Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32][C:33]([O:42][CH2:43][C@@H:44]1[CH2:46][O:45]1)([CH3:41])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][C:33]([O:42][CH2:43][C@@H:44]1[CH2:46][O:45]1)([CH3:32])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[N:36]1
Reactant: CC(C)(Cn1ccc(N)n1)OC[C@@H]1CO1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.12 g, 0.28 mmol), 1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3ylamine (52.4 mg, 0.248 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 0.212 g, 0.56 mmol) and iPr2NEt (0.25 mL, 1.4 mmol) in CH2Cl2 (3 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by column chromatography (4 g column, 1-100% ethyl acetate/heptane) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((5)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (58 mg, 35.4%) as an off-white solid. HRMS (ES+) m/z Calcd for C33H37Cl2F2N5O3+H [(M+H)+]: 660.2315. found: 660.2316.
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([O:6][NH2:7])[CH3:5].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:23]=[CH:22][C:18]3[S:19][CH:20]=[CH:21][C:17]=3[CH:16]=2)[CH2:12][C:11](=[O:24])[C:10]=1[C:25](=O)[CH2:26][CH3:27]>O.C(O)C.CN(C)C=O>[CH2:4]([O:6][N:7]=[C:25]([C:10]1[C:11](=[O:24])[CH2:12][CH:13]([C:15]2[C:23]3[CH:22]=[CH:18][S:19][C:20]=3[CH:21]=[CH:17][CH:16]=2)[CH2:14][C:9]=1[OH:8])[CH2:26][CH3:27])[CH3:5]
Reactant: CCC(=O)C1=C(O)CC(c2ccc3sccc3c2)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCON=C(CC)C1=C(O)CC(c2cccc3sccc23)CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of sodium hydroxide (0.15 g) in water (2 ml) and then ethoxyamine hydrochloride (0.37 g) were added to a solution of 3-hydroxy-5-(benzo[b]thien-5-yl)-2-propionylcyclohex-2-en-1-one (1.05 g) in ethanol/dimethylformamide (5:2 v/v; (70 ml). The mixture was stirred at room temperature for 12 hr, and was subsequently poured into water. the dried (MgSO4) diethyl ether extract was evaporated to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(benzo[b]thien-4-yl)cyclohex-2-en-1-one as a white solid, mp 76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][CH3:18])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:48])([F:47])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[C:43]([CH2:45][NH2:46])[CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:17][CH3:18])[C:12](=[CH2:16])[C:13]([NH:46][CH2:45][C:43]2[CH:42]=[CH:41][N:40]=[C:39]([C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]([F:48])([F:30])[F:47])=[CH:38][CH:37]=3)[CH:44]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
Acid 4D (221.45 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (1.1 equiv., 295 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in EtOAc (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:petroleum ether) afforded 100 mg of a white solid. Yield=18.5% 1HNMR (DMSO, 400 MHz) δ 1.08 (3H, t), 3.40 (2H, q), 4.42 (2H, d), 5.20 (1H, s), 6.08 (1H, s), 7.23 (1H, d), 7.45 (2H, d), 7.72 (4H, dd), 7.85 (1H, s), 8.20 (2H, d), 8.60 (1H, d), 8.74 (1H, bt) [M+1] 540.1 (C24H21ClF3N3O4S requires 539.95).
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25](O)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25]([NH:37][CH2:31][C:32]4[O:36][CH:35]=[CH:34][CH:33]=4)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCc1ccco1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)NCc2ccco2)c1
Yield: 10.5 %

Procedure:
To solution of 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-nicotinic acid (40 mg, 0.098 mmol), furfuryl amine (19.11 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.4 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-furan-2-ylmethyl-nicotinamide as a colorless solid (5 mg, 25.3% yield).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:18])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:17])[C:8]([CH3:16])=[C:9]([OH:15])[C:10]=2[CH3:14])[O:5]1>CCCCCC>[Br:1][CH2:14][C:10]1[C:9]([OH:15])=[C:8]([CH3:16])[C:7]([CH3:17])=[C:6]2[C:11]=1[CH2:12][CH2:13][C:4]([CH3:18])([CH3:3])[O:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C)O2
Reactant: BrBr
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(CBr)c1O)CCC(C)(C)O2
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of Br2 (0.540 mL, 10.5 mmol) in hexane (70 mL) was quickly added to the round bottom flask equipped with a CaCl2 drying tube and containing a stirred solution of 2,2,5,7,8-pentamethyl-6-chromanol (2.20 g, 10.0 mmol) in hexane (340 mL). After stirring the reaction mixture for 2 h the solvents were evaporated yielding of 5-bromomethyl-2,2,7,8-tetramethyl-chroman-6-ol as a pale yellow solid (3.0 g), which was immediately used in the next step without further purification. 1H-NMR (300 MHz, CDCl3) δ (ppm): 4.68 (s, 2H), 2.81 (t, J=7, 2H), 2.17 (s, 3H), 2.14 (s, 3H), 1.84 (t, J=7, 2H), 1.32 (s, 6H). MS (ESI-Pos) m/z 219.2 (M-Br+).
Reaction SMILES: [CH2:1]([B-:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Li+].[Br-].[CH3:26][S+:27]([CH3:38])([CH2:29]C(C1C=CC=CC=1)=O)=[O:28]>O.CO>[CH3:26][S+:27]([CH3:38])([CH2:29][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:28].[CH2:1]([B-:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[S+](C)(=O)CC(=O)c1ccccc1
Agent: CCCC[B-](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: C[S+](C)(=O)Cc1ccccc1

