Azzindani/Open_Reaction_Data huggingface dataset:
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][CH:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1>>[C:28]([CH: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)[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([OH:30])=[O:29]
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1c[nH]c2ccccc12)C(=O)O
Yield: 42 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-tryptophan to provide the title compound in 42% yield as yellow needles (recrystallization from isopropanol).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([F:31])=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:11][N:10]=1)(C)(C)C.Cl>[Pd].CO>[Cl:30][C:26]1[CH:25]=[C:24]([C:18]2[C:19]([O:22][CH3:23])=[CH:20][CH:21]=[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][NH2:7])=[N:10][CH:11]=3)[C:17]=2[F:31])[CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(Cc2ccc(CNC(=O)OC(C)(C)C)nc2)c(F)c1-c1cccc(Cl)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(Cc2ccc(CN)nc2)c(F)c1-c1cccc(Cl)c1
Reaction time: 18 h

Procedure:
Into a 100 mL round bottom flask was added P-355 (0.55 g, 1.56 mmol), methanol (20 mL), concentrated HCl (0.65 mL, 7.79 mmol), and 10% Pd/C (100 mg). The suspension was stirred under a H2 balloon for 18 hours, then filtered through Celite. The filtrate was concentrated. To the solid was added 1N aqueous NaOH and the product was extracted with dichloromethane. The dichloromethane was concentrated and purified by flash column chromatography eluting with 5-10% methanol/dichloromethane to give P-344 (89 mg, 16%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) 8.55 (d, J=1.2 Hz, 1H), 8.32 (br s, 3H), 7.71 (dd, J=1.9, 7.9 Hz, 1H), 7.50-7.37 (m, 3H), 7.36 (d, J=5.4 Hz, 2H), 7.27 (d, J=6.6 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 4.75 (br s, 2H), 4.14 (q, J=5.8 Hz, 2H), 4.01 (s, 2H), 3.73 (s, 3H) ppm. LC/MS=95.1%, 357.1 (APCI+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]2([CH3:24])[CH2:13][C@@H:12]([CH2:14][OH:15])[S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C(O)C.CCOC(C)=O.O.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>[OH:15][CH2:14][C@H:12]1[S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:9][C@:8]([CH3:24])([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:29]3[CH:30]=[N:25][CH:26]=[N:27][CH:28]=3)[CH:3]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(Br)c2)C[C@@H](CO)S1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(-c3cncnc3)c2)C[C@@H](CO)S1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
To a 110° C. solution of (+/−) tert-butyl (4S,6S)-4-(3-bromophenyl)-6-(hydroxymethyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate (150 mg, 0.36 mmol) in 1,2-dimethoxyethane (4.5 mL), ethanol (1.5 mL), and water (2.3 mL) is added pyrimidine-5-boronic acid (112 mg, 0.90 mmoles, 2.5 equiv), cesium carbonate (353 mg, 1.08 mmol, 3 equiv), and bis(triphenylphosphine)palladium(II) chloride (25 mg, 0.036 mmol, 0.1 equiv). The reaction is stirred at 110° C. After 20 minutes, the reaction mixture is diluted with EtOAc and H2O. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue is purified by column chromatography on silica gel (5% MeOH/DCM) to give the title compound (29% yield): MS (m/z): 415 (M+1)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([NH:16][C@@H:17]([C:19](O)=[O:20])[CH3:18])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>ClCCl.CCOC(C)=O>[CH3:18][C@@H:17]([NH:16][C:6](=[O:7])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:19](=[O:20])[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Pyrrolidine (1668 uL, 2 mmol), N-CBZ-D-alanine (446 mg, 2 mmol), and HOAt (272 mg, 2 mmol) were dissolved in 6 mL of dichloromethane. NMM (0.44 mL, 4 mmol) was added, followed by EDC (382 mg, 2 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with EtOAc, washed with water, saturated aqueous NaHCO3 solution, and saturated aqueous NH4Cl solution, then dried (Na2SO4) and evaporated to yield phenylmethyl [(1R)-1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]carbamate as a white solid (496 mg, 90%). LCMS: (M+H)+: 277.2.
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)[CH2:15][CH2:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Cl-].[NH4+]>CO.O.[Fe]>[F:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[NH2:27])[CH2:17][CH2:18]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)c(F)ccc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)c(F)ccc2n1
