Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[N:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([CH3:29])[N:28]=2)[CH:25]=1.[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Br:19][C:20]1[N:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([CH3:29])[N:28]=2)[C:25]=1[Cl:30]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cn2cc(Br)ncc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: Cc1cn2c(Cl)c(Br)ncc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Into a 1-neck round-bottom flask N,N-diisopropylamine (0.50 mL, 3.6 mmol) was dissolved in tetrahydrofuran (4.0 mL) and cooled at −78° C. 1.6 M n-butyllithium in hexane (1.9 mL, 3.1 mmol) was added. The reaction was stirred at −78° C. for 30 min and 6-bromo-2-methylimidazo[1,2-a]pyrazine (from Ark Pharm, 0.500 g, 2.36 mmol) in tetrahydrofuran (6.0 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 45 min and hexachloroethane (0.72 g, 3.1 mmol) was added. The resulting mixture was stirred at −78° C. for 1 h. The reaction was quenched with NH4Cl solution and then partitioned between EtOAc and water. The EtOAc extract was washed with brine, dried (MgSO4), and stripped in vacuo. The residue was chromatographed on silica gel eluting with 40% EtOAc in hexanes to give the desired product (0.25 g, 43%). LCMS calculated for C7H6BrClN3 (M+H)+: m/z=245.9. Found: 245.9. 1H NMR (CDCl3, 400 MHz) δ 8.72 (1H, s), 7.68 (1H, s), 2.56 (3H, s) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[N:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:31])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1cnc(C(F)(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(C(F)(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-trifluoromethyl-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a colorless oil. MS (ISP): m/z=434.2 [M+H]+.
Reaction SMILES: [C:1]([O:9][CH2:10]/[CH:11]=[C:12](\[CH3:28])/[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([O:22]C)[C:18]([CH3:24])=[C:17]([CH3:25])[C:16]=1[O:26]C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.C(#N)C>[C:1]([O:9][CH2:10]/[CH:11]=[C:12](\[CH3:28])/[CH2:13][CH2:14][C:15]1[C:16](=[O:26])[C:17]([CH3:25])=[C:18]([CH3:24])[C:19](=[O:22])[C:20]=1[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)c(C)c(OC)c(CC/C(C)=C/COC(=O)c2ccccc2)c1C
Solvent: O
Solvent: CC#N
Product: CC1=C(C)C(=O)C(CC/C(C)=C/COC(=O)c2ccccc2)=C(C)C1=O
Yield: 73.7 %

Procedure:
A solution of ceric ammonium nitrate (7.2 g; 13.1 mmol) in water (30 ml) was added dropwise while cooling with ice to a solution of (E)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl benzoate (2 g; 5.2 mmol) in acetonitrile (30 ml). After completion of the addition the mixture was diluted with water and extracted with chloroform. The extracts were washed with water, dried and freed from solvent. The residue crystallizes spontaneously and 1.35 g of (E)-3-methyl-5-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)-2-pentenyl benzoate was obtained. M.P, 74.5°-75.5° C.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:21]([CH3:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([F:25])[CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[C:18]([C:17]1[CH:20]=[C:21]([CH3:22])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([N:28]4[C@H:27]([CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:7])[CH2:9][CH2:10]2)=[N:15][CH:16]=1)#[N:19]
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2F)CC1
Yield: 76.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(4-bromo-2-fluorobenzoyl)piperazin-1-yl]-5-methylnicotinonitrile (215 mg) described in Preparation Example 134 and (R)-4-methyloxazolidin-2-one (81 mg) described in Preparation Example 25, the title compound (173 mg) was obtained.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[N:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:13][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[N:11]=[N:10][C:9]([O:8][CH2:7][C:6]([OH:22])=[O:5])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2F)nn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(-c2ccccc2F)nn1
Reaction time: 8 h

Procedure:
To the crude [6-(2-fluoro-phenyl)-pyridazin-3-yloxy]-acetic acid tert -butyl ester obtained in step (b) 5 ml of 90% aqueous TFA were added, and the mixture was allowed to stand at room temperature overnight. After evaporation, a sodium hydrogencarbonate solution was added, and the solution extracted with ethyl acetate. The aqueous phase was acidified to pH=4 and extracted with ethyl acetate. The combined extracts were dried and evaporated. Yield: 20 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:17]1([OH:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.[O-][Si]([O-])=O.[Mg+2]>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[C:17]1([O:27][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: O=[Si]([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(Oc2cccc3ccccc23)nc1
Temperature: 125 °C

Procedure:
To a solution of 17.0 g. (0.107 mol.) of 2-chloro-5-nitro pyridine in 250 ml of DMF was added 15.4 g. (0.112 mol.) of potassium carbonate and 15.5 g. (0.107 mol.) of 1-naphthol. The resulting mixture was heated up to 125° C. for 3 hours. Additional potassium carbonate (1.5 g., 0.011 mol.) was added. This mixture was continued heating for 7 hours, cooled, and concentrated to give a black gummy product. It was then dissolved in 200 ml. of ethyl acetate. Florisil (60-100 mesh, 40 g.) was added to the above solution and the resulting mixture was concentrated to give brown powder. This material was packed on top of a column (450 g. florisil in hexane). Elution with hexane/ethyl acetate (96:4) gave 14.3 g. (0.054 mol., 50.3% of bright yellow crystals; mp. 87.3°-89.3° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16]C(=O)C)[C:11]=1[F:20])[C:6](=O)[CH3:7])[CH3:2].[C:22]1(C=C[CH:27]=[C:25](O)[CH:24]=1)[OH:23].[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].O>C(OCC)(=O)C.C(O)C>[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].[F:20][C:11]1[C:12]([NH2:16])=[N:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:5]1[C:4](=[O:21])[O:3][C:1]2[CH:2]=[C:22]([OH:23])[CH:24]=[CH:25][C:27]=2[C:6]=1[CH3:7]
Reactant: CCOC(=O)C(Cc1ccnc(NC(C)=O)c1F)C(C)=O
Reactant: Oc1cccc(O)c1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(Cc2ccnc(N)c2F)c(=O)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.9 %

Procedure:
Under a nitrogen atmosphere, the oily product of step 3 (2.70 g) was dissolved in ethyl acetate (5.47 mL), resorcinol (1.32 g, 12.0 mmol) and methanesulfonic acid (8.20 mL, 126 mmol) were added while stirring at room temperature, and after warming to 50° C., the mixture was stirred for 4 hours. The reaction mixture was cooled to room temperature and allowed to stand for 16 hours, water (2.7 mL) was then added, and the mixture was stirred at 80° C. for 7 hours. The reaction mixture was again cooled to room temperature and allowed to stand for 16 hours, and after the mixture was warmed to 70° C., seed crystals (27.4 mg) were added. Water (5.5 mL) was then added, the mixture was stirred for 1 hour, ethanol (13.7 mL) was further added, and the mixture was stirred for 30 minutes. It was then cooled to 25° C., ethanol (38.2 mL) was added, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration, washed twice with ethanol (16.4 mL), and dried under reduced pressure to obtain the title compound (2.20 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]([NH:27][C:28](=[O:38])[CH:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH3:31])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Sn](Cl)Cl>>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]([NH:27][C:28](=[O:38])[CH:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH3:31])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(NC(=O)C(CC)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl[Sn]Cl
Product: CCOC(=O)CC(NC(=O)C(CC)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc(N)c2)c1

Procedure:
Corresponding to Example 3d, 5 g of (7c) were treated with tin-(II) chloride. A yellowish solid was obtained (yield: 1.8 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.O[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>>[CH:20]([O:19][C:10]1[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:9]=1[C:7]([N:4]1[CH2:5][CH2:6][CH:2]([O:1][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH2:3]1)=[O:8])([CH3:22])[CH3:21]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Yield: 28 %

Procedure:
Prepared in analogy to Example 4 from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 9(a)) and 4-hydroxybenzotrifluoride. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 28%). MS (m/e): 472.4 (M+H+, 100%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[O:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21](O)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[O:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21]([N:51]5[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]5)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1CNC1
Reactant: CC(C)Cc1ccc(-c2nc(-c3cc4c(o3)CCCC4O)no2)cc1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C2CCCc3oc(-c4noc(-c5ccc(CC(C)C)cc5)n4)cc32)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using 2-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-4,5,6,7-tetrahydro-1-benzofuran-4-ol (0.15 g, 0.45 mmol) that was obtained in Example 7 (7e), carbon tetrabromide (0.30 g, 0.90 mmol), triphenylphosphine (0.24 g, 0.90 mmol), ethyl 3-azetidinecarboxylate hydrochloride (0.11 g, 0.68 mmol), and N,N-diisopropylethylamine (0.20 ml, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:3) as the developing solvent to afford the title compound (27 mg) in a yield of 13% as a white crystalline solid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[CH3:5])=[N+]=[N-].[H][H]>CO.[C].[Pd]>[C:7]1([CH3:12])[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:4]([NH2:1])[CH3:5]
Reactant: Cc1ccccc1C(C)N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccccc1C(C)N
Yield: 77.2 %

