Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:29][CH3:30])=[CH:20][C:21]([CH:27]=O)=[C:22]([C:23]([F:26])([F:25])[F:24])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:31]1([Mg]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:27]([C:21]1[CH:20]=[C:19]([O:29][CH3:30])[C:13]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=3)=[N:11][C:12]=2[C:22]=1[C:23]([F:25])([F:24])[F:26])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C(F)(F)F)c(C=O)cc(OC)c21
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C(F)(F)F)c(Cc3ccccc3)cc(OC)c21

Procedure:
The title compound is prepared from 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole-5-carbaldehyde and phenylmagnesiumbromide as described in examples 35 and 51.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[N:24]=[C:23]([S:25][CH3:26])[N:22]=[C:21]([N:27]([CH3:29])[CH3:28])[CH:20]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][C:19]2[CH:20]=[C:21]([N:27]([CH3:28])[CH3:29])[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: CSc1nc(Cl)cc(N(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Nc2cccc(OCc3ccccc3)c2)cc(N(C)C)n1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 93.7 %

Procedure:
A mixture of 3-(benzyloxy)aniline (5.13 g) and NaH (1.37 g) in tetrahydrofuran (15 mL) was refluxed for 30 minutes and then cooled to room temperature. A solution of N-[6-chloro-2-(methylsulfanyl)-4-pyrimidinyl]-N,N-dimethylamine (3.5 g) in tetrahydrofuran (35 mL) was added to this mixture and the resulting solution was stirred for 22.5 hours. The reaction mixture was quenched with saturated NH4Cl. Then the crude product was concentrated under reduced pressure and redissolved in EtOAc. The organic layer was separated and washed with aqueous citric acid (2×300 mL), water (2×300 mL) and brine (2×300 mL). The crude product was purified by column chromatography [eluent: EtOAc/hexane (1:4)], giving the desired product (5.9 g, 94%).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]1[C:30]2=[CH:31][CH:32]=[CH:33][C:29]2=[CH:28][CH:27]=[C:26]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1/[CH:40]=[CH:41]/S(O)(=O)=O>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:25]1[C:30]2=[CH:31][CH:32]=[CH:33][C:29]2=[CH:28][CH:27]=[C:26]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1/[CH:40]=[CH:41]/[S:1]([Cl:5])(=[O:3])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=S(=O)(O)/C=C/c1ccccc1-c1ccc2cccc-2o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(Cl)/C=C/c1ccccc1-c1ccc2cccc-2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
Sulfurylchloride (0.21 mL, 2.6 mmol) was added to a solution of triphenylphosphine (0.68 g, 2.5 mmol) in CH2Cl2 (10 mL) at 0° C. The ice-bath was then removed and (E)-2-(4-benzofuran-2-ylphenyl)ethenesulfonic acid (0.38 g, 1.18 mmol) was added and the resulting mixture was stirred for 6 h at RT. A catalytic amount of tetrabutyl ammonium iodide was added and the reaction was stirred for an additional 12 h. The mixture was then filtered and the filtrate was concentrated in vacuo and the product was purified by column chromatography eluting with 20% EtOAc/hexanes to give the product as a yellow solid (0.27 g, 73%).
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[Br:18]N1C(=O)CCC1=O.S(=O)(=O)(O)O>ClCCl>[Br:18][C:6]1[CH:7]=[CH:8][C:9]2[CH2:1][CH2:2][CH2:3][C:4]=2[C:5]=1[OH:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1cccc2c1CCC2
Agent: O=S(=O)(O)O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Oc1c(Br)ccc2c1CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of indan-4-ol (24.2 g) in dichloromethane (200 mL) was added diisopropylamine (2.55 mL). To the solution was added N-bromosuccinimide (32.07 g) in small portions under ice-cooling, and the mixture was stirred at room temperature overnight. Diluted sulphuric acid (pH1, 200 mL) was added to the reaction mixture, and the mixture was separated. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1−1/1) to give the title compound (31.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)/C(=C\c1ccc(C)cc1)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C(=C\c1ccc(CBr)cc1)c1ccccc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a solution of the product of Step B (31 mg, 0.123 mmol) in dry CCl4 (1 mL) under N2 were added NBS (20 mg, 0.9 eq) and a catalytic amount of AIBN. The mixture was stirred at reflux under N2 for 1.5 hours. The mixture was cooled to room temperature, diluted with EtO2 and filtered to remove the precipitated succinimide. The filtrate was concentrated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 15:1 hexane/EtOAc to afford 27.4 mg (67%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.[Cl:24][C:25]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:32]=[C:31]([O:33][CH2:2][C:3]2[O:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: COc1ccc(-c2nc(COC3CCCCO3)c(CCl)o2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(COC3CCCCO3)c(COc3ccc(C#N)c(Cl)c3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.8 %

