Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11](Br)=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-:17].[K+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([OH:17])=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1Br
Reactant: [OH-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(-n2c(C)ccc2C)nc(C)c1O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 2.00 g (7.14 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-bromo-4,6-dimethylpyrimidine (4) in 16 mL of dioxane-degassed water 1:1 were added 132 mg (0.14 mmol) of Pd2dba3 followed by 242 mg (0.58 mmol) of 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbyphenyl (L1) and 1.2 g (21.42 mmol) of potassium hydroxide. The reaction mixture was stirred at 100° C. under argon atmosphere during 3 h. The reaction mixture was poured into 100 mL of water and extracted with two portions of 75 mL of ethyl acetate. The aqueous layer was acidified with HCl (pH 2-3) and then extracted with two portions of 100 mL of ethyl acetate. The combined organic solution was washed with a portion of 100 mL of brine, dried (MgSO4) and the concentrated under diminished pressure to afford the expected product as a light yellow crystals: yield 1.62 g (100%). 1H-NMR (CDCl3) δ 5.76 (s, 2H), 2.47 (s, 6H), 2.20 (s, 6H); 13C-NMR (CDCL3) δ 154.15, 149.87, 145.13, 128.74, 107.32, 18.40, 13.50.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]3[NH:21][C:20](=[O:22])[O:19][N:18]=3)=[N:9]2)=[N:6][CH:7]=1.[CH3:23]CN(C(C)C)C(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:14])([F:16])[F:15])=[CH:11][C:10]([C:17]3[N:21]([CH3:23])[C:20](=[O:22])[O:19][N:18]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: O=c1[nH]c(-c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)no1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cn1c(-c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)noc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Step-4: 3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazol-5(4H)-one: To a stirred and (0° C.) cooled solution of step-3 intermediate (106 mg, 0.303 mmol) and DIPEA (0.106 mL, 0.606 mmol) in DCM (15 mL) was added drop-wise a solution of triphosgene (35 mg, 0.121 mmol) in DCM (3 mL). The reaction was stirred at room temperature for 1 h before quenching with ice water (5 mL). Water (10 mL) was added to the above mixture followed by DCM (25 mL). The layers were separated and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to afford 100 mg (88%) of the title compound as brown solid. ESI-MS (m/z) 376, 378 [(MH)+, Br79,81].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:37]2[CH2:39][CH2:38]2)=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH:37]3[CH2:39][CH2:38]3)=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]([F:35])([F:36])[F:34])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: FC(F)(F)Oc1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine (example 150D]) to give the title compound as light yellow viscous oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5][CH2:6][CH2:7][NH:8][CH3:9])=[O:4].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:9][N:8]([CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:10])([F:11])[F:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CNCCNC(=O)C(F)(F)F
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN(C)CCNC(=O)C(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of 2,2,2-trifluoro-N-[2-(methylamino)ethyl]acetamide (5 g) in DMF (50 ml) were added ethyl 7-bromoheptanoate (3.6 ml) and potassium carbonate (7.7 g) and stirring was continued at room temperature for 18 hr. Potassium carbonate was removed by filtration and saturated aqueous sodium bicarbonate and water was added to the filtrate, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried with sodium sulfate, and concentrated. The residue was dissolved in toluene and purified by passing through the silica gel column (eluent; hexane to hexane-ethyl acetate (4:1) to ethyl acetate) to obtain the titled compound as a crude material (7 g).
Reaction SMILES: O.O.O.[CH2:4]([N:6]([CH2:10][CH3:11])[C:7](=[S:9])[S-:8])[CH3:5].[Na+].[CH:13]([C:15]1[CH:22]=[CH:21][C:18](CCl)=[CH:17][CH:16]=1)=[CH2:14].O>C(O)C>[CH:13]([C:15]1[CH:22]=[CH:21][C:18]([S:9][C:7](=[S:8])[N:6]([CH2:10][CH3:11])[CH2:4][CH3:5])=[CH:17][CH:16]=1)=[CH2:14]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: CCN(CC)C(=S)[S-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=Cc1ccc(SC(=S)N(CC)CC)cc1
Reaction time: 0.5 h

