Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:9]([OH:11])=[O:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1(C)[CH:17]=CC(S(O)(=O)=O)=[CH:14][CH:13]=1.COC1CCC(OC)O1.O>CN(C)C=O>[N:8]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]([OH:11])=[O:10])[CH:14]=[CH:13][CH:12]=[CH:17]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(C(=O)O)c1ccccc1
Agent: COC1CCC(OC)O1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C(c1ccccc1)n1cccc1
Reaction time: 1 h

Procedure:
15.1 g (0.1 mole) of alpha-phenylglycine were resuspended in 450 ml of dimethylformamide, followed by the addition of 15 g of p-toluene sulphonic acid and 13.2 g (0.1 mole) of 2,5-dimethoxytetrahydrofuran. The mixture was heated to boiling, and at about 95° C. all the solid product was dissolved, the boiling temperature being held for about 60 minutes. After this time, the mixture was cooled, 400 ml of cold water were added and the total mixture was cooled to between 0°-5° C. The mixture was extracted twice with 200 ml of ethyl ether each time, the ether phases being discarded. The aqueous phase was extracted with 500 ml chloroform at pH 1.5. The chloroform extract was treated with 600 ml water and the pH was adjusted to 11. After separating the phases, 500 ml of chloroform were added to the aqueous extract, the pH being adjusted to 1.5 with 2N HCl. The chloroform phase was concentrated to obtain an oil which was crystallised from methanol-water. After drying, the alpha-(N-pyrrolyl)-phenylacetic acid obtained weighed 5.8 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][C:11]3([CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:12][C:11]3([CH:17]4[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc2c(c1)CC1(CN3CCC1CC3)O2
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Yield: 97.9 %

Procedure:
A mixture of 5′-nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (1.4 g 5.36 mmol), and 10% palladium on carbon (48% water wet, 270 mg) in methanol (90 mL) was hydrogenated for 1 hour at 50 psi of hydrogen. The catalyst was filtered off through a pad of celite and the solvent was evaporated under reduced to obtain the amine (1.2 g, 5.25 mmol, 98%) as a tan solid: electrospray MS (m/z, relative intensity) 232 ([MH]+, 100).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29]([C@@H:31]1[O:33][CH2:32]1)Cl>CC(O)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:29][C@@H:31]5[CH2:32][O:33]5)=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: ClC[C@H]1CO1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 45 °C
Reaction time: 6 h
Yield: 95.4 %

Procedure:
To a solution of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (2.32 g, 4.91 mmol) in 2-propanol (60 mL) and 3 N aq. NaOH (6 mL), (R)-epichlorohydrine (4.55 g, 49.1 mmol) is added. The mixture is stirred at 45° C. for 6 h before it is diluted with EA (100 mL) and washed twice with 1 N aq. NaOH (2×15 mL) followed by brine (25 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with heptane:EA 1:1 to give (S)-5-(2-cyclopentyl-6-methoxypyridin-4-yl)-3-(3-ethyl-5-methyl-4-(oxiran-2-ylmethoxy)phenyl)-1,2,4-oxadiazole (2.04 g) as a colourless wax; LC-MS: tR=1.52 min, [M+H]+=436.11; 1H NMR (CDCl3): δ 7.88-7.90 (m, 1H), 7.85-7.88 (m, 1H), 7.51 (d, J=1.1 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 4.14 (dd, J1=11.1 Hz, J2=3.1 Hz, 1H), 4.02 (s, 3H), 3.83 (dd, J1=11.1 Hz, J2=6.0 Hz, 1H), 3.40-3.44 (m, 1H), 3.19-3.29 (m, 1H), 2.94 (dd, J1=4.9 Hz, J2=4.3 Hz, 1H), 2.75-2.83 (m, 3H), 2.41 (s, 3H), 2.06-2.16 (m, 2H), 1.84-1.94 (m, 4H), 1.70-1.79 (m, 2H), 1.33 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:33]1[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1cccc(I)c1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4cccc(C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-iodotoluene.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:33][CH2:34][N:35]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:36][CH2:37]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccn2)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]-isothiazole 1,1-dioxide (8.5 g), triethylamine (4.2 cc) and 1-(2-pyridyl)piperazine (4.7 cc) in toluene (8cc). The mixture is heated for 2 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (30 cc), 2-{3-[4-(2-pyridyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.2 g) is obtained, m.p. 101° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CN(C=O)C.[H-].[Na+].Cl[CH2:20][S:21][C:22]#[N:23]>O>[NH2:6][C:5]1[CH:7]=[C:8]([S:11][CH2:20][S:21][C:22]#[N:23])[CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: N#CSCCl
Reactant: Nc1cc(S)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CSCSc1ccc([N+](=O)[O-])c(N)c1
Reaction time: 0.5 h

