Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([CH:36]([OH:44])[CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH2:26][CH2:25][CH2:24][CH2:23]1>ClCCl>[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([C:36](=[O:44])[C:37]([C:38]3[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=3)=[O:2])[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COc1ccc(C(O)Cc2ccncc2)cc1OC1CCCC1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)C(=O)c2ccncc2)cc1OC1CCCC1
Reaction time: 1.5 h
Yield: 19.3 %

Procedure:
Pyridinium dichromate (3.6 g) in dry dichloromethane (40 mL) under nitrogen is treated with (±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol (2.0 g), in one portion. The resulting mixture is stirred for 1.5 hours, and then filtered through a pad of diatomaceous earth, and the pad is washed with diethyl ether. The combined filtrate and ethereal washings are washed with saturated aqueous cupric sulfate solution (2×30 mL), followed by water (30 mL), and then dried over magnesium sulfate. The solvent is removed under reduced pressure, and the resulting oily residue is subjected to flash chromatography on silica gel, eluting with ethyl acetate, to give 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethane-1,2-dione (0.4 g), in the form of a yellow solid, m.p. 117-119° C. [Elemental analysis: C, 70.1; H, 6.0; N, 4.1%. calculated: C, 70.1; H, 5.9; N, 4.3%].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: OCC1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCC(CO)CC3)ccc21
Yield: 106.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-piperidine methanol (84 mg, 0.729 mmol), acetic acid (0.168 mL, 2.93 mmol) and sodium triacetoxyborohydride (54 mg, 0.26 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and ethyl acetate, followed by extracting with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-[4-(hydroxymethyl)piperidinomethyl]indol-2-yl]isoindolinone (39.7 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.S(Cl)([Cl:14])=O>>[CH3:1][N:2]=[C:3]([Cl:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1
Reactant: CNC(=O)c1ccc(C)cc1
Reactant: O=S(Cl)Cl
Product: CN=C(Cl)c1ccc(C)cc1
Yield: 79.9 %

Procedure:
N-Methyl 4-methylbenzamide (10.02 g, 67.2 mmole) was treated with thionyl chloride (31.7 g, 267 mmole) as in Example I. Gas evolution ceased after the reaction had been heated for 45 minutes. The product was isolated as in Example I to yield 9.0 g (80%) of the title compound as a clear colorless liquid, b.p. 57° C. (~0.1 mm Hg).
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23]>[Cu]I.C(#N)C>[CH3:9][NH:8][C:5]1[N:4]=[C:3]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:2]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:7][N:6]=1
Reactant: CNc1ncc(Br)c(-c2cccs2)n1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNc1ncc(C#C[Si](C)(C)C)c(-c2cccs2)n1
Temperature: 90 °C