Procedure:
2.5 g 5-Chloromethyl-2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazole and 1.48 g 2-chloro-4-hydroxybenzonitrile were dissolved in 20 ml dimethylformamide. 4.82 g Cesium carbonate were added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with 200 ml ethyl acetate and washed five times with portions of 50 ml water and brine. The organic phase was dried over MgSO4 and the solvent was evaporated in vacuo to obtain 4.0 g crude 2-chloro-4-[2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-5-ylmethoxy]-benzonitrile. This material was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH:24]=O)[C:21]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].N1CCCCC1.C(O)(=O)C1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH2:24][CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:33]([O:41][CH2:42][CH3:43])=[O:40])[C:21]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:31][CH:32]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(Cc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A mixture of 1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (1.60 g), diethyl malonate (0.69 g), piperidine (0.12 ml), benzoic acid (0.09 g), and toluene (50 ml) was subjected to azeotropic dehydration for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). Sodium borohydride (105 mg) was added to a mixture of the obtained colorless oily substance, ethanol (20 ml), and tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel chromatography to obtain diethyl [1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methylmalonate (1.76 g, yield: 83%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:14]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:23][C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: ClCCCCSc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(O)cc21
Product: CC1(C)OC(=O)Nc2cc(Cl)c(OCCCCSc3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 4 from 7-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-chloro-phenylmercapto)-butylchloride.
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1)#[CH:2].I[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.C(OCC)(=O)C>C(N(CC)CC)C.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.[Cu]I>[C:19]([C:18]1[CH:22]=[CH:23][C:15]([C:2]#[C:1][C:3]2[C:4]3[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=3[S:6][CH:7]=2)=[CH:16][CH:17]=1)([OH:21])=[O:20]
Reactant: C#Cc1csc2cccc(OC)c12
Reactant: O=C(O)c1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc2scc(C#Cc3ccc(C(=O)O)cc3)c12
Yield: 97.7 %

Procedure:
3-Ethynyl-4-methoxybenzo[b]thiophene (0.2 g) was dissolved in triethylamine (4mL). To the solution were added 4-iodobenzoic acid (0.29 g), tetrakis(triphenylphosphine)palladium (0) (0.12 g) and copper (I) iodide (41 mg), and the mixture was heated for ref lux under an argon atmosphere overnight. The reaction mixture was poured into ethyl acetate-1 mol/L hydrochloric acid, and the insoluble material was removed by filtration. The organic layer was separated from the filtrate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-1/2) to give 3-[2-(4-carboxyphenyl)ethynyl]-4-methoxybenzo[b]thiophene (0.32 g). This material was dissolved in N,N-dimethylformamide (10 mL). To the solution were added potassium carbonate (0.29 g) and benzyl bromide (0.16 mL), and the mixture was stirred at room temperature for three hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give the title compound (0.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[S:11][C:10]=1[C:21]([O:23]C)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[S:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Temperature: 65 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-(4-chlorophenyl)thiophene-2-carboxylate a (0.135 g, 0.29 mmol) in 1:1 THF/MeOH (2 mL) at rt was added a 3 N aq NaOH (1 mL) and the resulting mixture was warmed to 65° C. for 30 min then cooled to rt and concentrated to remove the volatile solvents. The remaining aqueous portion was cooled in an ice bath and 1 N aq HCl was added until pH ˜2 was reached. The slurry was stirred for 1 h then collected the resulting solid by vacuum filtration, rinsed with water and dried under vacuum to afford 86 mg (66%) of an off-white solid as compound b. HPLC Ret time=4.32 min.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6](=[O:18])[C:7]2[C:12]([C:13]=1[CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][N:5]1[C:4]([CH3:3])=[C:13]([CH2:14][C:15]([OH:17])=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:18]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: Cc1[nH]c(=O)c2ccccc2c1CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2ccccc2c(=O)n1Cc1ccc(Cl)c(Cl)c1

