Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C[O-].[Na+].[O-]S(C(F)(F)F)(=O)=O.F[N+:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[Br:1][C:2]1[N:6]=[CH:5][N:4]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[N:3]=1
Reactant: Brc1nc[nH]n1
Reactant: F[n+]1ccccc1
Agent: C[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: Brc1ncn(-c2ccccn2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-Bromo-1H-1,2,4triazole (1.9 g, 12.8 mmol) was dissolved in anhydrous methanol (20 mL). NaOMe (51 mL of a 0.5 M solution in methanol, 25.6 mmol) was then added to the stirred solution and the resulting reaction mixture was cooled to −78° C. in an argon blanketed flask. 1-Fluoropyridinium triflate (4.9 g, 15 mmol) in anhydrous methanol (20 mL) was added dropwise to this stirred solution. The resulting yellow mixture was stirred at −78° C. for 1 h under argon atmosphere, then allowed to reach ambient temperature. The mixture was stirred for 16 h at ambient temperature, after which time it was concentrated in vacuo. The resulting residue was dissolved in EtOAc (100 mL), the EtOAc solution washed with H2O (100 mL), then brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane:EtOAc (90:10) to afford 2-(3-bromo-1H-1,2,4-triazol-1-yl)pyridine as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C(#N)C>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: COc1ccccc1CN
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1CNCCOc1cccc(-c2noc3ccsc23)c1
Temperature: 75 °C
Yield: 89.9 %

Procedure:
Mix 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole (0.324 g, 1 mmol), potassium carbonate (0.28 g, 2 mmol), 2-methoxybenzylamine (0.686 g, 5 mmol) and acetonitrile (anhydrous, 4 mL) and heat at 75° C. for 16.5 hours. Cool the reaction mixture and filter through a Waters Sep-Pak silica gel cartridge (1 g) using ethyl acetate. Combine the appropriate fractions and concentrate to give a residue. Purify the residue by column (10 g silica) chromatography using a step gradient of 60% ethyl acetate in heptane to 100% ethyl acetate to give the title compound (342 mg, 90% Yield). Purity by LC/MS (APCI)=99%, [M+H]+=381.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([NH:20][CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].N12CCN(CC1)CC2>CCO>[C:13]([O:17][C:18]([NH:20][CH:21]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:22]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccnc3cc(Cl)ccc23)C1

Procedure:
In a method similar to Example A 4,7-dichloroquinoline (0.49 g, 2.0 mmol), 3-(tert-butoxycarbonylamino)pyrrolidine (1.86 g, 10.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (1.12 g, 10.0 mmol) are heated in EtOH for 15 h at reflux. The reaction mixture is concentrated, diluted with EtOAc, washed with water, dried (MgSO4), and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding 245 mg of the product as a colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7](C(C)=C)[C:6]1=[O:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O.CC(C)CC(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:17])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 3.9 parts of 4-(4-fluorophenyl)-4-piperidinol, 5.3 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours with water-separator. The reaction mixture is cooled to room temperature, water is added and the whole is alkalized with 15 parts of a sodium hydroxide solution 60%. The layers are separated and the organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is dissolved in 2-propanone. The solution is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride, and the whole is stirred and refluxed for 15 minutes. The solvent is evaporated and the formed hydrochloride salt is dissolved in water. The free base is liberated in the conventional manner with a diluted sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 2.5 parts of 1-{3-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 135.4° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=2[F:34])[O:21][N:20]=1>>[F:34][C:25]1[CH:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[CH:29][C:24]=1[C:22]1[O:21][N:20]=[C:19]([CH2:18][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[N:23]=1
Reactant: Fc1ccc(C(F)(F)F)cc1-c1nc(CCl)no1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)ccc2F)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 3-(chloromethyl)-5-[2-fluoro-5-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 7.85 (m, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.65 (s, 1H), 5.50 (s, 2H), 2.68 (s, 3H); MS (ES) m/z 469 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.CC(C)=[O:18].C(OCC)(=O)C>C(O)(=O)C.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[O-:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2ccccn2)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: [O-][n+]1ccccc1Cc1ccccc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A stirred solution of 3.0 g (18 mmol) 2-benzylpyridine and 1.65 mL of 30% aqueous hydrogen peroxide in 5.0 mL of acetic acid was heated at 100° C. for 3 hr (S. Hibino and E. Sugino, J. Heterocycl Chem., 1990, 27, 175). After cooling to room temperature, the reaction was diluted with 30 mL ethyl acetate and neutralized with sodium carbonate. The sodium acetate was separated by filtration and the filtrate was dried (sodium carbonate) and concentrated to give a yellow oil. Flash column chromatography on 125 g of silica gel using 7 of L 20% acetone/ethyl acetate furnished 2,58 g (79% yield) of 2-benzylpyridine N-oxide as an amber syrup.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([OH:15])[C:13]#[CH:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(NCC)C>[OH:15][CH2:12][C:13]#[C:14][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1I
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: COC(=O)c1ccccc1C#CCO
Reaction time: 18 h

