Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[CH2:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21])[CH3:12].[OH-].[Na+]>O>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]([CH2:11][CH3:12])[CH:8]=[O:10])(=[O:22])[CH3:21]
Reactant: O=CO
Reactant: CCNc1ccccc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCN(C=O)c1ccccc1C(C)=O
Reaction time: 4 h

Procedure:
A mixture of acetic anhydride (23 ml) and formic acid (15.5 ml) was stirred at 50° for 4 hours and then cooled to 0° in an ice/salt bath. 2'-(Ethylamino)-acetophenone (20.5 g) was added in small portions over 15 minutes and the mixture allowed to stand at room temperature for 1 hour. The mixture was cooled to 0° and water (100 ml) followed by aqueous sodium hydroxide (specific gravity 1.5, 10 ml) was added dropwise whilst maintaining the temperature below 10°. The resultant mixture was extracted with dichloromethane (4×100 ml) and the combined extracts were dried over magnesium sulphate to give a solution of 2'-acetyl-N-ethylformanilide.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CN(CC(O)c1csc(C(F)(F)F)n1)C(C)Cc1ccc(OCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.21 g (0.005 mol) of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl) ethanamine is dissolved in 10 ml of butan-2-one, and 0.5 ml of ethyl bromoacetate and 0.5 g of potassium carbonate are added, and the mixture is stirred at room temperature for 16 hours. The inorganic products are removed by filtration, and the solvent is removed by distillation. The remaining oil is purified on a silica gel column using toluene/ethyl acetate=85:15 as eluant. A colourless oil is obtained.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:6][C@@H:5]1[OH:34])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)(Cl)Cl.C(O)C>[C:46]([O:34][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:6]1)(=[O:48])[CH3:47]
Reactant: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reaction time: 0.33 h

Procedure:
Ethyl 2β-ethoxy-3α-hydroxy-11α-(3-methylbutylamino)-5α-androstane-17β-carboxylate (200 mg) in chloroform (2.15 ml) containing dry toluene-4-sulphonic acid (PTSA; 172 mg) was stirred for 20 min, then treated with acetic anhydride (0.5 ml) and the mixture left for 18 h. The reaction mixture was diluted with ethanol and evaporated. The residue in ethyl acetate was washed with dilute ammonia solution (2×) and water (1×), dried and evaporated to give the title compound as an oil (220 mg), [α]D +25.8° (CHCl3C=1%), νmax 1720 cm-1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(O)(=O)C.C(O)(=O)C.[I:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[C:23]1([O:29][CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:30][O:29][C:23]1[CH:28]=[CH:27][C:26]([I+:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:25][CH:24]=1
Reactant: Ic1cccnc1
Reactant: COc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc([I+]c2cccnc2)cc1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
Trifluoroacetic acid (0.15 mL, 2 mmol) was added dropwise to a stirred solution of 3-iodopyridine diacetate (0.23 g, 1 mmol) in dichloromethane at −40° C. and stirred for 0.5 h when the solution was allowed to warm to room temperature for 1 h after which time it was re-cooled to −40° C. and anisole (0.11 mL, 1 mmol) added dropwise and the reaction mixture allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo to give a light brown oil. Crystallisation gave the title compound as a colourless crystalline solid (0.22 g, 0.52 mmol, 52%); mp 150-151° C. (from DCM-ether) silica gel TLC Rf 0.20 (9:2 DCM-MeOH); (Found C, 39.67; H, 2.53; N, 3.21. C14H11F31NO3 requires C, 39.55; H, 2.61; N, 3.29%.); νmax/cm−1 (neat) 3050, 1642, 1570, 1251, 1177, 1130; δH (300 MHz; d6-acetone) 8.93 (1H, d, H2 J 2 Hz), 8.74 (1H, d, H6, J 4 Hz), 8.39 (1H, dt, H4 J 5, 2 Hz), 7.91 (2H, d, H2′/H6′ J 5 Hz), 7.38 (1H, dd, H5 J 5, 3 Hz), 6.93 (2H, d, H3′/H5′ J 5 Hz), 3.84 (3H, s, OMe); δC (75 MHz; d6-Acetone) 163.99 (C4′), 154.59 (C2), 152.76 (C6), 143.06 (C4), 138.63 (C2′/C6′), 127.45 (C5), 118.68 (C3′/C5′), 116.64 (C1′), 107.60 (C3), 56.51 (OMe); m/z (ES) 312 (M+, 100%), 185 (20). [Found: M+], 311.9878.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[N:12]2)=[CH:6][CH:5]=1.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Cn2ccc(N)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
4-(3-Nitro-pyrazol-1-ylmethyl)-benzoic acid methyl ester (530 mg, 2.03 mmol) was dissolved in ethyl acetate (10 ml). Tin(II) chloride dihydrate (2.29 gm, 10.15 mmol) was added, reaction mixture was heated at 70 deg C. for 1 h. The reaction mixture was cooled to ambient temperature, the pH adjusted to pH 8-9 by addition of aq. saturated sodium carbonate and extracted with ethyl acetate (3×25 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 4-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (480 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](OC)[CH:15]=2)[C:5]=1[C:6]#[N:7])([O-])=O.CC(C)=O.[Cl-].[NH4+]>[Zn].O>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[C:6]#[N:7]
Reactant: COc1cccc(COc2cccc([N+](=O)[O-])c2C#N)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1c(N)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a mixture of 2-nitro-6-(3-methoxybenzyloxy)benzonitrile (Example 193c) (480 mg, 1.69 mmol) in 5:1 acetone:water (9 mL) was added zinc (552 mg, 8.44 mmol) and ammonium chloride (911 mg, 16.9 mmol). The reaction was stirred at room temperature for 30 minutes, then filtered and concentrated. The residue was purified by flash chromatography (55:45 EtOAc:Hexane) to provide 2-amino-6-(benzyloxy)benzonitrile (337 mg, 78%). 1H NMR (400 MHz, d-DMSO) δ 3.73 (s, 3H), 5.04 (s, 1H), 6.27 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.06-6.97 (m, 3H), 7.27 (t, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[N:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:5]1[S:1][N:2]=[CH:3][CH:4]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1ccns1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccns1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-isothiazole carboxylic acid (5 g, 38.7 mmol) in dichloromethane (200 mL), 4-(dimethylamino)pyridine (473 mg, 3.87 mmol), N,O-dimethylhydroxylamine hydrochloride (4.53 g, 46.4 mmol) (N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (8.17 g, 42.6 mmol) and triethylamine (13.63 μL, 97.0 mmol) were added and the reaction was stirred overnight at room temperature. The reaction mixture was then successively washed with 1N HCl, 1N NaOH and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 8.59 (s, 1H), 7.97 (s, 1H), 3.94 (s, 3H), 3.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=O)=[CH:4][N:3]=1.[NH2:20][NH2:21]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[NH:20][N:21]=[C:9]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:5]2=[CH:4][N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(Cl)nc1Cl
Reactant: NN
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1n[nH]c2nc(Cl)ncc12
Reaction time: 0.33 h

