Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:10][N:11]2[C:19]3[N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[C:14](=O)[NH:13][C:12]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:31].[OH-].[Na+]>N1C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:10][N:11]2[C:19]3[N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[C:14](=[S:31])[NH:13][C:12]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(Cn2c(=O)[nH]c(=O)c3[nH]c(C(C)C)nc32)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(Cn2c(=O)[nH]c(=S)c3[nH]c(C(C)C)nc32)cc1OC1CCCC1
Yield: 151 %

Procedure:
3.59 g of 3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-xanthine and 2.40 g of phosphorus pentasulfide were heated under reflux in 60 ml of pyridine for 8 hours. At −5° C., 11.9 ml of 2N NaOH were added slowly. The suspension was evaporated to dryness, the residue suspended in 100 ml of water, neutralized to pH 8, and the solid, collected, washed and dried to give the crude 6-thioxanthine (3.45 g). Purification by filtration chromatography (SiO2, 15g; chloroform) yielded a solid which was reprecipitated from NaOH by addition of HCl, to pH 6.5, collected, washed and dried to give the monohydrate of the title compound (3.38 g) as a white solid, mp 192-3° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:14])=O>ClC(Cl)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1ccc(F)cc1
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To a solution of 4-fluorobenzoic acid (5.0 g. 35.7 mmol) in dichloroethane (50 mL) was added oxalyl chloride (5.6 g, 44.6 mmol) drop wise. The reaction was stirred for 16 h. The excess oxalyl chloride and solvent were removed under reduced pressure. The residue was chased with benzene to give the desired product (5.4 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[N:18]=[C:17]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cccc(CCN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(CCNc2nc(Cl)ncc2Cl)c1
Yield: 95 %

Procedure:
To a solution of 3-methoxyphenethylamine (1.93 mL, 13.2 mmol) and 2,4,5-trichloropyrimidine (1.59 mL, 13.9 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (5.5 g, 40 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated to give the desired product as a yellow gel (3.74 g, 95%). LCMS for C13H14Cl2N3O (M+H)+: m/z=298.0, 300.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH2:6][C:7]1[CH:8]=[C:9]([N+:16]([O-])=O)[CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1.O.NN>CO.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH2:6][C:7]1[CH:8]=[C:9]([NH2:16])[CH:10]=[C:11]([NH2:13])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(COc2ccc(Cl)c(Cl)c2)cc([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cc(N)cc(COc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C

Procedure:
5-(3,4-dichlorophenoxymethyl)-1,3-dinitrobenzene in 5 ml MeOH was added to a solution of 10 ml 2.5 mmole hydrazine monohydrate and catalytic amount of Ra—Ni. The mixture was stirred under reflux for 30 min and then cooled to room temperature. GC-MS gave the peak of reduced product. The solution was filtered through Celite and MeOH was evaporated with rotaevaporation. The residue was used directly for next step without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH2:21][CH:22]([OH:25])[CH2:23]O)[CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:25][CH:22]([CH2:21][O:20][C:15]2[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][C:16]=2[CH3:19])[CH2:23][O:4]1
Reactant: Cc1ccc(Cl)cc1OCC(O)CO
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(Cl)cc1OCC1COC(CBr)(c2ccc(Cl)cc2)O1

Procedure:
A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone, 11.9 parts of 1-(4-chloro-o-tolyloxy)-2,3-propanediol, 2.5 parts of p-toluenesulfonic acid and 240 parts of benzene is stirred and refluxed for 24 hours in a four-necked round-bottomed flask equipped with a watertrap. The benzene solution is washed successively with a diluted sodium hydroxide solution and with water. The solvent is removed in vacuo. The residue is crystallized from methanol and the less pure fraction is recrystallized from diisopropylether, yielding A-2-(bromomethyl-2-(p-chlorophenyl)-4-(4-chloro-o-tolyloxymethyl)-1,3-dioxolane; m.p. 102.5°C. The methanol filtrate is evaporated in vacuo, yielding B-2-(bromomethyl)-2-(p-chlorophenyl)-4-(4-chloro-o-tolyloxymethyl)-1,3-dioxolane as a residue.
Reaction SMILES: [N+](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-])=O.BrBr.N12CCCN=C1CCCCC2.[OH:25][C:26]1[C:27](=[O:37])[C:28]2[C:33]([C:34](=[O:36])[CH:35]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2>ClCCl>[C:6]1([C:5]2[C:35]3[C:34](=[O:36])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27](=[O:37])[C:26]=3[O:25][CH:4]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: BrBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)c2c(-c3ccccc3)coc21
Yield: 69.7 %