Procedure:
10% palladium-carbon (water content: 50%, 50 mg) was added to a solution of 1-(1-azidoethyl)-2-methylbenzene (744 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure to obtain 482 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].OC1C2N=NNC=2C=CC=1.Cl.Cl.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:1](=[O:5])[CH2:2][OH:3])[CH2:30][CH2:31]1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C(O)CO
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CO)N1CCN(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a screw-cap vial was added glycolic acid (100 mg, 1.31 mmol), 1-(3-dimthylaminopropyl)-3-ethylcarbodiimide hydrochloride (277.3 mg, 1.45 mmol), hydroxybenzotriazole (195.5 mg, 1.45 mmol), 1-(2,4-dichlorophenyl)-piperazine dihydrochloride (439.8 mg, 1.45 mmol), triethylamine (0.55 mL, 3.94 mmol) and N,N-dimethylformamide (5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (8 mL), successively washed with water (8 mL), saturated aqueous sodium bicarbonate (2×8 mL) and water (8 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified on silica gel using hexanes:ethyl acetate=4:1 to 100% ethyl acetate in a gradient fashion, to isolate the desired product as yellow solid (171.1 mg, 45%). 1H NMR (300 MHz, CDCl3): δ 7.28 (d, 1H), 7.11 (dd, 1H), 6.85 (dd, 1H), 4.11 (br, 2H), 3.74 (t, 2H), 3.72 (br, 1H, OH), 3.36 (t, 2H), 2.92 (t, 4H)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)[C:21]([O:38][CH3:39])=[CH:20][CH:19]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu](I)I>[CH3:39][O:38][C:21]1[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[N:23][C:18]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(Br)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.4734 mmol; 100.0 mg), tert-butyl N-[(3S)-1-(6-bromo-3-methoxy-2-pyridyl)-3-piperidyl]carbamate (0.5681 mmol, 219.5 mg), N,N′-Dimethylethylenediamine (0.4734 mmol; 41.73 mg; 0.0471 mL), copper iodide (0.4734 mmol; 91.08 mg), and potassium carbonate (0.5208 mmol; 72.70 mg) in 1,4-Dioxane (10 mL) was purged with Argon, then sealed and stirred at 100° C. overnight. The mixture was cooled to room temperature, and then filtered through Celite. The filtrate was concentrated; the residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford tert-butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate as a tan solid (142.5 mg, 58%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][S:10]2)(=[O:3])[CH3:2].[C:17]([NH:20]C1C=CC(C)=C2C=1C(=O)CCS2)(=[O:19])[CH3:18]>>[C:17]([NH:20][CH:8]1[C:7](=[O:16])[C:6]2[C:11](=[C:12]([Cl:15])[CH:13]=[CH:14][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[S:10][CH2:9]1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)CCS2
Reactant: CC(=O)Nc1ccc(Cl)c2c1C(=O)CCS2
Product: CC(=O)Nc1ccc(Cl)c2c1C(=O)C(NC(C)=O)CS2

