Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28]O)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:28][CH:27]([C:24]2[CH:25]=[N:26][C:21]([Cl:20])=[CH:22][CH:23]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(O)cc1
Reactant: CCCCCCC(CO)c1ccc(Cl)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCC(COc1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
A solution of 3-(4-hydroxy-benzoylamino)-propionic acid tert-butyl ester (1.17 g, 4.4 mmol) and 2-(6-Chloro-pyridin-3-yl)-octan-1-ol (0.852 g, 3.55 mmol) in toluene (10.0 mL) is degassed and filled with nitrogen for 3 times. Tributylphosphine (1.34 mL, 5.32 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (1.34 g, 5.32 mmol). The reaction mixture is allowed to warm to room temperature and stirred over night, the mixture is loaded on silica gel column. Chromatography gives the title compound (180 mg).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][CH2:23][C:24]1[N:25]=[C:26]([CH2:29]O)[S:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>O.C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:29][C:26]5[S:27][CH:28]=[C:24]([CH2:23][F:22])[N:25]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1nc(CF)cs1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(CF)cs4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.7 %

Procedure:
To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (4-(fluoromethyl)thiazol-2-yl)methanol (105 mg), triphenylphosphine (280 mg) and THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (250 mg), and the mixture was stirred at room temperature for 2 h, then at 70° C. for 2 h. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/MeOH) to give the title compound (4.0 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:16][CH3:17])=[CH:6][C:7]2[CH2:12][O:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]=2[CH:15]=1)[CH:2]=[CH2:3].CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:39]C)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+].[Cl-].[Na+].C(O)(C)(C)C.[OH2:89]>>[OH:89][CH:2]([CH2:3][OH:39])[CH2:1][C:4]1[C:5]([O:16][CH3:17])=[CH:6][C:7]2[CH2:12][O:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]=2[CH:15]=1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Reactant: C=CCc1cc2c(cc1OC)COC(=O)N2C
Agent: O=S([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1cc2c(cc1CC(O)CO)N(C)C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
160 mg of 7-allyl-6-methoxy-1-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-one was dissolved in 20 ml of t-butanol-water (1:1). Thereafter, 0.96 g of AD-mix-β was added to the reaction solution, and the obtained mixture was then stirred at room temperature overnight. Thereafter, 1.03 g of sodium sulfite was added to the reaction solution while cooling on ice, and the obtained mixture was stirred at room temperature for 1 hour. A saturated sodium chloride aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 280 mg of 7-(2,3-dihydroxypropyl)-6-methoxy-1-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-one. This compound was used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:5]([F:20])=[CH:4][C:3]=1[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23].C(N(CC)CC)C.Cl[C:35]1[N:40]=[CH:39][C:38]([CH2:41][O:42][CH3:43])=[CH:37][N:36]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:35]3[N:40]=[CH:39][C:38]([CH2:41][O:42][CH3:43])=[CH:37][N:36]=3)[CH2:18][CH2:19]2)[C:5]([F:20])=[CH:4][C:3]=1[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23]
Reactant: COCc1cnc(Cl)nc1
Reactant: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N(C)C)cc3F)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2,5-difluoro-4-{2-[(1S,2R)-2-piperidin-4-ylcyclopropyl]ethoxy}phenyl-)-N,N-dimethylacetamide (40.0 mg, 0.109 mmol) in 1 ml anhydrous DMF at RT was added triethylamine (0.046 ml, 0.33 mmol) and 2-chloro-5-(methoxymethyl)pyrimidine (20.8 mg, 0.131 mmol). The mixture was stirred at RT for 2 hours. The mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD Sum 19×100 mm column; 35-65% acetonitrile in 0.1% formic acid in water gradient) to afford the title compound. LC/MS (m/z): 489.5 (M+H)+. Human EC50: 1.6 nM
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[C:14]1[NH:15][C:16]([S:20](Cl)(=[O:22])=[O:21])=[C:17]([CH3:19])[N:18]=1.O>O1CCOCC1>[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[C:14]1[NH:15][C:16]([S:20]([NH2:1])(=[O:22])=[O:21])=[C:17]([CH3:19])[N:18]=1
Reactant: Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1S(=O)(=O)Cl
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1S(N)(=O)=O
Reaction time: 3 h

