Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][C:12]=3[F:28])=[CH:6][N:5]2[CH:29]=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.O.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:30]1([C:33]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:13][C:12]=4[F:28])=[CH:6][N:5]3[CH:29]=2)=[O:34])[CH2:32][CH2:31]1
Reactant: Nc1cn2cc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)ccc2n1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of benzyl {4-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-3-fluorophenyl}carbamate (10.0 g, 25.5 mmol) in N,N-dimethylacetamide (100 mL) was added cyclopropanecarbonyl chloride (2.77 mL, 30.6 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (9.2 g, 78%) as a thin-brown solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH:25]=[CH2:26])[CH3:23])=[CH:11][CH:10]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:7][CH3:6])=[CH:10][CH:11]=1)[CH:25]=[CH2:26]
Reactant: C=CCN(C)CCCCCCOc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCN(C)CCCCCCOc1ccc(NC)cc1
Temperature: 25 °C

Procedure:
A solution of 30.3 g (80.5 mmol) of {4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid tert-butyl ester in 160 ml CH2Cl2 was treated at −20° C. with 180 ml TFA and warmed up to room temperature during 5 h. The reaction mixture was evaporated, treated with aqueous saturated NaHCO3 solution/Et2O (3×), dried (Na2SO4) and evaporated to yield {4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amine, MS: 277 (MH+).
Reaction SMILES: [Cl-].[Cl-].[Ca+2:3].C1N(CCO)CCN(CCS(O)(=O)=O)C1.CS(C)=O.[OH:23][P:24]([O-:27])([OH:26])=[O:25].[OH:28][P:29]([O-:32])([O-:31])=[O:30].[Na+].[Na+].[Na+].[Cl-].[Cl-].[K+].[K+]>O>[P:24]([O-:27])([O-:26])([O-:25])=[O:23].[Ca+2:3].[P:29]([O-:32])([O-:31])([O-:30])=[O:28].[Ca+2:3].[Ca+2:3]
Reactant: O=P([O-])([O-])O
Reactant: O=P([O-])(O)O
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Product: O=P([O-])([O-])[O-]
Reaction time: 0.33 h

Procedure:
Seventy-five micrograms (75 μg) of DNA were dissolved in 1.35 ml water in a 50 ml conical tube. One hundred and fifty microliters (150 μl) of 2.5 M CaCl2 were added, and this DNA-calcium mixture was added dropwise to 1.5 ml of 2× HeBES (HEPES buffered saline) in a 50 ml conical tube. The HeBES was bubbled with a pipettor while adding the DNA-calcium mixture with a Pasteur pipette. The mixture was mixed by vortex for 5 seconds and incubated at room temperature for 20 minutes. One milliliter (1 ml) of the DNA-calcium mixture was distributed evenly over each culture dish of adherent cells, grown and prepared for transfection in F12 medium as described above, and the cultures then incubated at 37° C. for four hours. After incubation, the plates were aspirated, and 2 ml of 10% dimethylsulfoxide (DMSO) in F12 medium was added to each plate (DMSO shock treatment). The DMSO shock continued for one minute after which the DMSO was diluted by the addition of 5 ml of PBS (phosphate buffered saline) to each plate. The plates were aspirated and washed two more times in PBS. Ten (10) ml of αMEM/5% FBS/HT was added, and the plates were incubated at 37° C. overnight.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(N(CC)CC)C.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>[CH3:9][C:4]1[N:3]=[C:2]([C:17]#[C:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: Cc1ccc(N)c(Br)n1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2ccccc2)n1
Temperature: 0 °C
Yield: 46.7 %

Procedure:
To a solution of Cul (10 mg, 50 μmol) in triethylamine (5 ml) were added (2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) and (PPh3)2PdCl2 (36 mg, 50 μmol). The reaction mixture was cooled to 0° C. and phenylacetylene (176 μl, 1.60 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated under reflux for 14 h. The solvent was evaporated and the crude residue was purified by flash chromatography (hexane/ethyl acetate 4:1) to yield 105 mg (0.50 mmol, 47%) of (6-methyl-2-phenylethynyl-pyridin-3-yl)amine as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:36](#[N:39])[CH:37]=[CH2:38].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C.C(N(CC)CC)C>[C:36]([CH:37]=[CH:38][C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:39]
Reactant: C=CC#N
Reactant: COC(=O)c1cnc(OC)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC)c(C=CC#N)c1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
Under a nitrogen atmosphere, to a mixture of methyl 5-bromo-6-methoxynicotinate (2.37 g), palladium acetate (430 mg), tri(o-tolyl)phosphine (1.17 g), triethylamine (4.0 mL) and DMF (20 mL) was added acrylonitrile (6.4 mL), and the mixture was stirred under microwave irradiation at 120° C. for 10 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate and THF. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (552 mg) as pale-yellow crystals. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[C:12](=[CH:14][C:15]#[N:16])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1>N.CO.[Co]>[CH3:1][C:2]1[S:3][C:4]2[C:13]3[C:12](=[CH:14][CH2:15][NH2:16])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc3c(c2s1)C(=CC#N)CC3
Agent: [Co]
Agent: N
Solvent: CO
Product: Cc1nc2ccc3c(c2s1)C(=CCN)CC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2-Methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]thiazol-8-ylidene)acetonitrile (170 mg, 0.75 mmol) was dissolved in 2N ammonia/methanol solution (30 mL), Raney cobalt (1.7 g) was added, and the mixture was stirred at room temperature for 1 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure to give the title compound. The obtained title compound was used for the reaction of Example 8 without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]1[CH2:24][CH2:23][N:22]([CH3:25])[C:21]1=[O:26]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:20]2[CH2:24][CH2:23][N:22]([CH3:25])[C:21]2=[O:26])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CN1CCC(Br)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OC2CCN(C)C2=O)c1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
To a stirred solution of Methyl 3,5-dihydroxybenzoate (20 g) [CAS No. 2150-44-9] in dry DMF was added potassium carbonate (48 g) and the suspension stirred at ambient temperature under nitrogen. To this 3-Bromo-1-methyl-pyrrolidin-2-one (40 g) (Intermediate 5) [J. Med. Chem., 1987, 30, 1995-98] was added in three equal portions in 4 h intervals at room temperature and stirred overnight at ambient temperature. It was then quenched with water. The aqueous suspension was extracted with DCM. The to combined extracts were washed with water, brine, dried over Na2SO4, and filtered, concentrated under reduced pressure to get the thick liquid residue. The crude product was purified by column chromatography using silica gel as stationary phase and ethyl acetate: petroleum ether as a mobile phase to yield the product as white solid (15 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][O:18][CH2:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1.O[C:23]1[CH:27]=[C:26]([CH3:28])[O:25][N:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:28][C:26]1[O:25][N:24]=[C:23]([O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH2:16][CH2:17][O:18][CH2:19][CH:20]=4)=[C:11]([F:21])[CH:10]=3)[CH2:4]2)[CH:27]=1
Reactant: Cc1cc(O)no1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCOCC2)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC[C@H]2CN(c3ccc(C4=CCOCC4)c(F)c3)C(=O)O2)no1
Yield: 46.1 %

Procedure:
5(R)-hydroxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one (300 mg, 1.02 mmol), 3-hydroxy-5-methylisoxazole (120 mg, 1.21 mmol), triphenylphosphine (270 mg, 1.03 mmol) and diisopropylazodicarboxylate (204 mg, 1.01 mmol) were reacted in THF (8.0 ml) using the general method of Example 1. The resultant product was purified by flash chromatography (Merck 9385 silica, EtOAc/isohexane (7:3) eluant) to give the title product (176 mg, 46%) as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH:11]([OH:13])[CH3:12].[CH3:14]COCC.CI.O>C1C=CC=CC=1.[OH-].[Na+].[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:14][O:13][CH:11]([CH3:12])[C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CCOCC
Reactant: Cc1ccc([N+](=O)[O-])cc1C(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CI
Product: COC(C)c1cc([N+](=O)[O-])ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(2'-methyl-5'-nitrophenyl)ethanol (0.9 g) is dissolved in 5 ml of benzene and 0.8 g of 50% aqueous sodium hydroxide, ca 10 mg of tetrabutylammonium chloride, 5 ml of ether and 1.25 ml of methyl iodide is added. The reaction mixture is stirred at room temperature for 2 hours and heated at 30°-35° for 4 hours. An additional 1.0 ml of methyl iodide is added and the mixture stirred at room temperature for 22 hours. Thin layer chromatography indicates starting material remaining therefore 0.52 ml of 50% NaOH solution and 2.0 ml of methyl iodide are added and the mixture stirred at room temperature for 5 days. Water is added and the mixture extracted with ether. The organic layer is washed with water and brine. The solution is evaporated to dryness giving 0.97 g of oil which is purified by column chromatography to give pure material, mp 35°-37° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16]O)=[CH:15][C:10]=2[N:9]=[CH:8]1.C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)Cl.O>[N:32]([CH2:16][C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:8]=[N:9][C:10]=2[CH:15]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc2c(c1)ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc2c(c1)ncn2C1CCCCO1
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a stirred solution of 24 (2.2 g, 9.6 mmol) in THF (20 mL) under nitrogen at RT was added diphenylphosphoryl azide (3.96 g, 14.4 mmol) and DIPEA (5 mL). The reaction was stirred for 18 h then diluted with DCM (200 mL) and water (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (2:1) to afford 1.2 g (48%) of 5-(azidomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (26) as yellow oil: MS (ESI) m/z=258.2 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[O:10][CH3:11].[N:13]([C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([S:24](Cl)(=[O:26])=[O:25])=[C:18]([F:28])[C:17]=1[F:29])=[N+:14]=[N-:15]>CO>[N:13]([C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([S:24]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([N:2]([CH3:12])[CH3:1])=[C:4]([O:10][CH3:11])[CH:5]=2)(=[O:26])=[O:25])=[C:18]([F:28])[C:17]=1[F:29])=[N+:14]=[N-:15]
Reactant: COc1cc(N)ccc1N(C)C
Reactant: [N-]=[N+]=Nc1c(F)c(F)c(S(=O)(=O)Cl)c(F)c1F
Solvent: CO
Product: COc1cc(NS(=O)(=O)c2c(F)c(F)c(N=[N+]=[N-])c(F)c2F)ccc1N(C)C
Reaction time: 0.25 h

Procedure:
4-Dimethylamino-3-methoxyaniline (1.66 g, 10 mmol) is added to a solution of 4-azido-2,3,5,6-tetrafluorophenylsulfonyl chloride (3.47 g, 12 mmol) in MeOH (20 ml) at ambient temperature. After stirng at room temperature for 15 min, the reaction mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate and filtered through a pad of silica gel. Concentration of the filtrate, followed by chromatography, provides the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH:18]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:31][CH2:18][CH2:17][CH:16]([C:10]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCCC1
Reactant: O=CCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Product: Brc1ccc(OCc2ccccc2)c(C(CCNC2CCCC2)c2ccccc2)c1

Procedure:
3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropanal, prepared as described in Example 20.1, (7.00 g, 17.71 mmol) was treated with cyclopentylamine as described in Example 31.1. Yield 4.9 g (59%); 1H NMR (CDCl3) δ1.20 (m, 2H), 1.40-1.80 (m, 6H), 2.18 (m, 2H), 2.55 (t, 2H), 2.98 (m, 1H), 4.45 (t, 1H), 5.00 (s, 2H), 6.75 (d, 1H), 7.10-7.45 (m, 12H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]([C:13](O)=[O:14])=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([C:7]2[CH:8]=[N:9][C:10]([CH2:13][OH:14])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3-phenyl-6-carboxypyridine (1.05 g, 5.27 mmol) in tetrahydrofuran (25 mL) at 0° C. was added 1.0M lithium aluminum hydride in tetrahydrofuran (10.0 mL, 10.0 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 6 hours, cooled to 0° C., and quenched by dropwise addition of water (0.50 mL), 4N aq. NaOH (0.50 mL), and water (1.5 mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, 0-5% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[N+:19]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:23]=[C:24]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=[N+]([O-])c1cccc(N=C=S)c1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc([N+](=O)[O-])c1
Yield: 87.6 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.243 g, 1.0 mmol) and 3-nitrophenyl isothiocyanate (0.183 g, 1.0 mmol). Trituration in hexanes/ethyl acetate (4:1) gave the product (0.370 g); m.p. 188-189° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:15][O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20].C(N(CC)CC)C.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][O:16][C:17](=[O:21])[CH2:18][N:19]([C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:20]
Reactant: CNCC(=O)OC
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a stirred solution of 3-nitrophenylacetic acid (25 g, 0.14 mol), sarcosine methyl ester hydrochloride (20.2 g, 0.15 mol), triethylamine (20 ml, 0.15 mol) and 4-dimethylaminopyridine (17.7 g, 0.15 mol) in dichloromethane (300 ml) was added, under nitrogen, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (27.8 g, 0.15 mol). The mixture was stirred at room temperature for 18 h then the solvent removed in vacuo. Ethyl acetate (300 ml) was added to the residue and the mixture partitioned with 1M HCl (2×200 ml), saturated sodium bicarbonate solution (2×200 ml), water (200 ml) and brine (200 ml). The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, using petrol:ethyl acetate (1:1) as the eluant, to afford the title amide (25 g, 68%) as a yellow oil. 1H NMR (360MHz, CDCl3) δ3.13 (3H, s), 3.75 (3H, s), 3.88 (2H, s), 4.16 (2H, s), 7.26-7.65 (2H, m), 8.09-8.14 (2H, m). MS (CI, NH3), 284 (M+NH4+).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:31](=[O:50])(=[O:49])[N:32](CC2C=CC(OC)=CC=2OC)[C:33]2[S:37][N:36]=[CH:35][N:34]=2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:22]=3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[CH3:12])[C:6]=2[CH:30]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[Br:1][C:2]1[C:3]([S:31]([NH:32][C:33]2[S:37][N:36]=[CH:35][N:34]=2)(=[O:50])=[O:49])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:22]=3[CH2:21][NH:20][CH2:19][CH2:18]4)[CH3:12])[C:6]=2[CH:30]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4cccc5c4CN(C(=O)OC(C)(C)C)CC5)c3cc2Br)c(OC)c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1cccc2c1CNCC2)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(Br)cc21
Reaction time: 1.5 h

Procedure:
Added 35-4 (120 mg, 0.153 mmol) to DCM (610 μl) and TFA (306 μl). After 90 min, diluted with 1 mL MeOH, filtered through Celite, washed with MeOH. Concentrated filtrate in vacuo and dissolved in 2 mL DMSO. Purified by reverse-phase HPLC (C18 column, 2-60% 0.1% TFA/CH3CN:0.1% TFA/H2O) to give 35-5 as a white solid
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[C:12]([CH3:21])=[CH:13][C:14]2[O:18][C:17](=[O:19])[CH2:16][C:15]=2[CH:20]=1>CN(C)C=O>[CH2:1]([NH:9][C:17](=[O:19])[CH2:16][C:15]1[CH:20]=[C:11]([OH:10])[C:12]([CH3:21])=[CH:13][C:14]=1[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1cc2c(cc1O)CC(=O)O2
Reactant: CCCCCCCCN
Solvent: CN(C)C=O
Product: CCCCCCCCNC(=O)Cc1cc(O)c(C)cc1O
Reaction time: 0.25 h

Procedure:
A solution of 7.75 g of n-octylamine dissolved in 15 ml of dimethylformamide is placed in a solution of 10 g of 5-hydroxy-6-methyl-3H-benzofuran-2-one dissolved in 15 ml of dimethylformamide. After 15 minutes at 100° C., the mixture is evaporated to dryness at reduced pressure. It is treated with 100 ml of ethyl acetate, rinsed with water, dried, then evaporated, yielding a white solid which is recrystallized from isopropyl acetate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:16]1([CH2:21][C:22]2[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=2)[O:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[N:16]1([CH2:21][C:22]2[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=2)[O:25][CH2:26][CH2:27][CH2:28][NH:29][C:4]2[N:5]=[N:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([CH3:1])[N:3]=2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Solvent: ClC(Cl)Cl
Product: Cc1nc(NCCCOc2cccc(CN3CCCC3)c2)nnc1-c1ccccc1
Temperature: 150 °C
Yield: 63.8 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (2.17 g) and 3-[3(1-pyrrolidinylmethyl)phenoxy]propylamine (3.04 g) was heated at 150° C. for 33 hours and dissolved in a small volume of chloroform after cooling. The solution was purified by column chromatgraphy on silica gel (100 g) with chloroform and then a mixture of chloroform and methanol (20:1) as eluents to give 3-[3-[3-(1-pyrrolidinylmethyl)-phenoxy]propylamino]-5-methyl-6-phenyl-1,2,4-triazine (2.57 g).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].NC(N)=[S:13]>C(O)CCC>[SH:13][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NC(N)=S
Reactant: Cc1ccc(C#N)c(Cl)n1
Solvent: CCCCO
Product: Cc1ccc(C#N)c(S)n1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture of 2-chloro-6-methylnicotinonitrile (220 mg, 1.45 mmol) and thiourea (348 mg, 4.57 mmol) was heated at reflux (118° C.) in n-butanol for 4 h. After cooling to room temperature, the yellow solution turned to a suspension containing light yellow solids. The solids were collected by filtration, rinsed with n-butanol, and dried in vacuo to give 2-mercapto-6-methylnicotinonitrile (218 mg, 100% yield). C7H6N2S; yellow powder; 1H NMR (400 MHz, CDCl3) δ 7.97 (1H, dt, J=8, 0.8 Hz), 7.79 (1H, dt, J=8, 0.8 Hz), 7.70 (1H, td, J=8, 1.2 Hz), 7.46 (1H, td, J=8, 1.2 Hz), 4.64 (2H, s); 13C NMR (100 MHz, CDCl3) δ 177.39, 154.77, 144.83, 117.1, 113.3, 112.7, 19.2; ESI-HRMS (negative mode) calcd for C7H5N2S: 149.0173. found: m/z 149.0172 [M−H]−.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([CH:16]([CH3:18])[CH3:17])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO.O>[OH:3][C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([CH:16]([CH3:18])[CH3:17])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(C(C)C)c(OC)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(O)c(C(=O)O)cc1C(C)C
Temperature: 25 °C
Yield: 69.6 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 0.2 ml) was added to a suspension of methyl 2-hydroxy-5-isopropyl-4-methoxybenzoate (420 mg, 1.88 mmol) in methanol (5 ml) and water (2 ml) and the mixture was stirred and held at reflux for 3 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford 2-hydroxy-5-isopropyl-4-methoxybenzoic acid (275 mg, 70%) as a colourless solid. 1H NMR (DMSO-d6) 13.50 (1H, br s), 11.40 (1H, br s), 7.53 (1H, s), 6.51 (1H, s), 3.83 (3H, s), 3.12 (1H, m), 1.13 (6H, d). MS: [M+H]+ 211.