Procedure:
An aqueous solution of 8.90 g of lithium butyltriphenylborate in 100 ml of water was added to a solution of 7.24 g of dimethylphenacyloxosulfonium bromide in 100 ml of methanol, and the resultant mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was filtered, and the resultant crystal was washed with water and dried to give 10.61 g of dimethylbenzyloxosulfonium-butyltriphenylborate as a white crystal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:14]2[N:13]=[CH:12][N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[C:9](=[O:22])[NH:8][C:7]1=[O:23])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)C=O>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:14]2[N:13]=[CH:12][N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[C:9](=[O:22])[N:8]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:7]1=[O:23])[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(CCc2ccccc2)c(=O)c2c1ncn2Cc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of (7-benzyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl)acetic acid ethyl ester (300 mg), anhydrous potassium carbonate (250 mg), 2-bromoethylbenzene (0.25 ml), and N,N-dimethylformamide (5 ml) was stirred with heating in an oil bath of 50° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 10–20% (20% 2-propanol/ethyl acetate)/hexane to give 366 mg of the title compound.
Reaction SMILES: C([Li])CCC.CCOCC.Br[C:12]1[C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=2[S:15][CH:16]=1.Cl([F:26])(=O)(=O)=O>O>[F:26][C:12]1[C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=2[S:15][CH:16]=1
Reactant: Cc1cccc2c(Br)csc12
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Cc1cccc2c(F)csc12

Procedure:
50 ml of a 1.6M solution of butyllithium in abs. ether are added dropwise at -78° to a solution of 18.1 g of 3-bromo-7-methylbenzo[b]thiophene in abs. ether. After 20 Minutes 9 g of perchlorylfluoride are introduced under inert gas and with stirring whereby the reaction temperature is maintained below -60°. The resulting mixture is stirred for 30 minutes at -78° and then slowly warmed to 0°, mixed with water and the organic phase separated, washed, dried and concentrated under vacuum. The residue is chromatographed over silica gel (eluant: hexane) to obtain the title compound as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>CN(C)C=O>[CH2:25]([NH:28][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1)[CH2:26][CH3:27]
Reactant: CCCN
Reactant: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)no1
Yield: 73.4 %

Procedure:
1.4 g (4 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature for 1 hour with 5.2 g (90 mmol) of propylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.07 g (73%) of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a]-[1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=5)=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:13][N:12]=3)[NH:7][C:6]=2[C:33]=1[F:34].FC1C=CC2N=C(NC3C=CC(OC4C(C5C=CN=C(S(C)(=O)=O)N=5)=CC=CN=4)=CN=3)[NH:41][C:40]=2C=1F.C1COCC1>CN.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26]([NH:41][CH3:40])[N:25]=5)=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:13][N:12]=3)[NH:7][C:6]=2[C:33]=1[F:34]
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nc4ccc(F)c(F)c4[nH]3)nc2)n1
Reactant: CS(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nc4ccc(F)c(F)c4[nH]3)nc2)n1
Agent: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nc4ccc(F)c(F)c4[nH]3)nc2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The mixture of 6,7-difluoro-N-(5-(3-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amine and 6,7-difluoro-N-(5-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amine (0.140 g, 0.28 mmol) in methylamine, 2.0 M solution in THF (2.1 ml, 4.2 mmol) was heated in a sealed tube to 70° C. After 4 h, the reaction was partitioned between EtOAc and 1 N NaOH, and the aqueous suspension was extracted 1×EtOAc, 3× dichloromethane, and the suspension was then filtered and rinsed with methanol. The solid material was combined with the combined organic layers adsorbed onto 2 g silica gel and purified with silica gel chromatography, eluting with 0-75% MC-90/10 MC/MeOH to give a white solid. The solid was sonicated in methanol and filtered, rinsing with Et2O. The resulting material was dried in vacuo to give 6,7-difluoro-N-(5-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amine as a white solid. MS m/z=447 [M+H]+. Calc'd for C22H16F2N8O: 446.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=3)[CH:20]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:32][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)[N:26]=3)[CH:20]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)C1
Reactant: NCCc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)S(C)(=O)=O)C1