Procedure:
Sodium hydride (48 mg., 2.0 mmol) (Ventron, washed free of mineral oil with hexane) and 2 ml. dimethylformamide were reacted with 1,2-dihydro-3-methyl-1-oxo-4-isoquinoline acetic acid (217 mg., 1.0 mmol). After homogeneity was observed, 3,4-dichlorobenzyl chloride (196 mg., 1.0 mmol) in 1 ml. dimethylformamide was added. The mixture was heated at 110° for 3 hr, cooled and partitioned between hydrochloric acid and ethyl acetate. The crude product obtained from the organic layer after several aqueous washings, drying over magnesium sulfate, filtration, and vacuum evaporation was column chromatographed on silica gel with ethyl acetate; 104 mg., 28%, mp 218°-220°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:21][N:22]([CH2:33][CH2:34][CH:35]=O)[C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:35][CH2:34][CH2:33][N:22]([CH3:21])[C:23]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:32])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CN(CCC=O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (1.21 g, 4.10 mmol) and phenylmethyl methyl(3-oxopropyl)carbamate (1.63 g, 7.39 mmol) in glacial acetic acid (15 mL) was treated with sodium trisacetoxyborohydride (1.74 g, 8.21 mmol) and stirred under nitrogen at ambient temperature. After approximately 1 hour, additional sodium triacetoxyborohydride (1.00 g, 4.72 mmol) was added. After an additional 3-4 hours, additional phenylmethyl methyl(3-oxopropyl)carbamate (1.00 g, 4.52 mmol) and sodium triacetoxyborohydride (1.00 g, 4.72 mmol) was added. The reaction mixture was evaporated in vacuo and the residue was dissolved in CH2Cl2 and treated with 2N KOH. After separating the layers, the aqueous phase was back-extracted with CH2Cl2 and the combined organic layers were washed with water, dried over MgSO4, filtered, evaporated in vacuo and purified on silica eluting with 3% MeOH in CH2Cl2 to provide the product as an oil: 1H NMR (CDCl3) δ 7.88 (1H, s), 7.77 (1H, s), 7.26-7.37 (5H, m), 7.11 (2H, b), 6.97 (2H, t, J=8.8), 6.74 (1H, d, J=31 Hz), 5.12 (2H, s), 4.42 (2H, q, J=7 Hz), 3.90 (2H, s), 3.41 (2H, t, J=7), 3.06-3.20 (2H, m), 2.92 (3H, s), 1.86 (2H, b), 1.42 (3H, t, J=7 Hz); ES+ MS: 480 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8][C:9]([F:12])([F:11])[F:10])=[C:6]([NH:13]C(=O)C(F)(F)F)[NH:5][N:4]=1)#[N:2].[OH-].[NH4+].Cl>CO.C(OCC)(=O)C>[C:1]([C:3]1[C:7]([S:8][C:9]([F:12])([F:11])[F:10])=[C:6]([NH2:13])[NH:5][N:4]=1)#[N:2]
Reactant: N#Cc1n[nH]c(NC(=O)C(F)(F)F)c1SC(F)(F)F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1n[nH]c(N)c1SC(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.6 %