Procedure:
To a stirred solution of (2,4-dichloro-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (602 mg, 2 mmol) in THF (8 m), hydrazine (Aldrich, 98%, 64 mg, 2 mmol) was added and the mixture was stirred for 20 minutes followed by a second portion of hydrazine (0.1 mL). The reaction finished in 5 minutes. The solvent was removed and the solid was washed with water/acetonitrile (3:1) to give a yellow solid. 456 mg, 82%. MS (M+H)+, 278.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:28][C:29]1[C:34]([C:2]2[CH:3]=[C:4]3[C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]4[CH:13]=[C:12]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)(C)COc1cc2c(cn1)Oc1ccc(-c3cccnc3F)cc1[C@@]21COCC(N)=N1
Temperature: 90 °C
Yield: 87.4 %

Procedure:
A vial was charged with (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (51 mg, 0.118 mmol), 2-fluoropyridin-3-ylboronic acid (33.2 mg, 0.236 mmol), potassium phosphate (75 mg, 0.354 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (4.18 mg, 5.90 μmol). The vial was flushed with Ar (g), then dioxane (442 μL) and water (147 μL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 20 min at 90° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography (30% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (S)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (46.23 mg) as an off-white solid. MS m/z=449.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][NH2:17])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: COc1nc2cc(Cl)ccc2nc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1nc2cc(Cl)ccc2nc1NN

