Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.CCN(C(C)C)C(C)C.[CH:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH:24]1[N:33]=[C:34]=[O:35])[CH2:30]2.Cl>C(Cl)Cl>[CH:25]12[CH2:31][CH:29]3[CH2:28][CH:27]([CH2:32][CH:23]([CH2:30]3)[CH:24]1[NH:33][C:34]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)=[O:35])[CH2:26]2
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Yield: 19.8 %

Procedure:
A vial was charged with (R)-tert-butyl pyrrolidin-3-ylcarbamate (21 mg, 0.11 mmol) and i-Pr2NEt (0.025 mL, 0.14 mmol). A solution of 2-adamantyl isocyanate (25 mg, 0.14 mmol) in CH2Cl2 (2 mL) was added with stirring. After stirring overnight the mixture was applied to a 10-mL ChemElut cartridge that had been prewetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was applied to a 2-g silica SPE cartridge. The cartridge was eluted sequentially with 0, 10, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each) to afford six fractions. Fractions 4 and 5 were pooled and concentrated to afford (R)-tert-butyl 1-(2-adamantylcarbamoyl)pyrrolidin-3-ylcarbamate (7.9 mg, 15%). LC-MS Method 1, tR=1.83 min, m/z=364; 1H NMR (CDCl3) 1.42 (s, 9H), 1.60-1.95 (15H), 2.17 (m, 1H), 3.21 (m, 1H), 3.46 (m, 2H), 3.61 (m, 1H), 3.96 (m, 1H), 4.22 (1H), 4.53 (d, 1H), 4.72 (1H)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[C:24]#[N:25])=[CH:13][CH:12]=2)[C:8]2[CH:26]=[C:27]([NH:30][C:31]([NH:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])[CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[C:24]3[NH:42][N:41]=[N:40][N:25]=3)=[CH:13][CH:12]=2)[C:8]2[CH:26]=[C:27]([NH:30][C:31]([NH:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])[CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2cc(Cl)ccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCCCc1nc2ccc(NC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2cc(Cl)ccc2-c2nnn[nH]2)cc1

