Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C.Cl.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:32][O:31][CH2:30][CH2:29][O:28][C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[N:20][N:21]=[C:22]2[CH:27]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Reaction time: 16 h
Yield: 76.7 %

Procedure:
To a solution of 8-(tert-butyldimethylsilyloxy)-2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline (0.070 g, 0.155 mmol) in THF (8 mL) was added 1M HCl (1.5 mL, 1.50 mmol). After stirring at ambient temperature for 2 hours 1 M HCl (5 mL) was added and the reaction mixture stirred for a further 16 hours. The mixture was neutralized with 1M NaOH and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 40 mg (77%) of desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]([OH:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1>O1CCCC1.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: COc1nc(Cl)ccc1C(O)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1nc(Cl)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
36.0 g of manganese(IV) oxide was added to a solution of 3.7 g of 6-chloro-3-(α-hydroxybenzyl)-2-methoxypyridine in 80 ml of tetrahydrofuran, followed by stirring at room temperature for 2 hours. Insoluble matters were filtered off and then the solvent was evaporated, to give 3.6 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][CH2:19][C:20]#[N:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][CH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H](CCc1nnn[nH]1)NC(=O)OCc1ccccc1
Temperature: 85 °C

Procedure:
3.20 g (11.0 mmol) ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butyrate are dissolved in 40 ml of toluene and 1.08 g (16.5 mmol) sodium azide and 2.28 g (16.5 mmol) triethylamine-hydrochloride are added. The reaction mixture is heated to 85° C. for 24 hours, cooled to ambient temperature and extracted with water. The combined aqueous phases are acidified to pH 2 with semiconc. hydrochloric acid, the resulting precipitate is suction filtered, washed with water and dried at 50° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:15]1([S:21]([N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOC(C)=O>ClCCCl>[C:1]1([CH2:7][C:8]([C:26]2[CH:27]=[CH:28][N:24]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[CH:25]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(Cc1ccccc1)c1ccn(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
Under N2, a mixture of phenyl-acetyl chloride (1.5 g, 9.7 mmol) in 1,2-dichloro-ethane (20 mL) was added AlCl3 (2.24 g, 16.8 mmol) and then stirred at room temperature for 15 minutes. 1-(phenylsulfonyl)-1H-pyrrole (1.74 g, 8.4 mmol) was added. The mixture was stirred at room temperature overnight, followed by a standard aqueous/EtOAc workup. Purified by column chromatography to afford the Intermediate 52 (1.4 g, yield 51.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([O:11][CH3:12])=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.[H-].[Na+].[C:23](C1NC=CN=1)(=[O:25])[CH3:24].Cl>C1COCC1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([O:11][CH3:12])=[C:6]([CH:8]([C:23](=[O:25])[CH3:24])[C:9]#[N:10])[CH:7]=1
Reactant: COc1c(CC#N)cc(F)cc1OCc1ccccc1
Reactant: CC(=O)c1ncc[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(OCc2ccccc2)cc(F)cc1C(C#N)C(C)=O
Temperature: 40 °C
Yield: 80 %

Procedure:
A solution of {5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}acetonitrile (5.3 g, 19.5 mmol) in THF (60 mL) was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 1.64 g, 41 mmol) was added followed by acetylimidazole (3.2 g, 29.3 mmol). The mixture was heated to 40° C. for 15 min before cooling to rt. Water was added, and this mixture was acidified with 1 N HCl (45 mL). Ethyl acetate was added and the layers were partitioned. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (70% hexanes, 30% ethyl acetate) to provide 2-{5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}-3-oxobutanenitrile as a colorless oil (4.9 g, 15.6 mmol, 80% yield). 1H NMR (400 MHz, CDCl3): (mixture of tautomers) δ 9.70 (s, 0.2H), 7.42-7.33 (m, 5H), 6.82 (dd, 0.2H), 6.75 (dd, 0.8H) 6.69-6.64 (m, 1H), 5.09 (s, 2H), 4.90 (s, 0.8H), 3.89 (s, 2.1H), 3.83 (s, 0.9H), 2.38 (s, 0.9H), 2.29 (s, 2.11H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ncnc21
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 99 %