Procedure:
A mixture of 4.9 g. (0.02 mole) of 2,6-dichloro-3-methoxyquinoxaline and 2.7 g. (0.053 mole) of hydrazine hydrate (2.6 ml.) in 75 ml. of ethanol was stirred at room temperature overnight (i.e., at ca. 20° C. for approximately 16 hours). Upon completion of this step, the resulting mixture was filtered and the recovered precipitate was washed with ethanol to ultimately afford 4.4 g. (98%) of pure 6-chloro-2-hydrazino-3-methoxyquinoxaline, m.p. 175°-179° C. (decomp.). Mass Spectrum: m/e, 224 (P); m/e, 226 (P+2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[CH:5]([C:15]1[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[CH:18]=[C:17]([O:24][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:16]=1[F:42])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:43])[CH:5]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=1)[C:15]1[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[CH:18]=[C:17]([OH:24])[C:16]=1[F:42])[CH3:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O)c1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
A solution of 27.6 g (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-5-ethoxy-2-fluoro-phenyl]-(4-cyano-phenylamino)-acetic acid ethyl ester described in example 3.4 in 470 ml THF was cooled to 0° C. and treated with 50.9 ml 1M tetrabutylammonium fluoride solution in THF. The reaction mixture was stirred at 0° C. for 4 hrs. The crude product was isolated by extraction with EtOAc and purified by chromatography on silica gel (cyclohexane/EtOAc) to yield 12.89 g (RS)-(4-cyano-phenylamino)-(5-ethoxy-2-fluoro-3-hydroxy-phenyl)-acetic acid ethyl ester as a yellow semisolid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl.C(=O)(O)[O-].[Na+]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNCC1
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: c1csc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thiophenecarboxaldehyde (1 g, 8.9 mmol) was dissolved in dichloroethane and treated with piperidine and sodium triacetoxyborohydride. The reaction was stirred at room temperature overnight. The reaction was diluted with dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated out, washed with water and brine and dried with sodium sulfate. The volatile were removed in vacuo and the residue was purified by column chromatography on silica gel using a gradient of 2 to 8% of methanol in dichloromethane to obtain a brown oil. Yield=1.5 g. MS (M+H)+ 182.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCN(Cc3ccccc3)CC2)c1
Reaction time: 1 h

Procedure:
3-Bromoanisole (50.0 g, 0.264 mol) was dissolved in 150 mL of THF and then chilled to −78° C. n-Butyllithium (1.6M, 175 mL, 0.276 mol) was then added while maintaining the reaction temperature at −70° C. or below. After complete addition, the reaction mixture was stirred for an additional 60 min. 1-Benzyl4-piperidone in 150 mL of THF was then added at such a rate as to maintain the reaction temperature at −70° C. or below. The reaction was stirred at −70° C. for an additional 15 min, then the dry ice-acetone bath was removed, and the reaction was allowed to come to room temperature. Brine (400 mL) was added, and the organic layer was separated and washed with an additional 300 mL of brine. The organic layer was separated, dried (K2CO3), and concentrated in vacuo. 6N HCl (250 mL) was added to the oily residue which was then washed with EtOAc. The aqueous layer was separated, basified with 50% NaOH, and extracted with EtOAc. The EtOAc layer was separated, dried (K2CO3), and concentrated in vacuo to give 75.7 g of 4-(3-methoxyphenyl)-1-benzyl4-piperidinol as an orange oil. A sample was chromatographed on silica gel using hexane/EtOAc (7:3) mixtures as the eluent to afford a yellow oil which was dissolved in ether and treated with ethereal hydrochloric acid to give 4-(3-methoxyphenyl)-1-benzyl-4-piperidinol hydrochloride as a white solid (mp 195-197° C.). 1H NMR (CDCl3) (free base) 5 (ppm) 1.64-1.75 (m, 2H), 2.09-2.21 (m, 2H), 2.41-2.51 (m, 2H), 2.71-2.80 (m, 2H), 3.51 (s, 2H), 3.80 (s, 3H), 6.77-6.81 (m, 1H), 7.06-7.09 (m, 2H), 7.23-7.35 (m, 6H). Anal. Calcd for C19H23NO2 HCl.1/2 H2O: C, 66.56; H, 7.06; N, 4.09. Found: C, 66.41; H, 7.31; N, 4.33.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]3[CH:15]=[CH:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]=3[O:12][C:11]([CH3:25])([CH3:24])[C:10]2=[O:26])[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[CH3:25][C:11]1([CH3:24])[C:10](=[O:26])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:33](=[O:35])[CH3:34])[CH:3]=2)[C:14]2[CH:15]=[CH:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]=2[O:12]1
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)c(N)c2)C1=O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(N2C(=O)C(C)(C)Oc3cc(NS(C)(=O)=O)ccc32)ccc1F
Reaction time: 1 h

Procedure:
To a solution of N-[4-(3-amino-4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 44; 13 mg) and pyridine (5.5 μL) in dichloromethane (5 mL) was added acetyl chloride (3.6 μL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was purified by column chromatography on silica gel (solvent; chloroform to chloroform/methanol (9/1) and triturated with diisopropylether to give N-(5-{2,2-dimethyl-7-[(methanesulfonyl)amino]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl}-2-fluorophenyl)acetamide (10 mg) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:10][C:9]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.[CH:26](=O)[CH:27](C)[CH3:28].N1CCC[CH2:32]1.C(#N)C>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][CH:17]([CH:27]([CH3:28])[CH3:26])[CH:16]([CH3:32])[C:15](=[O:18])[C:11]2=[CH:10][C:9]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1
Reactant: CCC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: C1CCNC1
Reactant: CC(C)C=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)C1Oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2C(=O)C1C
Temperature: 90 °C
Reaction time: 0.42 h