Procedure:
Prepared in analogous manner to Example 59 from 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonylamino)-benzimidazol-1-yl)-methyl]-5-chloro-2-cyano-biphenyl and sodium azide/ammonium chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:33])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@H:13]([CH2:16][O:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11]1.[F:34][C:35]1[CH:36]=[C:37]([C@H:42]([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[CH2:43][C:44](O)=[O:45])[CH:38]=[C:39]([F:41])[CH:40]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[F:53][C:50]1[CH:49]=[CH:48][C:47]([C@@H:42]([C:37]2[CH:38]=[C:39]([F:41])[CH:40]=[C:35]([F:34])[CH:36]=2)[CH2:43][C:44]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([F:33])[C:7]=2[CH2:8][CH2:9][C@H:10]2[O:15][CH2:14][C@H:13]([CH2:16][O:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[O:19])[N:12]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:11]2)=[O:45])=[CH:52][CH:51]=1
Reactant: O=C(O)C[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)C[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2R,5R)-2-(2-(3-amino-5-fluoropyridin-4-yl)ethyl)-5-(2,2,2-trifluoroethylaminocarbonyloxymethyl)morpholine-4-carboxylate (75 mg, 0.16 mmol) and (3S)-3-(3,5-difluorophenyl)-3-(4-fluorophenyl)propanoic acid (44 mg, 0.16 mmol) in pyridine (1.0 mL) was cooled to −10° C. in an ice-acetone bath. To the stirred solution was added POCl3 (0.016 mL, 0.17 mmol) and the mixture was stirred for 30 min. The reaction was quenched by the addition of aqueous NaHCO3 solution and the resulting mixture was extracted with two portions of EtOAc. The combined EtOAc layers were dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-70% EtOAc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give a gum. LC MS: RT=1.41 min, M+H=743 (2 min gradient)
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Ic1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccc1)O2
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 2.3 g (10 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6ol, 3.06 g (15 mmol) of iodobenzene, 0.39 g of triphenylphosphine. 95 mg of cuprous iodide 3 ml of triethylamine and 100 ml of acetonitrile was degassed with argon for 10 minutes. palladium acetate. 110 mg (0.5 mmol), was then added and stirring under argon was continued for 3 hours. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over sodium sulfate and evaporated. The crude product was chromatographed over 100 g of silica gel (Merck 70-230 mesh) using methylene chloride for elution. The clean fractions were combined and evaporated and the residue was crystallized from hexane to yield 2.1 g (68 %) of rac-3,4-dihydro-2,5,7,8-tetramethyl-2-(phenylethynyl)-2H-1-benzopyran-6-ol with m.p. 109-111° C. The analytical sample was recrystallized from hexane and had m.p. 111°-113° C. Anal. Calcd. for C21H22O2 : C, 82.32; H, 7.24 Found ; C, 82.02; H, 7.30
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:17](O)=[O:18].CN(C)CCCN=C=NCC.Cl.[F:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1>CN(C)C1C=CN=CC=1.ClCCl.CN(C=O)C>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:17]([NH:42][C:41]1[CH:43]=[CH:44][C:38]([F:37])=[CH:39][CH:40]=1)=[O:18]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccc(F)cc1F
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
389 mg (1.17 mmol) of 1-(2,4-difluorobenzyl)-5-nitro-1H-indole-2-carboxylic acid from Example XXII, 336 mg (1.76 mmol) of N′-(3-dimethylaminopropyl)-N-ethyl-carbodiimide×HCl and 71.5 mg (0.59 mmol) of 4-dimethylaminopyridine are initially charged in 30 ml of a 10:1 dichloromethane:DMF mixture. 156 mg (0.13 ml, 1.40 mmol) of 4-fluoroaniline are added, and the mixture is stirred at RT for 4 hours. For work-up the mixture is diluted and extracted with aqueous hydrochloric acid and ethyl acetate. The organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]2[N:7]([CH3:15])[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([OH:14])[C:13]=3[C@:5]2([CH3:16])[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.[CH3:28][CH:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH3:28][C@@H:29]([NH:36][C:37](=[O:38])[O:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C@@:5]1([CH3:16])[CH2:4][CH2:3][N:2]([CH3:1])[C@H:6]1[N:7]2[CH3:15])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN1CC[C@@]2(C)c3c(O)cccc3N(C)[C@@H]12
Reactant: CC(N=C=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)Oc1cccc2c1[C@@]1(C)CCN(C)[C@H]1N2C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
cis-(±)-1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo [2,3-b]indol-4-ol (2g) was dissolved in degassed THF (200 ml). DBU (0.8 ml) was added to the mixture followed by R-(+)-α-methylbenzyl isocyanate (2 g). The reaction was stirred at room temperature overnight under nitrogen. The solvent was evaporated under reduced pressure and the residue was purified using Prep 500 chromatography (4% MeOH/DCM) to yield 1.2 g of a solid. This material was combined with 600 mg of identically prepared material, which was found to be pure by thin layer analysis. The combined product was triturated with isopropyl ether and filtered to yield 1.8 g of (±)-(3aR*, 8aS*)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo [2,3-b]indol-4-yl (R)-(α-methylbenzyl)carbamate, m.p. 151°-155° C.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].S(Cl)([Cl:18])=O>>[Cl:18][C:7]([C@H:6]1[C@H:4]([CH:3]=[C:2]([Cl:1])[C:12]([F:15])([F:14])[F:13])[C:5]1([CH3:11])[CH3:10])=[O:8]
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Product: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl

Procedure:
A mixture of (+)-cis/trans-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (0.4 g) and thionyl chloride (5.0 ml) was heated at the reflux temperature for a period of 2 hours, after which the excess thionyl chloride was removed by distillation under reduced pressure, leaving (+)-cis/trans-1-chlorocarbonyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]=[C:12]2[N:14]([C:18]3[CH:23]=[C:22]([O:24][CH2:25][C:26]4[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]([F:34])[C:27]=4[F:35])[C:21]([O:36][CH3:37])=[CH:20][C:19]=3[F:38])[C:15](=[O:17])[NH:16][C:11]2=[CH:10][CH:9]=1)=[O:7])CCC.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[C:6]([C:8]1[N:13]=[C:12]2[N:14]([C:18]3[CH:23]=[C:22]([O:24][CH2:25][C:26]4[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]([F:34])[C:27]=4[F:35])[C:21]([O:36][CH3:37])=[CH:20][C:19]=3[F:38])[C:15](=[O:17])[NH:16][C:11]2=[CH:10][CH:9]=1)([OH:7])=[O:5]
Reactant: CCCCOC(=O)c1ccc2[nH]c(=O)n(-c3cc(OCc4c(OC)ccc(F)c4F)c(OC)cc3F)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(-n2c(=O)[nH]c3ccc(C(=O)O)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
To a mixture of 5-(n-butoxycarbonyl)-3-[2-fluoro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.11 g), tetrahydrofuran (2 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (43 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified by adding 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous sodium chloride solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2−ethyl acetate) to give the title compound (23 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH2:21])=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:7]=CC=CC=1.ClCCC[S:29]([N:32]([CH3:34])[CH3:33])(=[O:31])=[O:30]>>[NH2:21][C:15]1[N:14]2[CH2:22][CH2:23][N:24]=[C:13]2[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][CH2:2][CH2:7][S:29]([N:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[C:18]([O:19][CH3:20])[C:17]=2[N:16]=1
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Reactant: CN(C)S(=O)(=O)CCCCl
Product: COc1c(OCCCS(=O)(=O)N(C)C)ccc2c1N=C(N)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bistrifluoroacetate salt (Intermediate A) and 3-chloro-N,N-dimethylpropane-1-sulfonamide (Intermediate F). High vacuum drying gave the title compound (1.12 g, 86%): HPLC MS RT=1.28 min, MH+=382.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.15-2.20 (2H, m), 2.77 (6H, s), 3.18-3.23 (2H, m), 3.84 (3H, s), 4.18-4.21 (2H, m), 4.29-4.35 (4H, m), 7.30 (1H, d), 7.90 (1H, d).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:20]([NH:23][C:24]2[CH:28]=[CH:27][S:26][C:25]=2[C:29]([O:31]C)=[O:30])(=[O:22])=[O:21])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:20]([NH:23][C:24]2[CH:28]=[CH:27][S:26][C:25]=2[C:29]([OH:31])=[O:30])(=[O:21])=[O:22])=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1-c1ccc(N(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2cc(C(C)(C)C)ccc2S(=O)(=O)Nc2ccsc2C(=O)O)cc1
Temperature: 77.5 °C
Yield: 93.6 %

Procedure:
To a solution of 14 (50.0 mg; 0.11 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added aqueous lithium hydroxide (2 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a brown solid (47.2 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10]C)[CH:5]=[C:4]([O:12]C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[CH:5]=[C:4]([OH:12])[CH:3]=1
Reactant: COc1cc(Cl)c(C=O)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)cc(O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To the solution of 6-chloro-2,4-dimethoxy-benzaldehyde (8 g, 39.9 mmol) in dichloromethane (100 mL) was added boron tribromide (16 mL, 170 mmol) dropwise at −78° C. The reaction mixture was stirred overnight at room temperature and quenched by ice. The resulting mixture was extracted by EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gal (EtOAc/PE=1:5) to give the title compound as a yellow powder (4 g. Yield: 58%). 1H NMR (400 MHz, DMSO-d6) δ12.11 (s, 1H), 11.33 (s, 1H), 10.08 (s, 1H), 6.52-6.53 (d, J=2.0 Hz, 1H), 6.27-6.28 (s, J=2.0 Hz, 1H) MS (ESI) m/z=173 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1)=[O:4].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[F:1][C:2]([F:21])([C:14]([F:19])([F:20])[C:15]([F:18])([F:16])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:24][N:23]=[N:22][N:13]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: N#Cc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(-c2nnn[nH]2)cc1)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A mixture of 2,2,3,3,4,4,4-heptafluoro-N-[4-(cyano)phenyl]butanamide (1.5 g,) sodium azide (1.55 g), ammonium chloride (1.28 g) and dimethylformamide (20 mL) was heated in a 130°-135° C. oil bath overnight. The reaction mixture was then poured onto 200 mL of water and the resulting solid was filtered off and recrystallized from ethanol. The product was dried at 100° C. overnight using an abderhalden (drying pistol) to give the title compound, m.p. 266°-268° C.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][C@@H:15]([CH3:35])[C:16]([NH:18][CH:19]([C:26]2[CH:34]=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)[CH2:20][C:21]([O:23]CC)=[O:22])=[O:17])=[O:12])=[CH:6][CH:5]=1.[OH-].[Li+]>CO.O>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][C@@H:15]([CH3:35])[C:16]([NH:18][CH:19]([C:26]2[CH:34]=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)[CH2:20][C:21]([OH:23])=[O:22])=[O:17])=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(NC(=O)[C@H](C)CNC(=O)Nc1ccc(C=NN)cc1)c1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](CNC(=O)Nc1ccc(C=NN)cc1)C(=O)NC(CC(=O)O)c1ccc2c(c1)OCO2
Yield: 71.8 %

Procedure:
A portion of ethyl β-[[2(R)-[[[[4-(aminoiminomethyl)phenyl]amino]carbonyl]amino]methylpropanoyl]amino]-1,3-benzodioxole-5-propanoate (0.18 g; 0.37 mmoles)) was then treated with 1N lithium hydroxide in methanol/water (1:1; 10 ml) for 15 min. The solvents were evaporated under reduced pressure and the residue was dissolved in water/acetonitrile. The crude product was purified by HPLC (C-18 DeltaPak column) using a gradient of acetonitrile/water/trifluoroacetic acid. Both diastereomers were separated and the desired fractions were lyophilized to give 121 mg of white solid (71% combined yield). FAB-MS: MH+ =456.3 (isomer 1) and 456.2 (isomer 2).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([CH3:15])[C:8](=O)[CH:9]=[CH:10][N:11](C)[CH3:12])=[CH:4][CH:3]=1.[NH2:18][C:19]1N=C[NH:21][N:20]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([C:8]2[N:21]3[N:20]=[CH:19][N:18]=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH3:15])=[CH:4][CH:3]=1
Reactant: Nc1nc[nH]n1
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)C=CN(C)C
Solvent: CC(=O)O
Product: CC(Oc1ccc(Cl)cc1)c1ccnc2ncnn12
Temperature: 25 °C

Procedure:
A solution of 4-(4-chlorophenoxy)-1-(dimethylamino)-1-penten-3-one (9.80 g) in glacial acetic acid (50 ml) was added to a stirred solution of 3-amino-1,2,4-triazole (3.25 g) in glacial acetic acid (50 ml). The mixture was heated under reflux for 5 hours and then cooled to room temperature. The mixture was then poured into 300 ml of ice-water and extracted with toluene. The toluene extracts were washed with a 10% aqueous solution of sodium hydrogen carbonate, followed by water, then dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The residue was triturated with cold diethyl ether and the solid was collected by filtration and recrystallised from a mixture of ethyl acetate and petroleum ether (b.p. 40°-60° C.), to give 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 6.91 g, (mp 111°-112° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:19]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1>>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[C:19]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=3[S:21][CH:22]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: Fc1ccc2scc(CBr)c2c1
Product: O=C(O)c1cc2cc(Cl)ccc2n1Cc1csc2ccc(F)cc12

Procedure:
Using general procedure B, 5-chloro-1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) and the product obtained was hydrolyzed to give the title compound as white solid. MS: 358.1 ([M−H]−).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[C:10]([C:11]([NH:13]/[C:14](=[C:20](\[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[C:30]3[C:35]([Cl:36])=[CH:34][N:33]=[CH:32][C:31]=3[Cl:37])=[CH:24][CH:23]=2)/[CH3:21])/[C:15]([O:17]CC)=[O:16])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.CO>O1CCOCC1.O>[Cl:4][C:5]1[C:10]([C:11]([NH:13]/[C:14](=[C:20](\[C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:38])[C:30]3[C:31]([Cl:37])=[CH:32][N:33]=[CH:34][C:35]=3[Cl:36])=[CH:26][CH:27]=2)/[CH3:21])/[C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CCOC(=O)/C(NC(=O)c1cccnc1Cl)=C(\C)c1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: C/C(=C(/NC(=O)c1cccnc1Cl)C(=O)O)c1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1
Yield: 35.4 %

