Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8]N=C(C1C=CC=CC=1)C#N)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.Cl.Cl.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].O.C(Cl)Cl>O1CCOCC1>[C:1]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:8]
Reactant: NCCCCCN
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCN
Reaction time: 12 h
Yield: 53.7 %

Procedure:
A solution of 2-(Boc-oxyimino)-2-phenylacetonitrile (226 mg, 0.92 mmol) in 1,4-dioxane (30 mL) was added via syringe pump (rate=8 mL/hr) to a stirred solution of 1,5 diaminopentane dihydrochloride (1 g, 5.52 mmol) and TEA (1 ml, 7.12 mmol) in 1:1 1,4-dioxane:water (40 mL) under inert atmosphere at room temperature. The reaction was stirred for 12 h and DCM (20 mL) was added to the reaction mixture. The organic phase was extracted and concentrated in vacuo. The yellow residue was dissolved in diethyl ether (15 mL) and 5% HCl solution added. The acidic solution was washed with diethyl ether and then the pH of the aqueous layer adjusted to pH 14 with 2.5M NaOH solution. Ethyl acetate (20 mL) was added and the organic layer was washed with brine (2×50 mL), and dried (MgSO4). The solvents were evaporated in vacua to yield N-Boc-cadaverine as a yellow oil (100 mg, 55%). HPLC/MS (Hydrophilic/TFA) Rt=6.17 min; ESI MS (+ve) m/z=203 [M+1H); calc. m/z for C10H22N2O2: 202.3 g/mol,
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].Cl.[N:13]([O-])=O.[Na+].[C:17]([SH:21])([CH3:20])([CH3:19])[CH3:18]>O.CC(C)=O>[C:17]([S:21]/[N:13]=[N:1]/[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=N[O-]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: CC(C)(C)S
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)O)cc1/N=N/SC(C)(C)C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a stirred solution of 3-amino-4-methylbenzoic acid (5.0 g, 33 mmol) in a mixture of water (50 mL) and concentrated hydrochloric acid (15 mL) in an acetone-crushed ice bath is added a solution of sodium nitrite in water (12 mL) dropwise. The solution is stirred for 10 min, followed by the addition of tert-butyl mercaptan (1.8 mL, 16 mmol). The mixture is stirred for 1 h. The solid precipitate is filtered, washed with water and dried in vacuo to obtain 3.85 g (95%) of 3-[(E)-(tert-butylthio)diazenyl]-4-methylbenzoic acid as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ 13.2, 7.8, 7.5, 7.3, 2.1, 1.6.
Reaction SMILES: Br[C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.[Li]CCCC.Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].[NH4+].[Cl-]>C1COCC1.O.C(Cl)Cl>[O:20]([CH2:19][CH2:18][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1)[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
A suspension of compound 2.2 from Step A (2.0 g, 8.6 mmol) in THF (40.0 mL) was cooled to −78° C. under an argon atmosphere. n-BuLi (1.6M in hexanes, 13.4 mmol) was then added over 1.0 hr via syringe. A suspension formed and (2-bromoethoxy)-tert-butyldimethylsilane (7.4 mL, 34.4 mmol) was added via syringe while maintaining the reaction mixture at −78° C. The reaction mixture was allowed to slowly reach −30° C. and stirred for 2 h, then −30 to −10° C. for 1 h, and −10 to 0° C. for 1 hr. The reaction mixture became dark brown in color, was treated with NH4Cl, CH2Cl2 and water. The reaction mixture was extracted with CH2Cl2 and the extracts were dried over Na2SO4, filtered and evaporated. The beige residue was purified by flash column chromatography using 23% EtOAc in hexanes as eluent to give the desired compound 2.3 (1.16 g, 43%) as a white solid. (Brown, D. M. et al., J. Chem. Soc. PT-1, 3565-3570.)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1.[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:14][C:7]([C:4]1[N:3]=[C:2]([CH3:1])[O:6][N:5]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C)c1noc(C)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(Br)c1noc(C)n1
Temperature: 25 °C

