Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccnc(Br)c1

Procedure:
A mixture of 2-bromo-4-methylpyridine (12.2 g), N-bromosuccinimide (30 g) and 2,2′-azobis(2-methylpropionitrile) (100 mg) in carbon tetrachloride (200 ml) was heated at reflux for 2.5 hours. The mixture was allowed to cool and the insoluble material removed by filtration. The solvent was removed from the filtrate by evaporation and the residue was purified by filtration through a silica pad eluting with ethyl acetate/hexane (10/1) to give 2-bromo-4-bromomethylpyridine.
Reaction SMILES: S1C=CC(C(Cl)=O)=C1.[S:9]1[CH:13]=[CH:12][C:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])=[CH:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[S:9]1[CH:13]=[CH:12][C:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])=[CH:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38][C:17]([NH:16][C:14]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)=[O:15])=[S:18])=[CH:39][CH:40]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccsc1
Agent: O=C(N=C=S)c1ccsc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccsc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
3-Thiophenecarbonyl isothiocyanate was prepared using commercially available 3-thiophenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Thiophenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (45 mg, yield 68%).
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[S:17][C:16]2[CH2:18][CH2:19][CH2:20][C:15]=2[C:14]=1[C:21]#[N:22].[C:23]1([CH:29]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36]C=2)[C:30]([OH:32])=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:21]([C:14]1[C:15]2[CH2:20][CH2:19][CH2:18][C:16]=2[S:17][C:13]=1[NH:12][C:30](=[O:32])[CH:29]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:33]1[CH:34]=[CH:39][CH:38]=[CH:37][CH:36]=1)#[N:22]
Reactant: O=C(O)C(Cc1ccccc1)c1ccccc1
Reactant: N#Cc1c(N)sc2c1CCC2
Agent: CCN=C=NCCCN(C)C
Product: N#Cc1c(NC(=O)C(c2ccccc2)c2ccccc2)sc2c1CCC2
Reaction time: 19 h
Yield: 23.9 %

Procedure:
EDCI (59 mg; 0.308 mmol) was added to a solution of 2-Amino-3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophene (25 mg; 0.152 mmol) and 2,3-diphenylpropionic acid (70 mg; 0.309 mmol). After stirring for 19 h, the reaction mixture was applied directly to a silica gel column (Merck Silica gel 60; eluent: 10%–33% ethyl acetate/hexanes) to provide 13.0 mg (23%) of N-(3-Cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-2,2-diphenyl-acetamide as a white solid. EI-HRMS m/e calcd for C22H18N2OS (M+H+) 358.1140, found 358.1140.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[CH3:10][Sn:11](Cl)([CH3:13])[CH3:12].[Cl-].[NH4+].O>O1CCCC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Sn:11]([CH3:13])([CH3:12])[CH3:10])=[CH:3][CH:2]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([Sn](C)(C)C)cc1
Temperature: 25 °C

Procedure:
p-Tolylmagnesium bromide solution (Aldrich) (1.0M solution in diethyl ether) (53 ml, 0.0530 mol) was added dropwise to trimethyltin chloride (6.92 g, 0.0347 mol) in tetrahydrofuran (50 ml) under nitrogen at -10° C. The suspension was allowed to warm slowly to room temperature over 3 h then saturated ammonium chloride solution (10 ml) was added followed by sufficient water to dissolve the precipitate. The solution was extracted three times with diethyl ether-hexane (1:1). The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvents removed in vacuo. Vacuum distillation of the residue afforded a colorless liquid (39°-40° C., 0.1 mm Hg) which was further purified by flash chromatography (silica gel, hexane) to give p-tolyltrimethyltin as a colorless liquid; 1H NMR (300 MHz, CDCl3) δ7.40 (d, J=7.7 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 2.34 (s, 3H), 0.30 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:16].[CH3:17][O:18][CH2:19]Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:16][CH2:17][O:18][CH3:19]
Reactant: COCCl
Reactant: Oc1c(Br)c(C(F)(F)F)cc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(Br)c(C(F)(F)F)cc2ccccc12
Yield: 91 %

