Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:11]1[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:22])([F:1])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc12
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2c(Cl)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 115 °C
Yield: 98.4 %

Procedure:
To 2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methyl-3H-quinazolin-4-one (0.23 g, 0.76 mmol) were added DIEA (0.27 mL, 1.5 mmol) and POCl3 (5 mL, 55 mmol) and the mixture was heated at 115° C. for 6 h. The mixture was allowed to cool to rt and the mixture was concentrated under reduced pressure. The residue was treated with toluene and concentrated to dryness twice. The residue was partitioned between EtOAc (20 mL) and cold saturated aq NaHCO3 (10 mL). The separated EtOAc layer was diluted with of EtOAc (60 mL) and washed with saturated aq NaHCO3 (10 mL) and brine (10 mL×2), dried over MgSO4, filtered and concentrated under reduced pressure to afford 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methyl-quinazoline as a brown viscous oil (242 mg, 99%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[C:28]([O:32][C:33]([N:35]([CH2:41][CH2:42][OH:43])[CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:38](=[O:39])[CH2:37][CH2:36][N:35]([CH2:41][CH2:42][OH:43])[C:33](=[O:34])[O:32][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCO)CCC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), 3-[(tert-butoxycarbonyl)(2-hydroxyethyl)amino]propanoic acid (0.038 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.034 g, 0.000175 mol), N,N-diisopropylethylamine (0.034 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous dichldromethane (5 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(3-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-oxopropyl)-N-(2-hydroxyethyl)carbamate (0.040 g, 0.000070 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.3 min. MS: MH+ 574.
Reaction SMILES: CS(O)(=O)=O.[CH3:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13].[N-:14]=[N+]=[N-].[Na+]>COCCOC>[CH3:6][CH:7]1[NH:14][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC1CCCCC1=O
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: COCCOC
Product: CC1CCCCC(=O)N1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
Methanesulfonic acid (15 mL) was added to a solution of 2-methylcyclohexanone (2-1, 6.00 g, 53.5 mmol, 1 equiv) in DME (20 mL) at −40° C. Sodium azide (8.69 g, 134 mmol, 2.50 equiv) was added in four equal portions over 1 h as cooling was maintained. The cold bath was then removed and the reaction mixture was warmed to 23° C. and stirred for 20 h. The mixture was diluted with DME (20 mL) and basified to pH 9 with concentrated aqueous ammonium hydroxide solution. The resulting mixture was partitioned between brine (200 mL) and ethyl actetate (4×200 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 7-methylazepan-2-one (2-2) as a pasty white solid. 1H NMR (300 MHz, CDCl3) δ 5.50 (br s, 1H), 3.50 (m, 1H), 2.43 (m, 2H), 2.05-1.30 (m, 6H), 1.21 (d, 3H,J=7.1 Hz).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.Cl[C:14]1[CH:24]=[C:18]2[N:19]([CH3:23])[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=1>>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=[C:14]([O:10][CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=3)[CH:24]=[C:18]12
Reactant: OCc1cccc(C(F)(F)F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cccc(C(F)(F)F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-(trifluoromethyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C(C1SC2C(C)=C(OC(=O)CC)C(C)=C(C)C=2O1)C.[CH2:20]([CH:23]1[S:27][C:26]2[C:28]([CH3:38])=[C:29]([O:34]COC)[C:30]([CH3:33])=[C:31]([CH3:32])[C:25]=2[O:24]1)[CH:21]=[CH2:22].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:20]([CH:23]1[S:27][C:26]2[C:28]([CH3:38])=[C:29]([OH:34])[C:30]([CH3:33])=[C:31]([CH3:32])[C:25]=2[O:24]1)[CH:21]=[CH2:22]
Reactant: C=CCC1Oc2c(C)c(C)c(OCOC)c(C)c2S1
Agent: CCC(=O)Oc1c(C)c(C)c2c(c1C)SC(CC)O2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: C=CCC1Oc2c(C)c(C)c(O)c(C)c2S1
Temperature: 50 °C