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 6-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline (0.05 g; 1 eq) in methanol (3 mL) was added dropwise to a suspension of iron powder (0.05 g; 7 eq) and ammonium chloride (0.05 g; 7 eq) in water (3 mL). The reactants were heated at reflux for 8 hours, with additional amounts of iron powder (total 0.05 g; 7 eq) and ammonium chloride (0.05 g; 7 eq) added in 3 portions during the reaction. The reaction mixture was cooled to room temperature and filtered using a Millipore filter. The filtrate was concentrated under reduced pressure, diluted with water (5 mL) and a saturated aqueous solution of sodium hydrogen carbonate (2 mL) and extracted into ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound in 91% yield (0.04 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH:29]=[N:28][C:27]=4[CH3:31])[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH:29]=[N:28][C:27]=4[CH3:31])[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2scnc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2scnc2C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(4-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (284 mg) in a mixture of tetrahydrofuran (18 ml) and methanol (18 ml) was added 1N sodium hydroxide solution (6 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(4-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (201 mg) as yellow crystals.
Reaction SMILES: [O:1]1[C:7]2[C:8]([C:11]3(O)[CH2:14][CH2:13][CH2:12]3)=[CH:9][S:10][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH:11]1([C:8]2[C:7]3[O:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]=3[S:10][CH:9]=2)[CH2:12][CH2:13][CH2:14]1
Reactant: OC1(c2csc3c2OCCNC3)CCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1sc2c(c1C1CCC1)OCCNC2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To 1-(2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepin-8-yl)cyclobutanol (1.00 g) were added triethylsilane (4.90 ml) and trifluoroacetic acid (4.73 ml) in this order under ice-cooling, and the mixture was stirred at 70° C. for 1 hr. The solvent was evaporated under reduced pressure, ice water (10 ml) and 8N aqueous sodium hydroxide solution (10 mL) were added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 0→50% ethyl acetate/hexane) to give 8-cyclobutyl-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine as an oil. Ethyl acetate (5 mL) and 4N hydrogen chloride-ethyl acetate solution (5 mL) were added thereto, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of MeOH and Et2O to give 8-cyclobutyl-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride (360 mg, 47.7%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[NH:13][C:12](=O)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1.P(Cl)(Cl)([Cl:17])=O.[OH-].[Na+]>C(#N)C>[Cl:17][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[N:13]=1
Reactant: Cn1cc(Nc2nccc(=O)[nH]2)cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1cc(Nc2nccc(Cl)n2)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4(3H)-one (3.4 g) obtained in Step B in acetonitrile (35 mL) was added dropwise phosphorus oxychloride (3.2 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (3.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C(O)(=O)C.C([BH3-])#N.[Na+].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2Cc1ccccc1
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a solution of 5-methoxyindole (147 mg, 1.00 mmol) in 2.5 mL of tetrahydrofuran was added acetic acid (2.5 mL) and sodium cyanoborohydride (220 mg, 3.50 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 20 min, benzaldehyde (0.20 mL, 2.0 mmol) was added with additional stirring for 1 h. After the reaction mixture was diluted with water (20 mL) and a 1:1 solution (20 mL) of hexane and ethyl acetate, the aqueous layer was extracted with a 1:1 solution (20 mL) of hexane and ethyl acetate. The combined extracts were washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain 5-methoxy-1-benzylindoline (158 mg, 66%) as a sticky oil. To 5-methoxy-1-benzylindoline (4.30 g, 18.0 mmol) was added a solution of 50% hydrogen bromide-acetic acid solution (90 mL) at room temperature. After the reaction mixture was stirred at 115° C. for 22 h, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution (200 mL) and the solution was extracted with ethyl acetate (200 mL) twice. The combined extracts were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 70/30) to obtain the title compound (3.78 g, 93%) as a sticky oil.
Reaction SMILES: O.[C:2]1(C)[CH:7]=[CH:6][C:5]([S:8](O)(=O)=O)=[CH:4][CH:3]=1.[C:13](=[O:16])([O-])O.[Na+]>CO>[S:8]1[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:2]([CH2:7][CH2:6][CH2:13][OH:16])=[CH:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCCCc1csc2ccccc12

Procedure:
A solution of compound 80-2 (2.04 g) and p-toluenesulfonic acid monohydrate (10.0 mg) in methanol (80 ml) was stirred at room temperature for 20 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and methanol was evaporated under reduced pressure. Water was added to the obtained mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give the object product (1.48 g) as a brown oil.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([C:12]([N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[OH:15])=[O:13])[NH2:11])C1C=CC=CC=1>CCO.[Pd]>[C:19]([O:18][C:16]([N:14]([C:12](=[O:13])[C@@H:10]([CH2:9][OH:8])[NH2:11])[OH:15])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N(O)C(=O)[C@H](N)COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(O)C(=O)[C@H](N)CO

Procedure:
A solution of 20 (137 mg, 0.44 mmol) in EtOH (7 mL) containing 10% Pd—C (46 mg) was hydrogenated at 1 atm (1.5 h). The catalyst was filtered and the filtrate was concentrated in vacuo, and then crystallized with isopropyl ether to afford 21 as a solid. Yield, 81%; Rf=0.19 (10% MeOH—CHCl3); mp 108-110° C. (lit.6) mp 106-112° C. for L-isomer); IR (KBr) 3421, 3318, 2871, 1726, 1670, 1514, 1370, 1243, 1160 cm−1; 1H NMR (CD3OD, 300 MHz) δ1.44 (s, 9H), 3.69 (d, J=5.4 Hz, 2H), 4.06 (t, J=5.4 Hz, 1H); 13C NMR (CD3OD, 75 MHz) δ28.7 (3 C), 56.1, 63.2, 80.9, 157.6, 170.1; MS (+CI) 221 [M+1]+; Mr (+CI) 221.113 90 [M+1]+ (calcd for C8H17N2O5, 221.113 74).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:19]=[C:20]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][C:25]5=[O:30])[CH:21]=[CH:22][CH:23]=4)[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1.[BH4-].[Li+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:19]=[C:20]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH:25]5[OH:30])[CH:21]=[CH:22][CH:23]=4)[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCOCC5=O)c4)c3n2)cn1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCOCC5O)c4)c3n2)cn1
Yield: 10 %

Procedure:
To a solution of 4-(3-((6-(1-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one (45 mg, 0.12 mmol) in 4 mL methanol was added lithium borohydride (170 mg, 70 eq in seven portions every 10 min). The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, the combined organic phases dried over sodium sulfate and evaporated. The residue was purified with the preparative HPLC to yield the title compound (5 mg, 12 μmol, 10%). 1H NMR (d6-DMSO) δ 8.22 (s, 1H), 7.78 (s, 1H), 7.37-7.32 (m, 3H), 7.29-7.24 (m, 1H), 7.12-7.08 (m, 1H), 7.01 (s, 1H), 6.06 (s, 1H), 5.16 (s, 2H), 4.45 (s, 2H), 4.18 (s, 2H), 3.96-3.91 (m, 2H), 3.76 (s, 3H), 3.68-3.63 (m, 2H); LC-MS method B, (ES+) 407.2, RT=4.04 min.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:14]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[CH:16]=1)[OH:15]>CN(C)C=O>[Si:6]([O:15][C:14]1[CH:16]=[C:17]([OH:18])[CH:19]=[CH:20][CH:21]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
Imidazole (4.3 g, 62 mmol) and t-butyldimethylsilylchloride (5.5 g, 36 mmol) were added to a solution of resorcinol (2.8 g, 25 mmol) and dimethylformamide (100 mL) in a 250 mL round bottom flask under a nitrogen atmosphere at room temperature. The solution was heated in a 60° C. oil bath and allowed to stir for 2 hours. The resulting mixture was cooled to room temperature. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (40 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 2.7 g (48%) of 3-((t-butyldimethylsilyl)oxy)phenol.
Reaction SMILES: [N+:1]([C:4]1[CH:37]=[CH:36][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([O:26]CC4C=CC=CC=4)[CH:18]=3)[C:12]([F:34])=[C:11]([F:35])[N:10]=2)=[CH:6][C:5]=1[O:38]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:37]=[CH:36][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([OH:26])[CH:18]=3)[C:12]([F:34])=[C:11]([F:35])[N:10]=2)=[CH:6][C:5]=1[OH:38]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2nc(F)c(F)c(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c2F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2nc(F)c(F)c(Oc3ccc(N)c(O)c3)c2F)cc1O
Reaction time: 72 h
Yield: 93 %

Procedure:
99 g of 2,4-bis(4-nitro-3-benzyloxyphenoxy)-3,5,6-trifluoropyridine prepared as described in Example 5 (0.16 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 10 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The yellow-beige solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates in crystalline form. The reaction product is then collected and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 93%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH3:17])=[CH:13][C:14]=1[B:23]([OH:28])[OH:24])(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(B(O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.85 g (11.2 mmol) of N-t-butyl-4-n-propylbenzenesulfonamide (from Step A) in anhydrous THF (20 mL) cooled to -40° C. under N2 was added 2.5M n-BuLi solution (11.2 mL, 2.5 equiv). The mixture was warmed to room temperature and stirred for 2 hours. To the mixture, containing the bright red dianion at 0° C., was added triisopropyl borate (3.9 mL, 1.5 equiv). The next day, 2N HCl (3 mL) was added and the mixture was stirredfor 1 hour. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic solution was washed washed with 2N HCl, H2O and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled compound; Rf =0.5 (1:1 EtOAc-hexane). The material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:22]3[C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=[C:21]3[C:8]3([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:30]=1.O1CCOCC1>Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:22]3[C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=[C:21]3[C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[O:7][C:6]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(Cl)ccc1-n1c(C(F)(F)F)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc2n1-c1ccc(Cl)cc1OC21CCNCC1
Reaction time: 0.5 h

Procedure:
tert-Butyl 7-chloro-1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate (210 mg, 0.14 mmol) was dissolved in HCl in dioxane (2.0 mL of 4.0 M, 8.0 mmol). The reaction mixture was allowed to stand for 30 minutes. The reaction mixture was then evaporated to dryness to give 7-chloro-1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] hydrochloric acid. ESI-MS m/z calc. 342.7, found 343.3 (M+1)+; Retention time: 1.46 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:19][C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: O=C(CCCCCCBr)NOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCCCOc1ccc2c(c1)[nH]c1ccccc12)NOCc1ccccc1

Procedure:
In a manner analogous to that of example 1 (b), 7-bromo-heptanoic acid benzyloxy-amide (1.8 g, 5.7 mmol) was reacted with 2-hydroxycarbazole (1.05 g, 5.7 mmol) in the presence of potassium carbonate (1.2 g, 8.6 mmol) in dimethyl formamide to give 7-(9H-carbazol-2-yloxy)-heptanoic acid benzyloxyamide as an almost colorless wax (yield 0.53 g, 22%; purified by column chromatography using silica gel and ethyl acetate: heptane 4:6 to 6:4 as an eluent). MS (M−H+)=415.
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[C:4]([CH2:7][C:8](=[O:10])[CH3:9])(=[O:6])[CH3:5]>>[CH3:9][C:8]([O-:10])=[CH:7][C:4]([CH3:5])=[O:6].[CH3:9][C:8]([O-:10])=[CH:7][C:4]([CH3:5])=[O:6].[Ca+2:2]
Reactant: CC(=O)CC(C)=O
Agent: [Ca+2]
Agent: [OH-]
Product: CC(=O)C=C(C)[O-]
Reaction time: 4 h
Yield: 99.7 %

Procedure:
444 g (6 mol) of calcium hydroxide was added to the kneader used in Comparative Example 1, and stirred. Thereafter, 1,320 g [13.2 mol, calcium hydroxide/acetylacetone=1/2.2 (molar ratio)] of acetylaceton was dropped into the kneader over 3 hours. The reaction temperature was between 43 and 65° C. After completion of the dropping, at a temperature of from 65 to 66° C., the mixture was stirred and mixed for aging over 4 hours until the reaction was complete. The resultant powder was slightly moisture-laden. The resulting product was warmed under a flow of nitrogen gas. At the point where the temperature reached 68° C., the product was subjected to the drying step, and dried at 106 to 138° C. for 10 hours until the moisture or water content was reduced to 0.46% by weight. Thereafter, the dried product was cooled to give 1,425 g of white calcium acetylacetonate [yield 98.2 mol % (calcium hydroxide basis), purity 98.6% by weight].