Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CC(=O)C2C3C(C(OC)=O)=CC=CC=3NC=2C1.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[N:30]1[C:42]2[CH2:41][CH2:40][CH2:39][C:38]3=[N:43][NH:44][C:45](=[O:46])[C:35]4[C:36]([C:37]=23)=[C:31]1[CH:32]=[CH:33][CH:34]=4>>[CH2:21]([N:30]1[C:42]2[CH2:41][CH2:40][CH2:39][C:38]3=[N:43][NH:44][C:45](=[O:46])[C:35]4[C:36]([C:37]=23)=[C:31]1[CH:32]=[CH:33][CH:34]=4)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: Cn1c2c3c4c(cccc41)C(=O)NN=C3CCC2
Agent: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)(C)C3
Product: O=C1NN=C2CCCc3c2c2c1cccc2n3Cc1ccccc1

Procedure:
Compound 24 was prepared from methyl 2,2-dimethyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate and benzyl chloride according to the procedures for Compound 22 under appropriate conditions recognized by one of ordinary skill in the art. 1H NMR (DMSO-d6) δ 9.96 (s, 1H), 7.56 (d, 1H, J=8.4 Hz), 7.47 (d, 1H, J=7.8 Hz), 7.11-7.33 (m, 6H), 5.45 (s, 2H), 2.82-2.84 (m, 2H), 2.41-2.43 (m, 2H), and 1.97-2.00 (m, 2H). MS (ESI) m/e [M+1]+ 316.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22](Cl)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:25][C@H:26]1[CH2:30][NH:29][C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12>O.O1CCOCC1>[Cl:25][C@H:26]1[CH2:30][N:29]([C:22]([O:21][CH2:20][CH:18]2[C:19]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:16]3[C:17]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:23])[C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12
Reactant: O[C@H]1CO[C@H]2[C@@H]1NC[C@@H]2Cl
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1C[C@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of sodium carbonate (0.49 g, 4.63 mmol) in water (7.5 mL) followed by a solution of 9-fluorenylmethoxycarbonyl chloride (0.55 g, 2.13 mmol) in 1,4-dioxane (2.5 mL) was added dropwise over 15 minutes whilst stirring to a solution of aminoalcohol (69) in 1,4-dioxane (5 mL). The mixture was stirred for 60 minutes then water (50 mL) was added and the product extracted into dichloromethane (3×25 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a colourless oil. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 10:90 to 45:55 gave alcohol (70) (623 mg, 87%) as a white solid. TLC (Rf=0.45, EtOAc:heptane 1:1), analytical HPLC single main peak, Rt=16.54 min., HPLC-MS 386.1/388.1 [M+H]+, 408.1/410.1 [M+Na]+; [α]D27.5−51.9° (c=2.31, CHCl3); (proton complex) δC (125 MHz, CDCl3) 47.21/47.41 (Fmoc CH), 53.30/53.43 (FmocNCH2), 57.74/58.36 (CHCl), 66.04/67.42 (Fmoc CH2), 67.87/68.52 (FmocNCH), 74.81/75.09 (OCH2CHOH), 74.92/75.51 (OCH 2CHOH), 86.57/87.24 (CHCHCl), 119.80/119.82/120.00/120.64/124.55/124.63/124.90/127.04/127.08/127.40/127.51/127.78/127.80/127.87 and 127.91 (aromatic CH), 141.21/141.29/141.38/143.44/143.70/143.88 and 143.91 (aromatic quaternary), 154.13/154.79 (Fmoc C═O).