Procedure:
Step 1--A mixture of methyl o-iodobenzoate (9.17 g), propargyl alcohol (3.06 ml) and diethyl amine (90 ml) is treated with bis(triphenylphosphine)palladium chloride (1.23 g) and copper iodide (333 mg) and the reaction is stirred at 20°-25° under nitrogen for 18 hrs. The reaction is then filtered through a filter agent and concentrated. The resulting residue is partitioned between water and dichloromethane. The combined organic phases are washed once with saline, dried over magnesium sulfate, filtered and concentrated to an oil. Purification by silica gel chromatography gives methyl o-(1-hydroxy-2-propyn-3-yl)benzoate (CXIX).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][C@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:20]2)[C@H:16]([C:30](OCC)=[O:31])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:18][C@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:20][CH2:21]2)[C@H:16]([CH2:30][OH:31])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1C1(NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1([C@H]2CN(Cc3ccccc3)C[C@H]2CO)CC1
Temperature: -15 °C
Yield: 93.4 %

Procedure:
Under a nitrogen atmosphere, lithium aluminum hydride (195.6 mg, 5.153 mmol) was suspended in anhydrous tetrahydrofuran (40 ml) to which, while stirring at −15° C., was subsequently added dropwise an anhydrous tetrahydrofuran (10 ml) solution of ethyl cis-1-benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine-3-carboxylate (1.001 g, 2.577 mmol) over a period of 15 minutes. The reaction suspension was stirred for 3.5 hours in an ice bath, gradually mixed with cold water (5 ml) and then stirred for an additional 15 minutes at room temperature. The reaction suspension was filtered through celite (diethyl ether washing), and the resulting filtrate was concentrated under reduced pressure and dried, to thereby obtain 833.9 mg (93.4%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:47][O:48][C:49](=[O:57])[C@H:50]([CH2:52][C:53]([O:55][CH3:56])=[O:54])[NH2:51].C(N(CC)CC)C>CN(C)C=O>[CH3:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([NH:51][C@H:50]([C:49]([O:48][CH3:47])=[O:57])[CH2:52][C:53]([O:55][CH3:56])=[O:54])=[O:30])[N:27]=4)[CH:21]=3)[C:5]3[CH:33]=[CH:34][C:2]([CH3:1])=[CH:3][C:4]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)cs2)c(=O)[nH]c1=S
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)c1csc(Cn2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=S)[nH]c2=O)n1)C(=O)OC
Reaction time: 8 h

Procedure:
The product from example 8(0.4 g) was dissolved in dry dimethylformamide (15 ml) and treated with N,N-carbonyldiimidazole (0.16 g). After 30 minutes L-aspartic acid dimethyl ester (0.32 g) was added followed by triethylamine (0.5 ml). The mixture was stirred overnight and partitioned between ethyl acetate and 2M HCl. The organic phase was washed with brine, dried (MgSO4), evaporated and purified by chromatography eluting with 50% ethyl acetate in dichloromethane. Used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2)=[O:27]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Solvent: C1CCOC1
Product: Cc1nc2cccc(NC(=O)c3cccc(Cl)c3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 80 °C
Yield: 47.1 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.46 g, 1.5 mmol) in tetrahydrofuran (10 mL), was added 3-chlorobenzoyl chloride (0.68 mL, 5.3 mmol) and heated at 80° C. for three hours. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 3-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-benzamide as a white solid (300 mg, 46% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 7.04 min (98.2%); mp, 326-328° C.; 1HNMR (DMSO-d6) 2.18-2.28 (m, 1H, CHH), 2.61-2.92 (m, 6H, CHCH2, CH3), 5.36 (dd, J=6, 11 Hz, 1H, CH), 7.37-8.70 (m, 7H, Ar), 11.12 (s, 1H, NH), 12.72 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.39, 30.66, 40.41, 56.90, 115.69, 121.28, 125.21, 127.12, 131.13, 132.14, 135.78, 163.46, 169.30, 172.59, 172.62. LCMS MH=425, 427; Anal Calcd For C21H17N4O4Cl+0.3H2O: C, 58.62; H, 4.12; N, 13.02; Cl, 8.24. Found: C, 58.46; H, 3.74; N, 12.70; Cl, 7.98.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: COCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CCOC)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 27.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.0 mg) was obtained.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH3:15])[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH3:15])[CH:5]=1)=[O:16])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cccc(-c2ncsc2C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: Cc1scnc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
A sample of 3-(5-methyl-thiazol-4-yl)-benzoic acid methyl ester (1.05 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-[3-(5-methyl-thiazol-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (1.9 g) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)cc2)c1)c1ccc(Cl)nc1
Product: CC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(Cl)cc4)c3)cn2)CC1

