Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.Br[CH:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:33](=[O:34])[CH:32]([CH2:36][CH3:37])[C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(NCc1ccc(OC)cc1OC)C(=O)OCC
Reactant: CCC(Br)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)C(CC)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 6 h
Yield: 87 %

Procedure:
30 g (0.092 mole) of diethyl N-(2,4-dimethoxybenzyl)-amino-malonate prepared according to paragraph (b) of Example 1 are dissolved in a mixture of 90 ml of benzene and 15.6 ml (11.2 g, 0.111 mole) of triethyl amine and thereafter 20.5 g (0.111 mole) of 2-bromo butyric acid chloride are added dropwise under external ice-cooling. The reaction mixture is stirred under cooling for half an hour and thereafter at room temperature for half an hour. The precipitated crystalline substance is filtered off and washed twice with 20 ml of benzene. To the combined benzene mother liquor 31.2 g (22.4 g, 0.222 mole) of triethyl amine are added and the mixture is boiled for 6 hours. The precipitated crystalline substance is cooled and filtered. The mother liquor is extracted successively with 100 ml of water, twice with 100 ml of diluted hydrochloric acid each (a mixture of 90 ml of water and 10 ml of hydrochloric acid) and twice with 100 ml of water each. The organic layer is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. The residual oil is made crystalline by rubbing with petrolether. Thus 31.5 g of diethyl 1-(2,4-dimethoxy-benzyl)-3-ethyl-4-oxo-2,2-azetidinedicarboxylate are obtained. M.p.: 69° C. (from a mixture of benzene and petrolether).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:20])=[CH:18][C:11]=3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:29]#[C:30][NH2:31]>O1CCOCC1>[NH:2]([C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:20])=[CH:18][C:11]=3[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[C:30]([NH2:31])=[NH:29]
Reactant: COC(=O)CCCNC(=O)c1ccc2c(c1)nc(-c1cccc(N)c1)n2C
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCCNC(=O)c1ccc2c(c1)nc(-c1cccc(NC(=N)N)c1)n2C

Procedure:
Prepared from 2-(3-amino-phenyl)-5-[(3-methoxycarbonyl-propyl)-aminocarbonyl]-1-methyl-benzimidazole-hydrochloride by refluxing for 3 hours with cyanamide in dioxane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]3[CH2:15][CH2:14][CH2:13][CH:7]3[C:8](=S)[NH:9][C:10]=2[CH:11]=1.[NH3:16]>>[NH2:16][C:8]1[CH:7]2[CH2:13][CH2:14][CH2:15][CH:6]2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[N:9]=1
Reactant: Cc1ccc2c(c1)NC(=S)C1CCCC21
Reactant: N
Product: Cc1ccc2c(c1)N=C(N)C1CCCC21
Yield: 99 %

Procedure:
In a way that is similar to Example 4, 7-methyl-1,2,3,3a,5,9b-hexahy drocyclopenta[c]quinoline-4-thione (230 mg, 1.05 mmol) in 7N methanolic ammonia solution (25 ml) is reacted to form 210 mg (99%) of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH2:29][CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH2:29][CH3:30])[CH:28]=3)[C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1
Reactant: CCn1cc(Br)cn1
Reactant: COC(=O)c1cncc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCn1cc(-n2c(C)c(Sc3cncc(C(=O)OC)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 3, Step 1, using the following starting materials: 5-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-nicotinic acid methyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[C:17]([Cl:21])[N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[C:17]([Cl:21])[N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:26][CH:27]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.8 %

Procedure:
A mixture of 0.50 g of 1-(4-benzyloxybenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole, 0.50 g of 10% palladium/carbon and 40 mL of tetrahydrofuran was stirred at room temperature under hydrogen gas (1 atm.) for 6 hours. The mixture was filtered through Celite® under nitrogen, and the resulting solution was concentrated in vacuo. The crude product was extracted with hot chloroform. After cooling, the chloroform mixture was concentrated in vacuo, and the resulting solid was washed with hexane to afford 0.16 g of 1-(4-hydroxybenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, DMSO-d6): δ 9.43 (s, 1H); 6.81 (A2B2, 4H); 5.21 (t, 1H); 5.10 (s, 2H); 4.33 (d, 2H); 2.47 (t, 2H); 1.44 (quint 2H); 1.23 (sext., 2H); 0.79 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:20]([F:26])([F:25])C(OC)=O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:20]([F:26])[F:25])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(F)(F)Cl
Reactant: COC(=O)c1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC(F)F)ccc1Br
Temperature: 90 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
To a solution of methyl 2-bromo-5-hydroxybenzoate (5.63 mmol, 1.30 g) in DMF (8 mL) was added cesium carbonate (11.3 mmol, 3.67 g) and methyl chlorodifluoroacetate (6.75 mmol, 0.71 mL), and the reaction mixture stirred at 90° C. for 16 h. After cooling to rt and dilution with ethyl acetate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using hexane/EtOAc (9:1, v/v) as the eluent. The product was obtained as a light yellow oil (560 mg, 35%). GC-MS m/z: 280 (MH+).
Reaction SMILES: [C:1]1([C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH:12]=[C:11]([CH:13]=[CH:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[H][H].[Pd]>[C:33]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:17][CH2:16]3)[N:10]=[CH:9]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C(=CC1CCN(c2ccccc2)CC1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: c1ccc(N2CCC(CCc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)CC2)cc1

Procedure:
The product from Step E is dissolved in methanol and hydrogenated at 60 psi hydrogen with 10% palladium on carbon. When reaction is complete, the catalyst is filtered and the title compound obtained after evaporation of solvent.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH:7]([CH:9]2[CH2:11][CH2:10]2)[CH:6]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH2:5]1)[CH:2]=[CH2:3].[OH-:26].[K+]>CO.O>[C:2]1([C:1]([N:4]2[CH2:8][C@@H:7]([CH:9]3[CH2:10][CH2:11]3)[C@H:6]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH2:5]2)=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][CH:3]=1
Reactant: [OH-]
Reactant: C=CCN1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C2CC2)C1
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1cccc2ccccc12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Yield: 41.1 %

Procedure:
A solution of 6 g (48 mmol) of methyl-3-(cyclopropyl)acrylate (Example 1, Step 3) and 5.7 g (100 mmol) of KOH in 25 mL of MeOH and 2 mL of H2O was stirred at 40° C. for 2 h. The reaction mixture was concentrated. Addition of 2N HCl to the residue resulted in its precipitation as a white solid. The solid was collected by filtration and was washed with H2O and dried to give 4.5 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Fc1cccc(CBr)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Product: O=Cc1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Yield: 95 %

Procedure:
Prepared in analogy to example 8 from 2-hydroxy-5-nitrobenzaldehyde and 3-fluoro-benzylbromide. Colorless solid. Yield=95%. MS: m/e=275.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]=[O:9])=[C:4]([CH3:12])[CH:3]=1.[C:13]([NH2:17])(=[O:16])[CH2:14]O>O1CCCC1.CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]2[NH:17][C:13](=[O:16])[CH2:14][O:9]2)=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1OCC=O
Reactant: NC(=O)CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1OCC1NC(=O)CO1
Reaction time: 24 h
Yield: 18.2 %

Procedure:
A solution containing 4.6g (0.025 mole) of (4-chloro-2-methylphenoxy)acetaldehyde and 2.1g (0.028 mole) of glycolamide in 25 ml of tetrahydrofuran and 25 ml of ether was allowed to stand at ambient temperature for 24 hours. The resulting product was washed with 5% sodium carbonate and water, dried and purified by silica chromatography to give 1.1g of 2-(4-chloro-2-methylphenoxymethyl)-4-oxazolidinone as a white crystalline solid melting at 109°-112°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CC(O)C>[ClH:1].[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: Clc1cc(Nc2ccccc2)ncn1
Temperature: 84 °C
Yield: 40 %

Procedure:
250 mg of 4,6-dichloropyrimidine and 120 mg of aniline were dissolved in 2.5 mL of i-PrOH and 0.25 mL of 37% HCl was added. The mixture obtained was refluxed (84° C.) for 2.5 hours under nitrogen atmosphere. A colorless precipitate was formed which was collected by filtration. 6-Chloro-N-phenylpyrimidin-4-amine hydrochloride in the form of colorless crystals was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][CH2:31][O:32][C:25]=3[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][CH2:31][O:32][C:25]=4[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCCO3)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:37]2[CH2:42][CH2:41]CCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:41]1([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:42][CH2:37]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCc2ccc(C3CC3)cc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a yellow suspension of 2 g 7-Bromo-1-tetralone, 1 g boronic acid, 7.1 g potassium phosphate (pulverized) and 0.28 g tricyclohexylphosphine in 40 ml toluene and 2 ml water 0.1 g of palladium acetate is added under a argon atmosphere. The mixture is heated to 100° C. After 1 h, the reaction mixture is allowed to cool to rt and quenched with water. The reaction mixture is extracted with EtOAc. The combined organic phases are washed with brine, dried over sodium sulfate and filtered. The brown oil is purified by flash-chromatography (hexane/EtOAc=6/1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH2:23]([N:30]=[C:31]=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH2:23]([NH:30][C:31]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NCc1ccccc1
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@H]12
Solvent: c1ccncc1
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](OC(=O)NCc5ccccc5)CC[C@H]4[C@@H]3CC[C@@H]12
Reaction time: 18 h

Procedure:
To a solution of 17β-hydroxy-4-methyl-5α-4-azaandrostan-3-one (61 mg) in pyridine (0.60 ml) was added benzyl isocyanate (54 mg, 0.40 mmol). The mixture was stirred at 60°-70° C. under N2 for 18 hr and pumped in vacuo to remove pyridine. The residue was purified using a silica gel plate (2000 m) developed with ethyl acetate (Rf=0.37, run in EtOAc) to give the title compound; m.p. is 216°-217° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].Cl[CH2:10][O:11][CH2:12][CH2:13][CH2:14][Br:15]>CCOCC>[CH2:10]([O:11][CH2:12][CH2:13][CH2:14][Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: ClCOCCCBr
Agent: [Mg]
Solvent: CCOCC
Product: BrCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To the Grignard reagent prepared from bromobenzene (46.3 g., 0.294 mole) and magnesium (7.15 g., 0.294 mole) in ether (150 ml.) is added, dropwise over one hour at 0°, a solution of 3-chloromethoxy-1-bromopropane (55.0 g., 0.294 mole) in ether (50 ml.). The resulting solution is stirred at 25° for 16 hours, then heated at reflux for 1/4 hour, cooled to 0° and cautiously treated with ice water (200 ml.) with vigorous stirring. After separating the phases, the aqueous layer is extracted with ether (200 ml.). The combined organic extract is washed with water, 5% potassium carbonate, water and saturated brine, dried over sodium sulfate and evaporated in vacuo leaving a pale yellow oil (64.4 g., 96%) which is distilled to provide the title compound as a colorless liquid (92% recovery), b.p. 140°-141°/14 mm.; pmr (CDCl3)δ2.12 (2H,p), 3.51 (2H,t), 3.60 (2H,t), 4.50 (2H,t) and 7.31 (5H,s).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([C:23]4[N:27]=[N:26][N:25](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:24]=4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[C:8]([CH2:47][OH:48])=[C:7]([Cl:49])[N:6]=1.Cl.[OH-].[Na+]>C1COCC1>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:47][OH:48])=[C:7]([Cl:49])[N:6]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Reaction time: 12 h

Procedure:
In the '374 patent process, as in the '500 patent process, the tetrazole ring of 5-phenyltetrazole is protected with a trityl group before orthometallation of the phenyl moiety with n-butyl lithium in preparation for making the boronic acid Suzuki coupling partner. In the Suzuki coupling step, the boronic acid is reacted with 4-bromotoluene. The methyl group attached to one of the phenyl rings of the Suzuki product is then halogenated with N-bromosuccinamide and the benzylic bromine atom of that product is displaced with 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde. Reduction of the aldehyde group with sodium borohydride yields trityl losartan. The tetrazole group of trityl losartan was deprotected with 12% aqueous HCl in THF. After 12 hours, the pH of the reaction mixture was raised to 12.5 with 30% NaOH. The THF was then distilled off while make-up water was added to the mixture. After distillation, the mixture was cooled and the triphenyl methanol byproduct of deprotection, which had precipitated, was removed by filtration. The filtrate and rinsate, with which it was combined, were extracted with toluene. Then, ethyl acetate was added and 36% HCl was added until the pH of the reaction mixture was lowered to 3.8. The mixture was cooled, causing losartan to precipitate from the solution. Losartan was obtained in 83% theoretical yield starting from trityl losartan.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:15]>>[CH3:1][O:2][C:3]1[C:4]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[O:15][C:5]=2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(O)cc(OC)c1
Product: COc1cc(OC)c2cc(-c3ccc([N+](=O)[O-])cc3)oc2c1
Yield: 44 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(4-nitrophenyl)ethanone: Yield 44% following procedure A.2; m.p. 192-193° C.; IR 2943, 2914, 1594, 1504, 1319, 1145, 1104 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 8.26 (d, J=8.8 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.24 (s, 1H), 6.69 (s, 1H), 6.34 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H); 13C-NMR (75 MHz, δ ppm, DMSO-d6) 160.3, 156.7, 153.6, 150.6, 146.1, 135.9, 124.5, 124.3, 112.4, 103.9, 94.9, 88.5, 55.8, 55.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[O:23])=[CH:20][NH:19][C:15]=2[N:16]=[CH:17][N:18]=1>>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]([C:21]1[C:14]2[C:13]([NH:1][C:2]3[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=3)=[N:18][CH:17]=[N:16][C:15]=2[NH:19][CH:20]=1)=[O:23]
Reactant: Cc1ccccc1C(=O)c1c[nH]c2ncnc(Cl)c12
Reactant: CC(=O)Nc1cccc(N)c1
Product: CC(=O)Nc1cccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4C)c23)c1

Procedure:
N-(3-((5-(2-Methylbenzo yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)acetamide was synthesized using N-(3-aminophenyl)acetamide and ((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone according to the general procedure A. An off-white solid was obtained. M.p.>300° C.; 400 MHz 1HNMR (DMSO-d6) δ 11.36 (s, 1H), 10.01 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.57 (s, 1H), 7.49-7.45 (m, 2H), 7.39-7.28 (m, 4H), 2.34 (s, 3H), 2.02 (s, 3H); LCMS [M+H] 386.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=[O:9]>C(O)C.[Pd]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)C=Cc1cccs1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1cccs1
Yield: 77.6 %

Procedure:
To a solution of 3-(2-thienyl)acrylic acid (7 g) in ethanol was added 5% palladium on carbon and the mixture was hydrogenated at 50 psi in a Parr apparatus. The catalyst was filtered off and the solvent was removed by evaporation to yield the title compound (5.5 g) as an oil. Electrospray MS m/z 155 [M−H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CN1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCCN(C)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.16 mmol) in dichloromethane (4.00 mL) was added to a stirred solution of 1-methyl-1,4-diazepane (0.144 mL, 1.16 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.902 mL, 5.22 mmol) in dichloromethane (4.00 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-methyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (274 mg, 94%) as a white solid. This was used directly with no further purification.
Reaction SMILES: O[C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C([O-])(O)=O.[Na+].O>[CH:16]1([C:13]2[CH:12]=[CH:11][C:10]([C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)CC(C)(O)c1ccc(C2CCCCCCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C=C(C)c1ccc(C2CCCCCCC2)cc1
Yield: 81 %

Procedure:
To a solution of ethyl 3-hydroxy-3-(4′-cyclooctylphenyl)-butanoate (2d, 36 g) in benzene (350 ml) was added p-toluenesulfonic acid and refluxed for 2.5 h. The mixture was diluted with saturated NaHCO3 solution (20 ml) and water (50 ml) and benzene layer was separated out. Aqueous layer was extracted with benzene (2×200 ml) combined organic layer was washed with water (2×20 ml), dried over Na2SO4 and concentrated. Crude product was purified by column chromatography to furnish 27.5 g (81.1% yield) of ethyl 3-(4′-cyclooctylphenyl)-but-2-enoate (3d, formula 3, R=cyclooctyl) as oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1>CS(C)=O.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17](=[O:18])[CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:40][CH2:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)[N:7]=3)[CH:10]=2)=[CH:21][C:22]=1[C:27]([F:30])([F:29])[F:28]
Reactant: COc1ccc(CN)cc1
Reactant: O=C(CCc1cccc(Oc2ccnc(Cl)n2)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nccc(Oc3cccc(CCC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)n2)cc1
Temperature: 95 °C

Procedure:
To a solution of 3-{3-[(2-chloropyrimidin-4-yl)oxy]phenyl}-N-[4-chloro-3-(trifluoromethyl)phenyl]propanamide (0.200 g, 0.44 mmol) in DMSO (1 mL) were added 1-(4-methoxyphenyl)methanamine (0.056 mL, 0.44 mmol) and TEA (0.061 mL, 0.44 mmol). The reaction mixture was heated at 95° C. overnight and then cooled to rt, diluted with water and extracted with EtOAc. The combined organic solutions were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give A-224. 1H NMR (400 MHz, d6 DMSO) δ: 10.35 (s, 1H), 8.11-8.15 (m, 1H), 8.05-8.11 (m, 1H), 7.75-7.81 (m, 1H), 7.62 (d, 1H), 7.30-7.39 (m, 1H), 7.09-7.26 (m, 2H), 7.04-7.07 (m, 1H), 6.67-7.00 (m, 4H), 6.05 (d, 1H), 4.25-4.43 (br m, 1H), 3.96-4.10 (br m, 1H), 3.67 (s, 3H), 2.93 (t, 2H), and 2.67 (t, 2H). LCMS, FA: Rt=1.88 min, [MH+ 557.3].