Procedure:
To a 250 mL oven dried three-neck round bottom flask equipped with a stir bar, condenser, septa, nitrogen inlet and thermocouple was charged sodium hydride (NaH, 60 wt %, 1.56 g, 0.0391 mol, 1.2 equiv) and anhydrous tetrahydrofuran (THF, 26 mL, 0.320 mol). The mixture was chilled to 0-5° C. To a oven dried 100 mL round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 5.00 g, 0.0326 mol) and anhydrous tetrahydrofuran (42 mL, 0.520 mol), and the resulting slurry was then added portion wise via large bore canula over 15 minutes to the sodium hydride (NaH) suspension in THF. The reaction temperature rose to 6.8° C. after the addition of the substrate. The reaction mixture was stirred at 0-5° C. for 40 minutes before being charged neat triisopropylsilyl chloride (6.6 g, 7.24 mL, 0.0342 mol, 1.05 equiv) via syringe over 5 minutes. The cooling bath was removed and the reaction mixture was warmed to reflux for 4 hours. The reaction was monitored by TLC (80% hexane/ethyl acetate). When the reaction was deemed complete, the reaction mixture was cooled to room temperature and dilute with ethyl acetate (100 mL) and 20% aqueous brine (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic fractions were washed with 1M sodium bicarbonate (NaHCO3) aqueous solution (100 mL) and 20% aqueous brine (100 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 10% ethyl acetate/hexane gradient elution) to afford 4-chloro-7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidine (3d, 10.0 g, 10.10 g theoretical, 99%) as an amber oil. For 3d: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.61 (s, 1H), 7.67 (d, 1H, J=3.7 Hz), 6.76 (d, 1H, J=3.5 Hz), 1.86 (m, 3H), 1.02 (d, 18H, J=7.5 Hz); C15H24ClN3Si (MW, 309.91), LCMS (EI) m/e 310/312 (M++H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.Br[CH2:18][C:19]1[C:24]([CH2:25]Br)=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8]([C:7]4([CH:18]=[C:19]5[C:24]([C:23]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)=[CH:22][CH:21]=[C:20]5[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:25]4)[C:6]=2[CH:5]=1)=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: BrCc1c(-c2ccccc2)ccc(-c2ccccc2)c1CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)C1(C=c3c(-c4ccccc4)ccc(-c4ccccc4)c3=C1)c1ccccc1-2
Yield: 55.6 %

Procedure:
A 50 wt % aqueous NaOH solution (35 mL) is added to a solution of 2-bromofluorene (5) (2.36 g, 9.63 mmol) and 2′,3′-bis(bromomethyl)-p-terphenyl (4b) (4.0 g, 9.61 mmol) in toluene (70 mL). Subsequently, benzyltriethylammonium chloride (110 mg, 0.483 mmol) is added as a phase transfer catalyst. The reaction mixture is vigorously stirred for 5 h when an additional amount of 2-bromofluorene (5) (0.90 g, 3.92 mmol) is added. The reaction was allowed to continue until 2′,3′-bis(bromomethyl)-p-terphenyl (4b) is completely consumed, as monitored by thin-layer chromatography. The reaction mixture is then shaken with water (200 mL) and methylene chloride (200 mL). The organic phase is separated, and the aqueous phase is extracted with methylene chloride. The combined organic extracts are washed with brine and dried over anhydrous MgSO4. After the solvent is evaporated, the solid residue is washed with a large amount of acetone to yield 2.66 g of (6b) as a white solid product. After the acetone is evaporated, the solid residue is further purified on a silica gel column using petroleum ether/methylene chloride (4:1) as the eluent, yielding additional 0.45 g of (6b). The total yield is 65%.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:25])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=1)[CH2:8]2.Br[CH2:27][CH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:25])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:20][CH2:21][N:22]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:24]3)[N:14]=1)[CH2:8]2
Reactant: OCCBr
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(N2CCN(CCO)CC2)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
After N-(adamantan-2-yl)-6-(piperazin-1-yl)picolinamide (34 mg, 0.100 mmol) was dissolved in DMF (2 ml), 2-bromoethanol (19 mg, 0.150 mmol) and potassium carbonate (41 mg, 0.300 mmol) were added thereto, and then the resulting mixture was stirred at 100° C. under nitrogen stream for 18 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (10% MeOH/MC), to obtain 37 mg of colorless oil (96%). MS (ESI): 385 [M+H]+
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:7][CH:8]=1.[C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)#[CH:23]>CCCCCCC>[CH:24]1([C:22]#[C:23][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C#CC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(C(F)(F)F)c2)cc1
Solvent: CCCCCCC
Product: FC(F)(F)c1cccc(C#CC2CCCCC2)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 3-trifluoromethyl-phenyl ester and ethynyl-cyclohexane following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (82 mg, 65%); δH (CDCl3): 7.67 (s, 1H), 7.61-7.7.49 (m, 2H), 7.46-7.37 (m, 1H), 2.70-2.52 (m, 1H), 2.04-1.30 (m, 10H); LCMS m/z: 252.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.[Cl-].[Na+]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:16][CH2:15][C:14]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)=[N:11][O:12][C:13]=2[CH3:17])=[N:20][CH:21]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded the title compound (4.1 g, 68%) which was obtained as a white solid. MS: m/e=343.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)=[CH:4][C:3]=1[C:19]#[N:20].I([O-])(=O)(=O)=[O:22].[Na+]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:22])=[O:14])=[CH:11][C:10]([C:15]([F:17])([F:16])[F:18])=[N:9]2)=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2CO)ccc1F
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)ccc1F
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxymethylpyrazole (0.45 g, 1.58 mmol) in acetonitrile (10 mL) was added catalytic amount of ruthenium chloride at 0° C. followed by addition of a solution sodium periodate (0.71 g, 3.32 mmol) in water. The reaction was stirred at 0° C. to room temperature overnight. The next day the acetonitrile was evaporated and the residue was partitioned between ethyl acetate and water, washed with brine, dried over sodium sulfate, filtered and concentrated to give 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxycarbonylpyrazole (0.27 g, 57% yield) as pure compound: MS (ES−): 298 (M−H)− (40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:8][C:9](=O)[N:10]=2)[CH:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([Cl:14])[N:10]=2)[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CN2C=C(Br)C=CC2=N1
Product: Clc1cn2cc(Br)ccc2n1
Temperature: 105 °C