Procedure:
A solution of 3.4 g. of 2-nitro-5-mercaptoaniline in 20 ml. of DMF is treated with 0.5 g. of 100% sodium hydride, and 2.2 g. of chloromethylthiocyanate is added to the solution. After 30 minutes at 20°-25° C., the solution is diluted with water and extracted with chloroform. Removal of the chloroform leaves 1-amino- 2-nitro-5-(thiocyanatomethylthio)benzene.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12][CH2:13]2)(=[O:18])=[O:19])=[CH:21][CH:22]=1)(=[O:30])[CH:28]=[CH2:29]
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(NC(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
Diisopropylethylamine (0.14 ml, 0.8 mmol) was added in one portion to a stirred solution of N-[4-(4-amino-piperidine-1-sulfonyl)-phenyl]-acrylamide (0.1 g, 0.32 mmol) in THF (3 ml) at room temperature. To this mixture was added benzoyl chloride (0.048 ml, 0.42 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue purified by flash column chromatography (elution: 70% heptane, 30% ethyl acetate to 40% heptane, 60% ethyl acetate) to give the title compound (7 mg, 5% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Cl:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]1[N:15]=[C:16]([N:20]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[CH:27]3)[CH2:21][CH2:22][CH3:23])[S:17][C:18]=1[CH3:19]>CN(C)C=O>[Cl:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]1[N:15]=[C:16]([N:20]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH3:3])[CH:28]=[CH:27]3)[CH2:21][CH2:22][CH3:23])[S:17][C:18]=1[CH3:19]
Reactant: CCCN(c1ccc2[nH]ccc2c1)c1nc(-c2ccc(OC)cc2Cl)c(C)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(c1ccc2c(ccn2C)c1)c1nc(-c2ccc(OC)cc2Cl)c(C)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.045 g of 55% sodium hydride in oil and then 0.12 ml of methyl iodide are added, at 4° C., to 0.39 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(indol-5-yl)-N-propylamino]thiazole obtained above (EXAMPLE 7) in solution in 5 ml of dimethylformamide. After stirring for 5 hours at room temperature, the reaction mixture is poured into ice-cold water. The mixture is extracted with ethyl acetate and the organic phase is washed a number of times with water, dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel eluted with a 9/1 (v/v) cyclohexane/ethyl acetate mixture. The expected product is isolated in the form of a white solid; M.p.=146° C. 1H NMR (CDCl3): 0.92 (m, 3H), 1.58-1.73 (m, 2H), 2.01 (s, 3H), 3.81-4.0 (m, 8H), 6.51 (d, J=2.8, 1H), 6.85 (dd, J=2.2, 8.4, 1H), 6.99 (d, J=2.0, 1H), 7.09-7.20 (m, 2H), 7.35-7.40 (m, 2H), 7.62 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7](O)=[O:8].C1C=CC=CC=1.C(Cl)([Cl:24])=O.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7]([Cl:24])=[O:8]
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)Cl
Temperature: 35 °C

Procedure:
71.8 g. (0.288 moles) of α-(3,5-dichlorophenoxy) butyric acid and 75 ml. of benzene are placed in a 500 ml. flask to which a dropping funnel with dry-ice condenser is attached. The slurry is stirred and the 0.2 ml. dimethyl formamide is added. The mixture is heated to 35° C. and 10 g. of phosgene is condensed into the mixture to initiate reaction. The start of the reaction is evidenced by HCl evolution and foaming. 26.0 g. more phosgene is added in 5 gm. increments. At the conclusion of the reaction (HCl evolution ceasing), the reaction mixture is evaporated leaving a residual liquid α-(3,5-dichlorophenoxy) butyryl chloride 77.6 g., ND20 = 1.5345
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH2:15])[CH2:8]2)=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:23](O)=[O:24].C(N=C=NC(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(O)(C)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH:15][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:20]([Br:19])[CH:21]=3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cc1ccc(C(=O)NCC(=O)N[C@@H]2CCN(Cc3ccc(Cl)cc3)C2)cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) in CHCl3 (1.35 mL) and tert-butanol (0-15 mL) was treated with 3-bromo-4-methylbenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol), and HOBt (0.060 mmol). The reaction mixture was stirred at room temperature for 15 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH/CHCl3 1:1 (12 mL) and CH3OH (12 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford (R)-1-(4-chlorobenzyl)-3-[{N-(3-bromo-4-methylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 1098) (11.6 mg, 50%): The purity was determined by RPLC/MS (94%); ESI/MS m/e 466.0 (C21H23BrClN3O2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](Cl)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:11]([C:3]1[C:2]([NH:1][C:22]([C:19]2[S:20][CH:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:18]=2)=[O:23])=[C:7]([CH3:8])[C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)(=[O:13])[CH3:12]
Reactant: COc1ccc(C(C)=O)c(N)c1C
Reactant: CC(C)c1csc(C(=O)Cl)n1
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Yield: 66 %