Procedure:
A 75 mL thick wall glass tube with a teflon screw cap was charged with 5-bromo-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine (0.995 g, 3.68 mmol), acetonitrile (9 mL), triethylamine (3.00 ml, 3.68 mmol), dichlorobistriphenylphosphine palladium(II) (0.259 g, 0.368 mmol), copper(I) iodide (0.0351 g, 0.184 mmol), and ethynyltrimethylsilane (0.362 g, 3.68 mmol). The tube was capped and heated to 90° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0-100% ethyl acetate-hexane) to afford N-methyl-4-(thiophen-2-yl)-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine. MS m/z=288 [M+H]+. Calc'd for C14H17N3SSi: 287.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:29]([CH3:30])=[CH:28][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:26]([CH3:27])=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)[S:17][C:13]=2[C:12]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:40]1COCC1.CO>>[CH3:40][C@:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([C:11]1[C:29]([CH3:30])=[CH:28][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:26]([CH3:27])=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)[S:17][C:13]=2[C:12]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4[nH]cc(C)c4c3)sc2c1-c1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2nc(-c3cnc4[nH]cc(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@](C)(OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate: (8 mg, 0.015 mmol) in THF/CH3OH (0.5 mL/0.5 mL) was added 2N NaOH (75 μL, 0.15 mmol). The reaction mixture was heated at 50° C. for 2 h and the crude was purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C28H26ClN3O3S: 520.14 (M+H+); Found: 520.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.86 (d, J=1 Hz, 1H), 8.57 (d, J=1 Hz, 1H), 7.84 (s, 1H), 7.71-7.26 (m, 5H), 5.26 (s, 1H), 2.62 (s, 3H), 2.36 (s, 3H), 0.94 (s, 9H).
Reaction SMILES: [ClH:1].Cl.[CH:3]1([CH2:6][NH:7][NH2:8])[CH2:5][CH2:4]1.[CH3:9][C:10]([CH3:17])([CH3:16])[C:11](=O)[CH2:12][C:13]#[N:14]>C(O)C>[ClH:1].[C:10]([C:11]1[CH:12]=[C:13]([NH2:14])[N:7]([CH2:6][CH:3]2[CH2:5][CH2:4]2)[N:8]=1)([CH3:17])([CH3:16])[CH3:9]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNCC1CC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(CC2CC2)n1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A mixture of Example 3A (13.5 g, 85 mmol) and 4,4-dimethyl-3-oxopentanenitrile (11.7 g, 93 mmol) in ethanol (100 mL) was heated at reflux for 6 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL). The resulting white precipitate was filtered, washed with ether, and dried to yield 17.5 g (90%) of title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.42-0.54 (m, 4H), 1.16-1.27 (m, 1H), 1.28 (s, 9H), 4.38 (d, J=7.12 Hz, 2H), 4.80 (br, 2H), 5.53 (s, 1H), 15.5 (br, 1H); MS (DCI) m/z 194 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[OH:29][C:30]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].[OH-].[Na+].Cl>C(Cl)Cl>[OH:29][C:30]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:33]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1O
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 1.00 g (4.50 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 ml of dry methylene chloride, add 4.50 g (38.50 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.58 g (5.70 mmol) of triethylamine and a solution of 0.77 g (38.50 mmol) of 2-hydroxy-4-nitrobenzoyl chloride dissolved in 10 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H2O). This yields 0.50 g (34%) of 4-[2-(2-hydroxy-4-nitro-benzoylamino)benzoylamino]butanoic acid as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[C:32]([Cl:39])[CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[C:32]([Cl:39])[CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[CH:24][CH:23]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ccc3cccc(Cl)c3n2)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc3cccc(Cl)c3n2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(8-chloro-quinolin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: B(Br)(Br)Br.Br.[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:25][CH2:26][O:27]C)[N:19]([CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[C:15]=2[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.Cl.[OH-].[Na+]>ClCCl.CO>[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:25][CH2:26][OH:27])[N:19]([CH2:20][C:21]([CH3:22])([OH:23])[CH3:24])[C:15]=2[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: COCCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)O
Agent: Br
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)Cn1c(CCO)nc2c(N)nc3cccnc3c21
Reaction time: 16 h
Yield: 29.8 %

Procedure:
A solution of boron tribromide in dichloromethane (22.71 mL of 1 M) was added to a chilled (0° C.) suspension of 1-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol hydrobromide (3.00 g, 7.57 mmol) in dichloromethane (100 mL). The reaction mixture was allowed to come to ambient temperature with stirring for 16 hours. Methanol (30 mL) and hydrochloric acid (30 mL of 6 N) were added and the reaction mixture was heated at reflux for 2.5 hours. The reaction mixture was made basic with sodium hydroxide and the layers were separated. The aqueous layer was extracted with dichloromethane (100 mL). The extract was washed sequentially with water and brine, dried over magnesium sulfate, and then concentrated under reduced pressure to provide a pink solid. This material was crystallized from acetonitrile to provide 0.68 g of 1-[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol. The aqueous layer was combined with the water and brine washings and allowed to stand overnight. A precipitate was isolated by filtration, washed with water, and dried under vacuum at 95° C. for 3 hours to provide 1.16 g of 1-[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a pink crystalline solid, mp 194-195° C. Anal. calcd for C15H19N5O2: % C, 59.79; % H, 6.36; % N, 23.24. Found: % C, 59.51; % H, 6.59; % N, 23.34.
Reaction SMILES: [O:1]=[C:2]([CH:10]([C:14]([O:16][CH3:17])=[O:15])C(=O)C)[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].N>O1CCCC1>[CH2:7]([O:6][C:4]([CH:3]([CH3:9])[C:2](=[O:1])[CH2:10][C:14]([O:16][CH3:17])=[O:15])=[O:5])[CH3:8]
Reactant: CCOC(=O)C(C)C(=O)C(C(C)=O)C(=O)OC
Agent: N
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(=O)CC(=O)OC