Procedure:
A solution of sodium diethyldithiocarbamate trihydrate (3.5 g, 1.55×10−2 mol) in 20 mL of ethanol was added to a flask equipped with a stirrer, dropping funnel and a reflux condenser. To this solution was added a solution of 4-vinylbenzyl chloride (3.0 g, 1.96×10−2 mol) and ethanol (5 mL), dropwise, over a period of 0.5 h at a temperature of 0° C. The resultant solution was stirred at room temperature for 24 h before pouring into a large volume of water and extracting with diethyl ether. The ether phase was washed three times with water, dried over sodium sulphate, before finally removing the diethyl ether by evaporation. The residue was recrystallised three times from methanol, giving a yield of 2.6 grams (83%). 1H NMR (CDCl3) δ7.36 (s, 4H, C6H4), 6.70 (dd, J=11.6 and 17.5 Hz, 1H, CH═CH2), 5.73 (d, J=17.5 Hz, 1H, CH═CH2), 5.24 (d, J=11.5 Hz, 1H, CH═CH2), 4.54 (s, 2H, CH2S), 4.04 (q, J=7.3 Hz, 2H, NCH2), 3.73 (q, J=6.6 Hz, 2H NCH2), 1.19 (t, J=ca.7.0 Hz, 6H CH2CH3).
Reaction SMILES: [CH2:1]([O:15][C:16]1[C:17]2[C:25]([CH:26]=[C:27]3[CH:31]=[CH:30][S:29][C:28]=13)=[C:24]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:20]1[S:21][CH:22]=[CH:23][C:19]=1[CH:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Li])CCC.[CH3:52][Sn:53](Cl)([CH3:55])[CH3:54].O>C1COCC1>[CH3:52][Sn:53]([CH3:55])([CH3:54])[C:22]1[S:21][C:20]2[C:24]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:25]3[C:17](=[CH:18][C:19]=2[CH:23]=1)[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:28]1[S:29][C:30]([Sn:53]([CH3:55])([CH3:54])[CH3:52])=[CH:31][C:27]1=[CH:26]3
Reactant: CCCCCCCCCCCCCCOc1c2cc3ccsc3c(OCCCCCCCCCCCCCC)c2cc2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCOc1c2cc3cc([Sn](C)(C)C)sc3c(OCCCCCCCCCCCCCC)c2cc2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Compound (4b) (0.500 g, 0.752 mmol) was solubilized in anhydrous THF (40 mL) and cooled at −78° C. under N2. n-Butyllithium (0.75 mL, 2.5M) was then added and the stirring was continued for 30 minutes at this temperature and then 30 minutes at room temperature. The reaction mixture was cooled to −78° C. again before adding trimethylstannyl chloride (1.9 mL, 1.0 M). The reaction was warmed up to room temperature and stirred overnight. The reaction was stopped by adding water, and the mixture was extracted with diethyl ether, dried over MgSO4, filtered, and concentrated in vacuo. The crude monomer was solubilized in 5 mL of THF and then dropped in methanol (200 mL). The product was allowed to precipitate in the freezer overnight before filtering and washing with cold methanol to afford a yellow fluffy powder as the title compound (0.650 g, 86%). 1H NMR (500 MHz, CDCl3, 298 K): 8.45 (s, 2H); 7.53 (s, 2H); 4.38 (t, J=6.6 Hz, 4H); 2.01 (quintet, J=7.9 Hz, 4H); 1.65 (quintet, J=7.7 Hz, 4H); 1.39 (m, 40H); 0.89 (t, J=7.0 Hz 6H); 0.47 (s, 18H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): 149.07; 142.85; 141.22; 132.66; 130.48; 124.58; 109.85; 73.20; 31.96; 30.65; 29.76; 29.73; 29.70; 29.57; 29.41; 26.17; 22.73; 14.17; 8.38 ppm. HRMS (ESI-TOF-MS): m/z calcd for C48H80O2S2Sn2 990.3638. found 990.3670.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[NH:2]1.C(N(CC)C(C)C)(C)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH2:21]([N:2]1[C:1](=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3]1=[O:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1NC(=O)c2cnccc21
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccncc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (5.00 g) and N,N-diisopropylethylamine (20.00 mL) in acetone was added benzyl bromide (5.0 mL). The reaction mixture was heated to reflux for 5 h, then cooled to rt and filtered. The filtrate was poured into water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 2:1 (v/v) PE/EA) to give the title compound as a brown solid (4.00 g, 50.00%), HPLC: 92.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 239.2 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 4.92 (s, 2H), 7.26-7.34 (m, 3H), 7.45 (m, 2H), 7.60 (m, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.96 (d, J=10.4 Hz, 1H) ppm.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=2)[NH2:38])[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[C:37]([NH:38]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:39]=[CH:40][CH:41]=2)[CH2:30][CH2:29]1
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(Cc2cccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)c2)CC1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-(4-methylpiperazinomethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].O>C1COCC1>[C:15]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Sodium hydride (1.99 g, 50% in oil, 41.4 mmol, extracted with hexanes) was stirred in THF (50 ml) in a flame-dried flask at 0° C. under nitrogen. Indole-3-carboxaldehyde (5.00 g, 34.5 mmol) was added as a powder in small portions, and then the mixture was warmed to 40° C. for 30 min. The mixture was again cooled to 0° C., and benzyl chloroformate (4.92 ml, 34.5 mmol) was added. After warming to room temperature and stirring overnight, the mixture was poured into water (50 ml) and extracted with CH2Cl2 (50 ml). The organic layer was washed with water (50 ml), dried with MgSO4, filtered and evaporated to 9.2 g (95%) of a gold-brown oil. Crystallization from hot hexane gave 8.47 g (88%) of white crystalline product: mp 70°-71°
Reaction SMILES: C([O:8][C:9](=[O:27])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:26])[C@H:16]([CH3:25])[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:21]([O:20][C:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:27])=[O:8])=[O:26])[CH3:25])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 92.4 %

