Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH3:19][C:20]1([CH3:44])[C:24]([CH3:26])([CH3:25])[O:23][B:22](C2C=CC(NC3OC4C=CC(Cl)=CC=4N=3)=CC=2)[O:21]1>>[CH3:19][C:20]1([CH3:44])[C:24]([CH3:26])([CH3:25])[O:23][B:22]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)[O:21]1
Reactant: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Reactant: CC1(C)OB(c2ccc(Nc3nc4cc(Cl)ccc4o3)cc2)OC1(C)C
Product: Cc1ccc2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1

Procedure:
N2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-1,3-benzoxazol-2-amine was prepared from N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine (1.5 g, 4.95 mmol) using the method described for the preparation of N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-chloro-1,3-benzoxazol-2-amine. The product was formed as white floculent solid (0.79 g, 46%); RP-HPLC Rt 17.382 min, 98% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); 1H NMR (400 MHz, d6-DMSO) 1.29 (121H, s), 2.38 (3H, s), 6.94 (1H, d, J=8.1 Hz), 7.30 (1H, s), 7.36 (1H, d, J=8.1 Hz), 7.67 (2H, d, J=8.5 Hz), 7.75 (2H, d, J=8.5 Hz), and 10.74 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:24]1[N:25]([CH2:32][C:33]2([CH3:36])[CH2:35][O:34]2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1>CN(C=O)C>[CH3:35][C:33]1([CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)[O:34][C:24]2=[N:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][N:25]2[CH2:32]1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
Tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (364 mg, 1.31 mmol) was dissolved in DMF (10 ml). To the solution, sodium hydride (58 mg, 1.44 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (300 mg, 1.38 mmol) was added with cooling on ice-bath followed by stirring for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and then crystallized from methylene chloride-diisopropyl ether to afford tert-butyl 4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperidine-1-carboxylate (248 mg, yield 41%) as a white powder.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:23][CH2:24][CH3:25])=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:14]=2)[CH:5]=1.[C:27]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH3:28].[Li]>>[C:31]([O:30][C:27](=[O:29])[CH2:28][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:23][CH2:24][CH3:25])=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:14]=2)[CH:5]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCCc1sc(-c2cccc(C(=O)OC)c2)nc1COC1CCCCO1
Agent: [Li]
Product: CCCc1sc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc1COC1CCCCO1

Procedure:
3-[5-Propyl-4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-benzoic acid methyl ester (0.34 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-oxo-3-[3-[5-propyl-4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.42 g) as a pale-yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][Cl:21])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCCCc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
3.0 g of 4-(3-phenylpropyloxy)benzyl alcohol were dissolved in 30 ml of chloroform, and 1.77 g of thionyl chloride were further fed dropwise to the resultant solution. The solution was then stirred for 1 hour at room temperature. After completed the reaction, the solution reacted was poured into ice-water and extracted with chloroform. The organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was distillated under reduced pressure, thereby affording 3.2 g of 4-(3-phenylpropyloxy)benzylchloride.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:24]=[CH:23][C:10]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[O:13][C:9]=2[CH:8]=1)=[O:6].Cl>O.C1COCC1>[N+:20]([C:16]1[CH:15]=[C:14]([C:12]2[O:13][C:9]3[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:24]=[CH:23][C:10]=3[N:11]=2)[CH:19]=[CH:18][CH:17]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1ccc2nc(-c3cccc([N+](=O)[O-])c3)oc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3cccc([N+](=O)[O-])c3)oc2c1
Temperature: 60 °C
Yield: 82.5 %

Procedure:
A solution of lithium hydroxide (1.78 g, 65.0 mmol) in water (10 ml) was added to a solution of 2-(3-nitrophenyl)benzoxazole-6-carboxylic acid methyl ester (4.0 g, 14.8 mmol) in THF (30 ml). The reaction was heated to 60° C. for 4 h. The cooled reaction mixture was acidified with 2M HCl and the precipitate filtered, washed with water and dried under vacuum to give the subtitle compound (3.47 g, 92%). The product was used directly in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15].[F:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20]>>[F:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:14])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15])=[O:20]
Reactant: O=C(O)c1ccncc1F
Reactant: CN1C(=O)C(C)(C)c2cc(F)c(N)cc21
Product: CN1C(=O)C(C)(C)c2cc(F)c(NC(=O)c3ccncc3F)cc21

