Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[C:8]([NH2:11])=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)=[O:25].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCOCC1.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>[NH2:11][C:8]1[C:7]2[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:24]([NH:23][C:14]4[CH:15]=[C:16]([C:19]([F:20])([F:22])[F:21])[CH:17]=[CH:18][C:13]=4[F:12])=[O:25])=[CH:32][CH:31]=3)=[N:3][CH:4]=[CH:5][C:6]=2[NH:10][N:9]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Reactant: Nc1n[nH]c2ccnc(Br)c12
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Nc1n[nH]c2ccnc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 100 °C
Yield: 31.8 %

Procedure:
To a solution of 53 mg of 4-bromo-1H-pyrazolo[4,3-c]pyrid-3-ylamine in 6 mL of dioxane are added 127 mg of 1-(2-fluoro-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea, 60 mg of sodium bicarbonate in 1.8 mL of water and 30 mg of tetrakis(triphenylphosphine)palladium. The reaction is heated in a bath at 100° C. for 2 hours. The mixture is allowed to cool and ethyl acetate is then added. The mixture is washed with water. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The oily residue is purified on a prepacked Biotage KP-Sil column of 60 Å SiO2 32-63 μm (gradient: 90/10 to 70/30 dichloromethane/solution A; solution A=38/17/2 dichloromethane/methanol/aqueous ammonia). 34 mg of 1-[4-(3-amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea are obtained in the form of a cream-coloured solid, the characteristics of which are as follows:
Reaction SMILES: CO[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.[C:16](#[N:18])[CH3:17].[H-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:14][C:4]([CH3:13])([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[C:3](=[O:15])[CH2:17][C:16]#[N:18]
Reactant: COC(=O)C(C)(C)COC1CCCCO1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(COC1CCCCO1)C(=O)CC#N
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester (7.67 g, 35.46 mmol) and acetonitrile (2.6 mL, 49.65 mmol) in toluene (20 mL) is added dropwise to the refluxing suspension of 60% sodium hydride in mineral oil (1.99 g, 49.65 mmol) in toluene (40 mL). After the addition, the reaction mixture is stirred at reflux for 3 hours. After this time, the reaction mixture is cooled to room temperature and the aqueous layer is neutralized to PH˜6-7 by adding 1N hydrochloric acid aqueous solution. The layers are combined and the aqueous layer is extracted with ethyl acetate. The organic layers are combined and washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the title compound. It is used without purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[C:6]([OH:14])[CH:5]=1.Br[CH2:16][C:17]#[CH:18]>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[C:6]([O:14][CH2:18][C:17]#[CH:16])[CH:5]=1
Reactant: CCC(=O)c1ccc(F)cc1O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(F)ccc1C(=O)CC
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a mixture of NaH (95%, 278 mg, 11 mmol) in DMF (20 mL) at 0° C., was added 1-(4-fluoro-2-hydroxy-phenyl)-propan-1-one (1.68 g, 10 mmol) in DMF (5 mL). After 15 min at 0° C., was 3-bromo-propyne (3.02 g, 20 mmol) added to the reaction mixture. After 1 h at 0° C., was the reaction mixture allowed to assume room temperature. The reaction mixture was extracted with H2O (100 mL). The H2O phase was washed with Et2O (3×100 mL) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, CH2Cl2), to give 1.40 g (68%) of 1-(4-fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=O)[N:8]([CH3:17])[CH2:7][C:6]=12.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[S:27])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1Cc2c(Cl)ncn2-c2ccccc2C1=O
Solvent: Cc1ccccc1
Product: CN1Cc2c(Cl)ncn2-c2ccccc2C1=S