Procedure:
6-chloro-N-(4-chloro-3-(4-chlorobenzamido)phenyl)nicotinamide (0.16 mmol) was used in general procedure 3 with 1-acetylpiperazine (0.83 mmol). The product was purified by RP-HPLC to give 6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(4-chlorobenzamido)phenyl)nicotinamide. MS (Q1) 512.3 (M)+
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)cc1OCC1CC1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2OCC2CC2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-(cyclopropylmethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C20H17ClN4O2, 381. Found, 381.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O.P(Cl)(Cl)(Cl)=O>>[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=1[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: O=C1CCCCN1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)Cc1ccccc1N2C1=NCCCC1

Procedure:
Reaction of acridan, 2-piperidone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(3,4,5,6-TETRAHYDRO-2-PYRIDYL)ACRIDAN as a distillablle oil, b.p. 145°-150°C. at 0.15 mm Hg. Conversion of the free base to the hydrochloride salt affords 10-(3,4,5,5-TETRAHYDRO-2-PYRIDYL)ACRIDAN HYDROCHLORIDE as the hemihydrate, m.p. 190.5°-192.5°C. (corr.) by trituration with hot benzene in a 19% overall yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6](Cl)=[O:7])#[N:2].O[NH:17][C:18](=[NH:37])[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[N:22][N:23]2[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:7][N:17]=[C:18]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][N:23]4[CH2:28][C:29]([CH3:35])([CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:37]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Reactant: CCOC(=O)C(C)(C)Cn1ncc2c(C(=N)NO)cccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Cn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
3-Cyano-4-[(1-methylethyl)oxy]benzoyl chloride (D106) (0.398 mmol) in acetonitrile (3.00 ml) at room temperature was treated with ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}-2,2-dimethylpropanoate (D103) (101 mg, 0.332 mmol) followed by triethylamine (0.069 ml, 0.498 mmol). The resulting yellow solution was stirred at room temperature for 1 hr, refluxed overnight, for a further 24 hours and again overnight then cooled to room temperature and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave the title compound (107 mg, 68%) as a colourless solid. MS (ES) C26H27N5O4 requires 473, found 474 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]([CH3:14])[C:9]([O:11]CC)=[O:10])[CH:7]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]([CH3:14])[C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)C(C)n1cc(Br)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C(=O)O)n1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 2-(5-bromo-2-oxopyridin-1(2H)-yl)propanoate (5.0 g, 18 mmol) in 40 mL of 1:1 THF/MeOH are rt was added 25 mL of 1N NaOH. The reaction was stirred at rt for 5 hours and was then acidified with 2N HCl to pH˜2. The solid formed was collected and was washed with water and EtOAc to give white solid (4.2 g, 94% yield) as desired product. MS (ESI pos. ion) m/z (MH+): 245.9. Calc'd Exact Mass for C8H8BrNO3: 244.97.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][CH2:7][CH2:8][CH:9]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].Br[CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:7][CH2:8][CH:9]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:25][CH3:26])[CH3:2]
Reactant: CCOC(=O)CNCCC=C(c1ccccc1)c1ccccc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)CN(CC)CCC=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
A mixture of 0.158 g (0.5 mmol) of N-[(4,4-diphenyl)but-3-enyl]glycine ethyl ester (Compound A26), 0.234 g (2.1 mmol) bromoethane, 0.281 g (2 mmol) potassium carbonate and 0.068 g (0.4 mmol) potassium iodide was stirred under argon for 20 hours at room temperature. The reaction mixture was filtered, the solvent evaporated, and the residue chromatographed on a silica gel column with 20% ethyl acetate in hexanes to yield 0.112 g (66%) N-[(4,4-diphenyl)but-3-enyl]-N-ethylglycine ethyl ester (Compound A16) as an oil. NMR spectra showed: 1H NMR (CDCl3, 300 MHz) 7.60–7.00 (m, 10 H), 6.09 (t, 1 H), 4.13 (q. 2 H), 3.27 (s, 2 H), 2.72 (t, 2 H), 2.61 (q, 2 H), 2.28 (dt, 2 H), 1.23 (t, 3 H), 1.01 (t, 3 H); 13C NMR (CDCl3, 75 MHz) 171.77, 142.96, 142.86, 140.33, 130.09, 128.49, 128.35, 127.48, 127.27, 127.19, 60.58, 54.90, 53.98, 48.20, 28.19, 14.57, 12.70.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11](=[CH2:15])[C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.[C:16]([OH:19])(=[S:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([S:18][CH2:15][CH:11]([CH:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)[C:12]([OH:14])=[O:13])(=[O:19])[CH3:17]
Reactant: C=C(C(=O)O)C1CCc2cc(Br)ccc21
Reactant: CC(O)=S
Solvent: ClC(Cl)Cl
Product: CC(=O)SCC(C(=O)O)C1CCc2cc(Br)ccc21

Procedure:
The ethylene compound obtained in Step E (48.83 mmol) is dissolved in 100 ml of CHCl3 and thioacetic acid (170.89 mmol, 3.5 eq.) is added. The mixture is stirred at reflux for 16 hours. The solvent and excess thioacetic acid are removed by evaporation under reduced pressure to yield the title compound in the form of four stereoisomers that can be separated into two enantiomer pairs: