Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:7][N:6]1[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[O:31]=[C:22]1[N:21]([CH2:32][CH2:33][CH3:34])[C:20]2[N:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH:8]4[CH2:7][N:6]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:45])[F:43])[CH:37]=5)[CH:5]([C:3]([OH:4])=[O:2])[CH2:9]4)=[CH:17][CH:16]=3)[NH:26][C:25]=2[C:24](=[O:27])[N:23]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CC(C(=O)OC)N(Cc5cccc(C(F)(F)F)c5)C4)cc3)nc2n(CCC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CC(C(=O)O)N(Cc5cccc(C(F)(F)F)c5)C4)cc3)nc2n(CCC)c1=O
Reaction time: 2 h

Procedure:
A mixture of solution of 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-phenoxymethyl]-1-(3-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid methyl ester (25 mg, 0.039 mmol) in THF (3 ml) and MeOH (1 ml) was added aq. solution of LiOH (3 mg, 0.079 mmol) in H2O (1 ml) at 0° C. and it was stirred for 2 hrs. Reaction mixture was concentrated, residue was diluted with water and acidified with aq. HCl. The aqueous layer was extracted with ethyl acetate and washed with brine. The ethyl acetate layer was concentrated and purified by column chromatography to offer 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-phenoxymethyl]-1-(3-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid as viscous oil (18 mg, 75%).
Reaction SMILES: NC1CCC(C=C)C=1C(OCC)=O.C([O-])=O.[NH4+].C(N)=O.[CH:21]([CH:23]1[C:31]2[C:30](=O)[NH:29][CH:28]=[N:27][C:26]=2[CH2:25][CH2:24]1)=[CH2:22].O=P(Cl)(Cl)Cl.[OH-].[K+].[N:40]1([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>O.CC(O)C.C(Cl)Cl.C(#N)C>[CH:21]([CH:23]1[C:31]2[C:30]([N:43]3[CH2:42][CH2:41][N:40]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45][CH2:44]3)=[N:29][CH:28]=[N:27][C:26]=2[CH2:25][CH2:24]1)=[CH2:22]
Reactant: C=CC1CCc2nc[nH]c(=O)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: C=CC1CCC(N)=C1C(=O)OCC
Agent: O=C[O-]
Agent: [K+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: C=CC1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 140 °C
Yield: 20 %

Procedure:
Ethyl 2-amino-5-vinylcyclopent-1-enecarboxylate (2.132 g, 12.75 mmol) was mixed with ammonium formate (4.02 g, 63.75 mmol) and formamide (5.56 mL, 127.5 mmol) and heated at 140° C. for 16 hours. The mixture was diluted with water (50 mL) and 20% IPA-DCM (100 mL). Solids were filtered off (Celite). The organic layer was separated. The aqueous layer was extracted with 20% IPA-DCM (3×50 mL). The combined organic solutions were washed with brine (20 mL) and dried (Na2SO4). After filtration and concentration, toluene (10 mL) was added to the crude (1.543 g), mixed, and evaporated. The resulting 5-vinyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one was mixed with acetonitrile (30 mL) and POCl3 (2.62 mL, 28.54 mmol) and heated at 80° C. for 20 hours. The mixture was cooled to 0° C. 50% KOH (11.25 mL, 142.7 mmol) was added dropwise. t-Butyl piperazine-1-carboxylate (5.31 g, 28.53 mmol) was added. The mixture was heated at 80° C. for 24 hours. The contents were concentrated. Water was added. The mixture was extracted with DCM (2×) and dried (Na2SO4). The crude material was purified with flash chromatography to give tert-butyl 4-(5-vinyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (855 mg, 20% for 2 steps). 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.47 (s, 1H), 5.95-5.86 (m, 1H), 5.12-5.09 (,. 1H), 4.92-4.87 (m, 1H), 3.98-3.93 (m, 1H), 3.67-3.60 (m, 4H), 3.51-3.39 (m, 4 H), 2.94-2.76 (m, 2H), 2.35-2.27 (m, 1H), 1.90-1.82 (m, 1H), 1.47 (d,1.47 (s, 9H). MS: 331.3 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:25]=2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C(NC1C=C(NCCC2C=CC=CC=2)C=CC=1)(=O)C.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([N:15]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:34])=[O:3])=[CH:8][N:9]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CCc2ccccc2)c2cccc(NC(C)=O)c2)s1
Agent: CC(=O)Nc1cccc(NCCc2ccccc2)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CC(=O)Nc1cccc(N(CCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using (3-acetylamino-phenyl)-phenethylamine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([C:23](=O)C)C)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1.[CH3:26][C:27]1[N:32]=[C:31]([CH:33]=[CH2:34])[CH:30]=[CH:29][CH:28]=1.C([O-])(=O)C.[Na+].[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO.O>[CH3:26][C:27]1[N:32]=[C:31]([CH2:33][CH2:34][N:5]2[CH2:6][CH2:7][CH:8]([NH:11][S:12]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][CH3:23])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH2:9][CH2:10]2)[CH:30]=[CH:29][CH:28]=1
Reactant: C=Cc1cccc(C)n1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)NC2CCNCC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CNc1ccc(S(=O)(=O)NC2CCN(CCc3cccc(C)n3)CC2)cc1
Yield: 69.8 %