Procedure:
3.71 g (15 mmol) of 3-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 10 ml of toluene are heated to boiling under reflux for 4 hours together with 3.03 g (7.5 mmol) of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide. The solution is washed with water and evaporated. By chromatography on a silica gel column and subsequent recrystallization from ethyl acetate there is obtained 3-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-6-thione of melting point 197.5°-198.5°.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH:10]([CH3:12])[CH3:11])[C:4]([CH2:8]O)=[C:5]([Cl:7])[N:6]=1.P(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]1[N:29]=[C:28]([SH:30])[N:27]=[C:26]([OH:31])[CH:25]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([CH:10]([CH3:12])[CH3:11])[C:4]([CH2:8][S:30][C:28]2[N:27]=[C:26]([OH:31])[CH:25]=[C:24]([CH3:23])[N:29]=2)=[C:5]([Cl:7])[N:6]=1
Reactant: CC(C)n1c(Cl)nc(Cl)c1CO
Reactant: Cc1cc(O)nc(S)n1
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)nc(SCc2c(Cl)nc(Cl)n2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
[2,4-dichloro-1-(propan-2-yl)-1H-imidazol-5-yl]methanol was dissolved in chloroform (40 mL), followed by addition of PBr3 (1.9 mL, 20 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated and the crude mixture was dissolved in DMF (20 mL). Potassium carbonate (3 g) and 6-methyl-2-sulfanylpyrimidin-4-ol (1.4 g, 10 mmol) were added. The mixture was then stirred at room temperature for 2 hours. DMF was removed under vacuum and the crude residue was purified by column chromatography to provide 2-({[2,4-dichloro-1-(propan-2-yl)-1H-imidazol-5-yl]methyl}sulfanyl)-6-methylpyrimidin-4-ol (700 mg, 21% overall yield); 1H NMR (400 MHz, CD3OD): δ 1.59 (d, 6H), 2.24 (s, 3H), 4.56 (s, 2H), 4.59 (m, 1H), 6.03 (bs, 1H); M+333.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].C(O)C.[NH:12]1[CH:16]=[C:15]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[N:14]=[CH:13]1>O.C1COCC1>[OH:3][NH:2][C:19](=[NH:20])[C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[C:15]1[N:14]=[CH:13][NH:12][CH:16]=1
Reactant: N#Cc1ccccc1-c1c[nH]cn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccccc1-c1c[nH]cn1
Temperature: 80 °C
Yield: 25 %

Procedure:
Hydroxylamine hydrochloride (56 mg, 0.804 mmol) was added to a solution of NaHCO3 (68 mg, 0.804 mmol) in water (0.5 mL). Ethanol (1.5 mL) was added followed by 2-(1H-imidazol-4-yl)benzonitrile in THF (0.5 mL) and the reaction mixture was heated at 80° C. for 18 h. Solvents were removed under reduced pressure and the remaining solution poured into water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (10 mL), dried, and concentrated. The residue was purified by flash column chromatography (silica gel, 5%-30% MeOH/DCM) to afford the desired product as a white solid (20 mg, 0.099 mmol, 25%). 1H NMR (DMSO-d6): 3.13 (s, 1H), 5.75 (s, 1H), 7.16-7.38 (m, 3H), 7.65 (s, 1H), 7.79 (s, 1H), 7.92 (d, 1H, J=7.6 Hz), 9.27 (s, 1H)
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:25]=3[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:4][CH2:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:25]=3[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CC(=O)OCC(=O)N1CCCN(c2cnc(C(=O)Nc3ccc(C)cc3C(=O)Nc3ccc(Cl)cn3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(NC(=O)c2cnc(N3CCCN(C(=O)CO)CC3)cn2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 8 h

Procedure:
To a solution of 2-[5-[4-(acetoxyacetyl)hexahydro-1,4-diazepin-1-yl]pyrazin-2-ylcarbonylamino]-5-methyl-N-(5-chloropyridin-2-yl)benzamide (Example 86, 0.22 g) in methanol (5 mL) was added potassium carbonate (0.1 g) and water (1 mL). The mixture was stirred overnight, the methanol was evaporated, and the resulting solution acidified to pH 5 with acetic acid. The solids were filtered, washed with water (2×3 mL), ether (3 mL) and dried under vacuum. Yield=0.19 g.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:17]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[C:14]2[CH:15]=[CH:16][C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:13]=2)=[CH:3]1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: Cn1ccc2ccccc21
Product: Cn1cc(C(c2ccc(-c3ccccc3)cc2)c2cn(C)c3ccccc23)c2ccccc21