Procedure:
Aqueous ammonia solution (approximately33% w/w, 1.2 ml) was added dropwise with stirring to a solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methyl-imidazole-5-sulphonyl chloride (2.0 g, 0.005 mol) in dioxane (15 ml) and the mixture was stirred for 3 hours. It was poured into water (50 ml) and extracted with diethyl ether (3×25 ml). The combined extracts were washed with water (2×50 ml) dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by mplc on silica eluted with.a mixture of ethyl acetate and petroleum spirit (bp 60°-80° C.) (1:2). Recrystallization from a mixture of ethyl acetate and petroleum spirit (b.p. 60°-80° C.) (1:3) gave 2-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-methylimidazole-5-sulphonamide (0.45 g), m.p. 266°-267° C., as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([Cl:19])=[C:16]([Cl:18])[S:17][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C.C(Cl)Cl.CO>[ClH:18].[Cl:18][C:16]1[S:17][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[Cl:19]
Reactant: Clc1sc2c(c1Cl)CCN(Cc1ccccc1)CC2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CO
Product: Cl
Product: Clc1sc2c(c1Cl)CCNCC2
Temperature: 22 °C
Yield: 54 %

Procedure:
A solution of the product from step g) (727 mg, 2.33 mmol) in anhydrous dichloroethane (11.6 ml) was cooled to 0° C., treated with 1-Chloroethyl chloroformate (1.27 ml, 11.65 mmol) and the reaction was warmed to 22° C. for 1 hour. The reaction diluted with CH2Cl2 (50 ml) and washed with sat. NaHCO3 (25 ml). The sat. NaHCO3 was back extracted with CH2Cl2 and the combined organic layers were washed with brine (25 ml), dried (MgSO4) and concentrated providing an oily residue, which was taken up in anhydrous MeOH (75 ml) and refluxed for 1 hour. The MeOH was evaporated and the crude residue was triturated with ether and filtered providing 323 mg (54%) of the subtitle compound. 1H NMR (300 MHz, DMSO) δ 9.60 (br s, 2H); 3.14-3.28 (m, 6H); 2.97-3.50 (m, 2H); MS: ESI (positive): 222, 224 (M+H).
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][CH2:19]1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+].ClCCl>[CH2:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([O:17][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:19][CH2:20]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOC2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
tert-Butyl 4-(2-iodoethyl)piperidine-1-carboxylate (6.75 g) was mixed with dichloromethane (90 ml), and benzyl 4-hydroxypiperidine-1-carboxylate (4.0 g), silver trifluoromethane sulfonate (10.3 g), and 2,6-di-tert-butylpyridine (12 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-[2-({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)ethyl]piperidine-1-carboxylate (3.4 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][NH:12][CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9].ICC.CCN(C(C)C)[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][N:12]([CH:22]([CH3:24])[CH3:23])[CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Clc1ccc(C23CNCC2C3)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCI
Product: CC(C)N1CC2CC2(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 146.2 %

Procedure:
To a stirred solution of 1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride (10.0 g, 43.8 mmol) in DMF (20 mL) was added 2-iodoethane (9.67 g, 56.9 mmol) and DIPEA (7.35 g, 56.9 mmol). The resulting solution was stirred at ambient temperature for 6 h. After this time, the solvent was removed under vacuum and the residue was dissolved in CH2Cl2 (50 mL). The organic layer was washed with water (2×50 mL), 2N sodium hydroxide (50 mL) and brine (50 mL). The organics were dried (Na2SO4) and concentrated under vacuum. Three reactions were run in parallel and then combined for purification via column chromatography (silica gel, EtOAc) to provide the title compound (17.3 g, 49% yield) as a yellow oil: LC (ELS)/MS: 91%, m/z 271.6 [C14H17Cl2N+H]+; 1H NMR (300 MHz, CDCl3): δ 0.75 (dd, 1H, J=4.2 Hz, J==8.1 Hz), 1.05 (dd, 6H, J=4.7 Hz, J=6.3 Hz), 1.44 (t, 1H, J=4.2 Hz), 1.67 (td, 1H, J=3.9 Hz, J=8.0 Hz), 2.50 (m, 3H), 3.11 (d, 1H, J=8.6 Hz), 3.31 (d, 1H, J=8.4 Hz), 6.96 (dd, 1H, J=2.1 Hz, J=8.3 Hz), 7.22 (d, 1H, J=2.1 Hz), 7.32 (d, 1H, J=8.3 Hz).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:46])([O:28][C:29]([F:45])([F:44])[C:30]([F:43])([F:42])[O:31][C:32]([F:41])([F:40])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:24]([F:27])([F:26])[F:25].BrCCCCBr>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([O:31][C:30]([F:42])([F:43])[C:29]([F:44])([F:45])[O:28][C:23]([F:22])([F:46])[C:24]([F:25])([F:27])[F:26])([F:41])[F:40])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Solvent: BrCCCCBr
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1.995 g, 7.01 mmol) and 4-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromobutane (3.44 g, 7.36 mmol; prepared by combining 1,4-dibromobutane with 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol). The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with 15 volume percent ethyl acetate/hexane, to yield 4.12 g of purified product.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[OH-].[K+]>O1CCCC1.CO>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)/[CH:16]=[C:2]1/[C:1](=[O:11])[C:10]2[C:5]([CH2:4][CH2:3]/1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C1CCCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1/C(=C/c2cccc(Br)c2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 92.4 %