Procedure:
A carbon tetrachloride (30 mL) solution containing the intermediate from Step B (1.9 g, 10.3 mmol), N-bromosuccinimide (3.56 g, 20 mmol) and AIBN (0.1 g) was heated at reflux for 4 hours. The solution was cooled to room temperature, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. m/z=263.0 (M+H).
Reaction SMILES: ClC1C=C(C=C(C(O)(C)C)C=1)C=O.C(O)(=O)CC(O)=O.C([O-])(=O)C.[NH4+:25].[Cl:26][C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][C:39]([OH:41])=[O:40])[CH:30]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:32]=1>C(O)(C)C>[NH2:25][CH:37]([C:29]1[CH:30]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:32]=[C:27]([Cl:26])[CH:28]=1)[CH2:38][C:39]([OH:41])=[O:40]
Reactant: CC(C)(O)c1cc(Cl)cc(C=CC(=O)O)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: CC(C)(O)c1cc(Cl)cc(C=O)c1
Agent: O=C(O)CC(=O)O
Solvent: CC(C)O
Product: CC(C)(O)c1cc(Cl)cc(C(N)CC(=O)O)c1

Procedure:
A suspension of 3-chloro-5-(2-hydroxypropan-2-yl)benzaldehyde (2.35 g, 11.83 mmol), malonic acid (1.50 g, 14.41 mmol) and ammonium acetate (1.85 g, 24.00 mmol) in isopropanol (30.0 mL) was heated at reflux under nitrogen atmosphere for 4 h to afford a colorless suspension in a yellow-orange solution. The hot reaction mixture was filtered and the solid was washed with hot isopropanol (2×25 mL) and discarded. The filtrate was evaporated in vacuo to afford a mixture of the desired acid (40%) and the byproduct: 3-(3-chloro-5-(2-hydroxypropan-2-yl)phenyl)acrylic acid (60%) as a cream yellow foamy solid. The solid was recrystallized several times (×5) from ethyl acetate to afford the pure desired product, free from the byproduct impurity, as a colorless solid (632.8 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 258 (35ClM+H), m/z 260 (37ClM+H), m/z 240 (35ClM+H−H2O) and m/z 242 (37ClM+H−H2O); Calcd for C12H16ClNO3: 257.71. 1H NMR (400 MHz, DMSO-d6): δ 1.42 (s, 6H, (CH3)2C—), 2.30 (dd, J=8.0 and 6.0 Hz, 2H, —CH2—COOH), 4.21 (appt, J=7.0 Hz, 1H, —NH—CH—CH2—COOH), 6.33 (s, 1H, (CH3)2—C—OH), 7.31 (appt, J=1.60 Hz, 1H), 7.38 (appt, J=1.70 Hz, 1H), 7.42 ((d, J=9.0 Hz, 1H). 1H NMR spectrum of the sample was consistent with the suggested structure of the product.
Reaction SMILES: C1C(CC2CCC(N=C=[O:16])CC2)CCC(N=C=O)C1.C[O:21][C:22]1[CH:28]=[CH:27][C:25]([OH:26])=C[CH:23]=1.[N-:29]=[C:30]=[O:31]>O>[C:25]([OH:16])(=[O:26])[CH:27]=[CH2:28].[NH2:29][C:30]([O:21][CH2:22][CH3:23])=[O:31]
Reactant: O=C=NC1CCC(CC2CCC(N=C=O)CC2)CC1
Reactant: [N-]=C=O
Reactant: COc1ccc(O)cc1
Solvent: O
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
An amount of dicyclohexylmethane-4,4′-diisocyanate (H12MDI) was added to a reaction vessel at room temperature. Heating jacket temperature was adjusted to 45° C. suspended in a room temperature water bath and stirred. When the reaction batch temperature was 45° C., dibutyltindilaurate, as catalyst, and hydroquinone methyl ether, as free-radical polymerization inhibitor, were also added. Pentaerytritol triacrylate was added incrementally to control exothermic activity. When the exothermic activity ceased the result of Stage 1 was added and batch temperature was adjusted to 60° C. The batch was kept at 60° C. until no free isocyanate was detected by FTIR. Viscosity of the result was 11,750 cP at 25° C. and it readily mixes with water. When the result was diluted with equal amount (by weight) of water viscosity was 150 cP at 25° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[NH:14][N:13](C3CCCCO3)[CH:12]([C:21]([F:24])([F:23])[F:22])[CH:11]=2)[N:6]=[N:7][CH:8]=1.CO>Cl.O.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[NH:14][N:13]=[C:12]([C:21]([F:24])([F:22])[F:23])[CH:11]=2)[N:6]=[N:7][CH:8]=1
Reactant: COc1cnnc(OC2=CC(C(F)(F)F)N(C3CCCCO3)N2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cnnc(Oc2cc(C(F)(F)F)n[nH]2)c1
Reaction time: 1 h
Yield: 65 %