Procedure:
Ethyl 3,5-dioxo-4-methoxycarbonyl-2-methylhexanoate (176 mg; 0.72 mmole) was dissolved in tetrahydrofuran (1.3 ml), and 1.7N aqueous ammonia (0.85 ml) was added thereto at room temperature. The resultant mixture was allowed to stand at the same temperature overnight, followed by removal of tetrahydrofuran under reduced pressure. The reaction mixture was combined with lN hydrochloric acid (0.7 ml) and an aqueous sodium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 4-ethoxycarbonyl-3-oxopentanoate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20](I)[CH3:21]>O>[NH2:1][C:2]1[C:3]([C:11]([O:13][CH2:20][CH3:21])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCI
Reactant: CCCc1ccnc(C(=O)O)c1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCCc1ccnc(C(=O)OCC)c1N
Reaction time: 0.25 h
Yield: 80 %

Procedure:
3-Amino-4-n-propylpyridine-2-carboxylic acid (Preparation 4; 0.36 g, 0,002 mol) was added to a stirred mixture of cesium carbonate (0,325 g, 0.001 mol) in water (20 ml), then this mixture was evaporated under vacuum and the residue azeotroped with dimethylformamide (2×20 ml). The resulting cesium salt was suspended in dimethylformamide (3 ml) and the stirred suspension then treated dropwise with ethyl iodide (0.17 ml, 0.0021 mol). After a further 0.25 hour, the solvent was evaporated under vacuum and the residue partitioned between water (20 ml) and ethyl acetate (20 ml). The organic phase was washed with water (10 ml), dried (MgSO4) and evaporated under vacuum, then the residue crystallised from acetone:hexane to give the title compound as an off-white solid (0.35 g, 84%), m.p. 93°-96° C. Found: C,63.39; H,7.73; N,13.39. C11H16N2O2 requires C,63.44; H,7.74; N,13.45%.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[N:9]=[C:10]([C:15]#[C:16][Si](CC)(CC)CC)[C:11]([NH2:14])=[N:12][CH:13]=1>CN1CCCC1=O.CCOC(C)=O.O>[Br:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:16][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: CC[Si](C#Cc1nc(Br)cnc1N)(CC)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1cnc2[nH]ccc2n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
Potassium tert-butoxide (6.612 g, 58.92 mmol) was suspended/dissolved in dry N-methylpyrrolidinone (15 mL) and stirred at 80° C. while a solution of 5-bromo-3-(2-triethylsilylethynyl)pyrazin-2-amine (9.1992 g, 29.46 mmol) in dry N-methylpyrrolidinone (50 mL) was added slowly drop wise over 10 minutes. The dropping funnel was washed out with a further aliquot of dry N-methylpyrrolidinone (10 mL). The resultant was stirred at 80° C. for 1.5 hours. Reaction mixture cooled to ambient then diluted with EtOAc and water and EtOAc layer washed with small portions of water (×6). Organic layer dried (MgSO4), filtered and concentrated in vacuo to give a dark brown solid (4.1 g, 70.3%). 1H NMR (400.0 MHz, DMSO) δ 12.50 (s, 1H), 8.37 (s, 1H), 8.01 (s, 1H) and 6.64 (q, J=1.7 Hz, 1H) ppm; MS (ES+) 198.10.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([Mg]Br)[CH:16]=[CH2:17].[Cl-].[NH4+]>C(OCC)C>[CH2:17]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH:16]=[CH2:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h

