Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[N:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][CH:21]=[CH:20]5)=[CH:14][N:15]=3)[N:12]=2)OCC[O:3]1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[N:23]1[C:24]2[C:19](=[CH:18][C:17]([CH2:16][C:13]3[N:11]4[N:12]=[C:7]([C:2](=[O:3])[CH3:1])[CH:8]=[N:9][C:10]4=[N:15][CH:14]=3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC1(c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)OCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)c1cnc2ncc(Cc3ccc4ncccc4c3)n2n1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A solution of 6-((2-(2-methyl-1,3-dioxolan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline (130 mg, 0.37 mmol) in 3 N HCl (5 mL) was stirred at 90° C. for 0.5 h. The reaction mixture was cooled to room temperature, neutralized with saturated aqueous Na2CO3 solution, extracted with ethyl acetate, dried over Na2SO4. The solvent was removed in vacuo to afford 85 mg (75%) of the title compound as yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 9.06 (s, 1H), 8.91 (d, 1H), 8.12 (t, 2H), 8.04 (s, 1H), 7.74-7.71 (m, 2H), 7.48-7.39 (m, 1H), 4.60 (s, 2H), 2.70 (s, 3H). LCMS (method B): [MH]+=304, tR=1.81 min.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]1=O)[CH3:2].[OH-].[K+]>CCO.CCOC(C)=O>[CH2:1]([C:3]12[CH2:16][C:17](=[O:19])[CH:18]=[C:4]1[C:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8]([O:13][CH3:14])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCC1(CC(C)=O)CCc2cc(OC)ccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC12CCc3cc(OC)ccc3C1=CC(=O)C2

Procedure:
A solution of crude 2-ethyl-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-1(2H)-naphthalenone (758 mg, 3 mmol) in EtOH (15 mL) was treated with freshly prepared 2N KOH in EtOH (1.5 mL, 3 mmol). The resulting solution was heated at reflux for 24 hours. After cooling, the mixture was diluted with EtOAc (70 mL) and washed with 1N HCl (35 mL) followed by 5% NaHCO3 (35 mL). The NaHCO3 phase was back-extracted with EtOAc (60 mL). The combined organics were washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40 M (4×15 cm) silica gel column, eluting with 4:1 hexane-EtOAc, to provide 3a-ethyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:15]=[C:16]([C:20]([O:22]CC)=O)[NH:17][C:18](=[O:19])[C:7]1=[CH:6]2.[CH3:25][NH2:26]>C(O)C>[CH3:25][NH:26][C:20]([C:16]1[NH:17][C:18](=[O:19])[C:7]2[C:8]([N:15]=1)=[N:9][C:10]1[C:5]([CH:6]=2)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=1)=[O:22]
Reactant: CN
Reactant: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1
Solvent: CCO
Product: CNC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1

Procedure:
A mixture of ethyl 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (300 mg., 0.90 mM) and ethanol (75 ml.) saturated with anhydrous monomethylamine is heated at 95° C. for 24 hours in a stainless steel bomb. The bomb and contents are cooled, the contents removed and concentrated to dryness under reduced pressure. The residue is recrystallized from chloroform/ethyl acetate to give 250 mg. (88%) of product, m.p. 334° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)#[CH:2].[N:14]([CH2:17][C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([F:20])[F:19])=[N+:15]=[N-:16].C(N(CC)C(C)C)(C)C>O1CCCC1.[Cu]I>[F:19][C:18]([F:20])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:17][N:14]1[CH:2]=[C:1]([C:3]2[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=2)[N:16]=[N:15]1
Reactant: [N-]=[N+]=NCC(F)(F)c1ccccc1
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2cn(CC(F)(F)c3ccccc3)nn2)nc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 67.4 %

Procedure:
To a degassed solution of ethyl 2-ethynyl-4-methylthiazole-5-carboxylate (0.10 g, 0.51 mmol) and (2-azido-1,1-difluoroethyl)benzene (0.14 g, 0.77 mmol) in tetrahydrofuran (5 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.61 mmol), and copper(I) iodide (0.002 g, 0.01 mmol). The reaction mixture was stirred at ambient temperature under nitrogen for 17 hours, and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid (0.13 g, 67%): 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.45-7.31 (m, 5H), 5.02-4.93 (m, 2H), 4.20 (q, J=7.1 Hz, 2H), 2.65 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); MS (ES+) m/z 379.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([NH:8][NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7].[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22](Cl)=[O:23].[OH-].[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([NH:8][N:9]([C:22](=[O:23])[C:21]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:19]([CH3:18])[CH:20]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: COc1cccc(C(=O)NNC(C)(C)C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1C
Yield: 84.1 %