Procedure:
Lithium hydroxide monohydrate (4.4 mg, 1.05 mml) was added to the compound of Example 16 (280 mg, 0.525 mmol) in a mixture of dioxane (10 ml) and water (10 ml). The mixture was heated at reflux for 2 h. The dioxane was removed in vacuo, the aqueous residue acidified with dilute HCl, the precipitate formed filtered off, washed with water and dried to give a brown solid. Trituration with hot methanol gave the title compound as a pale brown solid (94 mg). δH (DMSO-d6), 12.75 (1H,v br s,CO2H), 10.99 (1H, s, CONH), 9.75 (1H, s, CONH), 8.79 (2H, s, PyH), 8.44 (1H, dd, 14.8, 1.9 Hz, PyH), 7.68-7.64 (3H, m, ArH+PyH), 7.46 (1H, dd, J 7.5, 4.8 Hz, PyH), 7.38 (2H, d, J 8.6 Hz, ArH) and 2.33 (3H, s, Me); m/z (ESI, 70V) 505 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=1.Cl>[Pd].CO>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Fc1c(C2=CCNCC2)cccc1C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1c(C2CCNCC2)cccc1C(F)(F)F

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (4.2 g, 17.1 mmol), methanol (20 ml), palladium on carbon (0.42 g) and hydrochloric acid (0.2 ml, conc). Yield: 1.8 g. MS m/z (relative intensity, 70 eV) 247 (M+, 22), 190 (8), 177 (5), 169 (7) 56 (bp).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[NH:6])(=[O:3])[CH3:2].Cl[CH2:9][C:10](=O)[CH3:11]>C(#N)C>[CH3:11][C:10]1[N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[NH:7][CH:9]=1
Reactant: CC(=O)CCl
Reactant: CC(=O)NC(=N)N
Solvent: CC#N
Product: CC(=O)Nc1nc(C)c[nH]1

Procedure:
N-Acetylguanidine (1.516 g, 15 mmol, 3 equivalents, commercially available Aldrich) was added to 1-chloropropan-2-one (0.462 g, 5 mmol, 1 equiv) in acetonitrile (30 ml). The reaction mixture was heated to reflux for 12 hours under argon. Upon cooling, the reaction mixture was evaporated to dryness and the isolated residue was washed with water, filtered and air-dried to give 0.324 g N-(4-methyl-1H-imidazol-2-yl)acetamide. 1H-NMR (400 MHz, DMSO-d6): δ 13.3 (bs, 1H), 10.29 (bs, 1H), 6.80 (s, 1H), 2.27 (s, 3H), 2.02 (s, 3).
Reaction SMILES: C([N:20]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][C:34]([CH2:37][N:38]3[C:42](=[O:43])[N:41]([CH2:44][C:45]4[CH:50]=[CH:49][C:48]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=5[C:57]5[N:61](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:60]=[N:59][N:58]=5)=[CH:47][CH:46]=4)[C:40]([CH2:81][CH2:82][CH2:83][CH3:84])=[N:39]3)=[CH:33][CH:32]=2)=[N:23][N:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)(=O)C>[NH:23]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][C:34]([CH2:37][N:38]3[C:42](=[O:43])[N:41]([CH2:44][C:45]4[CH:50]=[CH:49][C:48]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=5[C:57]5[NH:58][N:59]=[N:60][N:61]=5)=[CH:47][CH:46]=4)[C:40]([CH2:81][CH2:82][CH2:83][CH3:84])=[N:39]3)=[CH:33][CH:32]=2)=[N:20][N:21]=[N:22]1
Reactant: CCCCc1nn(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 91 %

Procedure:
Deprotection of 2,4-bis[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one in 50% aqueous acetic acid was accomplished by the procedure of Example 3, Step B. After work-up, the residue was flash chromatographed over silica gel (15 mL for 0.091 mmole, gradient elution using 2-30% MeOH/CH2Cl2) to give the desired material as a solid in 91% yield, homogeneous by TLC in 10% MeOH/CH2Cl2, mass spectrum (FAB) m/e 610 (M+1)+, mp 150°-151° C.