Procedure:
5-Methoxy-3-[[2-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (Compound No. 36, 0.75 g (0.0021 mole), 4 drops of 37% hydrochloric acid, and 10 mL of methanol were heated and held at 50° C. for 1 hour. The mixture was cooled, diluted with 30 ml water and neutralized with sodium bicarbonate. Filtration gave 5-methoxy-3-[[3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (0.36 g, 65% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]([CH2:12][Br:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)ccc2cccnc12
Solvent: c1ccccc1
Product: Clc1ccc2cccnc2c1CBr

Procedure:
7-Chloro-8-methylquinoline (1 g.) [Bradford et al., J. Chem. Soc., p. 437 (1947)] is dissolved in 20 ml. of benzene and brominated with one equivalent of N-bromosuccinimide in the presence of catalytic amounts of peroxide. The product, 7-chloro-8-(bromomethyl)-quinoline is isolated by evaporation.
Reaction SMILES: [C:1]1([N:7]=[C:8]([OH:22])[C:9]2[C:10](=[C:14](Br)[C:15](Br)=[C:16](Br)[C:17]=2Br)[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[SH:31].[C:32](=[O:35])([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]1([N:7]=[C:8]([OH:22])[C:9]2[C:10](=[C:14]([S:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:35][CH3:32])[C:15]([S:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])=[C:16]([S:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[C:17]=2[S:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1S
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(Br)c(Br)c(Br)c(Br)c1C(O)=Nc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1Sc1c(Sc2ccccc2OC)c(Sc2ccccc2OC)c(C(O)=Nc2ccccc2)c(C(=O)O)c1Sc1ccccc1OC

Procedure:
2 g (3.71 millimols) of tetrabromophthalic acid N-phenylimide, 2.34 g (16.7 millimols) of o-methoxythiophenol, 3.34 g (24.2 millimols) of potassium carbonate and 20 ml of tetrahydrofuran are stirred at 25° C. for 24 hours. After acidification, the mixture is extracted with methylene chloride, the extracts are dried and evaporated and the residue is recrystallised from toluene. This yields 2.75 g (96% of theory) of the title imide; melting point 142°-6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][CH2:11][CH:12]([CH2:14]O)[OH:13].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:13][CH:12]1[CH2:11][O:10][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[O:6][CH2:14]1
Reactant: OCC(O)CO
Reactant: O=Cc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: OC1COC(c2cccc(Cl)c2)OC1
Yield: 42.2 %

Procedure:
A mixture of 3-chlorobenzaldehyde (28.1 g, 0.2 mole), glycerol (18.4 g, 0.2 mole) and p-toluenesulfonic acid (0.1 g) in 150 ml of benzene was heated at reflux under a Dean-Stark apparatus until water was no longer collecting (3.6 ml). The solution was cooled, washed with 2% sodium bicarbonate solution (2 × 100 ml) and with water (2 × 100 ml). The washed solution was dried over magnesium sulfate and concentrated under reduced pressure. The oil remaining was distilled to give 18.1 g of colorless liquid which distilled at a pot temperature of 124°-128° C under 1 × 10-4 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:31])[C:7](=[O:30])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23](C(O)=O)[CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.CC[N:34](CC)CC.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:31])[C:7](=[O:30])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH2:34])[CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN(CC)CC
Reactant: CCN1c2ncc(CCc3ccnc(C(=O)O)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: CCN1c2ncc(CCc3ccnc(N)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 16.3 %