Procedure:
The compound Bis(1-methylindol-3-yl)-(1,1′-biphenyl-4-yl)methane was prepared following procedure A, starting from N-methyl indole and 4-biphenyl carboxaldehyde. LC: Tr 2.92 min, MS: 427 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1.N12CCCN=C1CCCCC2.Cl>O>[N:25]1([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C:10]3[C:9]([F:24])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=3)=[CH:22][N:21]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: C1CNC1
Reactant: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1ccc(Cc2ccc(N3CCC3)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 160 °C
Yield: 93.9 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456,150 mg, 0.434 mmol), azetidine (88.0 uL, 1.30 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (306 uL, 2.17 mmol). The mixture was heated to 160° C. for 1 hour and then cooled to room temperature. The reaction mixture was treated with water (4 mL) and 1M HCl (6 mL). The aqueous portion was extracted with dichloromethane (2×30 mL), the organic portions were combined, washed with brine (15 mL), dried (MgSO4) and concentrated to produce 156 mg of P-569 as a white solid in 94% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH2:20].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Br:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: Nc1ccc(Cl)cc1Br
Reactant: N#Cc1cnc2c(c1Cl)C=C1N=CN=C1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2c(c1Nc1ccc(Cl)cc1Br)C=C1N=CN=C1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
A mixture of 0.25 g (1.10 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.27 g (1.3 mmol) of 2-bromo-4-chloroaniline, and 0.13 g (1.12 mmol) of pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at reflux temperature for 1 hour, cooled to room temperature, poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried. The solid is purified by silica gel chromatography utilizing a gradient of methylene chloride/methanol(97:3 to 90:10) to yield 0.10 g of 8-(2-bromo-4-chlorophenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as an yellow solid, mp 244-246° C. (shrinks at 200° C.).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:10][CH3:11])[S:5][C:6]=1[C:7](=[O:9])[CH3:8].[H-].[Na+].[CH3:14]I>C1COCC1.CCOC(C)=O>[CH3:11][N:10]([CH3:14])[C:4]1[S:5][C:6]([C:7](=[O:9])[CH3:8])=[C:2]([CH3:1])[N:3]=1
Reactant: CI
Reactant: CNc1nc(C)c(C(C)=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1sc(N(C)C)nc1C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-methyl-2-methylamino-thiazol-5-yl)-ethanone (0.40 g, 2.4 mmol) in THF (2 mL) was treated with NaH (0.113 g, 4.7 mmol). After heating at 40° C. for 0.5 h MeI (0.35 g, 2.4 mmol) was added. Heating was continued for a further 2 h. After cooling, the solution was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was evaporated to afford 1-(2-dimethylamino-4-methyl-thiazol-5-yl)-ethanone as a yellow solid. 1H-NMR (CDCl3) δ: 2.36 (s, 3H, CH3), 2.51 (s, 3H, CH3), 3.10 (s, 6H, CH3).
Reaction SMILES: [C:1]1([C@@H:7]([O:9][C:10](=[O:25])[CH2:11][C:12]([CH:14]=[CH:15][C:16]2C=C[CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]([CH3:39])=[CH:28][C:29](=[O:38])[CH2:30][S:31]([NH:34][CH:35]([CH3:37])[CH3:36])(=[O:33])=[O:32].[CH:40](O)(C)[CH3:41]>CN(C)C=O.CCOCC>[C:1]1([C@@H:7]([O:9][C:10](=[O:25])[C:11]2[C@H:12]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=3)[C:28]([C:29](=[O:38])[CH2:30][S:31](=[O:32])(=[O:33])[NH:34][CH:35]([CH3:36])[CH3:37])=[C:27]([CH3:39])[NH:26][C:40]=2[CH3:41])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)O
Reactant: CC(N)=CC(=O)CS(=O)(=O)NC(C)C
Reactant: C[C@H](OC(=O)CC(=O)C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)CS(=O)(=O)NC(C)C)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)O[C@@H](C)c2ccccc2)=C(C)N1
Reaction time: 8 h

