Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Br:12][C:13]1[CH:18]=[C:17]([CH2:19]Br)[CH:16]=[CH:15][C:14]=1[O:21][CH3:22].[Cl-].[NH4+]>CN(C=O)C.ClCCl>[Br:12][C:13]1[CH:18]=[C:17]([CH:16]=[CH:15][C:14]=1[O:21][CH3:22])[CH2:19][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccc(CBr)cc1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2ccc3ccccc32)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of indole (250 mg, 2.14 mmol) in DMF (15 mL) was cooled in an ice bath. To this solution was added sodium hydride (64.3 mg, 2.68 mmol), followed by 2-Bromo-4-bromomethyl-1-methoxy-benzene (500 mg, 1.79 mmol). The reaction was warmed to room temperature and stirred overnight. To the reaction was added saturated aqueous ammonium chloride (75 mL) and the layers separated. The organic extract was washed with saturated aqueous ammonium chloride (2×75 mL), water (3×75 mL) and brine (50 mL). The extract was dried over sodium sulfate, and the solvent removed under reduced pressure. To residue was purified by flash silica gel column chromatography eluting with 1:3 hexanes: dichloromethane to give the title compound (I-107, X═CH) (490 mg, 87% yield) which was taken into further reactions.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(N(CC)CC)C.[CH:29]#[C:30][CH3:31]>CN(C)C=O.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]#[C:30][CH3:31]
Reactant: C#CC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: -78 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-iodopyrazole (0.904 g, the compound of Example A1) in dimethylformamide(2 ml) and triethylamine (10 ml) contained in a stainless steel bomb was added cuprous iodide (60 mg) and bis(triphenylphosphine)palladium(II) chloride (120 mg). The reaction vessel was cooled to −78° C. and propyne (2 g) condensed into it. The vessel was sealed and then heated at 70° C. for 18 hours and then left at room temperature for 2 days. The reaction mixture was partitioned between ether and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane : hexane (1:1) to provide the title compound as a white solid m.p. 226-8° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:25])[NH:11][C:12]2[CH:24]=[CH:23][C:15](OC(C)(C)C(O)=O)=[CH:14][CH:13]=2)[CH:5]=[C:6](Cl)[CH:7]=1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:10]([NH:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]1)([NH:11][CH:12]1[CH2:24][CH2:23][CH2:15][CH2:14][CH2:13]1)=[O:25]
Reactant: CC(C)(Oc1ccc(NC(=O)Nc2cc(Cl)cc(Cl)c2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
A mixture of 383 mg. (1 mmole) of 2-(4-(3,5- dichlorophenylureido)phenoxy)-2-methyl-propionic acid prepared according to Example 4 of U.S. Pat. No. 5,093,367 and 126 mg. (1.1 mmole) of N-hydroxysuccinimide, 26 mg. (1.1 mmole) of dicyclohexylcarbodiimide in 15 ml of tetrahydrofuran was stirred at room temperature for 4 hours, Dicyclohexylurea formed and was filtered off. The solid product was washed with 5 ml of tetrahydrofuran and evaporation under vacuum yielded 450 mg of a powder. mp 106-162° C. The NMR and elemental 2 analysis is consistent with the N-hydroxysuccinimide ester of 2-(4-(3,5-dichlorophenylureido)phenoxy)-2-methyl-propionic acid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(O)CCC>CC(C)=O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCCCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a mixture of NaOH (1 eq.) and butan-1-ol (15 ml). The mixture was stirred at about 80° C. for 1.5 h, after which the starting material was not detected by HPLC. Then, 40 ml of acetone was dripped into the solution and the mixture was cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 1.09 g (53.5%) of fluvastatin sodium Form VII.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6](=O)[CH2:5]2.[BH4-].[Na+].Cl>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH:6]=[CH:5]2
Reactant: COc1ccc(CN2C(=O)Cc3cc(Br)ccc3C2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-2-(4-methoxy-benzyl)-4H-isoquinoline-1,3-dione (product of step iii)) (2.6 g) in dichloromethane:methanol (3:1, 80 mL) was added sodium borohydride (1.0 g) portionwise over 2 hours. The reaction mixture was acidified with hydrochloric acid and stirred for 30 minutes. The reaction mixture was evaporated and the residue partitioned between dichloromethane and water. The organic phase was washed with brine, dried, filtered and evaporated. The residue was purified (SiO2, 1:4 ethyl acetate:iso-hexane as eluent) to yield the sub-title compound (1.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:12][NH2:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH3:10])=[N:13][NH:12][C:5]2=[N:6][CH:7]=1
Reactant: NN
Reactant: CC(=O)c1cc(Br)cnc1Cl
Product: Cc1n[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Starting material 1-(5-bromo-2-chloropyridin-3-yl)ethanone (5.8 g, 24.7 inmol) and 100 ml anhydrous hydrazine was charged into 500 ml round bottom flask and the resulting mixture was allowed to stir at room temperature for overnight. After removing the excess hydrazine via rotatory evaporation under reduced pressure, the remaining residue was diluted with distilled water and solid was appeared. After filtering the water, the resulting solid was taken up in ethylacetate and saturated aqueous sodium bicarbonate and was extracted by ethylacetate twice. The combined organic layer was washed with water and brine and dried over sodium sulfate. The crude product was eluted through a short silica gel column (3 inch in length) with ethylacetate as a white solid (4.0 g, y=77%).
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:45]=[C:46]([C:50]2[C:51]([C:56]([OH:58])=O)=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:47]=[CH:48][CH:49]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH3:59][N:60]([CH3:64])[CH2:61][CH2:62][NH2:63]>C1COCC1>[CH3:59][N:60]([CH3:64])[CH2:61][CH2:62][NH:63][C:56]([C:51]1[C:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:45]=2)=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:58]
Reactant: O=C(O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1
Reactant: CN(C)CCN
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (2-dimethylamino-ethyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (1.02 g, 2.8 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.46 g, 2.86 mmol, 1.02 eq.) and N,N-dimethylethylenediamine (0.30 g, 3.36 mmol, 1.2 eq.) as described. When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[S:51]([CH3:54])(=[O:53])=[O:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[S:51]([CH3:54])(=[O:53])=[O:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1ccccc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3S(C)(=O)=O)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(methylsulfonyl)benzene and isolated as white solid. MS(m/e): 451.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([OH:17])=O)[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][N:18]=4)=[CH:29][N:28]=3)=[O:17])[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cc(CC(=O)O)ccn2)ccn1
Reactant: Nc1ccc(-c2cnccn2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(CC(=O)Nc3ccc(-c4cnccn4)cn3)ccn2)ccn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(2′-methyl-2,4′-bipyridin-4-yl)acetic acid 238-3 (46 mg, 0.2 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (34 mg, 0.2 mmol), 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol) and 4-(dimethylamino)pyridine (4 mg, 0.04 mmol) in DMF (0.9 mL) was stirred at room temperature for 10 hours. The crude product was filtered to remove the insoluble and the filtrate was submitted directly for reverse phase HPLC purification to give 2-(2′-methyl-2,4′-bipyridin-4-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 238 as white solid. MS m/z 383.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.14 (s, 1H), 9.30 (d, 1H), 9.11 (dd, 1H), 8.73-8.71 (m, 1H), 8.67 (d, 1H), 8.62 (d, 1H), 8.56 (d, 1H), 8.52 (dd, 1H), 8.21 (d, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.84 (dd, 1H), 7.45 (dd, 1H), 3.95 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:24])[C@@H:21]([CH3:23])[NH2:22])=[CH:15][CH:14]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:6]2[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[C:20](=[O:24])[C@@H:21]([CH3:23])[NH:22][C:33]4=[O:35])=[CH:17][CH:18]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c2c(C)noc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c2c(C)noc2c1
Reaction time: 0.08 h