Procedure:
The N-(4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide acetate (3.71 g, 10.0 mmol), 6-methyl-2-vinylpyridine (1.43 g, 12.0 mmol) and sodium acetate (0.82 g) were dissolved in a mixture comprising methanol (20 ml) and water (20 ml). The obtained solution was heated under reflux for 5 hours, followed by the addition of sodium hydroxide (3.20 g). The obtained mixture was heated under reflux for additional three hours and acidified with 2N aqueous hydrochloric acid. The pH of the mixture was adjusted to about 8 with an aqueous solution of sodium hydrogencarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated. The obtained oily residue was purified by column chromatography (chloroform:methanol:aqueous ammonia=90:9:1) and recrystallized from ethyl acetate/ether to give the title compound as a white crystal (2.71 g, overall yield of two steps: 70%). m.p. (°C.): 80 to 84
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([O:13][CH2:14][C@@H:15]([NH:17][C:18](=[O:20])[CH3:19])[CH3:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[CH:24]([CH3:26])[CH3:25]>>[CH:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([O:13][CH2:14][C@@H:15]([NH:17][C:18](=[O:20])[CH3:19])[CH3:16])=[CH:9][CH:8]=2)=[CH:21][CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(C)Br
Reactant: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(O)cc2)nc1
Product: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(OC(C)C)cc2)nc1

Procedure:
N—{(S)-2-[6-(4-Hydroxyphenoxy)pyridin-3-yloxy]-1-methylethyl}acetamide (33 mg, 0.1 mmol) and 2-bromopropane (16 mg, 0.13 mmol) were reacted in analogy to example 1a. Yield: 23 mg (62%), M+H+: 345.19.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:8]([CH2:29][CH3:30])[CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([CH2:20][NH2:21])=[C:15]3[S:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:13]([C:14]=23)=[N:12]1)[CH3:7].N1C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:29]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([CH2:20][NH:21][S:2]([CH3:1])(=[O:4])=[O:3])=[C:15]3[S:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:13]([C:14]=23)=[N:12]1)[CH3:30]
Reactant: CCN(CC)CCn1nc2c3c(c(CN)ccc31)Sc1ccccc1-2
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCn1nc2c3c(c(CNS(C)(=O)=O)ccc31)Sc1ccccc1-2
Temperature: 0 °C
Yield: 117.9 %

Procedure:
To a solution of methanesulfonyl chloride (0.172 g, 1.50 mmol) in CH2Cl2 (30 mL) is added the freebase of the compound of example 8 (0.51 g, 1.28 mmol)) and pyridine (0.4 mL) with stirring at 0° C. After the mixture is allowed to warm to ambient temperature over 5h CHCl3 (30 mL) and 2N NaOH (5 mL) is added to the mixture. The organic layers are separated, washed with water, dried over Na2SO4, and concentrated in vacuo to give the crude product. Purification by chromatography with 0.5% Et3N in CH2Cl2 gives 0.650 g of gum. Recrystallization from ether-methanol (90:10) gives the compound (0.460 g, 84%), mp: 120°-125° C. 1H NMR (CDCl3) 0.98 (6H; t), 2.58 (4H; q), 2.84 (3H; s), 2.92 (2H; t), 4.26 (2H; d), 4.38 (2H; t), 4.48 (1H; b), 6.90 (1H; d), 7.08-7.30 (4H; m), 8.06 (1H; m)ppm. MS m/z 431 (MH+). Anal. (C21H26N4O2S2.1/2H2O) C, H, N.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=3[F:35])=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=2[F:35])=[C:20]([C:36]([F:39])([F:37])[F:38])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: Cc1ccc(F)c(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(F)c(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 45-5 (640 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (480 mg) as a white powder.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.[F:11][C:12]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:13]=1[C:14]#[N:15]>O1CCCC1>[F:10][C:5]1[CH:4]=[C:3]([CH:20]([OH:21])[C:17]2[CH:18]=[CH:19][C:12]([F:11])=[C:13]([CH:16]=2)[C:14]#[N:15])[CH:8]=[C:7]([F:9])[CH:6]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: N#Cc1cc(C(O)c2cc(F)cc(F)c2)ccc1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a stirred suspension of magnesium turnings (2.6 g, 109 mmol) in anhydrous tetrahydrofuran under argon (10 mL), a solution of 1-bromo-3,5-difluoro-benzene (21 g, 109 mmol) in dry tetrahydrofuran (90 mL) was slowly added. The reaction mixture was stirred and heated at 90° C. until all magnesium was consumed (1 hour). Thereafter, the reaction was cooled at −10° C. and a solution of 2-fluoro-5-formyl-benzonitrile (13.5 g, 90.6 mmol) in 100 mL of anhydrous tetrahydrofuran was added during 30 min. After 1 hour, the reaction mixture was quenched by adding dropwise 200 mL of 20% ammonium chloride solution. Ethyl acetate was added, the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. Organic layers were collected, washed with brine, dried and evaporated. Crude was triturated with isopropyl ether/hexane 1:1 (100 mL), filtered and washed with the same mixture (50 mL) to afford 16 gr of final product. Purification of the resulting organic phase by chromatography over silica gel (hexane/EtOAc 4:1) afforded 4.5 g of the title compound (total amount 20.5 g, 87% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccc(C)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccc(C)cc1OC)C(F)(F)F

Procedure:
Analogously to Example 7, 4.84 g of 4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoic acid ethyl ester is reacted with 7 ml of trifluoromethyltrimethylsilane and 3 ml of tetrabutylammonium fluoride solution (1 M in THF) in 56 ml THF to form 4.14 g of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid ethyl ester. The product is reduced with 856 mg of lithium aluminum hydride in 170 ml of diethyl ether to 3.58 g of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol. The oxidation of the diol is carried out analogously to Example 7 under Swern conditions with 1.1 ml of oxalyl chloride, 2.1 ml of DMSO and 8.0 ml of triethylamine to 3.01 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[CH2:4][N:5]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]1[CH3:11].C(=O)([O-])[O-].[K+].[K+].O.[NH2:25][C:26]1[N:35]=[C:34]([C:36]([N:38]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39]2)=[O:37])[C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[N:27]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:25][C:26]1[N:35]=[C:34]([C:36]([N:38]2[CH2:39][C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:46]2)=[O:37])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:2]3[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=3[CH2:4][N:5]3[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]3[CH3:11])[CH:32]=2)[N:27]=1
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Reactant: CC1CCC(C)N1Cc1cc(F)c(F)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC1CCC(C)N1Cc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 120 °C

Procedure:
143 mg of 1-(2-bromo-4,5-difluorobenzyl)-2,5-dimethylpyrrolidine, 100 mg of potassium carbonate, 7 μl of water and 17 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 150 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 4 ml of ethanol under argon. The mixture is heated at 120° C. for 30 min; the hot mixture is filtered through kieselguhr, and the filtrate is evaporated. and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:30]=[N:29][NH:28][N:27]=3)=[CH:18][CH:19]=2)[C:11]2[C:10]([C:31]([O:33]C(OC(OC3CCCCC3)=O)C)=[O:32])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.C(OC1NC2C(CC3C=CC(C4C=CC=CC=4C4NN=NN=4)=CC=3)=CC=C(C(O)=O)C=2N=1)C.[C:79](Cl)([C:92]1[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=1)([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>>[CH2:2]([O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:27]([C:79]([C:80]4[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=4)([C:92]4[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=4)[C:86]4[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=4)[N:28]=[N:29][N:30]=3)=[CH:18][CH:19]=2)[C:11]2[C:10]([C:31]([OH:33])=[O:32])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1)[CH3:1]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: CCOc1nc2c(C(=O)O)ccc(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2[nH]1
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
U.S. Pat. No. 5,196,444 discloses Candesartan cilexetil and a process for its preparation by the reaction of 2-ethoxy-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid with trityl chloride in presence of triethyl amine in methylene chloride and purification by column chromatography gives 2-ethoxy-1-[[2′-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid, which upon condensation with cyclohexyl 1-iodoethyl carbonate in presence of potassium carbonate in DMF followed by purification with column chromatography gives a colorless powder which is recrystallized in ethanol yields ‘C’ type crystals of Candesartan cilexitil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:21]/[CH:22]=[O:23])=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccnc2ccccc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-quinolinecarboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[S:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37]C)=[O:36].O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[S:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([OH:37])=[O:36]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)sc5ccccc54)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)sc5ccccc54)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.9 %

Procedure:
To a solution of methyl 3-((4-oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.17 g, 0.3 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.025 g, 0.6 mmol) in water (1 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.06 g, 36%); 1H NMR (DMSO-d6): δ 1.60 (d, 2H, J=14 Hz), 1.85 (t, 2H, J=5.6 Hz), 2.48-2.53 (m, 7H), 2.66-2.75 (m, 4H), 4.04 (t, 2H, J=8.4 Hz), 4.59 (d, 2H, J=8.4 Hz), 6.77 (t, 1H, J=7.6 Hz), 6.85 (d, 2H, J=8.4 Hz), 7.18-7.24 (m, 3H), 7.33 (t, 1H, J=7.2 Hz), 7.45-7.51 (m, 3H), 7.64 (d, 1H, J=7.2 Hz), 7.85 (d, 2H, J=8 Hz); MS for C31H32N4O4S m/z 556.95 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH2:17]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:30](CC)CC)C.CS(Cl)(=O)=O.C1OCCOCCOCCOCCOC1.[C-]#N.[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:16][CH2:17][C:28]#[N:30])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)OC(C)(C)C)C(CCO)c1ccc(OCc2ccccc2)cc1
Reactant: CCN(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C(CCC#N)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
t-Butyl N-[1-(4-benzyloxyphenyl)-3-hydroxypropyl]-N-methylcarbamate (1.50 g, 4.0 mmol) obtained from Example 115b was dissolved in tetrahydrofuran (20 ml) under an atmosphere of nitrogen. To the solution was added triethylamine (0.84 ml, 6.0 mmol) and then methanesulfonyl chloride (0.37 ml, 4.8 mmol), in an ice bath. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (20 ml) and to the solution was added 15-crown-5 (1.2 ml, 6.0 mmol) and then sodium cyanide (294 mg, 6.0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane ethyl acetate=80:20 to 70:30 as the eluent to afford the desired compound (1.41 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:19][CH2:20][CH3:21])[C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[CH:22]1(B(O)O)[CH2:24][CH2:23]1.N1C=CC=CC=1>C1COCC1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:22]1([N:16]2[CH:15]=[C:14]([C:13]3[C:12]([O:19][CH2:20][CH3:21])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=3[O:3][CH2:1][CH3:2])[CH:18]=[N:17]2)[CH2:24][CH2:23]1
Reactant: OB(O)C1CC1
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cnn(C2CC2)c1
Temperature: 25 °C

Procedure:
To a mixture of methyl 3,5-diethoxy-4-(1H-pyrazol-4-yl)benzoate (20 mg), cyclopropylboronic acid (24 mg) in THF (2 ml) were added Cu(OAc)2 (37 mg), pyridine (45 ul) and TEA (48 ul) at room temperature and irradiated with microwave at 120° C. for 15 min. After cooling to room temperature, the mixture was diluted with EtOAc, filtered through celite pad and the filtrate was evaporated under reduced pressure. The residue was purified by p-TLC (hexane/EtOAc) to give the title product as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:18]([C:19]([O:21]C)=[O:20])[C:13]=2[N:12]=[C:11]1[CH3:29].[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:13]=2[N:12]=[C:11]1[CH3:29]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate (65 mg, 0.15 mmol) and LiOH (19 mg, 0.5 mmol) in THF (5 mL) and water (5 mL), was stirred overnight at rt. Then the pH of the reaction mixture was neutralized with 1N aq. HCl. Then the mixture was stirred at rt for 1 h, filtered to give the product (47 mg, 74%, with about 10% monochloride as the impurity) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.53 (s, 3H), 3.12 (t, 4H, J=4.5 Hz), 3.73 (t, 4H, J=4.5 Hz), 5.66 (s, 2H), 6.42 (d, 1H, J=7.8 Hz), 7.26 (t, 1H, J=7.8 Hz), 7.42 (s, 1H), 7.48 (s, 1H), 7.62 (d, 1H, J=7.8 Hz); LC-MS: m/e=420 [M+1]+