Procedure:
To a stirred solution of N-(3-methoxy-2-methylbenzoyl)-N'-tert-butylhydrazine (506 g, 2.14 mole) in methylene chloride (1.5 L) at 5° C. were simultaneously added solutions of 3,5-dimethylbenzoyl chloride (360 g, 2.14 moles) in methylene chloride (500 mL) and sodium hydroxide (50% aqueous, 171.2 g, 2.14 moles) diluted with water (400 mL), at such a rate that the temperature of the mixture did not exceed 10° C. Following the addition, the reaction mixture was allowed to reach room temperature and stirred continuously for 1 additional hour, whereupon the reaction mixture was diluted with methylene chloride (12 L), washed with water, dried over magnesium sulfate, filtered and stripped to give N-(3-methoxy-2-methylbenzoyl)-N'-(3,5-dimethylbenzoyl)-N'-tert-butylhydrazine (663 g), melting at 204°-204.5° C.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][C@:6]1([CH2:13][CH3:14])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12].[OH-].[Na+]>C(O)C>[CH2:13]([C@@:6]1([CH2:5][CH2:4][C:3]([OH:15])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])[CH3:14]
Reactant: CC[C@@]1(CCC(=O)OC)CCCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@]1(CCC(=O)O)CCCCC1=O
Reaction time: 0.25 h

Procedure:
A solution of (S)-1-ethyl-2-oxocyclohexanepropanoic acid methyl ester (3.25 mol, 689 g) in 1.4 L of ethanol was treated with 1.4 L of 2.5M sodium hydroxide. After 15 minutes at room temperature, the ethanol was removed on a rotary evaporator and the aqueous solution was extracted with ether (2×500 mL). It was acidified with 1 L of 6M hydrochloric acid and extracted with 1×1 L and 2×500 mL of ether. The extracts were combined, dried (magnesium sulfate) and concentrated to a yellow oil (605 g, 3.64 mol, 112%) which was used as in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23](F)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[C:23](=[O:24])[NH:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)F
Reactant: CCOC1OC(=O)C=C1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC1OC(=O)C=C1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 4-amino-5-ethoxy-5H-furan-2-one (0.05 g, 0.35 mmol) and 2-fluorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.09 g, 0.42 mmol) in tetrahydrofuran (5 mL) at room temperature under nitrogen was added sodium tert-butoxide(0.05 g, 0.49 mmol). The reaction was stirred 3 h at reflux. After cooling, the mixture was diluted with ethyl acetate, was washed with 10% potassium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 4:6 ethyl acetate:hexanes afforded (R)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.075 g, 63% yield). Also recovered was starting 4-amino-5-ethoxy-5H-furan-2-one (0.016 g, 32% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39])=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1[CH:34]=[C:35]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:12])[F:13])=[C:4]([Cl:27])[CH:3]=2)[CH:36]=[CH:37][C:38]=1[F:39])=[O:32])[CH3:29]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
The title compound was prepared in analogy to Example 117 from 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 116, step 8) by Suzuki coupling with 3-ethoxycarbonyl-4-fluoro-phenylboronic acid [CAS Reg. No. 874219-36-0]. MS (m/e)=552.3 [M+H+], MS (m/e)=506.1 [(M-CH3CH2O−)+].
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[ClH:13].C(O)(=O)C.N([O-])=O.[Na+]>O.O.[Cu](Cl)Cl.C(Cl)(Cl)Cl.O>[Cl:13][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1
Reactant: Cl
Reactant: Nc1ncc(-c2ccccc2)s1
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1ncc(-c2ccccc2)s1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-amino-5-phenylthiazole described in Journal of Medicinal Chemistry, 1983, Vol. 26 (8), 1158-1163, (1.00 g; 5.67 mmol), copper (II) chloride dihydrate (1.94 g; 11.3 mmol), concentrated hydrochloric acid (8 ml) and acetic acid (8 ml) was added sodium nitrite (0.47 g; 6.80 mmol) under ice-cooling. The mixture was stirred at 40° C. for 1 hour. After returning the reaction solution to room temperature, water and chloroform were added and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (methylene chloride) to give 2-chloro-5-phenylthiazole as pale yellow crystal (0.68 g; 62%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([NH2:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.CCO.O.O1CCOCC1>C(Cl)Cl>[NH2:17][C:15]1[N:14]2[N:18]=[CH:19][CH:20]=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:16]=1
Reactant: Nc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1cc(C2CCC(=O)CC2)nc2ccnn12
Temperature: 80 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
In a 40 mL scintillation vial is combined 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-amine (5.54 mmol, 1.52 g), EtOH (10 mL), H2O (4 mL) and 4N HCL:dioxane (4 mL). The vial was capped, sealed and the reaction was heated to 80° C. overnight. After 18 hours, the reaction mixture was cooled to room temperature and diluted with DCM (100 mL). The solution was washed with saturated NaHCO3(aq) and extracted with DCM twice more. The combined organics are dried over Na2SO4 and the solvent removed in vacuo to yield 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (1.18 g, 93% yield) as pale orange solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:11]1([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2ccc(Cl)cc2Cl)CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a solution of 4-(2,4-dichloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.38 g, 1.1 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred at room temperature for 15 min. Solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 4-(2,4-dichloro-phenyl)-piperidin-4-ol as a white solid (0.23 g, 85%). The material was used as is without further purification.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:17][CH2:16][CH2:15][C:9]=3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1.[Mg].C(O)(=O)C.Cl>CO>[OH:1][CH2:3][CH2:2][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1
Reactant: O=c1[nH]c2cc(C3CO3)ccc2c2c1CCC2
Agent: Cl
Agent: [Mg]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1Nc2cc(CCO)ccc2C2CCCC12
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
A solution of 0.59 g (2.6 mmol) of 7-oxiranyl-1,2,3,5-tetrahydrocyclopenta[c]-quinolin-4-one in 100 ml of methanol is mixed with 1.26 g (52.0 mmol) of magnesium and 0.06 ml of acetic acid. The batch is stirred for 4 hours at room temperature and mixed with another 0.63 g (26.0 mmol) of magnesium. After 15 hours at room temperature, the reaction mixture is acidified with 200 ml of 10% hydrochloric acid and extracted with ethyl acetate (3×200 ml). The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 0.39 g of product.
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][O:11][C:7]=2[C:6]([OH:18])=[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:4]=1)#[CH:2].[CH2:24]([N:31]=[N+:32]=[N-:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(Cl)Cl.O>[CH2:24]([N:31]1[CH:2]=[C:1]([C:3]2[C:8]3[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:10][O:11][C:7]=3[C:6]([OH:18])=[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:4]=2)[N:33]=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C#Cc1nc(C(=O)OCC)c(O)c2onc(-c3ccccc3)c12
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2cn(Cc3ccccc3)nn2)c2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
Ethyl 4-ethynyl-7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (185 mg, 0.60 mmol), benzyl azide (0.087 mL, 0.66 mmol), CuSO4-5H2O (7.5 mg, 0.03 mmol), and sodium ascorbate (18 mg, 0.09 mmol) were added to a mixture of CH2Cl2 (2 mL) and water (2 mL). The mixture was stirred at room temperature for 16 h. Another equiv. of benzyl azide was added, and the mixture was stirred for an additional 16 h. The mixture was diluted with CH2Cl2 (20 mL) and water (20 mL). The aqueous layer was extracted with additional CH2Cl2 and the combined organic layer was dried over MgSO4 and concentrated. The crude product was purified twice by flash chromatography (first with 0-100% EtOAc/hexanes, then with 0-50% CH2Cl2/EtOAc) to afford 100 mg of the title compound. MS: (+) m/z 442.33 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:18](C([O-])=O)(C([O-])=O)[C:19]([O:21]C)=[O:20])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:29]([CH3:31])[CH3:30])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C>C(O)C>[C:19]([OH:21])(=[O:20])[CH3:18].[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:29]([CH3:31])[CH3:30])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C(=O)[O-])(C(=O)[O-])C1CCCc2nc(C(C)C)n(Cc3ccc(I)cc3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1nc2c(n1Cc1ccc(I)cc1)C(CC(=O)O)CCC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 132.4 %

Procedure:
To a stirred solution of Intermediate 89 (11.1 g) in Ethanol (150 mL) was added 2M Aqueous Sodium Hydroxide (36.4 mL). The reaction mixture was then stirred at 80° C. and under nitrogen for 3 h. The reaction mixture was concentrated in vacuo, glacial acetic acid (41.6 mL, 727 mmol) added and allowed to stir at 120° C. and under nitrogen for 2 h. The reaction mixture was concentrated under vacuum. The white solid was suspended and stirred in ether (500 mL) for 5 mins. The white solid was filtered off under vacuum. The solid was suspended in EtOAc (500 mL) and the suspension was refluxed for 45 mins. The white solid was hot filtered under vacuum and washed with EtOAc (100 mL). The filtrate was concentrated under vacuum to give the title compound as a white solid (6.8 g). LC/MS MH+ 439, Rt 1.90 min (5 min run).
Reaction SMILES: [CH3:1][C@H:2]1[O:9][C:7](=[O:8])[C@H:6]([CH3:10])[O:5][C:3]1=[O:4]>O>[CH3:1][CH:2]1[O:9][C:7](=[O:8])[CH:6]([CH3:10])[O:5][C:3]1=[O:4]
Reactant: C[C@@H]1OC(=O)[C@@H](C)OC1=O
Solvent: O
Product: CC1OC(=O)C(C)OC1=O

Procedure:
When DL-lactic acid is used as a raw material, the crude lactide has a high meso-lactide content. When the crude lactide is gradually cooled, DL-lactide is precipitated and allowed to persist in the form of crystals in the molten meso-lactide phase and the whole crude lactide assumes a slurry state. The crude lactide in the slurry state is mixed with a substantially equal weight of water and the resultant mixture is immediately cooled to the vicinity of 30° C. for the purpose of preventing DL-lactide from undergoing hydrolysis and kept stirred at this temperature for a period in the range of 30 minutes to one hour, with the result that meso-lactide is dissolved in water and, at the same time, part of the dissolved meso-lactide undergoes hydrolysis. The crystals of DL-lactide are separated by filtration from the water phase and are dissolved in such an organic solvent as acetone or MIBK thereby recrystallizing therefrom to produce easily DL-lactide crystals of high purity.
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[C:15]2[C:10]=1[C:11](=[O:34])[C:12]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:13][N:14]2[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1>CCO.CC(O)=O.[Pd]>[NH2:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[C:15]2[C:10]=1[C:11](=[O:34])[C:12]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:13][N:14]2[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cn(CCc2ccccc2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(CCc2ccccc2)c2cc(F)c(F)c(N)c2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To a suspension of ethyl 5-benzylamino-6,7-difluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylate (700 mg, 1.51 mmol) in a mixture of EtOH (2 mL) and AcOH (2 mL), was added 10% Pd—C (70.0 mg), the whole mixture was stirred at room temperature for 4 h under H2 atmosphere (1 atm). After insoluble materials were filtered off, the filtrate was concentrated in vacuo. To a solution of the residue in AcOH (2 mL), a suspension of 10% Pd—C (70 mg) in AcOH (2 mL) was added, the whole mixture was stirred at room temperature for 4 h under H2 atmosphere (1 atm). After insoluble materials were filtered off and washed with DMF, the combined filtrate and washing was concentrated in vacuo. Trituration of the residue with EtOH gave ethyl 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylate (499 mg, 89%) as pale brown powder.
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[C:28](Cl)(=[O:33])[CH:29]=[CH:30][CH2:31][CH3:32]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:33])[CH:29]=[CH:30][CH2:31][CH3:32])[CH2:24][CH2:23]2)[N:9]=1
Reactant: CCC=CC(=O)Cl
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC=CC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.33 h
Yield: 50.3 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.78 g of 2-pentenoyl chloride, after which the mixture was stirred at room temperature for 15 hours. The resulting crystals were collected by filtration, washed with water and recrystallized from ethanol, to give 1.23 g of the desired Compound No. 5 in the form of pale brown needles melting at 246°-247° C.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC=CC=1C#N)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: N#Cc1ccccc1COC(=O)c1cc(Br)ccc1OCc1ccccc1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1COc1ccc(Br)cc1C(=O)O
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A solution of lithium hydroxide (328 mg, 7.83 mmol) in water (20 m) was added dropwise to a stirred solution of (2-cyanophenyl)methyl 5-bromo-2-{[(2-cyanophenyl)methyl]oxy}benzoate (may be prepared as described in Description 34; 350 mg, 0.78 mmol) in THF (20 ml) over 1 min. The reaction mixture was stirred at 20° C. for 18 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The residual water phase was extracted with ethyl acetate (3×20 ml). The organic phase was then evaporated in vacuo to yield the title compound as a light yellow solid. 160 mg.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CNCCN1Cc1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.9 %

Procedure:
To a solution of the title compound from step A (320 mg, 1.1 mmol) in DCM (5 ml) was added TFA (2.1 ml, 27.5 mmol) and the resulting mixture stirred at RT for 4 h. Mixture evaporated and residue dissolved in MeOH and passed through an SCX cartridge (eluting with 2M ammonia in methanol) to form free base. Evaporated and residue lypholized from CH3CN/water to afford the title compound 44 mg (21%) as an orange oil. 1H NMR (CDCl3): 1.14 (d, J 6.2 Hz, 3H), 2.24 (m, 1H), 2.47 (m, 1H), 2.64 (dd, J 12.3 and 9.3 Hz, 1H), 2.73 (m, 1H), 2.87-2.97 (m, 3H), 3.44 (d, J 14.2 Hz, 1H), 4.14 (d, J 14.3 Hz, 1H), 7.17 (dd, J 7.0 and 5.4, 1H), 7.47 (d, J 7.8, 1H), 7.66 (m, 1H), 8.56 (d, J 4.7 Hz, 1H).