Yield: 37.7 %

Procedure:
N1-{4-[(3,6-dimethyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-D-alaninamide (Intermediate 23, 54 mg) was dissolved in 7.0 ml of ethyl acetate. Then triethylamine (0.051 ml, 0.37 mmol) was added followed by a solution of triphosgene (24.6 mg, 0.083 mmol) in 2.0 ml of ethyl acetate. After stirring for 5 minutes, DMAP (10.1 mg, 0.083 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. After quenching with an aqueous solution of NaHCO3, the mixture was extracted two times with ethyl acetate and the collected organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with a gradient c-Hex/EtOAc from 100/0 to 0/100 to afford the title compound (11 mg)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Br[C:15]1[S:16][C:17]([S:20][CH3:21])=[N:18][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[CH3:21][S:20][C:17]1[S:16][C:15]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[N:19][N:18]=1
Reactant: OB(O)c1ccc2cnccc2c1
Reactant: CSc1nnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1nnc(-c2ccc3cnccc3c2)s1
Temperature: 90 °C
Yield: 93.5 %

Procedure:
To a stirred mixture or isoquinolin-6-ylboronic acid (83 mg, 0.33 mmol) (prepared as described in US Patent Publication No. US 2007/0173506), 2-bromo-5-(methylthio)-1,3,4-thiadiazole (82 mg, 0.39 mmol) (prepared as described in WO 97/30981) and Pd(PPh3)4 (19 mg, 0.016 mmol) was added dimethoxyethane (5.0 mL) and sodium carbonate (0.41 mM, 2.0 M aq, 0.82 mmol). The mixture was heated at 90° C. under a reflux condenser overnight. After cooling, the mixture was filtered through a short path of Celite and washed with EtOAc (3×10 mL). The combined organic layers were evaporated and purified by flash column chromatography (eluting with a gradient of 1:1 EtOAc in hexanes to pure EtOAc) to provide 6-(5-(methylthio)-1,3,4-thiadiazol-2-yl)isoquinoline (80 mg, 95%) as a pale yellow solid. LCMS (M+H) 260.4 calc. for C12H10N3S2 260.0. 1H NMR (400 MHz, CDCl3): δ ppm 9.33 (d, J=1.17 Hz, 1H) 8.62 (s, 1H) 8.31 (s, 1H) 8.23 (d, J=8.80 Hz, 1H) 8.11 (d, J=8.80 Hz, 1H) 7.74-7.83 (m, 1H) 2.88 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:21][CH:22]1[CH2:24][CH2:23]1.[H-].[Na+]>CN(C=O)C>[CH:22]1([CH2:21][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:18]=4[CH3:19])[C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: Cc1ccncc1N1CCc2ccc(O)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccncc1N1CCc2ccc(OCC3CC3)cc2C1=O
Yield: 413.6 %

Procedure:
7-hydroxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (27A: 50 mg, 0.196 mmol) was reacted with bromomethyl-cyclopropane (32 mg, 0.236 mmol) and 60% NaH (10 mg, 0.236 mmol) in DMF (2 mL) to afford the crude product. Purification by column chromatography on silica gel (15% ethylacetate in hexane) afforded 250 mg of the product (50% yield).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([O-])([O-])=O.[K+].[K+].[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CN(C=O)C.O>[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(Br)c1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a stirred solution of phthalimide (0.64 g, 4.4 mmol) in DMF (10 ml) was added K2CO3 (1.65 g, 12.00 mmol), followed by 3-bromobenzyl bromide (1 g, 4.0 mmol) at 0° C. and the reaction mixture was stirred at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the mixture was diluted with cool water (50 ml), resultant solid was filtered and dried under vacuum for 3 h to get the desired compound as a white solid (1.2 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ 7.92-7.84 (m, 4H), 7.54 (s, 1H), 7.50-7.45 (m, 1H), 7.33-7.26 (m, 2H), 4.77 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1.O=P(Cl)(Cl)[Cl:14]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([Cl:14])=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc(Br)c[n+]([O-])c1
Solvent: ClCCl
Product: CCOc1cc(Br)cnc1Cl
Temperature: 45 °C
Yield: 33.3 %

Procedure:
To a solution of 3-bromo-5-ethoxypyridine 1-oxide (40 g, 183 mmol) in DCM (200 mL) at 0° C. was slowly added POCl3 (159 mL, 1701 mmol) over 30 min. Then the resulting solution was warmed to 45° C. for 15 h. The mixture was concentrated and extracted with DCM (2×200 mL), dried over Na2SO4, filtered, and concentrated to give 5-bromo-2-chloro-3-ethoxypyridine (30 g, 60.9 mmol, 33.2% yield): 1H NMR (400 MHz, CD3OD) δ 8.00-7.99 (d, J=2.0 Hz, 1H), 7.65-7.64 (d, J=2.0 Hz, 1H), 4.17-4.12 (m, 2H), 1.44 (t, J=7.0 Hz, 2H); ES-LCMS m/z 235 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C[O-].[Na+].CO.Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>C1C=CC=CC=1>[CH3:20][O:19][C:17](=[O:18])[CH:16]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(O)cc1C
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc(C)c(C)c1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1

Procedure:
To a mixture of 3.05 g of 3,4-dimethylphenol, 1.19 g of sodium methoxide, 40 ml of methanol and 10 ml of benzene is added 8.27 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate. The mixture is refluxed for 24 hours and the solvent removed under reduced pressure. The residue is chromatographed over silica gel with dichloromethane as eluent. The product is obtained as a viscous oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].CC[O:31][C:32]([C:34]1C(C2C=CC=CC=2Cl)C(C(OC)=O)=C(C)[NH:36][C:35]=1[CH2:52][O:53]CCN)=[O:33].C(/C(O)=O)=C/C(O)=[O:60]>ClCCl>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[NH2:36][C@H:35]([C:52]([O-:53])=[O:60])[CH2:34][C:32]([O-:31])=[O:33]
Reactant: O=C(O)/C=C\C(=O)O
Agent: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: ClCCl
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
16 g of amlodipine and 12 g of amlodipine maleate are melted in a 300 ml flask. The melted substance is cooled to room temperature and dissolved in 300 ml of dichloromethane. The mixture is extracted with 300 ml of a 1M NaOH solution. The organic layer is discarded and the aqueous layer acidified with 55 ml of a 6 M HCl solution. The mixture is extracted with 300 ml of dichloromethane. The layers are separated and the organic layer dried over Na2SO4. The mixture is evaporated to dryness and the resulting waxy solid recrystallized from ethanol. The obtained sticky solid is dried in a vacuum oven at 40° C. leaving 4.7 g of an off white product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[CH3:29][N:30]1[C:34](=[O:35])[CH2:33][S:32][C:31]1=[S:36]>C(O)(=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:33]3[S:32][C:31](=[S:36])[N:30]([CH3:29])[C:34]3=[O:35])=[CH:14][CH:13]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: CN1C(=O)CSC1=S
Reactant: CCCc1c(COc2ccc(C=O)cc2)ccc(C(C)=O)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1c(COc2ccc(C=C3SC(=S)N(C)C3=O)cc2)ccc(C(C)=O)c1O
Temperature: 100 °C

Procedure:
Under a nitrogen atmosphere in a three-neck round bottom flask 4-[(4-acetyl-3-hydroxy-2-propylphenyl)methoxy]benzaldehyde (90.0 mg, 0.29 mmol) was dissolved in acetic acid (1.5 ml) with stirring. To this solution was added sodium acetate (82.8 mg, 1.00 mmol) and N-methylrhodanine (42.5 mg, 0.29 mmol). The reaction mixture was then heated to 100° C. and maintained at this temperature for about two hours at which time the reaction mixture was raised to the reflux temperature and allowed to reflux for about 28 hours. The reaction progress was monitored by thin layer chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([N:24]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>O1CCOCC1>[CH2:35]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[N:26]=[CH:27][N:28]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=[CH:6][CH:7]=2)[C:30]=1[N+:31]([O-:33])=[O:32])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a solution of tert-butyl 3-aminophenyl(methyl)carbamate (20) (4.6 g, 20.8 mmol) and N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (7 g, 19.8 mmol) in dioxane (100 mL) was added Et3N (6 mL) and the reaction mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature, the solvent was evaporated before water (200 mL) and EA (100 mL) was introduced. Organic layer was separated and extracted with EA (60 mL×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by column chromatography (silica gel, 0 to 30% ethyl acetate in petroleum ether) to give tert-butyl 3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl(methyl)carbamate (21) 6.7 g as yellow solid (yield 63%). LC-MS (ESI): m/z (M+1) 541.