Procedure:
To the solution of 5 grams (33.5 mmoles) of [(E)-2-nitroethenyl]benzene in 100 mL of dichloromethane, 5.6 grams (35.2 mmoles) of bromine was added. The mixture was refluxed for 12 hours, and then evaporated to dryness. To the residue solution in 150 mL of tetrahydrofuran cooled in ice bath, 5.3 grams (35.2 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was dropped slowly over 20 minutes while stirring vigorously. The reaction mixture was further stirred for 30 minutes in ice bath, then 5.8 grams (33.5 mmoles) of 2-hydroxy-1,4-naphthoquinone and 5.3 grams (35.2 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) were added. The mixture was reflux for 3 hours, and then evaporated to sticky residue. The residue was dissolved in 300 mL of dichloromethane, and washed with 300 mL of water, 300 mL of 2% aqueous citric acid solution, successively, and dried with 30 grams of anhydrous sodium sulfate. The 3-phenyl-naphtho[2,3-b]furan-4,9-dione product was purified with silica gel column using dichloromethane/hexane (3:1) as elution solvent. 6.4 grams of product (overall yield 70%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 7.44-7.52 (m, 3H), 7.77-7.79 (m, 2H), 7.89-7.93 (m, 2H), 8.10-8.15 (m, 2H), 8.58 (s, 1H). Mass (M+H) is 275.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Reaction time: 1.5 h

Procedure:
6.8 g tert-butyl 5-nitro-2,3-dihydro-indole-1-carboxylate are dissolved in 120 ml of methanol. To this are added 600 mg of palladium on charcoal (10%) and the mixture is hydrogenated for 1.5 hours at ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2)[NH2:5].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.Cl.[OH-].[Na+]>O>[NH2:32][C:22]1[N:21]=[C:20]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:11]=3[CH:12]=[N:13][NH:14]4)=[C:2]([F:1])[CH:3]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: Nc1ccc(Oc2cccc3[nH]ncc23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3cccc4[nH]ncc34)c(F)c2)cc(-c2ccncc2)n1

Procedure:
45 mg (0.19 mmol) of 3-fluoro-4-(1H-indazol-4-yloxy)aniline (from example XXVI) and 40.1 mg (0.19 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) are suspended in 2 ml of water, and 27 μl of concentrated hydrochloric acid are added. The reaction mixture is heated at reflux overnight, resulting in the formation of a brown precipitate. Using 1N sodium hydroxide solution, the suspension is adjusted to pH 10. The precipitate is filtered off from the aqueous phase, and the filtrate is discarded. The crude product is purified by HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:45])[CH:3]1[CH2:6][C:5]([NH:38]C(=O)C(F)(F)F)([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][C:20]4[C:19]5=[N:29][N:30]=[C:31]([C:32]6[N:37]=[CH:36][CH:35]=[CH:34][N:33]=6)[N:18]5[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)[CH2:4]1.[OH-].[K+].CCOC(C)=O.C([O-])(O)=O.[Na+]>CCO.[Cl-].[Na+].O>[CH3:1][N:2]([CH3:45])[CH:3]1[CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][C:20]4[C:19]5=[N:29][N:30]=[C:31]([C:32]6[N:37]=[CH:36][CH:35]=[CH:34][N:33]=6)[N:18]5[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)([NH2:38])[CH2:6]1
Reactant: CN(C)C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C1CC(N)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Temperature: 100 °C

