:36][CH2:37][NH2:38])([O-:34])=[O:33]>O1CCCC1>[N+:32]([O:35][CH2:36][CH2:37][NH:38][C:25]([C@@H:20]1[C@@H:19]([CH3:18])[S:23][C:22](=[O:24])[NH:21]1)=[O:27])([O-:34])=[O:33]
Reactant: NCCO[N+](=O)[O-]
Reactant: C[C@H]1SC(=O)N[C@@H]1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Product: C[C@H]1SC(=O)N[C@@H]1C(=O)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 65.1 %

Procedure:
1.33 ml of triethylamine and 0.36 ml of diethyl cyanophosphonate were added, whilst ice-cooling and stirring, to a suspension of 322 mg of (4R,5R)-5-methyl-2-oxothiazolidine-4-carboxylic acid and 406 mg of N-(2-nitrooxyethyl)amine nitrate in 40 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 1 hour and 25 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with ethyl acetate. The resulting mixture was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residual yellow oil thus obtained was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 324 mg of the title compound as a pale yellow oil.
Reaction SMILES: [Li]CCCC.[S:6]1[C:10]2[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[S:13][C:9]=2[CH:8]=[CH:7]1.[Sn:17](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:26]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[C:15]1[S:16][C:11]2[C:10]3[S:6][CH:7]=[CH:8][C:9]=3[S:13][C:12]=2[CH:14]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cc2sc3ccsc3c2s1
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc2sc3ccsc3c2s1

Procedure:
2.5 M of n-BuLi (2.04 mL/hexane, 5.09 mmol) was added to dithieno[3,2-b;2′,3′-d]thiophene 20 (1 g, 5.09 mmol/THF (20 mL)) and reacted at 0° C. for 1 hour under a dry and anaerobic operation condition to form a solution. SnBu3Cl (1.58 mL, 5.6 mmol) was then added to the solution and reacted at 0° C. for 30 minutes. After returning to room temperature, the solution was continuously reacted for 8 hours. After the reaction was completed, the solution was extracted by ether (30 mL) and deionized water (50 mL). An organic phase was collected. After removal of ether by a rotary concentrator, the organic phase was purified by reduced-pressure distillation to form a transparent pale yellow oily product (25, 2.1 g, 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][CH2:6][C:5](=[CH:8][CH2:9][N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13]([NH2:20])=[N:14][C:15]=3[Cl:19])[CH2:4][O:3]1>[Pd].O1CCCC1>[NH2:20][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[CH:18][N:10]2[CH2:9][CH2:8][CH:5]2[CH2:4][O:3][C:2]([CH3:1])([CH3:21])[O:7][CH2:6]2)=[C:15]([Cl:19])[N:14]=1
Reactant: CC1(C)OCC(=CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
5% Palladium on carbon (1.5 g) in tetrahydrofuran (40 ml) was prehydrogenated for 30 min at 50 p.s.i. 2,2-Dimethyl-5-[2-(2-amino-6-chloropurin-9-yl)]ethylidene-1,3-dioxane (3.0 g) in tetrahydrofuran (80 ml) was added and washed in with tetrahydrofuran (30 ml). The mixture was hydrogenated overnight at 50 p.s.i. with stirring. The catalyst was removed by filtration to give a colourless solution. The solvent was removed under reduced pressure and the residue recrystallised from IPA to give the title compound (1.92 g, 62.2% yield).
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:20][NH:21][CH3:22]>CN(C=O)C.O.C(Cl)Cl>[CH3:20][N:21]([CH3:22])[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: N#Cc1c(Br)n(-c2ccc(O)cc2)c2ccccc12
Reactant: CNC
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)c1c(C#N)c2ccccc2n1-c1ccc(O)cc1
Temperature: 80 °C

Procedure:
2-Bromo-1-(4-hydroxy-phenyl)-1H-indole-3-carbonitrile (Example 1) was mixed with excess dimethylamine in DMF (1:3) and the mixture was stirred in a sealed vial at 80° C. over night. The reaction-mixture was cooled to rt, diluted with H2O and DCM and then the phases were separated. The organic phase was evaporated to dryness and subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC, ES/MS m/z: 278.1 (M+H), 276.1 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.42 (m, 1H), 7.33 (m, 2H), 7.17 (m, 1H), 7.09-7.05 (m, 3H), 6.95 (m, 1H) and 2.93 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C@@H:10]([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.I[CH:14]([CH3:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH:14]([CH3:16])[CH3:15])[C@@H:10]([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CC(C)I
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)N1c2cc(Cl)nc(=O)n2C[C@@H]1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-7-chloro-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.27 mmol) and 2-iodopropane (68.7 mg, 0.404 mmol) in acetonitrile (1 mL) was added Cs2CO3 (176 mg, 0.539 mmol). The reaction mixture was stirred at 90° C. for 1 h, then cooled to room temperature, filtered and concentrated to give the residue as a brown solid. The crude was used into next step without purification.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=2B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][O:29][C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][C:35]=2[C:2]2[C:3]3[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(Cl)nc(C)nc12
Reactant: Cc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C)ccc3OCC3CC3)nc(C)nc12