Procedure:
800 ml solution of 25.0 g tert-butyl 4-oxo-1-piperidinecarboxylate in diethyl ether was cooled in ice/methanol, and 138 ml solution of allylmagnesium bromide (1 M in diethyl ether) was added dropwise thereinto. The reaction mixture was stirred for 3 hr and 10 min. The reaction solution was poured into a mixture of saturated aqueous ammonium chloride and ice. The diethyl ether layer was recovered and washed with brine. It was dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated, and the resulting residue was purified by silica gel column chromatography to give 15.9 g of tert-butyl 4-allyl-4-hydroxy-1-piperidinecarboxylate.
Reaction SMILES: C1(COC([S:8][CH:9]2[N:12]([C:13](=[C:18]([O:21]C(OCC3CC3)=O)[CH2:19][Br:20])[C:14]([O:16][CH3:17])=[O:15])[C:11](=[O:29])[CH:10]2[N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])=O)CC1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[SH:8][CH:9]1[N:12]([C:13](=[C:18]([OH:21])[CH2:19][Br:20])[C:14]([O:16][CH3:17])=[O:15])[C:11](=[O:29])[CH:10]1[N:30]1[C:31](=[O:40])[C:32]2=[CH:39][CH:38]=[CH:37][CH:36]=[C:33]2[C:34]1=[O:35]
Reactant: COC(=O)C(=C(CBr)OC(=O)OCC1CC1)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1SC(=O)OCC1CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(=C(O)CBr)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of methyl α-[4-cyclopropylmethoxycarbonylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-(2-bromo-1-cyclopropylmethoxycarbonyloxyethylidene)-acetate (500 mg) in methylene chloride (20 ml) is added aluminum chloride (510 mg) at once and the mixture is stirred at room temperature. After 1 hour, the mixture is poured into cold 3% hydrochloric acid (20 ml), and extracted with methylene chloride. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give methyl α-[4-mercapto-3-phthalimido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)-acetate (252 mg). Yield: 72.5%. IR: νmaxCHCl3 1790, 1783, 1728, 1670, 1620 cm-1. NMR: δCDCl3 1.80d(11Hz)1H, 3.87s3H, 4.22+4.56AB2(10Hz)2H, 5.38dd (11; 5Hz)1H, 5.70d(5Hz)1H, 7.76m4H, 12.3s1H.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[N:12]=[C:13]([C:17]([O:19]CC)=[O:18])[NH:14][C:15](=[O:16])[C:6]1=[CH:5]2.[OH:22][C:23]1C=C2C(=CC=1)N=C1N=C(C(O)=O)NC(=O)C1=C2>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:22][CH3:23])[N:8]=[C:7]1[N:12]=[C:13]([C:17]([OH:19])=[O:18])[NH:14][C:15](=[O:16])[C:6]1=[CH:5]2
Reactant: CCOC(=O)c1nc2nc3ccc(O)cc3cc2c(=O)[nH]1
Reactant: O=C(O)c1nc2nc3ccc(O)cc3cc2c(=O)[nH]1
Product: COc1cc2nc3nc(C(=O)O)[nH]c(=O)c3cc2cc1O