Procedure:
Intermediate 36 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 468. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 2H), 8.0 (d, 1H) 7.6 (d, 1H) 7.5 (t, 1H), 7.2 (d, 1H), 7.1 (d, 2H), 6.7 (d, 2H), δ 4.6 (s, 2H), 3.5-3.4 (m, 6H), δ 3.2-3.1 (m, 1H), 3.0 (s, 3H), δ 2.9 (t, 2H), δ 2.2-2.0 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:31])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:33][NH:34][CH3:35]>CS(C)=O>[CH3:33][N:34]([CH3:35])[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:31])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Reactant: CNC
Solvent: CS(C)=O
Product: CN(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
Through a solution of 18 g (0.041 mole) of 4'-fluoro-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone in 150 ml of dimethylsulfoxide (DMSO) was vigorously bubbled dimethylamine for 6 hours at 100°C. Most of the DMSO was removed at reduced pressure and a temperature of 120°C. The remaining mixture was poured into water and sodium carbonate to which was added a small amount of methanol. The resulting solid was filtered and dissolved in warm methanol and isopropyl alcohol, treated with charcoal filtered, and cooled. The solid which formed upon cooling was filtered off and recrystallized from acetone-heptane to give the desired product, M.P. 148°-150°C.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>C1COCC1>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([O:7][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:8][C:9]=1[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1cc(C(C)(C)C)c(OCOCCOC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in a manner similar to that of Example 1, by dissolving 2,5-Di-tert-butylhydroquinone (0.2 mmol) in anhydrous THF (20 ml). Sodium hydride (0.6 mmol) and 2-methoxyethoxymethyl chloride (0.4 mmol) was added to the solution. The reaction was stirred at room temperature overnight. After removal the solvent, the residue was partitioned between dichloromethane and aqueous NaHCO3 (0.1M). The organic portion was separated and dried over Na2SO4. After solvent removal in vacuo, the crude product was chromatographed (silica, hexanes/DCM from 5:1 to 1:1) to afford 1,4-bis[(2-methoxyethoxy)methoxy]-2,5-di-tert-butyl-benzene in an 80% yield. The product was characterized by 1H NMR (300 MHz, CDCl3, δ/ppm): 7.14 (s, 2H), 5.25 (s, 4H), 3.85 (t, J=4.5 Hz, 4H), 3.61 (t, J=4.5 Hz, 4H), 3.40 (s, 6H), 1.36 (s, 18H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1Cl)[CH3:2].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:16][CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22]1)[CH3:2]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CCOCCn1c(Cl)nc2ccccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOCCn1c(NC2CCN(C(=O)OCC)CC2)nc2ccccc21
Temperature: 170 °C
Reaction time: 12 h

Procedure:
Combine 1-(2-ethoxyethyl)-2-chloro-1H-benzimidazole (3.06 g, 13.62 mmol) and ethyl 4-aminopiperidine-1-carboxylate (5.16 g, 30 mmol) and heat to 150° C. After 12 hours, heat to 170° C. After 8 hours, cool the reaction mixture and partition between dichloromethane (150 mL) and water. Separate the layers and extract the organic layer with water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate/hexane 1/1 to give (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonyl-piperidin-4-yl)amine: Rf=0.15 (silica gel, ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][Cl:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]([OH:14])[C:9]([CH3:12])([CH3:13])[CH2:10][Cl:11])=[CH:15][CH:16]=1
Reactant: CC(C)(CCl)C(=O)COc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CCl)C(O)COc1ccc(Cl)cc1
Yield: 87.8 %

Procedure:
Into a 100-ml egg plant type flask were placed 2.6 g of 1-(p-chlorophenoxy)-3,3-dimethyl-4-chloro-2-butanone and 40 ml of methanol, and 0.2 g of sodium borohydride was further placed into the flask with cooling and stirring. After stirring the mixture at room temperature for 1 hour, the reaction mixture was concentrated in a vacuum, and 50 ml of water was added to the resulting residue, followed by extraction with 30 ml of ether twice. The combined ethereal extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The residue obtained was purified by silica gel column chromatography, giving 2.3 g of the above-identified desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].O(C(C)(C)C)[K].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1cc(Br)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccn1
Temperature: 100 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a degassed solution of 4-bromo-2-methyl-pyridine (1.99 g, 11.55 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.78 g, 13.86 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (3.24 g, 28.87 mmol, 2.5 equiv), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.11 g, 0.23 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone) dipalladium(0) (0.96 g, 0.92 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100° C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with a gradient of ethyl acetate/triethylamine (10:0→9:1) to provide 1.75 g (52%) of the title compound in 90% purity according to 1H NMR. 1H NMR (400 MHz, DMSO): δ 1.14-1.29 (m, 2H), 1.40 (s, 9H), 1.84 (d, J=12.8 Hz, 2H), 2.24 (s, 3H), 2.90 (br s, 2H), 3.40-3.53 (m, 1H), 3.86 (d, J=13.0 Hz, 2H), 6.23-6.33 (m, 2H), 6.35 (s, 1H), 7.87 (d, J=5.8 Hz, 1H). MS (ESI): 292.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[N:38]([CH3:40])[CH3:39])[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].C(O[C:45]([CH2:47][CH2:48]C1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C=C(C2C=CSC=2)C=1)C(O)=O)=O)C.N1CCCCC1>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37]([N:38]3[CH2:40][CH2:48][CH2:47][CH2:45][CH2:39]3)=[O:41])[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Reactant: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Solvent: C1CCNCC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCCCC3)cc(-c3ccsc3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(3-dimethylcarbamoyl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-thiophen-3-yl-benzoic acid and piperidine.