Procedure:
A solution of 6.8 g of (S)-3-nitrobenzylideneacetoacetic acid 1-phenylethyl ester in a mixture of 20 ml of isopropanol and 10 ml of dimethylformamide was treated under argon with 4.40 g of 4-amino-N-isopropyl-2-oxo-3-pentenesulfonamide and the mixture was thereupon heated to reflux for 8 hours. After concentration under reduced pressure the oily residue was chromatographed on 800 g of silica gel with methylene chloride/ethyl acetate (4:1) as the elution agent, whereby the two expected epimers were eluted as a mixture. The homogeneous fractions yielded an oil which was taken up in 300 ml of ether and left to stand at room temperature overnight. The crystallized-out product was filtered off, washed with a small amount of ether and recrystallized from ethanol. There were obtained 2.3 g of (R)-1,4-dihydro-5-[(isopropylsulfamoyl)acetyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid (S)-1-phenylethyl ester in the form of yellow crystals, m.p. 151°-153°, specific rotation: [α]54620 =+518° (c=1.0% w/v, ethanol). On the basis of the NMR spectrum this was the (+)-enantiomer of the racemate A described in Example 14.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccccc1
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 84.7 %

Procedure:
208 mg Of styrene, 328 mg of triethoxysilane, and 52 mg of toluene were placed in a glass reaction tube and 0.004 ml of acetic acid was added. Then, 0.002 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 1 hour in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 89.4% and phenethyltriethoxysilane was produced at a yield of 84.7%. The yield of α-(methylbenzyl)triethoxysilane was 0.7%.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[CH:2]=1.C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:10][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1cccc(C(=O)Cl)c1

Procedure:
Meanwhile, the 3-methylbenzoyl chloride acylating agent was prepared by suspending 3.016 g (22.0 mmol) of m-toluic acid in 100 ml benzene. To this solution was added 2.0 equiv. (3.84 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at O° C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
Reaction SMILES: C(C(C)=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=3)[S:16][CH2:15][C:14]2([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH3:27])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][Cl:47]>O>[Cl:47][CH2:46][CH2:45][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=3)[S:16][CH2:15][C:14]2([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:32][CH:33]=2)[CH3:27])=[CH:9][CH:8]=1
Reactant: ClCCBr
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCCl)cc2)cc1
Yield: 47.8 %