Procedure:
Starting from methyl 4-chloro-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A.11) and 2-(2-cyclopropylmethoxy-5-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c8) the title compound is obtained as off white solid.
Reaction SMILES: I[CH:2]([C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]([F:11])([F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([SnH](CCCC)CCCC)CCC>>[F:10][C:4]([F:11])([CH2:3][CH2:2][C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:19])([F:20])[C:15]([F:16])([F:18])[F:17])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(F)(F)CC(I)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCCC[SnH](CCCC)CCCC
Product: CCOC(=O)C(F)(F)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
The compound ethyl 4-iodo-2,2,5,5,6,6,7,7,8,8,8-undecafluorooctanoate prepared from Example 5 (99.2 g, 0.2 mol) was added dropwise into a well-stirred tributyltin hydride liquid (58.5 g, 0.201 mol). The reaction temperature was controlled at ~30° C. during the process. After addition was complete, the mixture was stirred at 50° C. for 2 hr. The product ethyl 2,2,5,5,6,6,7,7,8,8,8-undecafluorooctanoate (65.0 g, 88% yield) was isolated by distillation as a clear, colorless liquid having a boiling point of 38°-39° C. at 3 mmHg.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:36]1([CH:41]2[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:43]4[CH2:44][CH2:45][CH:41]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH2:42]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: C1CCN(C2CCNC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N5CCCC5)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-pyrrolidinyl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 472 [M+H]
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[N:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.N(CCO)CCO>C1(C)C=CC=CC=1>[Br:1][CH2:2][C@@H:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[N:13]=2)[N:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: COc1ccc2nccc(C(=O)CBr)c2n1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: OCCNCCO
Solvent: Cc1ccccc1
Product: COc1ccc2nccc([C@@H](O)CBr)c2n1
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Bromomethyl-(6-methoxy-[1,5]-naphthyridin-4-yl)-ketone (6.6 g, 0.023 mol) in toluene was treated with (+)-B-chlorodiisopinocamphenylborane ((+)-DIP-chloride) (12 g, 0.037 mol) and stirred overnight, then diethanolamine (15 g, 0.14 mol) added and the mixture stirred for 3 hours, filtered and evaporated. Chromatography on silica gel (ethyl acetate-hexane) gave a white solid (4.73 g, 73%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:18]([C:19](O)=[O:20])=[CH:17][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1>C1COCC1>[ClH:1].[OH:20][CH2:19][C:18]1[C:4]([O:3][CH3:2])=[CH:5][C:6]2[N:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[CH:17]=1
Reactant: COc1cc2ncn(-c3ccccc3)c2cc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc2ncn(-c3ccccc3)c2cc1CO
Reaction time: 3 h

Procedure:
Borane-methyl sulfide complex (1.11 mL of 10.0N, 0.011 mol) was added dropwise at room temperature under nitrogen to a stirred sclution of 5-methoxy-1-phenylbenzimidazole-6-carboxylic acid hydrochloride(1.00 g, 3.73 mmol) in THF (60 mL). After stirring at this temperature for 3 hours, the excess of reagent was destroyed by careful addition of MeOH, followed by water, and the solution was acidified with 3N HCl and stirred at room temperature for a further 30 minutes. The aqueous solution was washed with EtOAc, then basified with conc. NH3 solution, extracted with EtOAc, and the organic portion worked up to give an oily solid which was chromatographed on silica gel. EtOAc eluted foreruns, while MeOH/EtOAc (1:15) eluted the alcohol Example 53 (0.77 g, 81%). HCl salt: mp (MeOH/Et2O) 260° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].[CH2:11]([Mg]Br)[CH3:12]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:2][C:1]1([C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)[CH2:12][CH2:11]1
Reactant: N#Cc1ccc(C#N)cc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: N#Cc1ccc(C2(N)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1,4-dicyanobenzene (3.30 g, 25.8 mmol) in dichloromethane was added titanium(IV) isopropoxide (7.56 mL, 25.8 mmol) followed by ethylmagnesium bromide (3M in ether, 15.5 mL, 46.4 mmol) dropwise (exothermic, gas evolution after one eq of reagent added) and the mixture was stirred at r.t. for 45 min. Borontrifluoride diethyl etherate (5.71 mL, 46.4 mmol) was added and the mixture was stirred at r.t. for 2 h, quenched with NH4Cl and HCl and separated. The aqueous phase was washed once with ether and then the pH was adjusted to 9-10 with 10N NaOH (precipitate formation). The mixture was filtered through celite and the cake washed with water/EtOAc. The phases were separated and the aqueous phase extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product as a viscous oil which solidified at −20° C. The crude was used directly without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(O)cc(O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)cc(O)c1

Procedure:
To a solution of 3,5-dihydroxybenzoic acid (30.0 g) in methanol (300 mL) was added dropwise thionyl chloride (20 mL) at 0° C., and the mixture was heated under reflux for 2 hr. The reaction mixture was concentrated, and the obtained crystals were washed with diethyl ether to give the title compound (30.0 g) as a white solid.