Procedure:
A mixture of 1.4 g of 6-bromo-3H-imidazo[1,2-a]pyridin-2-one in 5 ml of POCl3 is heated at 105° C. for 2 hours and then cooled to ambient temperature and concentrated under reduced pressure. The residue is taken up between water and dichloromethane and a 30% aqueous solution of NH4OH is added until a basic pH is obtained. The organic phase is then separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue is then purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 760 mg of compound are obtained.
Reaction SMILES: Cl.[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].CC(C)([O-])C.[Na+].Br[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][N:23]2[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[CH:22][N:23]3[C:28]2[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: CSc1nccc(-n2ccc3c(Br)cccc32)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: CSc1nccc(-n2ccc3c(N4CCC(S(C)(=O)=O)CC4)cccc32)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
4-Methylsulfonyl-piperidine hydrochloride (6.89 g, 34.5 mmol) was grinded into fine powder and mixed with fine powder of sodium tert-butoxide (7.65 g, 79.6 mmol) in dry dioxane (180 mL). After 30 minutes of stirring, 4-bromo-1-(2-(methylthio)pyrimidin-4-yl)-1H-indole (8.5 g, 26.5 mmol) was added followed by dry dioxane (10 mL) and the mixture was bubbled with argon for 10 minutes. Bis(tri-tert-butylphosphine)palladium (1.02 g, 2.0 mmol) was added followed by dry dioxane (10 mL). The mixture was bubbled with argon for 5 minutes and then sealed. The sealed thick wall bottle was put into oil bath at 65° C. and heated to 120° C. The mixture was stirred at 120° C. for 1.5 hr. The resulting mixture was cooled to 50° C. and filtered through a thin layer of Celite, rinsed with dioxane (100 mL). The filtrate was concentrated and extracted with dichloromethane and saturated ammonium chloride solution. The organic layer was dried and concentrated to a volume about 25 mL. The mixture was treated with ethyl acetate (150 mL) and the yellow solid was filtered to give the desired compound (4.65 g). The filtrate was concentrated and dissolved in dichloromethane and purified through ISCO flash column chromatography (200 g silica gel, 20% to 100% ethyl acetate in hexanes) to give second batch of desired product as a yellow solid (1.67 g, combined total 6.32 g, yield 59.1%). LC-MS calcd for C19H22N4O2S2 (m/e) 402.12, obsd 402.9 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][CH2:10][N:9]([C:14](=[O:21])[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:8]=2[CH:22]=1)([O-])=O>[Pd].O1CCCC1.C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][CH2:10][N:9]([C:14](=[O:21])[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:8]=2[CH:22]=1
Reactant: O=C(CN1CCCC1)N1CCCOc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc2c(c1)N(C(=O)CN1CCCC1)CCCO2