Procedure:
2-Bromo-3-(trifluoromethyl)-1-naphthalenol (179) (0.23 g, 0.79 mmol) was treated with chloromethyl methyl ether in the presence of diisopropylethylamine in THF to give 0.24 g (91%) of the title compound (180) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.75 (s, 3H), 5.29 (s, 2H), 7.59-7.65 (m, 1H), 7.65-7.71 (m, 1H), 7.91 (d, J=8.1 Hz, 1H), 8.05 (s, 1H), 8.22 (d, J=8.4 Hz, 1H). LCMS (ESI): m/z 335 (M+H)+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14](=[O:24])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:7]=1.CO.Cl>O>[C:22]([C:18]1[CH:17]=[C:16]([NH:15][C:14]([CH2:13][O:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:5]([OH:25])=[O:4])=[O:24])[CH:21]=[CH:20][CH:19]=1)#[N:23]
Reactant: COC(=O)c1cccc(OCC(=O)Nc2cccc(C#N)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1cccc(NC(=O)COc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.8 %

Procedure:
Add lithium hydroxide (0.15 g, 6.3 mmol) to a suspension of 3-[(3-cyano-phenylcarbamoyl)-methoxy]-benzoic acid methyl ester (0.94 g, 3.1 mmol) in a 1:1 mixture of MeOH:water (30 mL). Stir the mixture at room temperature for 15 h then adjust the pH of the reaction to slightly acidic by the addition of a 2 N solution of hydrochloric acid. A solid precipitates from solution. Collect by filtration, wash with water, and dry on the filter pad to provide 0.650 g of 3-[(3-cyano-phenylcarbamoyl)-methoxy]-benzoic acid as a solid.
Reaction SMILES: [CH:1]1([NH:8][C:9](=[O:30])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:29])[C@H:16]([CH3:28])[NH:17][C:18]([O:20]CC2C=CC=CC=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)CC)(=O)[CH2:32]C>Br.C(O)(=O)C.CCOCC>[CH:1]1([NH:8][C:9](=[O:30])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:29])[C@H:16]([CH3:28])[NH:17][C:18](=[O:20])[CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCC1
Reactant: CCC(=O)OC(=O)CC
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2.6 g (0.0063 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline cycloheptylamide were dissolved in 15 ml of 4-N hydrogen bromide in acetic acid and the mixture was stirred at room temperature for 1 hour. 100 ml of anhydrous ether were added and an oil precipitated from the solution. The ether phase was decanted off and the oil washed with 100 ml of anhydrous ether. The ether layer was again decanted off and the oil dissolved in 30 ml of dry pyridine. 1.6 g (0.0126 mol) of propionic anhydride were added and the solution was stirred at room temperature for 2 hours. The pyridine was removed by evaporation, 50 ml of toluene were added to the residue and the mixture was again evaporated. The solid residue was taken up in 100 ml of chloroform and the solution was washed with sodium chloride solution and dried over magnesium sulphate. The chloroform was removed by evaporation to yield an oil. This oil was dissolved in the minimum volume of ether and petroleum ether was added, whereby a white solid crystallised out of the solution. There was obtained 1.85 g (88.1%) of N-propionyl-L-alanyl-L-proline cycloheptylamide of melting point 155°-156° C. [α]D20 =-119.4° (c=0.91% in methanol).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([Cl:16])=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(Cl)C(C)=CN(Cl)N=C1.[Br-].[F:28]C1C=CC(C[Zn+])=CC=1>>[Cl:16][C:11]1[N:10]=[N:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([F:28])=[CH:6][CH:7]=2)=[C:13]([CH3:14])[C:12]=1[CH3:15]
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Agent: CC1=CN(Cl)N=CC1(C)Cl
Agent: [Br-]
Product: Cc1c(Cl)nnc(Cc2ccc(F)cc2)c1C