Procedure:
To a mixture of N-(3-(dimethylamino)-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)-2,2,2-trifluoroacetamide (4-4) (10 mg, 0.016 mmol) in EtOH (1.0 mL) was added KOH (1M in water, 0.1 mL, 0.10 mmol), and the mixture was heated under microwave irradiation at 100° C. for 40 minutes. To the mixture was added EtOAc, sat. NaHCO3, and brine. The resulting solid was collected by filtration to give N3,N3-dimethyl-1-{4-[9-phenyl-3-(2-pyrimidinyl)-[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}-1,3-cyclobutanediamine (4-5) as colorless solid. HRMS (M+H)+: observed=513.2515, calculated=513.2510.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=2[O:24][CH2:25][CH:26]2[CH2:28][O:27]2)[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1>O1CCCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:23]1[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18][C:12]1[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]([O:9][CH3:8])[CH:11]=1)[CH2:5][CH2:6][OH:7]
Reactant: COc1cc(CCCCc2ccccc2OCC2CO2)cc(OC)c1
Reactant: OCCNCCO
Solvent: C1CCOC1
Product: COc1cc(CCCCc2ccccc2OCC(O)CN(CCO)CCO)cc(OC)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
530 mg of diethanolamine were added to a solution of 345 mg of 2-{2-[4-(3,5-dimethoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in Example 11(a)] in 10 ml of tetrahydrofuran, and the resulting mixture was stirred at 50° C. for 24 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 7:1 by volume mixture of methylene chloride and methanol as the eluent, to give 333 mg of the title compound as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:27])[C:18]([C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)=[N:19][OH:20])[C:14](=[O:28])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3].C([O-])(=O)C.[Na+:33]>CO>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:27])[C:18]([C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)=[N:19][OH:20])[C:14](=[O:28])[N:9]2[C:10]=1[C:11]([O-:13])=[O:12])=[N+:2]=[N-:3].[Na+:33]
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1

Procedure:
The product of Example 1 was added to 3 ml of a molar solution of sodium acetate in methanol and the mixture was vacuum filtered to remove slight insolubles. 1 ml of ethanol was added to the filtrate and the mixture was vacuum filtered. 5 ml of ethanol were added to the filtrate and the mixture was vacuum filtered to obtain 0.4 g of the syn isomer of sodium 3-azidomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [N:1]1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=3[S:8](=[O:21])(=[O:20])[N:7]=2)C=CN=[CH:2]1.[CH2:22](N)[CH2:23]C>>[CH2:2]([NH:1][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:17])[F:18])=[CH:15][C:9]=2[S:8](=[O:20])(=[O:21])[N:7]=1)[CH2:22][CH3:23]
Reactant: CCCN
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ccc(C(F)(F)F)cc21
Product: CCCNC1=NS(=O)(=O)c2cc(C(F)(F)F)ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide was treated with propylamine according to the general procedure Method A to give the title compound; m.p. 241-243° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.[C:24]([OH:27])(=[O:26])[CH3:25]>>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:10]2[CH2:11][CH2:12][N:8]([CH2:25][C:24]([OH:27])=[O:26])[CH2:9]2)=[CH:15][CH:16]=1
Reactant: CC(=O)O
Reactant: FC(F)(F)c1ccc(CC2CCN(Cc3ccccc3)C2)cc1
Product: O=C(O)CN1CCC(Cc2ccc(C(F)(F)F)cc2)C1