Procedure:
To a solution of 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-[2-(2-carboxypyrid-4-yl)ethyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (92 mg, 0.21 mmol) and Et3N (0.03 mL, 0.22 mmol) in t-butanol (20 mL) was added diphenylphosphoryl azide (0.046 g, 0.21 mmol). The reaction mixture was heated at reflux under argon for 16 hours. Solvents were removed by rotary evaporation, and the residue was dissolved in ethyl acetate, washed with saturated aq. sodium bicarbonate, dried (magnesium sulfate), and concentrated. The residue was treated with 2N hydrochloric acid in ethanol at 25°-50° C. for 30 hours. The reaction mixture was concentrated, basified with 6N sodium hydroxide, and extracted with ethyl acetate. Purification by flash chromatography (elution with methanol-dichloromethane) and recrystallization (diethyl ether-petroleum ether) afforded 14 mg (16%) of the title compound, m.p. 95° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O-].[Na+].CI.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CI
Product: CSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-bromobenzenethiol (5 g, 26.44 mmol) was added to a solution of sodium methoxide (1.43 g, 26.48 mmol) in 20 ml of anhydrous methanol. The mixture was stirred for 30 min under nitrogen at room temperature and a solution of methyl iodide (4.51 g, 31.77 mmol) in 20 ml anhydrous methanol was then added. The reaction mixture was stirred overnight at room temperature, poured into 2 M aqueous NaOH solution (30 ml) and extracted three times with ether (60 ml×3). The combined organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of solvent, the product was purified by distillation at 80° C. (0.3 mmHg) and isolated in 86.1% (4.62 g) yield. 1H NMR(CDCl3, 500 MHz) δ ppm: 2.44 (s, 3H, CH3), 7.1-7.4(m, 4H, Ar—H)GC-MS(relative intensity %): 202, 204(1:1, 100, M+), 187, 189(1:1, 11, 3-BrPhS+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:24][CH2:25][CH2:26]Cl)[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[I-].[Na+].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>CN(C=O)C.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:24][CH2:25][CH2:26][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(CCCCl)C(C(=O)OC)C(C)C)cc1
Reactant: CCNCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(CCCN(CC)CC)C(C(=O)OC)C(C)C)cc1
Temperature: 80 °C
Yield: 90.2 %

Procedure:
To a solution of 0.45 g (1.08 mmol) of methyl 2-[{[4-(2-butynyloxy)-phenyl]-sulfonyl}(3-chloropropyl)amino]-3-methylbutanoate in 5.0 mL of DMF was added 0.163 g (1.08 mmol) of sodium iodide and 0.34 mL (3.24 mmol) of diethylamine. The reaction was heated to 80° C. for 3 h and then cooled to room temperature. The mixture was then diluted with water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.441 g of methyl 2-{{[4-(2-butynyloxy)-phenyl]sulfonyl}[3-(diethylamino)propyl]amino}-3-methylbutanoate as a brown oil. Electrospray Mass Spec 453.5 (M+H)+
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]([CH3:10])[NH:7][CH2:6][CH:5]1[CH3:11])[CH:2]=[CH2:3].C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[OH-].[Na+].ClCCl>C(O)C>[CH2:1]([N:4]1[CH2:9][C@H:8]([CH3:10])[NH:7][CH2:6][C@H:5]1[CH3:11])[CH:2]=[CH2:3]
Reactant: C=CCN1CC(C)NCC1C
Agent: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: C=CCN1C[C@H](C)NC[C@H]1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of racemic 1-allyl-2,5-dimethylpiperazine (3.82 g, 24.8 mmol, Example 42, infra) and (+)-di-p-toluoyl-D-tartaric acid (9.55 g, 24.8 mmol) in absolute ethanol (40 mL) was heated to reflux and allowed to cool gradually to room temperature. After standing for one day the salt was collected by filtration, washed with ethanol and dried to give 11.0 g. This was recrystallized four times from absolute ethanol to give the salt (4.5 g, 68% of theoretical for one enantiomer) as a white solid. The salt (3.3 g, 6.1 mmol) was partitioned between 2N sodium hydroxide solution and dichloromethane. The dichloromethane phase was separated, the alkali washed twice with dichloromethane, and the combined dichloromethane phases were dried with magnesium sulfate and evaporated to give (-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine, (0.92 g, 98% recovery from the salt), [α]D20 =-55.7° (ethanol, c=1.8).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[C:13](=[O:18])[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:11]3)[N:4]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:44]1[CH2:49][C@@H:48]2[CH2:50][C@H:45]1[CH2:46][NH:47]2)=O)(C)(C)C>CC#N.O>[CH:45]12[CH2:50][CH:48]([NH:47][CH2:46]1)[CH2:49][N:44]2[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[C:13](=[O:18])[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:11]3)[N:4]=1
Reactant: Cc1cc(-c2noc(CCl)n2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-c2noc(CN3CC4CC3CN4)n2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 72.9 %