Procedure:
Compound 217b was synthesized from compound 201b and compound 214 as a beige solid in 66% yield, according to the procedure as described for compound 217a. MS (ESI, EI+): m/z=333 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)#[N:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[I-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:25]2[CH2:26][CH2:27][CH:22]([C:20]#[N:21])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Reactant: N#CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 130 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
2.13 g of 1-bis(4-fluorophenyl)methoxy-2-chloroethane and 0.95 g of 4-cyanopiperidine were dissolved in 15 ml of dimethylformamide. After this, 4.00 g of anhydrous sodium carbonate and 0.08 g of sodium iodide were added to the resulting solution, and the mixture was stirred for 4 hours at 130° C. At the end of this time, the mixture was poured into ice water and extracted with ethyl acetate. The oily extract obtained was purified by silica gel chromatography. Elution with a 2:1 by volume mixture of ethyl acetate and hexane afforded 2.36 g (yield 88%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].[C:22](OC)(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[SH:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:21])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=[O:30])[N:20]=2)[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:10])([CH3:9])[CH3:11])=[O:4]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(Cc1ccnc(C#N)c1)C(=O)OCC[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(Cc1ccnc(-c2nc(=O)c3ccccc3s2)c1)C(=O)OCC[Si](C)(C)C
Yield: 53.6 %

Procedure:
2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(2-cyano-4-pyridyl)propionate (0.68 g, 2.2 mmol) and methyl thiosalicylate (0.60 g, 3.6 mmol) were dissolved in toluene (2.5 ml), and triethylamine (0.56 ml, 4.0 mmol) was added thereto. The reaction mixture was refluxed for 16 hrs and subjected to a silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected and concentrated to give the titled compound (0.52 g, 53%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCc1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
A mixture of 3-(4-bromophenyl)-propylamine (6.21 g, 29 mmol), 2-bromomethyl-benzoic acid methyl ester (6.57 g, 29 mmol), and K2CO3 (6.91 g, 50 mmol) in toluene (100 mL) was heated at reflux with stirring for 1.5 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(4-bromophenyl)-propyl]-2,3-dihydroisoindol-1-one (7.24 g, 88%). GC/MS gave: m/z (rel.int.) 331 (M+, 9), 329 (M+, 9), 147 (100), 146 (54) 119 (34), and 91 (33). 1H NMR (300 MHz, CDCl3): δ 1.97 (dt, 2H), 2.64 (t, 2H), 3.66 (t, 2H), 4.35 (s, 2H), 7.08 (dd, 2H), 7.38 (dd, 2H), 7.46 (m, 2H), 7.51 (dt, 1H), 7.85 (d, 1H). 13C NMR (300 MHz, CDCl3): δ 29.9, 32.5, 41.9, 49.9, 119.7, 122.7, 123.6, 128.0, 130.2 (2C), 131.2, 131.4 (2C) 132.9, 140.3, 141.1, 168.5.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si](C)(C)C)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][CH:12]=2)[C:3]([OH:23])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trimethylsilanylethynyl-phenyl)-propionic acid methyl ester (600 mg, 1.83 mmol) in methanol (10 mL) and water (10 mL) was treated with lithium hydroxide (877 mg, 20.9 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was re-dissolved in water (40 mL) which was then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with a half-saturated aqueous sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-ethynyl-phenyl)-propionic acid (448 mg, 100%) as a tan solid: mp 80-83° C.; EI-HRMS m/e calcd for C16H18O2 (M+) 242.1306, found 242.1309.
Reaction SMILES: CC(C)([S@@]([NH:6][C@:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])[CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)=[O:10])=O)C.Cl.O1CCOCC1>CO>[NH2:6][C@:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])[CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)=[O:10]
Reactant: Cc1cccc(NC(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)c2ccccc2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cccc(NC(=O)C[C@@](C)(N)c2ccccc2)c1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of (R)-3-((S)-1,1-dimethylethylsulfinamido)-3-phenyl-N-m-tolylbutanamide (300 mg, 0.81 mmol) in MeOH (5 mL) was added 4M HCl/dioxane (3 mL, 12 mmol). The solution was stirred for 1 h and concentrated to give (R)-3-amino-3-phenyl-N-m-tolylbutanamide (218 mg, 90%) without purification.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6]>O1CCOCC1.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([CH:4]=[O:2])=[O:6])=[CH:8][CH:9]=1
Reactant: O=[Se]=O
Reactant: CC(=O)c1ccc(F)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccc(F)cc1
Reaction time: 12 h
Yield: 71.1 %