Procedure:
To methyl ethyl ketone solution (3 ml) of (3RS,4RS)-4-(4-hydroxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-thiochroman (126 mg, 0.28 mmol) were added potassium carbonate (96 mg, 0.70 mmol) and 1-bromo-2-chloroethane (115 ml, 1.38 mmol), and the mixture was heated under refluxing for 70 hours. After adding water, the reaction solution was extracted with ethyl acetate. The extract was distilled under reduced pressure to remove the solvent and the crude product thus obtained was then purified using silica gel plate (ethyl acetate:hexane=1:2) to obtain 69 mg (yield: 48%) of the title compound.
Reaction SMILES: [CH2:1]([N:5]([CH2:18][CH2:19][C@H:20]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:21]([N:23]1[CH2:27][C@H:26]([OH:28])[CH2:25][C@H:24]1[C:29]([NH:31][C@:32]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][C@H:33]1[CH:35]=[CH2:36])=[O:30])=[O:22])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH2:2][CH:3]=[CH2:4].N1([C:55]([N:57]2[CH:61]=[CH:60]N=[CH:58]2)=[O:56])C=CN=C1.C(N(C(C)C)C(C)C)C.Cl.[F:72][C:73]1C=[CH:80][CH:79]=[C:78]2[C:74]=1CNC2>C1(C)C=CC=CC=1>[F:72][C:73]1[CH:74]=[CH:78][CH:79]=[C:80]2[C:60]=1[CH2:61][N:57]([C:55]([O:28][C@@H:26]1[CH2:25][C@@H:24]([C:29](=[O:30])[NH:31][C@:32]3([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][C@H:33]3[CH:35]=[CH2:36])[N:23]([C:21](=[O:22])[C@@H:20]([NH:42][C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:19][CH2:18][N:5]([CH2:1][CH2:2][CH:3]=[CH2:4])[S:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH2:27]1)=[O:56])[CH2:58]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=CCCN(CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: Fc1cccc2c1CNC2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCN(CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N2Cc3cccc(F)c3C2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
(1R,2S)-ethyl 1-((2S,4R)-1-((S)-4-(N-(but-3-enyl)-2-nitrophenylsulfonamido)-2-(tert-butoxycarbonylamino)butanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (1.60 g, 2.26 mmol) in toluene (20 mL) was added di(1H-imidazol-1-yl)methanone (0.48 g, 2.94 mmol) in one portion. The reaction was stirred at rt for 3 hrs. To the reaction was then added the N-ethyl-N-isopropylpropan-2-amine (1.97 ml, 11.30 mmol), followed by 4-Fluoroisoindoline hydrochloride (1.27 g, 4.52 mmol). The reaction was stirred at 60° C. for 3 hrs. The solvent was removed. The residue was partitioned between ethyl acetate (30 mL) and saturated sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:2) to give (3R,5S)-1-((S)-4-(N-(but-3-enyl)-2-nitrophenylsulfonamido)-2-(tert-butoxycarbonylamino)butanoyl)-5-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate as white solid (1.65 g, 84%). MS: Calcd.: 870; Found: [M+H]+ 871.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6](Br)[C:5]=1[OH:12])([O-:3])=[O:2].[CH2:13]([N:15](CC)CC)C.CN(C1C=CC=CN=1)C.[Cu]C#N>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:13]#[N:15])[C:5]=1[OH:12])([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1Br
Reactant: CCN(CC)CC
Agent: N#C[Cu]
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(O)c1C#N
Temperature: 80 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
2-Nitro-5-methyl-6-bromophenol (100 mg, 0.433 mmol) was dissolved in dimethyl formamide (2 mL) followed by the addition of triethylamine (0.175 g, 1.73 mmol). The addition of a catalytic amount dimethylamino pyridine was then made, followed by addition of copper (I) cyanide (155 mg, 1.73 mmol). The mixture was allowed to stir at 80° C. for 4 hours. The solvent was evaporated and chromatography of the resulting solid on silica gel (2% MeOH/CH2Cl2) gave the desired product (70 mg, 91%). 1H NMR (CD3COCD3): δ 8.30 (d, 1H), 7.15 (d,1H), 2.61 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([NH:19][C@@H:20]2[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH2:21]2)[C:16]([N+:30]([O-:32])=[O:31])=[CH:15][N:14]=1>C1COCC1>[N+:30]([C:16]1[C:17]([NH:19][C@@H:20]2[CH2:21][CH2:22][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:25]2)=[CH:18][C:13]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:14][CH:15]=1)([O-:32])=[O:31]
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: OCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2[N+](=O)[O-])CC1
Reaction time: 0.5 h

Procedure:
To a nitrogen purged, cooled (0° C.) suspension of 2-(piperidin-1-yl)ethanol (0.577 g, 4.46 mmol) in THF was added sodium hydride (0.196 g of 60% oil dispersion, 4.91 mmol), and the resulting mixture was stirred for 30 minutes. A solution of cis-methyl 4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylate (1.40 g, 4.46 mmol) in THF (14 mL) was added, and the reaction was stirred overnight at RT. The reaction mixture was quenched with water (10 mL) and the product extracted with DCM (30 mL). The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-30% of 90/10/1 DCM/MeOH/NH4OH in DCM) to afford cis-methyl 4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylate (0.6 g, 33.1% yield). MS m/z=407.2 [M+H]. Calc'd for C20H30N4O5: 406.2.