Procedure:
Prepared in analogy to Example A1(d) from 1-Benzyl-3-(4-trifluoromethyl-benzyl)-pyrrolidine (CAS: 336182-64-0) by replacing HCl with acetic acid to yield the title compound as an light brown oil. MS (m/e): 230.4 (M+H+, 100%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([CH2:11][Cl:12])[O:10][CH2:9][CH2:8][O:7]1)(=[O:3])[CH3:2].C[Si]([C:17]#[N:18])(C)C>C(Cl)Cl.[I-].[Zn+2].[I-]>[C:1]([O:4][CH2:5][C:6]([C:17]#[N:18])([O:10][CH2:9][CH2:8][OH:7])[CH2:11][Cl:12])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC(=O)OCC1(CCl)OCCO1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)OCC(C#N)(CCl)OCCO
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of (2-(chloromethyl)-1,3-dioxolan-2-yl)methyl acetate (67.8 mmol), trimethylsilyl cyanide (20.29 g, 204 mmol, TCI America) and zinc iodide (3.65 g, 11.4 mmol) was heated (40° C., oil bath) for 6 hrs, then at ambient temperature for 16 hrs. The mixture was diluted with CH2Cl2 (100 mL) and stirred with silica gel (50 g) for several hours. The mixture was loaded onto a flash silica gel column (350 g silica) and eluted with CH2Cl2 then increasing amounts of Et2O to a final eluent of 30% Et2O in CH2Cl2. Product fractions were pooled and concentrated in-vacuo to give the title compound as an amber oil: 1H NMR (500 MHz, CDCl3) δ ppm 4.44 (1H, d, J=-11.90 Hz), 4.35 (1H, d, J=11.90 Hz), 3.83-3.88 (2H, m), 3.79-3.84 (4H, m), 2.13-2.16 (3H, m); LC/MS m/z 222.16 (M+H).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH:12]([CH3:17])[C:13]2=[O:16])=[CH:9][C:8]=1[O:18][CH3:19])([CH3:6])([CH3:5])[CH3:4].CC([O-])=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:1][C:9]1[C:8]([O:18][CH3:19])=[C:7]([C:3]([CH3:4])([CH3:6])[CH3:5])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH:12]([CH3:17])[C:13]2=[O:16]
Reactant: BrBr
Reactant: COc1cc2c(cc1C(C)(C)C)C(=O)C(C)C2
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: COc1c(C(C)(C)C)cc2c(c1Br)CC(C)C2=O
Reaction time: 16 h

Procedure:
Bromine (4.4 ml, 86 mmol) was added at 0° C. to a mixture of 6-tert-butyl-5-methoxy-2-methyl-1-indanone (20 g, 86 mmol), NaOAc (20.4 g) and tetrabutylammonium bromide (0.5 g) in CH2Cl2 (50 ml) and H2O (150 ml). After 16 h, 2.5 ml of Br2 and 12 g of NaOAc were added. After 24 h of stirring, the organic phase was separated, washed with water, 10% aq. Na2SO3, aq. NaHCO3, dried over MgSO4 and evaporated. The residue was used without purification.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:8][NH:9][C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[S:11])(=O)[C:4]([NH2:6])=[O:5].Cl>O>[C:4]([C:3]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:10]([SH:11])=[N:9][N:8]=1)(=[O:5])[NH2:6]
Reactant: COc1ccc(CNC(=S)NNC(=O)C(N)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cn2c(S)nnc2C(N)=O)cc1
Yield: 94.6 %

Procedure:
Sodium hydroxide (0.4 g., 0.01 mole) and 1-oxamoyl-4-(p-methoxybenzyl)-3-thiosemicarbazide (2.82 g., 0.01 mole) were heated in water (20 ml.) on a steam bath for a period of two hours. The clear solution was then cooled and acidified with dilute hydrochloric acid. The resulting solid was filtered and subsequently dried in vacuo at 50° C. to afford 3-carbamoyl-4-(p-methoxybenzyl)-1,2,4-triazole-5-thiol (2.5 g., 94% yield), m.p. 240°-242° C. The analytical sample melted at 243°-245° C. after being crystallized from a mixture of dimethylformamide and diethyl ether.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]=[CH2:5].C([Li])CCC.[CH3:11][Si:12]([CH3:15])([CH3:14])Cl>C(OCC)C>[CH3:11][Si:12]([CH:1]=[CH:2][CH2:3][CH:4]=[CH2:5])([CH3:15])[CH3:14]
Reactant: C=CCC=C
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C=CCC=C[Si](C)(C)C
Reaction time: 8 h