Procedure:
Analogous to compound 42 above, 3-chloro-6-(4-fluoro-benzyl)-4,5-dimethyl-pyridazine is prepared from 4,5-dimethyl-1,4-dichloro-pyridazine and para-fluoro benzyl zinc bromide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[C:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCOCC>[OH:27][C:24]1([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:25][CH2:26][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:23]1
Reactant: COc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)C2)cn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
5-bromo-2-methoxypyridine (324 μL, 2.50 mmol) was added dropwise to a stirred suspension of n-butyllithium (1.72 mL of a 1.6 M hexanes solution, 2.75 mmol) in ether (10.0 mL) at −78° C. After 10 min, a solution of N-Boc-3-pyrrolidinone (463 mg, 2.50 mmol) in ether (2.00 mL) was added dropwise, and the reaction mixture was allowed to stir at −78° C. After 2 h, the reaction was quenched with satd. aq. NH4Cl and extracted with EtOAc. The combined organics were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-80% EtOAc/hexanes as eluent) afforded the title compound i-5a. m/z (ES) 295 (MH)+. 1H NMR (500 MHz, CDCl3): δ 8.31 (s, 1H), 7.71 (d, 1H, 7.1 Hz), 6.79 (dd, 1H, J=2.2, 8.6 Hz), 3.97 (s, 3H), 3.40-3.80 (m, 4H), 2.25 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:10]1[CH2:14]OC[CH2:11]1>C(OCC)C.[Ti]>[C:2]1([C@H:1]([OH:8])[CH2:14][CH:10]=[CH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1
Agent: [Ti]
Solvent: CCOCC
Solvent: O
Product: C=CC[C@@H](O)c1ccccc1
Temperature: -74 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 2.25 mmol of the titanium compound of Example 1b in 120 ml of diethyl ether is cooled to -74° C. and 0.2 ml (2.0 mmol) of freshly distilled benzaldehyde is added. The beige suspension is stirred for a further 2 hours at -74° C. and 5 ml of a 5N H2O/THF solution are added. The beige suspension is warmed to RT, stirred for a further hour at this temperature, filtered with suction and concentrated on a rotary evaporator. The crude product (1.53 g of yellow-brown oil) is flash-chromatographed twice (80 g of silica gel, 25 cm long, cross-section 2 cm, 10 ml/fraction, 0.5 bar, 20:1 toluene/ethanol); (50 g of silica gel, 25 cm long, cross-section 2 cm, 15 ml/fraction, 0.5 bar, 15:1 toluene/ethanol). 0.2 g of product are obtained. Yield: 66%, ee: 82%.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=[O:20])[CH2:17][N:16]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=[C:15]3[C:14]=2[CH:28]=1>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=[O:20])[CH2:17][N:16]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:27]([Cl:1])=[C:15]3[C:14]=2[CH:28]=1
Reactant: O=C1Cn2c(cc3ccccc32)-c2cc(Cl)ccc2N1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C1Cn2c(c(Cl)c3ccccc32)-c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A solution of 2.08 g N-chlorosuccinimide in 50 ml dimethylformamide was added dropwise at 15° C. to a solution of 4.00 g 2-chloroindolo[1,2-d][1,4]benzodiazepin-6(7H)-one in 125 ml dimethylformamide. The solution was stirred for two hours at room temperature. Upon dilution with water, a solid precipitated, which was collected and washed with hexane. Recrystallization from toluene yielded 2.67 g solid, m.p. 267°-271° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]2[C:19](=O)[C:18](=[CH:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH2:17][O:16][CH2:15]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:34][C:35]1[S:36][CH2:37][CH2:38][N:39]=1.CCO>C(Cl)(Cl)Cl>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:13]2[N:39]3[CH2:38][CH2:37][S:36][C:35]3=[N:34][C:19]3[C:18](=[CH:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][O:16][CH2:15][C:14]2=3)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: NC1=NCCS1
Reactant: COc1cc(C=C2COCC(=Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc(C=C2COCC3=C2N=C2SCCN2C3c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC

Procedure:
A stirred solution of tetrahydro-3,5-bis[(3,4,5-trimethoxyphenyl)methylene]-4H-pyran-4-one (3.0 g, 6.5 mmole) and 2-amino-2-thiazoline (0.8 g, 7.8 mmole) in 75 ml of CHCl3 is heated at reflux for 44 hours. After cooling, the solution is filtered to remove a small amount of insoluble material. The solvent is evaporated to give an oily residue which solidifies when treated with a small amount of EtOH. The yield is 2.2 g, m.p. 166°-168°. Crystallization from 10 ml of MeCN gives 1.5 g (42%) of light yellow solid, m.p. 153°-155°. The m.p. of a sample of this material does not change when recrystallized from MeCN.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]1[O:33][C:32]2[CH:31]=[CH:30][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[S:26](Cl)(=[O:28])=[O:27])=[CH:14][C:13]=2[O:12]1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[CH:31][C:32]2[O:33][CH2:11][O:12][C:13]=2[CH:14]=1)(=[O:28])=[O:27]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1c(Cc2ccc3c(c2)OCO3)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc4c(c3)OCO4)sc3ccccc23)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride (1.1 mmoles, 0.40 g) and THF (7 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from chloroform and hexanes provided 0.23 g (45%) of a tan crystalline solid, m.p. 164-165° C.
Reaction SMILES: Cl.C1C2C(=CC=CC=2)CCN1CCC[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[CH:27]=[CH:28][CH:29]=[C:22]3[C:23]=2[C:18](=[CH:19][CH:20]=[CH:21]3)[C:17]1=[O:30].[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]CBr.BrCCCCBr>>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:15][N:16]1[C:17](=[O:30])[C:18]2[CH:19]=[CH:20][CH:21]=[C:28]3[C:27]=2[C:24](=[CH:23][CH:22]=[CH:29]3)[C:25]1=[O:26]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCc2ccccc2C1
Reactant: BrCCCCCCBr
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr

Procedure:
Following the procedure of part (a) of example 39 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 95°-96°.
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][O:15][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCc1cccc(Nc2ccccc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2cccc(Nc3ccccc3)c2)cc1
Temperature: 0 °C
Yield: 49.7 %

Procedure:
To a mixture of (3-anilinophenyl)methanol (1.12 g, 5.62 mmol), methyl 3-(4-hydroxyphenyl)propanoate (1.22 g, 6.75 mmol), triphenylphosphine (1.92 g, 7.31 mmol) and tetrahydrofuran (20 mL) was added diethyl azodicarboxylate toluene solution (40%, 3.32 mL) with stirring at 0° C. and the mixture was stirred at room temperature for 14 hrs. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-2/1) to give the title compound (1.01 g, yield 50%) as beige crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15].CN(C)[CH:22]=[O:23]>>[CH:17]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([CH:22]=[O:23])[CH:3]=1)[N:10]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15])([CH3:19])[CH3:18]
Reactant: CN(C)C=O
Reactant: CCCN1CCC(C)(C)c2cc(C(C)C)cc(Br)c21
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C=O)c21

Procedure:
Following General Procedure B, 8-bromo-6-isopropyl-4,4-dimethyl-1-n-propyl-1,2,3,4-tetrahydro-quinoline (Intermediate 6, 5.64 g, 19.6 mmol) and N,N-dimethylformamide (6.0 g, 78.5 mmol) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:13])[CH2:9][CH2:10][C:11]#[CH:12].C(N(CC)CC)C>ClCCl.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>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]#[C:11][CH2:10][CH2:9][CH2:8][OH:13]
Reactant: C#CCCCO
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCCC#Cc1ccccn1
Yield: 54.7 %