Procedure:
To 6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-propionylpyridin-2(1H)-one (350 mg, 0.940 mmol), was added isobutyraldehyde (0.384. mL, 4.23 mmol), pyrrolidine (0.117 mL, 1.41 mmol) and acetonitrile (1.5 mL) The reaction was heated in a CEM Discover microwave system to 90° C. in a sealed microwave tube for 50 min. An additional charge of isobutyraldehyde (0.4 mL, 4.4 mmol) was added and the reaction was heated by microwave to 100° C. for 25 min and then 110° C. for 25 min. The reaction was diluted with EtOAc and washed with brine. The reaction was concentrated and the residue was purified by flash chromatography on silica gel gradient eluted with 0-60% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 426.1 (M+1), 428.1 (M+3); Rt=4.45 min.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:12][C:11]=2O)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:25]=[O:26].[ClH:27]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[C:12]([CH2:11][Cl:27])[C:25]=2[OH:26])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cl
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CC(C)(C)CC(C)(C)c1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
2-(2H-Benzotriazol-2-yl)-4-(1,1,3,3-tetramethyl-butyl)phenol (45.0 g, 140 mmol) is dissolved in acetic acid (200 mL) at 90° C. Zinc chloride (2.0 g, 14 mmol) and paraformaldehyde (18 g, 600 mmol) are added and HCl gas is passed through the reaction mixture for 12 hours at 90° C. The product, which precipitates after cooling to room temperature, is filtered off, washed with cold pentane and dried at 60° C. under vacuum to yield 36 g of 2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-(1,1,3,3-tetramethyl-butyl)-phenol.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[C:5]2[NH:6][C:7](=[O:20])[C:8]3[C:13]([CH3:14])=[N:12][C:11]4[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:10]=4[C:9]=3[N:4]2[N:3]=1.Cl[CH2:23][CH2:24][NH2:25].CN(CCCCl)C>>[NH2:25][CH2:24][CH2:23][N:6]1[C:7](=[O:20])[C:8]2[C:13]([CH3:14])=[N:12][C:11]3[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:10]=3[C:9]=2[N:4]2[N:3]=[C:2]([CH3:1])[CH:21]=[C:5]12
Reactant: NCCCl
Reactant: CCn1ncc2c1nc(C)c1c(=O)[nH]c3cc(C)nn3c12
Agent: CN(C)CCCCl
Product: CCn1ncc2c1nc(C)c1c(=O)n(CCN)c3cc(C)nn3c12

Procedure:
By substituting the 2,6-dimethyl-8-ethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one obtained in Example 16 in the procedure of Example 4 and substituting 2-chloroethylamine for the dimethylaminopropyl chloride, 4-(2-aminoethyl)-2,6-dimethyl-8-ethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[CH2:11][NH2:12].C(N(CC)CC)C.Cl[C:21](=[O:27])[C:22]([O:24]CC)=O.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][NH2:37])=[N:33][CH:34]=1>C(#N)C>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[CH2:11][NH:12][C:22](=[O:24])[C:21]([NH:37][CH2:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([CH3:28])=[CH:34][N:33]=1)=[O:27]
Reactant: COc1cc(C)ccc1CN
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1ccc(CCN)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(C)ccc1CNC(=O)C(=O)NCCc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a mixture of 1.8 g of (2-methoxy-4-methylphenyl)methanamine hydrochloride salt and triethylamine (5.1 mL, 3 equiv.) in dry acetonitrile (45 mL) was added ethyl 2-chloro-2-oxoacetate (1.47 mL, 1 equiv.) dropwise at 0° C. under nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours and 2-(5-methylpyridin-2-yl)ethanamine (2.52 g, 1.4 equiv.) was added. The reaction was heated at reflux for 24 hours. After removal of the solvent, the residue was dissolved in ethyl acetate and washed successively with water and brine, dried over MgSO4, filtered, and evaporated. The residue was washed with methyl t-butyl ether (20 mL) and recrystallized from ethanol to give 1.3 g of N1-(2-methoxy-4-methylbenzyl)-N2-(2-(5-methylpyridin-2-yl)ethyl) oxalamide as a white powder (yield 30%).