Procedure:
Prepared in analogy to example 26 from 6-amino-5-fluoro-1,3,3-trimethylindolin-2-one (example 20 f) and 3-fluoroisonicotinic acid. The title compound was obtained as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]1([C:39]([NH2:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]3([C:39]([NH2:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: NC(=O)C1(S(=O)(=O)c2ccccc2Br)CCCC1
Product: NC(=O)C1(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)CCCC1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-(2-bromophenylsulfonyl)cyclopentanecarboxamide. MS (ESI): mass calcd. for C22H21FN4O3S, 440.13; m/z found, 441.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 2H), 7.98 (d, J=7.7, 1H), 7.75 (m, 1H), 7.65 (m, 1H), 7.54 (m, 1H), 7.42 (s, 1H), 7.36-7.34 (m, 2H), 7.28-7.22 (m, 2H), 6.93 (s, 2H), 2.27-2.16 (m, 2H), 2.04-1.91 (m, 2H), 1.57 (s, 2H), 1.49-1.35 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH:13]3[CH2:15][CH2:14]3)(O)[CH3:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.FC(F)(F)C(O)=O.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:31]3[C:30]4[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=4)[NH:33][CH:32]=3)([CH:13]3[CH2:15][CH2:14]3)[CH3:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc2sccc2c1)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc4sccc4c3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (2.75 mmol) of the compound from Example 141A and 0.25 ml (3.30 mmol) of trifluoroacetic acid were added to 487 mg (2.75 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient) and once by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1). 404 mg (39% of theory) of the title compound were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>C(O)CCC.C(O)C>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[F:26][C:13]([F:12])([F:27])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[CH2:10][CH2:9][CH2:8][C:7]3=[O:11])[CH2:24][CH2:25]2)[CH:15]=1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Reactant: O=C1CCCN1CCCCBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCO
Product: O=C1CCCN1CCCCN1CCN(c2cc(C(F)(F)F)ccn2)CC1
Yield: 52 %

Procedure:
2 7 g of 1-(4-bromobutyl)-2-pyrrolidinone were mixed with 2.2 g of 1-[4-(trifluoromethyl)-2-pyridinyl]piperazine dissolved in 30 ml of butanol, after which 1.3 g of sodium carbonate were added. The mixture was refluxed for 2 hours, after which the precipitate was filtered and washed with butanol. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent 3.4 g of 1-[4-[4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl]butyl]-2-pyrrolidinone were obtained. To make the monofumarate, 1 g of fumaric acid dissolved in absolute ethanol was mixed with the free base. The resulting compound was recrystallized twice from acetonitrile, after which 2.4 g (52% yield) of 1-[4-[4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl]butyl]-2pyrrolidinone (E)-2-butenedioate (1:1) salt were obtained with a melting point of 140° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=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:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:7]=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCC(=O)c1cccc(Br)n1
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: CCCCC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.8 %

Procedure:
A solution of 1-(6-bromo-2-pyridinyl)-1-pentanone (2.51 g, 10.37 mmol) in DME (13 mL) was treated with 4-(triflouromethyl)benzeneboronic acid (2.36 g, 12.43 mmol), Pd(PPh3)4 (1.19 g, 1.03 mmol) and then a slurry of Na2CO3 (3.29 g, 31.04 mmol) in water (13 mL). The resulting mixture was then heated to reflux over 30 minutes and then stirred at this temperature for 17 hours. The mixture was then allowed to cool to rt and was reduced and the residue partitioned between EtOAc (200 mL) and water (200 mL). The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with saturated aqueous NaHCO3 (250 mL), brine (250 mL), dried (MgSO4), filtered and reduced to give a brown orange solid residue. Purification by Biotage™ chromatography (silica) eluting with cyclohexane:EtOAc (gradient 1:0 to 10:1) afforded the title compound as a white solid (3.02 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](I)[CH3:31]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH2:30][CH3:31])[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2nc(-c3ccccc3)[nH]c2Sc2ccc(Cl)cc2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(-c2ccccc2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Reaction time: 0.08 h