Procedure:
A solution containing 1,4-pentadiene (5 g, 73 mol) in diethylether (100 ml) was lowered to −78° C. and n-butyllithium was added dropwise (72 mmol, 1.6M soln. in hexanes, 45 ml). The flask was stirred overnight and the temperature was allowed to warm to ambient. Solvents were removed in vacuo and a bright yellow powder was isolated. The sample was then re-dissolved in fresh diethyl ether (100 ml) and the temperature was lowered to −78° C. Trimethylchlorsilane (7.9 mmol, 10 ml) was added dropwise. The reaction was allowed to slowly warm to ambient and the flask contents stirred overnight. Solvents were removed in vacuo. 1M-NMR: CTHF-d8) d, ppm; 6.25 (m, 2H), 5.9 (m, 2H), 5.65 (m, 2H), 4.95 (s, 1H), 4.90 (s, 1H), 4.80 (s, 1H), 4.75 (s, 1H), 1.5 (d, 2H), 0 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>CS(C)=O.ClCCl.[Cl-].[NH4+].[Cu]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][N:3]=1
Reactant: Nc1ncc(I)cn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1cnc(N)nc1
Temperature: 80 °C

Procedure:
To the Schlank flask containing 2-amino-5-iodopyrimidine (2.210 g, 10.00 mmol) and copper powder (0.953 g, 15.0 mmol) in anhydrous DMSO (10 mL) was added ethyl bromodifluoroacetate (1.285 mL, 10.00 mmol). The reaction mixture was heated at 80° C. under nitrogen overnight. Reaction mixture was cooled to room temperature and diluted with dichloromethane (80 mL) and 2N aqueous ammonium chloride (150 mL). The mixture was extracted with dichloromethane (2×60 mL). The organic layer was washed with brine (2×50 mL), and concentrated. The residue was purified by Biotage SP1 column chromatography on silica gel [40+M], eluting with 5-60% ethyl acetate/hexanes, 24 CV; 60% ethyl acetate/hexanes, 6 column volumes. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 2H), 7.35 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]([NH:18][C:19]3[CH:51]=[CH:50][C:22]([C:23]([N:25]([CH3:49])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[O:41])=[CH:36][N:35]=4)=[O:24])=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([N:25]([CH3:49])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[O:41])=[CH:36][N:35]=4)=[O:24])=[CH:50][CH:51]=3)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CN1CCN(C(=O)c2ccc(COc3ccccc3N(C)C(=O)c3ccc(NC(=O)c4ccccc4-c4ccc([N+](=O)[O-])cc4)cc3)nc2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCN(C(=O)c2ccc(COc3ccccc3N(C)C(=O)c3ccc(NC(=O)c4ccccc4-c4ccc(N)cc4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A mixture of 4-(4′-nitrobiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-ylcarbonyl)pyrid-2-ylmethoxy]phenyl]benzamide (300 mg) and iron powder (122 mg) in a mixture of ethanol (10 ml) and acetic acid (1 ml) was refluxed for 3 hours and the mixture was evaporated in vacuo. The residue was stirred in a mixture of chloroform (20 ml) and saturated aqueous sodium hydrogen carbonate (20 ml) at ambient temperature for 30 minutes and the mixture was filtered through a bed of Celite. The organic phase of the filtrate was separated and washed with brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a syrup. The crude product was purified by silica gel column (chloroform:methanol:conc. ammonia=10:1:0.1) to give 4-(4′-aminobiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-ylcarbonyl)pyrid-2-ylmethoxy]phenyl]benzamide (157 mg) as a pale yellow amorphous.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:44])[C:30]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)([CH3:35])[CH2:31][S:32]2)=[CH:27][CH:26]=1.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:29]1([OH:44])[C:28]2[C:33](=[CH:34][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[S:32][CH2:31][C:30]1([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[CH3:35])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C#CCCCCCCCO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 9-(t-butyldimethylsilyloxy)-1-nonyne (12 g, 47.15 mmol) in dry tetrahydrofuran (150 ml) was added dropwise n-butyl lithium (25.5ml, 42.43 mmol, 1.66 mole/l in tetrahydrofuran) at −78° C., which was then stirred at −20° C. for 1 hour. Then, to this reaction mixture was added 7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one (3 g, 9.54 mmol) dissolved in tetrahydrofuran at the same temperature for 30 minutes, and the resulting mixture was stirred at −10° C. for 24 hours. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane:ethyl acetate=9:1) to stoichiometrically give the title compound (5.40 g) as a colorless oil.