Procedure:
N-t-butyloxycarbonyl-L-alanyl-L-proline benzyl ester (6.4 g, 17 m mole) was dissolved in methanol (100 ml). Hydrogen was passed for 3 hours through the solution in the presence of 10% palladium-carbon as a catalyst. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure. The residue was crystallized in ethyl acetate-n-hexan to give N-t-butyloxycarbonyl-L-alanyl-L-proline (4.5 g, yield: 92.4%) having melting point of 155° to 157° C. and specific rotatory power [α]D25 =-90.5° (C=1, ethanol). The product gave a single spot on thin layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([OH:14])=O.[F:15][C:16]1([F:33])[CH2:21][CH2:20][N:19]([CH:22]([C:25]2[CH:26]=[N:27][C:28]([S:31][CH3:32])=[N:29][CH:30]=2)[CH2:23][NH2:24])[CH2:18][CH2:17]1>>[F:33][C:16]1([F:15])[CH2:21][CH2:20][N:19]([CH:22]([C:25]2[CH:26]=[N:27][C:28]([S:31][CH3:32])=[N:29][CH:30]=2)[CH2:23][NH:24][C:12]([C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[N:8][C:9]=3[CH:10]=[CH:11][C:2]=2[Cl:1])=[O:14])[CH2:18][CH2:17]1
Reactant: O=C(O)c1c(Cl)ccc2ncccc12
Reactant: CSc1ncc(C(CN)N2CCC(F)(F)CC2)cn1
Product: CSc1ncc(C(CNC(=O)c2c(Cl)ccc3ncccc23)N2CCC(F)(F)CC2)cn1

Procedure:
Compound 582, 6-chloro-quinoline-5-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-2-(2-methylsulfanyl-pyrimidin-5-yl)-ethyl]-amide was prepared analogous to Example B.30 by coupling 6-chloro-quinoline-5-carboxylic acid and 2-(4,4-difluoro-piperidin-1-yl)-2-(2-methylsulfanyl-pyrimidin-5-yl)-ethylamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(F)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Yield: 83 %

Procedure:
To a degassed solution of 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (270 mg, 1.0 mmol), 4-fluorobenzeneboronic acid (155 mg, 1.0 mmol), 2N Na2CO3 (1.5 mL) in DME (10 mL) was added tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) under argon. The mixture was heated to 85° C. for 6 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (5-20% methylene chloride in heptane) to give the product as an off white solid (275 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=7.91 Hz, 2H), 8.12 (dd, J=5.27, 9.04 Hz, 2H), 7.74 (d, J=8.29 Hz, 2H), 7.54 (d, J=3.01 Hz, 2H), 7.18 (t, J=8.67 Hz, 2H), 2.50 (s, 3H). MS m/e 332.3 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]([N:9]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]2)[CH3:10])=[O:8])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:29][NH:30][CH2:31][CH2:32][CH2:33][OH:34]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[O:8])[N:9]([CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18](=[O:20])[N:30]([CH2:31][CH2:32][CH2:33][OH:34])[CH3:29])[CH2:16][CH2:17]2)[CH3:10])=[CH:21][CH:22]=1
Reactant: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CNCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C[C@H]1CC[C@H](C(=O)N(C)CCCO)CC1)C(=O)Oc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
A solution of 0.09 g (0.276 mmol) of trans-4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid in 2.5 mL of CH2Cl2 was treated at RT with 1 drop of DMF. 0.026 mL (0.304 mmol, 1.1 eq) of oxalyl chloride was added within 5 min and stirring was continued for 90 min. The solution was evaporated, redissolved in 2.5 mL of CH2Cl2 and added to a solution of 0.197 mL (2.21 mmol, 7.2 eq) of 3-(methylamino)-1-propanol [Powell et al., Synthesis (1986), (4), 338-40]at 0° C. The reaction was kept over night at RT, then partitioned between Et2O (×3)/aqueous saturated NaHCO3. The organic phases were washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 5 g silica gel (EtOAc:CH2Cl2 1:9 to 9:1) gave 0.064 g (58%) of pure trans-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohexylmethyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 397 (MH+, 1Cl).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:15]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[CH2:16][CH3:17])[CH3:14].C([N-]C(C)C)(C)C.[Li+].C[O:35][C:36](=O)[C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[N:39][CH:38]=1>O1CCCC1>[CH2:13]([N:15]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][C:21](=[C:36]([OH:35])[C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH3:43])[CH:42]=2)[C:20]1=[O:25])[CH2:16][CH3:17])[CH3:14]
Reactant: COC(=O)c1cncc(C)c1
Reactant: CCN(CC)CN1CCCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCN(CC)CN1CCCC(=C(O)c2cncc(C)c2)C1=O
Temperature: 25 °C
Yield: 13.2 %

Procedure:
To a solution of diisopropylamine (4.4 mL, 31.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (12 mL, 30 mmol). The solution was allowed to warm to rt over 30 min and was re-cooled to −78° C. A solution of 1-diethylaminomethyl-piperidin-2-one (3.87 g, 21.0 mmol) in tetrahydrofuran (10 mL) was added to the lithium diisopropylamide via syringe. The reaction mixture was maintained at −78° C. for 1 h and was treated with a solution of 5-methylnicotinic acid methyl ester (2.12 g, 14.0 mmol) in tetrahydrofuran (20 mL) via syringe. The reaction mixture was allowed to warm to rt and was maintained overnight. The reaction mixture was quenched with water (30 mL) and was extracted with ether (2 x). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography [1/0 to 1/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] to provide 560 mg (13%) of 1-diethylaminomethyl-3-[hydroxy-(5-methylpyridin-3-yl)methylene]piperidin-2-one. To a solution of the piperidin-2-one (550 mg, 1.8 mmol) in acetone (101 mL) was added conc. hydrochloric acid (2 L) and the reaction mixture was heated at 100° C. overnight. The reaction mixture was allowed to cool to rt, diluted with isopropyl alcohol, and allowed to stand at 0° C. The product was isolated by filtration, thus providing 400 mg (85%) of 5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl dihydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]2[CH2:15][CH2:14][Si:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.O1CCCC1.[Cl-].[F:33][C:34]1[CH:35]=[C:36]([Zn+])[CH:37]=[CH:38][C:39]=1[F:40].[Cl-].[NH4+]>C(O)C.[Pt]=O>[CH2:22]([Si:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:15][CH:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:37]2[CH:36]=[CH:35][C:34]([F:33])=[C:39]([F:40])[CH:38]=2)[CH2:11][CH2:12]1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C=Cc2ccc(Br)cc2)CC1
Reactant: Fc1ccc([Zn+])cc1F
Agent: O=[Pt]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCC[Si]1(c2ccccc2)CCC(CCc2ccccc2-c2ccc(F)c(F)c2)CC1
Yield: 86 %

Procedure:
42.8 g of 4-(2-(4-bromophenyl)ethenyl)-1-n-pentyl-1-phenyl-1-silacyclohexane was dissolved in 200 ml of ethanol at room temperature and then hydrogenated at normal pressures in the presence of a catalyst made of 200 mg of platinum oxide. After consumption of a theoretical amount of hydrogen, the catalyst was removed by filtration and the resultant flitrate was concentrated. 200 ml of tetrahydrofuran and 180 mg of tetrakis(triphenylphosphine) palladium (0) were added to the resulting residue. Thereafter, 120 ml of a tetrahydrofuran solution of 1.0 mole of 3,4-difluorophenylzinc chloride, followed by agitation at 40° C. for 12 hours. The reaction mixture was poured into an ammonium chloride aqueous solution and extracted with ethyl acetate. After ordinary washing, drying and concentrating operations, the resultant product was purified through silica gel column chromatography to obtain 39.6 g (yield: 86%) of 4-(2-(4-n-pentyl-4-phenyl-4-silacyclohexyl)ethyl-3',4'-difluorobiphenyl.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:20][CH:21]=3)[N:10]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)c1cccc2[nH]c(C(=O)Nc3ccc(N4CCOCC4=O)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1nc(C(=O)Nc1ccc(N3CCOCC3=O)cc1)n2Cc1cccc(OC)c1
Reaction time: 4 h

Procedure:
366.5.0 mg (0.929 mmol) 2-[4-(3-Oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 15 mL DMF. Sequentially 192.6 mg (1.394 mmol) K2CO3 and 156.1 μl (1.394 mmol) 1-bromomethyl-3-methoxy-benzene were added and the resulting mixture was stirred for 4 h at 80°. The mixture was diluted with 300 mL toluene and washed with 50 mL of a saturated NaHCO3-solution. The product was not completely soluble in toluene, so ethyl acetate had to be added. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) (separation of isomers) to give 1-(3-Methoxy-benzyl)-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester as a light brown amorphous solid.