Procedure:
As in example 1, 15.8 g of 2-bromopyridine and 8.4 g of 4-pentyn-1-ol were reacted together in 125 mL of dichloromethane in the presence of 4.2 mL of triethylamine, 2.1 g of bis(triphenylphosphine)palladium dichloride and 0.135 g of cuprous iodide. After 48 hours at reflux, the reaction was worked up in the usual manner. Distillation of the crude product yielded 8.8 g of 5-(2-pyridinyl)-4-pentyn-1-ol (bp 115°-120° C./0.25 mm).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16](S(C)(=O)=O)[N:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([S:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=2[C:4]([OH:6])=[O:5])[N:15]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cc1cccc(S)c1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Sc2cccc(C)c2C(=O)O)n1
Temperature: 115 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
Then, 3.6 g of 2-mercapto-6-methylbenzoic acid, 4.7 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 3.5 g of unhydrous potassium carbonate were dissolved in 20 ml of dimethylformamide, and then the mixture was stirred at from 110 to 120° C. for one hour. The reaction solution was poured into a large amount of water, and concentrated hydrochloric acid was added thereto. Then, the mixture was extracted with chloroform. The chloroform layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. The crude crystals were purified by column chromatography by using a developing solvent of hexane/ethyl acetate and recrystallized from ethyl acetate to obtain 0.8 g of 2-[(4,6-dimethoxypyrimidin-2-yl)thio]-6-methylbenzoic acid as white powder. Melting point: 131°-132° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cnn2ccc(Oc3cccc(Cl)c3)nc12
Temperature: 70 °C
Yield: 92.7 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in DMF was added 3-chlorophenol (42 mg, 0.331 mmol) and K2CO3 (190 mg, 1.380 mmol). The mixture was heated at 70° C. for several hours. Water was added and the solid formed was isolated by filtration and air dried to yield 70 mg 5-(3-chlorophenoxy)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde as an orange solid (93% yield). LCMS (M+1=274)
Reaction SMILES: OC[C@@H](N)C(C)CC.COC(=O)[C@H]([C@H](CC)C)N.OCCN.[CH3:23][C:24]1[CH:31]=[C:30]([N+:32]([O-])=O)[C:29]([CH3:35])=[CH:28][C:25]=1[C:26]#[N:27].NC1C=CC=CC=1.C([C:45]1C(C)=[CH:49][C:48]([N:52]=[C:53]=[S:54])=[C:47]([CH3:55])[CH:46]=1)#N>>[C:26]([C:25]1[C:24]([CH3:23])=[CH:31][C:30]([N:32]=[C:53]2[NH:52][C@@H:48]([CH:47]([CH2:46][CH3:45])[CH3:55])[CH2:49][S:54]2)=[C:29]([CH3:35])[CH:28]=1)#[N:27]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C#N
Reactant: Cc1cc(N=C=S)c(C)cc1C#N
Agent: CCC(C)[C@H](N)CO
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Solvent: Nc1ccccc1
Solvent: NCCO
Product: CCC(C)[C@H]1CSC(=Nc2cc(C)c(C#N)cc2C)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 2,5-Dimethyl-4-nitrobenzonitrile was converted to 4-cyano-2,5-methylaniline according to Method A1a. The aniline was converted to 4-cyano-2,5-dimethylphenyl isothiocyanate as described in Method A2a, Step 3. 4-Cyano-2,5-dimethylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-cyano-2,5-dimethylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2,5-dimethylphenylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.[O-:25][C:26]#[N:27].[Na+]>C(O)(=O)C.O>[CH3:17][S:14]([NH:13][C:11]1[C:10]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:9][C:6]2[C:7](=[O:8])[C:2]([NH:1][C:26]([NH2:27])=[O:25])=[CH:3][O:4][C:5]=2[CH:12]=1)(=[O:15])=[O:16]
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Nc1cc2occ(NC(N)=O)c(=O)c2cc1Oc1ccccc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
500 mg of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 20 ml of acetic acid and 10 ml of water. The solution was heated to 35° C. Thereto was dropwise added a solution of 190 mg of sodium cyanate dissolved in 5 ml of water, in 5 minutes. The mixture was stirred for 30 minutes at the same temperature. 20 ml of water was added thereto. The resulting crystal was collected by filtration and recrystallized from acetic acid to obtain 350 mg (yield: 62.3%) of 7-methylsulfonylamino-6-phenoxy-3-ureido-4H-1-benzopyran-4-one having a melting point of >250° C.