Procedure:
The reaction was carried out in the same manner as in Example 12-(1), except that 477 mg of the compound prepared in (1) above was used instead of 5-acetylamino-8-methyl-4-thiochromanone of Example 12-(1). The reaction product was post-treated to produce 171 mg of the title compound. NMR(CDCl3)δ: 2.08(3H, s), 2.20(3H, s), 3.20(1H, d, J=13 Hz), 3.51(1H, dd, J=13.9 Hz), 4.7-4.9(1H, m), 7.50(1H, d, J=9.2 Hz), 8.54(1H, d, J=9.2 Hz)
Reaction SMILES: [OH-].[Na+].CO.C[O:6][C:7](=[O:37])[CH2:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:17]=2)[C:13]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:12]=2[NH:11][C:10]1=[O:36]>O>[C:27]([O:26][C:24]([NH:23][CH2:22][C:18]1[CH:17]=[C:16]([C:14]2[C:13]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:12]=3[NH:11][C:10](=[O:36])[CH:9]([CH2:8][C:7]([OH:37])=[O:6])[N:15]=2)[CH:21]=[CH:20][CH:19]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)CC1N=C(c2cccc(CNC(=O)OC(C)(C)C)c2)c2cc(Cl)ccc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C2=NC(CC(=O)O)C(=O)Nc3ccc(Cl)cc32)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
A 1N aqueous solution of sodium hydroxide (1.5 ml) was added to a methanol solution (6 m.) of 5-(3-tert-butyloxycarbonylaminomethylphenyl)-7-chloro-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid methyl ester (0.6 g), the compound produced in Example 97-(1). The mixture was stirred for 2 hours at 60° C. The reaction mixture was diluted with water (50 ml), which was acidified, followed by extraction with ethyl acetate (50 ml) twice. The extracts were combined and washed with a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5-(3-tert-butyloxycarbonylaminomethylphenyl)-7-chloro-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid (0.64 g) as a colorless amorphous solid product.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([N:12]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:13]([CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:5]([N:12]([C:13]1([CH:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16]2)[CH2:2][CH2:1]1)[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)C(=O)C2CCN(Cc3ccccc3)C2)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)C2(C3CCN(Cc4ccccc4)C3)CC2)CC1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A solution of ethylmagnesium bromide (3.0 M in ethyl ether, 13.0 mL, 39.1 mmol, 2.5 equiv) in THF (100 mL) was cooled to −78° C. To this was added a solution of titanium (IV) isopropoxide (4.8 mL, 16.3 mmol, 1.04 equiv) in THF (10 mL) dropwise with the temperature below −70° C. After stirring for thirty minutes, a solution of (R/S)-N-benzyl-N-(1-tert-butoxycarbonylpiperidin-4-yl)-1-benzylpyrrolidine-3-carboxamide (7.5 g, 15.6 mmol) in THF (10 mL) was added. The resulting solution was warmed to RT, heated at reflux for one hour. The mixture was then cooled to 8° C., and ethylmagnesium bromide (3.0 M in ethyl ether, 11.0 mL, 33.1 mmol, 2.1 equiv) was added, followed immediately by a solution of titanium (IV) isopropoxide (4.2 mL, 14.2 mmol, 0.91 equiv) in THF (10 mL). The reaction mixture was stirred at room temperature for one hour then partitioned between 1:1 EtOAc—H2O (500 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (5:1 hexanes-EtOAc to 100% EtOAc) to give a pale yellow oil (4.7 g, 61%). ESI MS m/z 490.3 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.34-7.11 (m, 10H), 4.18-3.98 (br m, 1H), 3.92 (app s, 2H), 3.64 (app t, J=13.2, 1H), 3.55 (d, J=12.5, 1H), 3.00-2.78 (m, 4H), 2.75-2.37 (m, 4H), 2.33-2.21 (m, 1H), 2.10-1.89 (m, 2H), 1.73-1.62 (m, 2H), 1.50-1.37 (s+m, 11H), 1.37-1.14 (m, 2H), 0.71 (app s, 1H), 0.60-0.49 (m, 1H). 13C NMR (400 MHz, CDCl3) δ 154.20 (C═O), 143.1 (Ph), 138.8 (Ph), 128.5 (Ph), 128.4 (Ph), 127.9 (Ph), 127.7 (Ph), 126.6 (Ph), 125.9 (Ph), 78.8 (t-Bu), 60.6, 58.4, 55.5, 53.2, 48.9, 45.2, 43.3 (br), 42.7 (br), 38.6, 32.1 (br), 28.1 (t-Bu), 7.6 (c-Pr).
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH3:19])[C:7](=[O:18])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]#[C-:17])=[O:5])#[N:2].[OH-].[Na+]>O>[NH2:2][C:1]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]#[C-:17])[C:7](=[O:18])[N:6]([CH3:19])[C:4](=[O:5])[CH:3]=1
Reactant: [C-]#[N+]c1ccccc1CNC(=O)N(C)C(=O)CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [C-]#[N+]c1ccccc1Cn1c(N)cc(=O)n(C)c1=O
Temperature: 80 °C
Yield: 76 %

Procedure:
To 3-(2-cyano-acetyl)-3-methyl-1-(2-isocyanobenzyl)-urea (120 g) were added water (962 ml) and 2N aqueous sodium hydroxide solution (24.9 ml), and the mixture was stirred with heating at 80° C. for 1 hr. After allowing to cool to room temperature, the crystals were collected by filtration and dried to give 6-amino-1-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione in 76% yield.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:18][C:15]2[CH:16]=[N:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(N)ccc1I
Reactant: COc1ccc(C=O)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(CNc2ccc(I)c(C)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
5-Iodo-6-methyl-pyridin-2-ylamine (28, 1.7 g, 7.3 mmol) and 6-methoxy-pyridine-3-carbaldehyde (29, 1.1 g, 8.0 mmol) were combined in a round bottom flask with trifluoroacetic acid (2.80 mL, 36.3 mmol), triethylsilane (5.80 mL, 36.3 mmol) and 50 mL of acetonitrile. The reaction was stirred at room temperature overnight, then heated to reflux for 6 hours. The reaction was concentrated under vacuum, combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel flash column chromatography, eluting with 10-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (30, 1.80 g). MS (ESI)[M+H+]+=356.80.