Procedure:
In like manner, ethyl 7-hydroxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylate hemitrifluoroacetate (210 mg.) is converted to 7-hydroxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylic acid. Yield - 191 mg., 91%; m.p. 340° C (dec.)
Reaction SMILES: [OH:1][CH2:2][C@@:3]([NH:24]C(=O)OC(C)(C)C)([CH3:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][CH:7]=1.[ClH:32]>O1CCOCC1>[ClH:32].[NH2:24][C@:3]([CH3:23])([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])=[CH:10][CH:11]=1)[CH2:2][OH:1]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(OCCCC(F)(F)C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@](N)(CO)CCc1ccc(OCCCC(F)(F)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To tert-butyl {(R)-1-hydroxy-2-methyl-4-[4-(4,4,5,5,5-pentafluoro-pentyloxy)-phenyl]-but-2-yl}-carbamate (25 mg, 0.055 mmol) is added 4 M HCl in dry dioxane (1 ml). The clear colorless solution is stirred for 2 h protected from moisture. Then, the solution is evaporated to dryness and the partially crystalline residue is taken up in dry ether (5 ml). Sonication for 10 min gives a precipitate of colorless crystals. The product is filtered off, washed with cold ether (3×1 ml), and dried in vacuo to afford the title compound in form of a non hygroscopic colorless microcrystalline powder: mp. 186-189° C. MS (ESI+): 356 (MH+), 1H-NMR (400 MHz, CD3OD): δ 1.35 (s, 3H, 2-Me), 1.91 (cm, 2H, 3-CH2), 2.06 (cm, 2H, 2′-CH2), 2.35 (cm, 2H, 3′-CH2), 2.63 (cm, 2H, 4-ArCH2), 3.55 (d, 1H, 2J=12.1, 1-CHα), 3.63 (d, 1H, 2J=11.9, 1-CHβ), 4.06 (t, 3H, 3J=7.1, 1′-OCH2), 6.88 (‘d’, 2H, J=11.0, ArH), 7.18 (‘d’, J=10.8 Hz, ArH).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Cl:20])C(=O)C1.CCOC(C)=O>CN(C=O)C.CCCCCC>[Cl:20][C:3]1[C:2]([OH:1])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cncc(O)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(Cl)c(O)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of ethyl 5-hydroxynicotinate (20 g, 0.119 mol, in DMF (200.0 mL) was added NCS (19.18 g, 0.143 mol, Aldrich). The reaction mixture was stirred for 2 h at 80° C. After completion of the reaction (monitored by TLC, 30% EtOAc in hexane), the reaction mixture was quenched with sat'd NaHCO3 solution (50 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, and purified by column chromatography, silica gel (100-200 mesh), using 10-15% EtOAc in petroleum ether as the eluent to give the title compound as a solid. 1H NMR (400 MHz, CDCl3) δ: 8.61 (d, J=2.1 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 5.94 (br. s., 1H), 4.53 (q, J=6.9 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H). MS (ESI, positive ion) m/z: 202.1 (M+H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:5]=1[C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][O:31][CH2:32][CH3:33])=[CH:24][C:23]=2[O:34][CH3:35])=[CH:18][CH:17]=1)[C:10]([O:12]CC)=[O:11])=[O:7].Cl>O.O1CCCC1>[F:3][C:4]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:5]=1[C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]([O:34][CH3:35])=[CH:24][C:25]([CH2:30][O:31][CH2:32][CH3:33])=[CH:26][C:27]=2[O:28][CH3:29])=[CH:20][CH:21]=1)[C:10]([OH:12])=[O:11])=[O:7]
Reactant: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)OCC)cc2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(OC)c1
Reaction time: 4 h
Yield: 96 %

Procedure:
To a solution of sodium hydroxide (2.9 g) in water-tetrahydrofuran (317 ml-159 ml) was added ethyl (αS)-α-[(2,6-difluorobenzoyl)amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionate (31.7 g) at 15° C. and the mixture was stirred for 4 hours at the same temperature. After neutralizing with 1N HCl, the organic solvent was removed in vacuo. The aqueous layer was cooled, the crystalline precipitates were collected by filtration and recrystallized from ethanol-water to yield (αS)-α-[(2,6-difluorobenzoyl)amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionic acid (28.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:26])[CH2:14][NH:15][C:16]3[CH:25]=[CH:24][C:19]4NC(=O)O[C:18]=4[CH:17]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:29][O:30]C1C=CC(N)=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:26])[CH2:14][NH:15][C:16]3[CH:25]=[CH:24][C:19]([O:30][CH3:29])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)=[CH:27][CH:28]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(CNc1ccc2[nH]c(=O)oc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Solvent: CCOCC
Product: COc1ccc(NCC(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-1-[4-(4-chloro-phenoxy)-piperidin-1-yl]-ethanone (Example 233) and 4-methoxy-aniline according to the method described in Example 206. Melting Point: 127-130° C. (diethylether)