Reaction SMILES: Br.[C:2]1([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19]Br)[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C(O)C>[C:2]1([C:8]2[N:12]=[C:11]3[C:13]4[C:14]([CH2:19][N:10]3[N:9]=2)=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1-c1nc(-c2ccccc2)n[nH]1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2nc3n(n2)Cc2ccccc2-3)cc1
Yield: 76.8 %

Procedure:
3-Phenyl-5-(o-bromomethylphenyl)-s-triazole hydrobromide (41 g) is added to a solution of 6.55 g of 80% sodium hydride in 525 ml of ethanol at about 20° C. The obtained mixture is refluxed for about two hours, then the solvent is distilled off. The crude residue is extracted with 620 ml of benzene and the organic phase is evaporated, yielding 18.6 g of 2-phenyl-5H-s-triazolo[5,1-a]isoindole, which is purified by crystallization from ethanol. M.p. 156°-8° C. The starting compound 3-phenyl-5-(o-bromomethylphenyl)-s-triazole hydrobromide is obtained by evaporation of a solution of 3-phenyl-5-(o-hydroxymethylphenyl)-s-triazole in acetic acid saturated with hydrogen bromide. M.p. 193°-5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:25][C:26]([F:37])([F:36])[C:27]1[N:31]2[CH2:32][CH2:33][NH:34][CH2:35][C:30]2=[N:29][N:28]=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([N:34]1[CH2:33][CH2:32][N:31]2[C:27]([C:26]([F:37])([F:25])[F:36])=[N:28][N:29]=[C:30]2[CH2:35]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F

Procedure:
(3R)-3-[N-(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (07) was coupled with 3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (11) to obtain Boc-protected sitagliptin free base, 7-[(3R)-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (12). The coupling was preferably carried out by using coupling agents such as EDC-HCl, 1-hydroxybenzotriazole and a suitable base such as N,N-diisopropylethylamine. The coupling was preferably carried out in an aprotic solvent such as N,N-dimethylformamide or N,N-dimethylacetamide at 0-30° C. for 1-12 hours, preferably at 25-30° C. for 8-10 hours. The Boc-protected sitagliptin free base (12) was preferably isolated by an aqueous work up procedure, preferably involving removal of N,N-dimethylformamide at 50-55° C. under reduced pressure followed by basification preferably using sodium carbonate, and extraction of the product into an organic solvent such as ethyl acetate. The Boc-protected sitagliptin free base (12) was preferably isolated by removal of the organic solvent under reduced pressure to obtain a white solid, which was preferably triturated with a non-polar solvent such as hexane.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]12[CH2:14][CH2:13][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH2:11][CH2:12]1)[CH2:9][CH2:8]2.[F:20][C@@H:21]1[CH2:25][N:24]([C:26](=[O:38])[CH2:27]OS(C2C=CC=CC=2)(=O)=O)[C@H:23]([C:39]#[N:40])[CH2:22]1.[I-].[K+]>>[CH2:18]([O:17][C:15]([C:10]12[CH2:9][CH2:8][C:7]([NH:6][CH2:27][C:26]([N:24]3[CH2:25][C@@H:21]([F:20])[CH2:22][C@H:23]3[C:39]#[N:40])=[O:38])([CH2:14][CH2:13]1)[CH2:12][CH2:11]2)=[O:16])[CH3:19]
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Agent: CS(=O)(=O)O
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 78.6 %

Procedure:
Using ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate methanesulfonate (645 mg), (2S,4S)-4-fluoro-1-[2-(benzenesulfonyloxy)acetyl]pyrrolidine-2-carbonitrile (625 mg) and potassium iodide (33.2 mg), the same procedure was followed as in Example 7 to give (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carbonitrile (553 mg, 79% yield). This compound was identical to the compound obtained in Example 7.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[CH3:16][O:17][C:18](=[O:21])[CH:19]=[CH2:20].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.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>[CH3:16][O:17][C:18]([CH:19]=[CH:20][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1)=[O:21]
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c2cc(Br)ccc2c2c1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Temperature: 120 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A suspension of 7-bromo-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (528 mg, 2.0 mmol), acrylic acid-methyl ester (0.36 ml, 4.0 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) and triethylamine (0.56 ml, 4.0 mmol) in DMF (25 ml) is stirred for 3 hours at 120° C. The batch is diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation in a vacuum. Purification of the residue on silica gel with dichloromethane-ethanol yields 550 mg (99%) of product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:14])[CH2:11][C:12]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)=[O:26].[Cl-].[NH4+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([O:8][CH2:9][CH:10]([CH3:14])[CH2:11][CH:12]=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CC#N)COCc1ccccc1
Reactant: CCOC=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(CC=O)COCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 5.8 g. (0.0307 mole) of rac. 4-benzyloxy-3-methylbutyronitrile in 290 ml. of hexane was stirred at -65° C. to -70° C. while 22.4 ml. (4.78 g.; 0.0337 mole) of 25% diisobutylaluminum hydride solution in toluene was added dropwise. The resulting solution was stirred at -65° C. to -70° C. for 0.5 hours then at room temperature for 5 hours whereupon 2.8 ml. of ethyl formate was added dropwise. The reaction mixture was then treated with 250 ml. of saturated aqueous ammonium chloride solution. Stirring was continued for 20 minutes at which point 125 ml. of 5% by weight aqueous sulfuric acid was added and stirring was continued for an additional 10 minutes. The organic layer was separated and the aqueous layer was extracted with ether. The organic solutions were combined and processed as in Example 1 giving 4.79 g. (81.3%) of rac. 4-benzyloxy-3-methylbutanal as a yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C:13](=[O:15])[N:14]1[CH2:23][C:24]([O:26][CH3:27])=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)CC[C@@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-pyrrolidinone (11.2 g) in tetrahydrofuran (97 mL) were potassium tert-butoxide (6.27 g) and methyl bromoacetate (8.11 g) at 0° C. and the solution was stirred for 2 hours. To the reaction solution were added water, ethyl acetate and hexane and the reaction solution was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (14.3 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[CH:23]=1)(=[O:21])=[O:20])([CH:6]1[CH2:18][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)[CH3:5].CC([O-])(C)C.[Na+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:29])[C:4]([CH:6]1[CH2:18][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH:23]=1)(=[O:21])=[O:20])[CH3:5]
Reactant: COC(=O)C(C)(C1Cc2[nH]c3ccc(Cl)cc3c2C1)S(=O)(=O)c1cccc(Br)c1
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C1Cc2[nH]c3ccc(Cl)cc3c2C1)S(=O)(=O)c1cccc(N2CCCC2)c1
Reaction time: 4 h
Yield: 35.9 %

Procedure:
A solution of 40 mg (0.08 mmol) (RS, SR)-2-(3-bromo-benzenesulfonyl)-2-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-propionic acid methyl ester (example 103) in toluene was treated with 13 mg (0.13 mmol) of NaOtBu, 2 mg (0.007 mmol) of 2-(di-tbutylphosphino)biphenyl, 0.03 mL (0.4 mmol) of pyrrolidine and 4 mg (0.004 mmol) of tris(dibenzylideneacetone)dipalladium. The resulting suspension was stirred at 80° for 4 hrs, treated with a diluted aqueous NaHCO3-solution and extracted twice with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated to give 14 mg (35%) of (RS, SR)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-(3-pyrrolidin-1-yl-benzenesulfonyl)-propionic acid methyl ester as a light brown solid, MS: 488 (MH+).
Reaction SMILES: S(O[CH2:12][CH:13]1[O:17][CH2:16][N:15]([C:18]2[CH:27]=[C:26]3[C:21]([C:22](=[O:37])[N:23]4[C:34]5[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=5)[C:28](=[O:36])[C:24]4=[N:25]3)=[CH:20][CH:19]=2)[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+].C(Cl)(Cl)Cl>CN(C=O)C>[N:38]([CH2:12][CH:13]1[O:17][CH2:16][N:15]([C:18]2[CH:27]=[C:26]3[C:21]([C:22](=[O:37])[N:23]4[C:34]5[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=5)[C:28](=[O:36])[C:24]4=[N:25]3)=[CH:20][CH:19]=2)[CH2:14]1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(c3ccc4c(=O)n5c(nc4c3)C(=O)c3cc(F)ccc3-5)CO2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NCC1CN(c2ccc3c(=O)n4c(nc3c2)C(=O)c2cc(F)ccc2-4)CO1

Procedure:
To a solution of 3-(5-tosyloxymethyloxazolidin-3-yl)-8-fluoroindolo[2,1-b]-quinazoline-6,12-dione (0.2 mmol) in DMF is added sodium azide (0.21 mmol). The reaction mixture is allowed to stir for 18 h at room temperature after which time CHCl3 is added and the organic layer is washed with water, dried (MgSO4) and the solvent is evaporated. Silica gel chromatography (1% MeOH/CHCl3) gives 3-(5-azidomethyloxazolidin-3-yl)-8-fluoroindolo[2,1-b]quinazoline-6,12-dione.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([C@H:16]2[NH:21][C@@H:20]([C:22](OC)=[O:23])[CH2:19][CH2:18][CH2:17]2)[CH:11]=[C:12]([F:15])[C:13]=1[F:14].O.[OH-].[Na+]>C1COCC1>[F:15][C:12]1[CH:11]=[C:10]([C@H:16]2[NH:21][C@@H:20]([CH2:22][OH:23])[CH2:19][CH2:18][CH2:17]2)[CH:9]=[C:8]([F:7])[C:13]=1[F:14]
Reactant: COC(=O)[C@H]1CCC[C@@H](c2cc(F)c(F)c(F)c2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OC[C@H]1CCC[C@@H](c2cc(F)c(F)c(F)c2)N1
Temperature: -20 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
LAH (75 mg) was added in three portions to a solution of methyl(2R,6S)-6-(3,4,5-trifluorophenyl)piperidine-2-carboxylate (270 mg) in THF (5 mL) at −20° C. over 15 minutes. The reaction solution was stirred at −20° C. for one hour, and water (0.1 mL), a 5 N sodium hydroxide solution (0.1 mL), and water (0.3 mL) were sequentially added to the reaction solution. The mixture was heated to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to obtain 242 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[N:34]1([CH2:39][CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[N:50]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:38]=[N:37][N:36]=[N:35]1.C(N(CC)C(C)C)(C)C.CO.ClCCl>C(#N)C.ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][N:34]4[CH:38]=[N:37][N:36]=[N:35]4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: c1ccc2c(c1)nc(N1CCCNCC1)n2CCn1cnnn1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Agent: I
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CCn4cnnn4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.34 g, 0.72 mmol), 4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.41 g, 0.72 mmol), and N,N-diisopropylethylamine (0.33 g, 2.53 mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool to ambient temperature and dilute the reaction mixture with dichloromethane and extract with twice water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia). Combine the product containing fractions, evaporate in vacuo, dissolve in dichloromethane, and extract with water, dry over Na2SO4, filter, and evaporate invacuo to to give the title compound: Rf=0.30 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:31])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[NH:1][C:15](=[O:31])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1F
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(4-methanesulfonylbenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>O>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)c1cccnc1Cl
Solvent: O
Product: O=C(O)c1cccnc1Nc1cccc(Cl)c1
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A mixture of 2-chloro-3-pyridinecarboxylic acid (78.75 g, 0.500 mol), 3-chloroaniline (127.6 g, 1.00 mol), paratoluenesulfonic acid.H2O (8.5 g, 45 mmol), and H2O (500 mL) was refluxed 4 hrs. The solids dissolved, and after 1 hr, the solution gave a precipitate. The cooled mixture was filtered, and the collected yellow solid was washed with cold H2 0 and was dried (60° ) to give 2-[(3-chlorophenyl)amino]-3-pyridinecarboxylic acid (116.0 g, 93.3%), mp 197°-199° C. B. Stirring 2-[(3-chloro-phenyl)amino]-3-pyridinecarboxylic acid (30.8 g, 124 mmol) with SOCl2 (50 mL, 680 mmol) and DMF (0.5 mL) at 25° C. for 1 hr gave a solution which deposited a precipitate. Excess thionyl chloride was evaporated, the residue was mixed with benzene, and the solvent was evaporated to give crude, solid 2 -[(3-chlorophenyl)amino]-3-pyridinecarbonyl chloride which was used directly in the next step C. Collecting, washing with benzene and petroleum ether, and drying the precipitate gave 2-8 (3-chlorophenyl)amino]-3-pyridinecarbonyl chloride (32 g, 96%) as a yellow solid, mp 112°-115° C. C. A solution of N(C2H5)3 (1.3 mL, 9.3 mmol) and 1-(1-pyrrolidinyl)cyclohexene (1.41 g, 9.3 mmol) in toluene (5 mL) was added dropwise over 10 min. to a magnetically stirred, cooled (ice-acetone bath at -10° C.) suspension of crude acid chloride (prepared by the procedure of Step 26B above from 9.3 mmol of the corresponding acid) and toluene (40 mL). The solid dissolved, and the dark red reaction mixture was kept 2 hrs. between -5 to +5° C. and then warmed to room temperature over 0.5 hr. The reaction mixture was then heated in an oil bath for 4 hrs; the oil bath temperature was 80° C. The reaction mixture was allowed to cool and to stand at room temperature for 12 hrs., after which toluene was evaporated. The residue was dissolved in CH2Cl2 (100 mL) and the solution was washed with 100 mL portions of H2O, 1N HCl, 1M Na2CO3, and with H2O. Aqueous extracts were backextracted with CH2Cl2, and combined organic solutions were dried over Na2SO4, filtered, and evaporated. The residue was crystallized from acetonitrile to provide the desired product 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8]naphthyridin-5(7H)-one
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[BH4-].[Na+]>CO>[OH:16][CH:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]1[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2ccccc2C(O)N1Cc1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a suspension of 11 (700 mg, 2.88 mmol) in methanol (15 mL) at 0° C. was added sodium borohydride (164 mg, 4.32 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 2 hours. The reaction mixture was concentrated in vacuo to remove methanol and the residue was taken up in ethyl acetate and poured onto 1N HCl and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to provide 612 mg of 12 as a yellow solid (706 mg theoretical, 87% yield).
Reaction SMILES: ClC(C[C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])N(C(F)F)C(C)=N2)[C:10](Cl)=[CH:9][C:8]=1[Cl:24])C(O)=O.Cl[C:26]1C=CC(N)=C[CH:27]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:24][C:8]1[CH:7]=[CH:12][C:11]([NH:13][C:17](=[O:18])[CH2:26][CH3:27])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 0.50 g (0.0013 mole) of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionic acid (Compound 2), 0.16 g (0.0013 mole) of 4-chloroaniline, 0.17 g (0.0013 mole) of 1-hydroxybenzotriazole hydrate, and 0.18 g (0.0014 mole) of N,N-diisopropylethylamine in approximately 15 mL of tetrahydrofuran was cooled to 0° C. To this cold reaction mixture was added 0.26 g (0.0013 mole) of 1,3-dicyclohexylcarbodiimide. After complete addition, the reaction mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The reaction mixture was filtered. The filtrate was diluted with carbon tetrachloride and was washed in succession with a 1N hydrochloric acid solution, an aqueous 10% sodium hydroxide solution, water, and an aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give 0.28 g of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]-N-(4-chlorophenyl)propionamide as an oil, Compound 23 of Table 1.