Procedure:
To a solution of 5-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one (100 mg, 0.228 mmol) in MeCN (4 mL) was added K2CO3 (95 mg, 0.684 mmol) and (1s,4s)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (90 mg, 0.451 mmol). After 48 hours the mixture was diluted with water, then extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated to a yellow oil. This residue was dissolved in 1:1 TFA/CH2Cl2 (6 mL) for 30 minutes, then the reaction mixture was concentrated and basified with NaHCO3 to pH˜9-10. The product was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica (2-8% 2M NH3 in MeOH/CH2Cl2) to provide 5-[5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-3-yl]-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one as a light yellow solid (83 mg). 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.91 (s, 1H), 7.34 (d, 2H), 7.18 (d, 2H), 4.77 (s, 2H), 4.28 (s, 2H), 4.05 (dd, 2H), 3.57 (d, 2H), 3.20 (d, 1H), 3.13 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 3H), 2.61 (d, 1H), 1.86 (d, 1H), 1.64 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[N:5]([CH:13]([CH3:15])[CH3:14])[C:4](=[O:16])[CH2:3]1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:9][CH:10]=2)[N:5]([CH:13]([CH3:15])[CH3:14])[C:4](=[O:16])[CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)N1C(=O)CC(C)(C)c2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)N1C(=O)CC(C)(C)c2ccc(C#C[Si](C)(C)C)cc21
Temperature: 50 °C

Procedure:
To a solution of 0.40 g (1.36 mmol) of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-1-iso-propyl-7-bromoquinoline (Compound 24) in 5.0 ml of triethylamine which was degassed under argon for 15 min in a sealable tube, were added successively 0.069 g (0.36 mmol) of copper(I)iodide, (1.0 ml, 7.1 mmol) of (trimethylsilyl)acetylene, and 0.147 g (0.21 mmol) of bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was degassed for an additional 5 min. The tube was sealed and the reaction mixture was heated at 50° C. for 72 h. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as an oil. PNMR (CDCl3) d 0.25 (9H, s), 1.26 (6H, s), 1.54 (6H, d, J=7.1 Hz), 2.39 (2H, s), 4.60 (1H, p, J=7.1 Hz), 7.17 (3H, m).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[C:18]([CH3:19])=[CH:17][C:10]([O:11][C@@H:12]2[CH2:15][C@H:14]([NH2:16])[CH2:13]2)=[CH:9][C:8]=1[CH3:20].C(N(CC)CC)C>ClCCl>[Br:6][C:7]1[C:18]([CH3:19])=[CH:17][C:10]([O:11][C@@H:12]2[CH2:15][C@H:14]([NH:16][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13]2)=[CH:9][C:8]=1[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(O[C@H]2C[C@@H](N)C2)cc(C)c1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O[C@H]2C[C@@H](NS(C)(=O)=O)C2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (0.16 mL), cis-3-(4-Bromo-3,5-dimethylphenoxy)cyclobutanamine (300 mg) and triethylamine (0.3 mL) are stirred at 0° C. in dry dichloromethane (25 mL). After 10 min, the reaction mixture is warmed to ambient temperature. After stirring for 3 hours, the mixture is diluted with dichloromethane, washed with 10% aqueous solution of KHSO4, then with 10% aqueous solution of K2CO3. The organic phase was passed through a phase separator and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→50:50) to give the title compound. Yield: 200 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:8]([C:20]#[N:21])=[C:7]2[CH2:22][CH2:23][CH2:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.[C:36]1([CH3:45])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.[F-].[Cs+]>COCCOC.CO.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>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH3:45])[C:7]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[C:8]2[C:20]#[N:21])=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2c(C#N)c(CCCOc3cccc4ccccc34)c3cccc(Br)c32)cc1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COc1ccc(Cn2c(C#N)c(CCCOc3cccc4ccccc34)c3cccc(-c4ccccc4C)c32)cc1

Procedure:
To a mixture of EXAMPLE 581C (300 mg) and o-tolylboronic acid (93 mg) in 1,2-dimethoxyethane (10 ml) and methanol (5 ml) was added tetrakis(triphenylphosphine)palladium(0) (33 mg) and CsF (260 mg). The mixture was stirred at reflux under nitrogen for 4 hours. The mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate (300 mL) and water (100 ml). The aqueous layer was further extracted with ethyl acetate and the combined extracts were washed with water, brine and dried over Na2SO4. After filtration, concentration of the solvent and column purification (5 to 10% ethyl acetate in hexane) gave Example 581D.