Procedure:
A 250 mL flask was charged with tetralone (5.2 g, 35.6 mmol) and 3-bromobenzaldehyde (8.51 g, 56 mmol). This was dissolved in warm tetrahydrofuran (20 mL), and to this yellow solution was slowly added a 4 wt % solution of KOH in methanol (160 mL). The reaction was stirred for 4 days at room temperature. The mixture was concentrated and reduced to approx 10% vol. The residue was filtered and washed with MTBE (3*50 mL), dried, to afford a light yellow powder (10.3 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)S(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Product: CC(C)S(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
2 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 2-propanethiol to afford 2-chloro-4-(isopropylthio)benzonitrile. 1.6 g of 2-chloro-4-(isopropythio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(isopropylthio)benzoic acid. 1 g of 2-chloro-4-(isopropylthio)benzoic acid was reacted via Procedure R to give 2-chloro-4-(isopropylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(isopropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide. MS (Q1) 449.1 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5](=[C:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:6]#[N:7])[CH3:2].[CH3:14][O:15][C:16]1C=[CH:23][CH:22]=[CH:21][C:17]=1C[Mg]Cl.[Cl-].[NH4+]>O1CCCC1>[C:6]([CH:5]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)[C:4]1[CH:23]=[CH:22][CH:21]=[CH:17][C:16]=1[O:15][CH3:14])#[N:7].[CH2:1]([O:3][C:4](=[O:13])[CH3:5])[CH3:2]
Reactant: COc1ccccc1C[Mg]Cl
Reactant: CCOC(=O)C(C#N)=C1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)=O
Product: COc1ccccc1C(C#N)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 39.9 g cyclopentylidene cyanoacetic acid ethyl ester in 350 ml tetrahydrofuran is added dropwise to a solution of 2-methoxybenzyl magnesium chloride (produced from 5.3 g magnesium and 31.2 g 2-methoxybenzyl chloride in 400 ml ether). The mixture is stirred for 2 hours at room temperature. The mixture is treated with a 300 ml 15% ammonium chloride solution. The product is extracted with ether and the ethereal solution concentrated to yield crude α-cyano-[1-(2-methoxybenzyl)cyclopentane]-acetic acid ethyl ester which distilled at 140°-180°/0.002 mm Hg.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[CH:8][N:7]=[C:6]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[C:5]=12.CN(C=O)C.[Br:28]N1C(=O)CCC1=O>O>[Br:28][C:9]1[N:4]2[N:3]=[N:2][N:1]=[C:5]2[C:6]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[N:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccn3nnnc23)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3nnnc23)CC1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A 3 L round bottom flask was charged with tert-butyl 4-(tetrazolo[1,5-a]pyrazin-8-yl)piperazine-1-carboxylate (500 g, 1.6 mol) and DMF (2 L). To the above was added N-bromosuccinimide (320 g, 1.8 mol) in portions at 10° C. The resulting mixture was stirred at 10° C. for 0.5 h. Work-up: the reaction mixture was poured into water (3 L). The resulting crystalline solid was collected by filtration, washed with water (300 mL), and dried to afford 500 g (79%) of the product as a red solid. MS m/z: 384 (M+H+).
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([C:29]([O:31]CC)=[O:30])[C:8]2[CH2:9][CH2:10][N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)[C:12](=[O:19])[C:13]=2[C:14]=1[O:15]C(=O)C)(=O)C.[OH-].[Li+]>C1COCC1.CO.O>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[C:14]([OH:15])[C:5](=[O:4])[NH:6][C:7]=2[C:29]([OH:31])=[O:30])[C:12]1=[O:19]
Reactant: CCOC(=O)c1nc(OC(C)=O)c(OC(C)=O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 90 °C

Procedure:
A solution of ethyl 3,4-bis(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-5-oxo-5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (1.00 g, 2.09 mmol; Example 12, step 8) and lithium hydroxide (0.70 g, 16.70 mmol) in a mixture of THF-methanol-water (30 mL, 1:1:1 by volume) was heated under reflux in an oil bath at 90° C. overnight. The product mixture was acidified and concentrated under vacuum. The residue was triturated with diethyl ether. The solid precipitated was filtered and washed with ether to provide the titled compound. ES MS M+1=367.
Reaction SMILES: [CH3:1][C:2]1[Te:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[IH:11]>CC(C)=O>[I-:11].[CH3:1][CH:2]1[NH2+:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[Te:3]1
Reactant: Cc1nc2ccccc2[te]1
Reactant: I
Solvent: CC(C)=O
Product: CC1[NH2+]c2ccccc2[Te]1
Product: [I-]
Reaction time: 0.17 h