Procedure:
1-(2-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-2-pyrrolidin-1-yl-ethanone (0.402 g, 1.32 mmol) and 10% Palladium on Carbon (50% Wet) (0.1 g) in Tetrahydrofuran (10 mL; EMD) and Ethanol (10 mL) was shaken under an atmosphere of Hydrogen (25 psi) overnight. Filtration and washing with ethanol (50 mL) followed by conc. afforded 1-(2-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-2-pyrrolidin-1-yl-ethanone as an oil in quantitative yield. 1H-NMR (CDCl3): 6.93 (d, 1H, J=8 Hz), 6.58 (d, 1H, J=8 Hz), 6.57 (s, 1H), 4.77 (m, 1H), 4.36 (m, 1H), 4.01 (br s, 2H), 3.76 (m, 1H), 3.56 (m, 1H), 3.10 (m, 1H), 2.94 (m, 4H), 2.71 (m, 1H), 2.25 (m, 1H), 1.91 (m, 4H), 1.71 (m, 1H), 0.86 (m, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>CN(C=O)C.O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][N:7]1[CH:8]=[CH:9][C:4](=[O:3])[CH:5]=[CH:6]1
Reactant: BrCCOC1CCCCO1
Reactant: Oc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn(CCOC2CCCCO2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
Sodium hydride (1.27 g of a 50% suspension in mineral oil, 26.4mmol) was added to a solution of 4-hydroxypyridine (2.5 g, 26 mmol) in DMF (50 ml) and the mixture stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (5.0 g, 23.9 mmol), (J. Am. Chem. Soc. 1948, 70, 4187), in DMF (5 ml) was added and the mixture heated at 80° C. for 3 hours. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 1-[2-(tetrahydropyran-2-yloxy)ethyl]-1,4-dihydro-4-pyridone (1.5 g, 28%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=1)=[O:19])C>>[Cl:30][C:25]1[CH:24]=[C:23]([CH:21]2[CH2:22][CH:20]2[C:18]([OH:19])=[O:17])[CH:28]=[CH:27][C:26]=1[O:29][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: ClCc1cccc(SC2CCCC2)n1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SC3CCCC3)n2)c(Cl)c1
Yield: 64.6 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (42 mg, 0.18 mmol) obtained in Step C of Preparation Example 27 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (49 mg, 0.20 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (47 mg, 72%).
Reaction SMILES: Cl[Si](Cl)(Cl)[Si](Cl)(Cl)Cl.[CH3:9][N-:10][CH3:11].[Li+].CC[C@@H]([C@H](N1N=NC([C@@H](N)CO)=C1)C(N1CCN(C2N=C(NCCOCCOCCOCC#C)N=C(N3CCN(C([C@@H](N4N=NC([C@@H](N)CO)=C4)[C@H](CC)C)=O)CC3)N=2)CC1)=O)C.Cl.[CH3:77][N:78]([Si:80]([N:92]([CH3:94])[CH3:93])([N:89]([CH3:91])[CH3:90])[Si:81]([N:86]([CH3:88])[CH3:87])([N:83]([CH3:85])[CH3:84])Cl)[CH3:79]>CCCCCC>[CH3:9][N:10]([Si:81]([N:86]([CH3:88])[CH3:87])([N:83]([CH3:85])[CH3:84])[Si:80]([N:89]([CH3:91])[CH3:90])([N:92]([CH3:93])[CH3:94])[N:78]([CH3:77])[CH3:79])[CH3:11]
Reactant: C[N-]C
Reactant: CN(C)[Si](Cl)(N(C)C)[Si](N(C)C)(N(C)C)N(C)C
Agent: C#CCOCCOCCOCCNc1nc(N2CCN(C(=O)[C@H]([C@@H](C)CC)n3cc([C@@H](N)CO)nn3)CC2)nc(N2CCN(C(=O)[C@H]([C@@H](C)CC)n3cc([C@@H](N)CO)nn3)CC2)n1
Agent: Cl
Agent: Cl[Si](Cl)(Cl)[Si](Cl)(Cl)Cl
Solvent: CCCCCC
Product: CN(C)[Si](N(C)C)(N(C)C)[Si](N(C)C)(N(C)C)N(C)C
Temperature: 0 °C

Procedure:
The synthesis of ClSi2(NMe2)5 has been done from the ammonolysis of hexachlorodisilane and lithium dimethylamide. Hexachlorodisilane (HCD) is used as the starting material so that the Si-Si direct bond remains in the molecule. n-hexane is used as a solvent and cooled at 0° C. A mixture of pentakis(dimethylamino) chloro disilane and hexakis(dimethylamino) disilane is obtained. Lithium dimethylamide is added to form a “lithium dimethylamide solution”. HCD is added dropwise in the 0° C. lithium dimethylamide solution. Then the solution is stirred for 2 h at 0° C. then for 15 h at RT. The salt LiCl is then removed from the solution, and the n-hexane removed in vacuo. The resulting ClSi2(NMe2)5 and other byproducts are separated by fractional distillation.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8](O)[CH2:7][CH2:6]2.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]2[C:9]([CH:8]=[CH:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: OC1CCc2cc(C(F)(F)F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2c(c1)CC=C2
Yield: 96.2 %

Procedure:
A mixture of 5-(trifluoromethyl)indan-1-ol (1.6 g, 7.9 mmol) and p -toluenesulfonic acid (0.02 g, 0.1 mmol) in toluene (20 mL) was refluxed through a Dean-Stark trap for about 3 h. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica eluting with 5% EtOAc/hexane to afford the desired product as an oil (1.4 g, 96%).