Procedure:
The product of Step E (55 g, 181 mmoles) was dissolved in methanol. 100 ml of ammonium hydroxide were added, the solution was refluxed for 3 hours and then stirred at room temperature for 15 hours. The methanolic solution was brought to pH7 using concentrated aqueous hydrochloric acid and diluted with ethyl acetate. The organic layer was washed several times with water and brine, dried over MgSO4 and concentrated to dryness to give an oily brown residue which was recrystallized from methyl tert-butyl ether to afford 33 g of the title compound, m.p. around 187° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH2:19]O)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.P(Br)(Br)[Br:28]>C1(C)C=CC=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:19][Br:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)cc1C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(CBr)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.72 g (10 mmol) of the above benzyl alcohol (a), 30 ml of toluene and 800 μl (10 mmol) of pyridine were introduced into a three-necked flask. A solution of 940 μl (10 mmol) of phosphorus tribromide in 9 ml of toluene was added dropwise, at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction medium was evaporated to dryness and the residue was taken up in water and ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was triturated from hexane, filtered and dried. 2.35 g (70%) of the expected benzyl bromide, having a melting point of 95°-9° C., were recovered.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13]([C:15]2O[C:17]([NH:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[N:18][N:19]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>ClCCl>[N:26]1([C:17]2[N:20]([CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:15]([C:13]([NH:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:14])=[N:19][N:18]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CC(C)=CCNc1nnc(C(=O)NCc2cccc3ccccc23)o1
Reactant: C1CNCCN1
Solvent: ClCCl
Product: CC(C)=CCn1c(C(=O)NCc2cccc3ccccc23)nnc1N1CCNCC1
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
A mixture of 0.10 g 5-(3-methyl-but-2-en-1-ylamino)-[1,3,4]oxadiazole-2-carboxylic acid-(naphth-1-ylmethyl)-amide and 1.28 g piperazine is stirred for 15 min at 200° C. in a microwave. After cooling to ambient temperature dichloromethane is added, the organic phase is washed with water, dried over sodium sulphate and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→7:3).
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:17])(=[O:16])[C:8]2=[CH:9][CH:10]=[CH:11][C:12]3=[CH:13][CH:14]=[CH:15][C:6](=[C:7]23)[NH:5][CH2:4]1.Br[CH2:19][C:20]([NH2:22])=[O:21]>CN(C)C=O>[O:17]=[S:3]1(=[O:16])[C:8]2=[CH:9][CH:10]=[CH:11][C:12]3=[CH:13][CH:14]=[CH:15][C:6](=[C:7]23)[NH:5][CH:4]1[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: NC(=O)CBr
Reactant: O=S1(=O)CNc2cccc3cccc1c23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)CC1Nc2cccc3cccc(c23)S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.011 g of sodium hydride is suspended in 0.5 mL of dimethylformamide, and 0.06 g of 2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide in 1 mL of dimethylformamide is added. The mixture is stirred for 1 hour at ambient temperature and then 0.042 g of 2-bromoacetamide are added batchwise. Then the mixture is stirred for 18 hours at ambient temperature. The reaction mixture is poured onto ice water and extracted with dichloromethane. The organic extracts collected are dried with sodium sulfate and, after evaporation in vacuo, purified by chromatography. Yield: 0.043 g; m.p.: 195° C.–196° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:13][S:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=2[N:16]=1.C(=O)([O-])[O-:27].[K+].[K+]>>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:13][S:14]([C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=2[N:16]=1)=[O:27]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(N)c(CSc2nc3cc(OC)ccc3[nH]2)c1
Agent: [K+]
Product: CCOC(=O)c1ccc(N)c(CS(=O)c2nc3cc(OC)ccc3[nH]2)c1

Procedure:
The title compound was prepared by the method of Example 3 using 557 mg of the title product of Example 72 instead of the title product of Example 2. The reaction mixture was passed three times through a column of potassium carbonate powder and concentrated in vacuo to dryness. Crystallization for acetonitrile gave 257 mg of the title compound. Anal. Calc'd. for C18H19N3O4S: C, 57.90; H, 5.13; N, 11.25; S, 8.59. Found: C, 57.63; H, 5.15; N, 11.32; S, 8.65.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][O:25][CH2:26][CH:27]([NH2:29])[CH3:28]>O1CCOCC1>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:29][CH:27]([CH3:28])[CH2:26][O:25][CH3:24])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: COCC(C)N
Solvent: C1COCCO1
Product: COCC(C)Nc1c([N+](=O)[O-])cnc2cc(-c3c(C)noc3C)c(OC)cc12
Temperature: 70 °C
Yield: 111.5 %

Procedure:
To a solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (Manchester Organics) (20 g, 59.9 mmol) in 1,4-dioxane (200 ml) was added 1-methoxypropan-2-amine (31.6 ml, 300 mmol) and the reaction mixture heated at 70° C. for 1.5 h. The solvent was removed under reduced pressure and the resulting solid partitioned between ethyl acetate (3×750 ml) and water (750 ml). The organic layers were combined, dried (hydrophobic frit) and evaporated under reduced pressure to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N-(1-methoxypropan-2-yl)-3-nitroq uinolin-4-amine (25.8 g), which was used without further purification in the subsequent step.