Procedure:
To a solution of 2-methylbenzotellurazole (Example 18) (0.81 g, 0.0033 mole) in acetone (25 ml), chilled in an ice bath, was added slowly with stirring 55 mole percent hydriodic acid (1 ml). The product began precipitating from solution. After the addition was complete, the mixture was stirred at ice bath temperature for approximately 10 minutes. The solid was isolated by filtration, washed with diethyl ether, and dried under vacuum at room temperature. Yield 1.13 g (92%) of yellow powder, m.p. 209°-211° C. The C, H, and N elemental analyses and the infrared, nuclear magnetic resonance, and mass spectra of the sample were in agreement with that expected for the structural formula.
Reaction SMILES: [N:1]1([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([C@H:28]([CH:41]4C[CH2:45][CH2:44][CH2:43][CH2:42]4)[C:29]([O:31]CC4C=CC(OC)=CC=4)=[O:30])[CH2:18]3)[CH2:12][CH2:11]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[N:1]1([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][N:19]([C@H:28]([CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45]4)[C:29]([OH:31])=[O:30])[CH2:18]3)[CH2:12][CH2:11]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4cnc5ccccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)[C@@H](C1CCCC1)N1C[C@H](CN2CCC(n3cnc4ccccc43)CC2)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.5 %

Procedure:
To 26.5 mg of α-(R)-(3-(S)-((4-benzoimidazol-1-yl-piperidin-1-yl)methyl)-4-(S)-phenyl-pyrrolidin-1-yl)- cyclohexaneacetic acid, 4-methoxy-benzyl ester (from Step D) was added 0.2 mL of anisole and 2 mL of TFA. After stirring at room temperature for 1.5 hours, concentrated under pressure. The residue was purified by flash chromatography eluting with 10% CH3OH in CH2Cl2, then 15% CH3OH/1% NH4OH in CH2Cl2 to give 24 mg of the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ1.17-3.73 (m, 28H), 4.35 (m, 1H), 7.27 (m, 3H), 7.46(m, 4H), 7.55(s. 1H). 7.65(d, J=7.4 Hz, 1H), 8.17(d, J=5.0 Hz, 1H). ESI-MS 510 (M+H); HPLC A: 1.67 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([C:26]1[C:36]([NH2:37])=[N:35][C:29]2[N:30]=[C:31](Cl)[N:32]=[CH:33][C:28]=2[CH:27]=1)=[O:25])[CH3:22].CCCCCC.C(OCC)(=O)C>O1CCOCC1>[CH2:21]([O:23][C:24]([C:26]1[C:36]([NH2:37])=[N:35][C:29]2[N:30]=[C:31]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]4)=[CH:19][CH:18]=3)[N:32]=[CH:33][C:28]=2[CH:27]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1cc2cnc(Cl)nc2nc1N
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc2nc1N
Yield: 16 %

Procedure:
A solution of the product of Example 12 and the product of Example 129 in dioxane is heated under reflux for 1.5 hours. The reaction is poured into hexane/ethyl acetate (1:1), and the solid is collected. Flash chromatography using dichloromethane as eluant gave 0.08 g (16%) of the product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14](I)[N:9]3[N:8]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14]([C:25]4[CH:26]=[C:21]([N:19]([CH3:20])[CH3:18])[CH:22]=[CH:23][CH:24]=4)[N:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: Fc1ccc(Oc2nn3c(I)cnc3s2)cc1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1cccc(-c2cnc3sc(Oc4ccc(F)cc4)nn23)c1
Temperature: 140 °C
Yield: 10.2 %

Procedure:
2-(4-Fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.13 g, 0.36 mmol) was suspended in 1,4-dioxane (1.5 mL) at room temperature and argon was bubbled into the mixture while tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.036 mmol), 3-(N,N-dimethylamino)phenylboronic acid (68 mg, 0.41 mmol), cesium carbonate (235 mg, 0.72 mmol, 2.0 eq), and water (1.5 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140° C. for 1 hour. On cooling, the mixture was diluted with dichloromethane (7 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 2:8). The obtained residue was crystallized from methanol:1,2-dichloroethane (1:1, 1.5 mL) and filtered to give {3-[2-(4-fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-phenyl}-dimethyl-amine as a white solid (13 mg, 10% yield).