Procedure:
To 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1H-imidazol-4-yl}benzonitrile (Example 2, 10 mg) in THF (1 mL) was added NaH (60% wt, 15 mg) at 0° C. After stirring for 5 min, EtI (0.05 mL) was added. The reaction was stirred at 50° C. overnight, then quenched with aq NH4Cl to adjust the pH to 6-8. The product was extracted with EtOAc and the combined extracts were washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was subject to silica column chromatography (0-15% EtOAc in hexanes) to give the title compound. LCMS: m/z 416 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O-:25])=[O:24])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:12]([O-:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:37][C@H:38]2[C@H:42]([CH2:43][O:44][S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[O:41][C:40]([CH3:56])([CH3:55])[O:39]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O:25][C:11]([CH3:15])([CH3:12])[CH3:10])=[O:24])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:37][C@H:38]2[C@H:42]([CH2:43][O:44][S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[O:41][C:40]([CH3:56])([CH3:55])[O:39]2)=[CH:20][CH:21]=1)[C:12]([O:14][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2OC(C)(C)O[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)[O-])C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2OC(C)(C)O[C@H]2COc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 100 °C
Yield: 65.5 %

Procedure:
To 0.47 g (1 mmol) (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-L-glutamate and 0.47 g (1 mmol) [(4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl]dimethanediyl bis(4-methylbenzenesulfonate) in 15 mL DMF was added potassium carbonate (0.28 g, 2 mmol). The mixture was heated in a microwave for 2 h at 100° C. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (silica, 20% ethyl acetate in hexane) to afford 0.25 g (33%) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-{[(4S,5S)-2,2-dimethyl-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,3-dioxolan-4-yl]methoxy}benzyl)-L-glutamate.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](C(C3C=CC=CC=3)C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1cccc2c1Oc1ccccc1N2C(C)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cccc2c1Oc1ccccc1N2

Procedure:
4-methyl-N-(α-phenylethyl)phenoxazine in 30 ml of ethyl acetate and 130 ml of ethanol was hydrogenated at atmospheric pressure (585 mm Hg) in the presence of 1.5 g of 10% palladium-charcoal as catalyst, until the calculated amount of hydrogen was consumed (16 hours). The catalyst was then separated by filtration through celite and the solvent removed under reduced pressure. Chromatography of the solid residue (1 g) on 100 g of silica gel in a column, using hexane-ethyl acetate (80:20) as the eluting solvent produced 4-methylphenoxazine, a white solid, which was recrystallized from pentane, mp: 91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:20]2[CH2:19][CH2:18][CH:17]([CH2:16][O:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[O:12][CH3:11])[CH2:22][CH2:21]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ccccc1OCC1CCNCC1
Reactant: COc1ncccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1OCC1CCN(Cc2cccnc2OC)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
200 mg of 2-methoxy-3-(chloromethyl)pyridine, 380 mg of 4-[(2-methoxyphenoxy)methyl]piperidine and 235 mg of potassium carbonate were added in 10 ml of acetonitrile, and the mixture were stirred at room temperature for 3 hours 15 minutes. After filtering the reaction solution, the solvent was evaporated, and the crude product was purified by silica gel column chromatography (hexane:ethyl acetate=3:2), to give 359 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][C:6](=[CH2:11])[CH2:7][C:8]([OH:10])=[O:9])([CH3:4])[CH3:3].[N+](=[CH2:14])=[N-].C(O)(=O)C>C(OCC)C>[CH3:1][Si:2]([CH2:5][C:6](=[CH2:11])[CH2:7][C:8]([O:10][CH3:14])=[O:9])([CH3:4])[CH3:3]
Reactant: C=C(CC(=O)O)C[Si](C)(C)C
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: C=C(CC(=O)OC)C[Si](C)(C)C