Procedure:
Selenium dioxide (6.70 g, 61.0 mmol) was added to a solution of 4-fluoroacetophenone (8.43 g, 61.0 mmol) in dioxane (100 mL) and water (3 mL), and the resulting mixture was heated at 55° C. until complete dissolution of selenium dioxide had occurred. The reaction mass was then refluxed for 5-6 hrs. After completion of the reaction (TLC), the mixture was filtered and the filtrate was concentrated in vacuo affording a viscous oil. Water (50 mL) was added and the resulting mixture was stirred for 12 hrs, after which time the solid was collected on a filter, washed with water (25 mL) and dried in vacuo, affording 4-fluorophenylglyoxal (6.60 g, 85%).
Reaction SMILES: [H-].[Ba+2:2].[H-].[CH2:4]([O:6][CH2:7][CH2:8][OH:9])[CH3:5]>C1(C)C=CC=CC=1>[CH2:4]([O:6][CH2:7][CH2:8][O:9][Ba:2][O:9][CH2:8][CH2:7][O:6][CH2:4][CH3:5])[CH3:5]
Reactant: CCOCCO
Reactant: [Ba+2]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOCCO[Ba]OCCOCC

Procedure:
Three grams of powdered barium hydride was stirred and reacted overnight with 2 ml. of 2-ethoxyethanol in 10 ml. of toluene, under argon atmosphere, yielding a slurry of di(2-ethoxyethoxy)-barium in toluene. To the slurry was added 10 ml. of a 1.7 molar solution of n-butyl-lithium in n-pentane. The mixture was stirred for 3 hours at room temperature, during which time a reaction ensued between the di(2-ethoxyethoxy)-barium, the n-butyl-lithium, and the toluene to give a partly hydrocarbon-soluble, lithium-containing, organometallic product having tolyl functionality.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[N:14]=[C:13](Cl)[N:12]=[C:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)O1>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.COCCOC>[CH:1]12[N:8]([C:9]3[CH:10]=[C:11]([CH2:16][N:17]([CH3:19])[CH3:18])[N:12]=[C:13]([C:34]4[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=4)[N:14]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: CN(C)Cc1cc(N2C3CCC2COC3)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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
Product: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(N)cc2)n1
Temperature: 120 °C
Yield: 75.7 %

Procedure:
A microwave vial was charged with 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-dimethylmethanamine (0.400 g, 1.42 mmol) and sodium carbonate (2M in water, 2.12 mL, 4.24 mmol). DME (7 mL) was then added to give a yellow biphasic solution. The solution was degassed with nitrogen for 10 minutes, and tetrakis(triphenylphosphine)palladium(0) (0.098 g, 0.085 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.372 g, 1.697 mmol) were added. The vial was sealed and heated to 120° C. for 40 minutes under microwave irradiation. LCMS indicated that the reaction had not gone to completion. Additional tetrakis(triphenylphosphine)palladium(0) (0.049 g, 0.043 mmol) was added and the reaction was heated to 120° C. for an additional 80 minutes under microwave irradiation. The vessel was then cooled to room temperature and the reaction mixture was filtered through Celite™. The filter cake was washed with ethyl acetate and the filtrate was then concentrated under reduced pressure to provide a brown oil. The crude product was added to a silica gel column and was eluted with 0-10% methanol in methylene chloride to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)aniline (0.365 g, 76%) as a light orange solid. HRMS; [M+H]+ Obs'd=340.2133, [M+H]+ Calc'd=340.2131