Procedure:
To a solution of 3-(trimethylsilylmethyl)but-3-enoic acid (36.5 g) in diethyl ether (200 ml) at 10°-15° C. was added a solution of diazomethane in diethyl ether (ca 0.6M solution, 400 ml). The excess of diazomethane was decomposed by addition of acetic acid. The resultant solution was concentrated in vacuo to 200 ml and the concentrate was washed with an aqueous sodium bicarbonate and brine. Drying over magnesium sulfate and evaporation of the solvent left a yellow oil, which was distilled in vacuo to give methyl 3-(trimethylsilylmethyl)but-3-enoate (34.74 g) as a colorless oil, bp 74°-75° C. (10 Torr).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:12]([C:15]1[C:16]([S:21](Cl)(=[O:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:21]([C:16]2[C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:23])=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=[N+]([O-])c1cccnc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccnc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 42 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (1.3 g, 9.36 mmol), 3-nitro-pyridine-2-sulfonyl chloride 445 (2.7 g, 12.2 mmol), pyridine (2.25 ml, 28.1 mmol), DMAP (cat.) and DCM (100 ml) gave the title compound (1.3 g, 42%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][CH2:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2cccc(F)c2)N1
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(F)c1
Yield: 87.6 %

Procedure:
Following the procedure described for Preparation 8, Step C, 5-[4-(3-fluoro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (2.23 g, 8.87 mmol) was reacted with tert-butyldimethylsilyl chloride (1.47 g, 9.76 mmol). Purification by medium pressure chromatography using a solvent gradient (1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-pyrrolidin-2-one (2.84 g). 1H NMR (CDCl3) δ7.23 (m, 1H), 6.88 (m, 3H), 5.75 (m, 1H), 3.85 (m, 1H), 3.57 (m, 1H), 2.71 (m, 2H), 2.30 (m, 2H), 2.25 (m, 1H), 1.70-1.38 (m, 5H), 0.84 (s, 9H), 0 (s, 3H), −0.2 (s, 3H).
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[S:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH2:27])(=[O:26])=[O:25])(=[O:16])=[O:15])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.CO.[H][H].C(OCC)(=O)C.CO>CCOC(C)=O>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH2:27])(=[O:25])=[O:26])(=[O:15])=[O:16])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccc(C2=CCCC2)cc1
Reactant: [H][H]
Solvent: CCOC(C)=O
Solvent: CO
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(C2CCCC2)cc1
Yield: 57.1 %

Procedure:
(E)-2-(2-(4-Cyclopentenylphenyl)vinylsulfonamido)benzenesulfonamide (25.00 mg, 0.06 mmol) was dissolved in EtOAc (1.6 mL) and MeOH (1.6 mL) and hydrogenated under continuous flow hydrogenation conditions (full hydrogen, flow 1 ml/min, ethyl acetate/methanol 1:1 as eluent) at 50° C. using an H-Cube system. The solvent was removed in vacuo and the residue was purified by column chromatography on silica using heptane/ethyl acetate gradient mixtures as eluent (0-100% ethyl acetate) to give the product as a solid (14 mg, 55%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[N+:24]([O-:26])=[O:25])=[N:14][NH:15][CH:16]=1>N1C=CC=CC=1>[O:4]([C:2]([C:16]1[NH:15][N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[N+:24]([O-:26])=[O:25])[C:12]=1[Cl:11])=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1c(Cl)cccc1-c1n[nH]cc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1[nH]nc(-c2cccc(Cl)c2[N+](=O)[O-])c1Cl
Reaction time: 8 h

Procedure:
1.0 ml of phenyl chloroformate is added, in small portions, to a solution, cooled to 0° C., of 1.3 g of 4-chloro-3-(2-nitro-3-chlorophenyl)pyrazole in 20 ml of pyridine. Stirring is continued for 8 hours at room temperature. The reaction mixture is concentrated dryness under reduced pressure and taken up in 100 ml of an H2O/ethyl acetate (1/1) mixture. The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residual solid is purified by recrystallisation from diisopropyl ether.