Procedure:
0.9 g of 2 allyl-5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 89) was dissolved in 8 ml of acetic acid, and 3 drops of 10% v/v aqueous sulfuric acid were added to the resulting solution, which was then heated at 50° C. for 30 minutes. The solution was then cooled down to room temperature, and the reaction mixture was condensed by evaporation under reduced pressure. The condensate was dissolved in benzene, and the solution was washed with water and then dried over anhydrous sodium sulfate. The benzene was distilled off, and the resulting crude product was purified by silica gel Lobar column chromatography. The title compound, melting at 78.5°-79.5° C., was obtained from the fraction eluted with benzene.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH:2]([CH3:12])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])=[O:4])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1ccccc1C(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccccc1C(=O)C(C)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 25 g of 2-bromo-2'-methylpropiophenone, 70 ml of dry acetonitrile, 30 g of potassium carbonate and 19 g of 4-benzylpiperidine is stirred for 4 hours at ambient temperature. It is filtered in order to separate off the inorganic residue, and the filtrate is diluted with 200 ml of diethyl ether, which causes precipitation of 4-benzylpiperidine hydrobromide. This is filtered off; the filtrate deposits a second crop of hydrobromide, which is also separated off. The filtrate is then acidified with 300 ml of 3N hydrochloric acid. The intermediate propiophenone hydrochloride is an oil which is insoluble in both phases. The acid aqueous phase is extracted twice with methylene chloride, the extract is washed with water, and aqueous ammonia solution is added. The mixture is stirred and left to separate, the organic phase is dried, filtered and treated with about 100 g of silica in order to retain the traces of 4-benzylpiperidine, the mixture is filtered and the filtrate is evaporated. 10.9 g of an oil are collected.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:26](=[O:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (10 ml) was suspended 60% sodium hydride (44 mg). The compound 1 (200 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, acetoxyacetyl chloride (100 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-acetoxyacetylquinoline (compound 11, 140 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [SH:1][C@H:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)(=[O:9])=[O:8])[C@H:4]([C:20]([N:22]([CH2:31][C:32]([OH:34])=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([S:1][C@H:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)(=[O:9])=[O:8])[C@H:4]([C:20]([N:22]([CH2:31][C:32]([OH:34])=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH2:3]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: O=C(O)CN(CCc1ccccc1)C(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: CC(=O)S[C@@H]1C[C@@H](C(=O)N(CCc2ccccc2)CC(=O)O)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
A solution of 124 mg (0.2 mmol) (2S,4R)-{[4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid in 3.2 ml pyridine were treated at 0° C. with 0.04 ml (0.4 mmol) acetyl chloride and stirred for 10 min at RT. The reaction was poured on ice water and extracted wit 1N HCl/EtOAc (3×). The organic phases were washed with aqueous 1 N HCl and 10% NaCl, dried over Na2SO4 and evaporated. Precipitation from CH2Cl2/Pentane (4° C.) gave 30 mg (28%) (2S,4R)-{[4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid, mp: 190-193° C.; MS: 539 (M-H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)=[O:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To an ice-cooled solution of 1-(4-nitro-phenyl)-piperazine (prepared as described in Reference Example 29; 5 g, 24 mmol) in DCM (40 mL) was added pivaloyl chloride (4.36 g, 36.2 mmol) and triethylamine (8.73 mL, 60 mmol) at 0-5° C. The mixture was warmed to room temperature and stirred for 1 hour then diluted with DCM (150 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate and concentrated to dryness to afford 2,2-dimethyl-1-[4-(4-nitro-phenyl)-piperazin-1-yl]-propan-1-one (6 g, 85.7%) as a yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCCC1.C(OCC)(=O)C>CO.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
To a solution of 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (2.64 g, 4.77 mmol) in methanol (150 ml) and tetrahydrofuran (15 mg) was added 10% Pd-C (850 mg), which was then stirred at room temperature under hydrogen (atmospheric pressure) for 1 day. Ethyl acetate was added to the reaction solution. The resulting solution was filtered, extracted several times with ethyl acetate, and concentrated under reduced pressure to remove the organic solvent. Hydrogenation reaction was repeated three times under the same condition. After the organic solvent was removed, the residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=9:1) to give the title compound (2.20 g, yield 83%) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][OH:11].[CH2:12](Cl)[O:13][CH3:14].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][O:11][CH2:12][O:13][CH3:14]
Reactant: COc1nccc(I)c1CO
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1c(I)ccnc1OC
Yield: 99.8 %

Procedure:
Following the procedure in Example 2, the reaction was carried out with 2b (1.77 g, 6.68 mmol), MOMCl (1.52 mL, 20 mmol) and iPr2EtN (3.49 mL, 20 mmol) in dry CH2Cl2 (40 mL) to afford 3b as an orange-yellow oil (2.06 g, 100%). The crude product was sufficiently pure for the subsequent reaction. IR (CH2Cl2, NaCl, cm−1) 2949, 1561, 1459, 1380, 1265, 1039, 741; 1H NMR (300 MHz, CDCl3) δ3.45 (s, 3H), 3.96 (s, 3H), 4.72 (s, 2H), 4.75 (s, 2H), 7.35 (d,J=5.4 Hz, 1H), 7.71 (d,J=5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ54.35, 55.80, 67.89, 96.70, 114.20, 123.97, 128.10, 147.11, 162.39; HRMS (EI) m/z calcd for C9H12NO3I (M+) 308.9862, found 308.9860; LRMS (EI) m/z 309(M+, 19), 277(20), 264(45), 248(100), 218(68), 152(39), 92(50), 79(35).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[N:14][NH:15][C:9]=2[C:8]2[S:16][CH:17]=[CH:18][C:7]1=2)=[O:5].C(N(CC)CC)C.[F:31][C:32]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:33]=1[C:34](Cl)=[O:35].O>C(Cl)Cl>[NH:15]1[C:9]2[C:8]3[S:16][CH:17]=[CH:18][C:7]=3[N:6]([C:4]([C:3]3[CH:19]=[CH:20][C:21]([NH:23][C:34](=[O:35])[C:33]4[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:32]=4[F:31])=[CH:22][C:2]=3[Cl:1])=[O:5])[CH2:12][CH2:11][C:10]=2[CH:13]=[N:14]1
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Reactant: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)c(Cl)c1)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 129.6 %

Procedure:
To an ice bath cooled mixture of 345 mg of 6-(2-chloro-4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine in 3.5 ml of methylene chloride under argon is added 417 μl of triethylamine followed by a solution of 482 mg of 2-fluoro-5-chlorobenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. An additional 40 ml of methylene chloride is added followed by 20 ml of water. The organic layer is washed with 20 ml each of 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2SO4), filtered through hydrous magnesium silicate and the filtrate evaporated in vacuo to give 650 mg of the desired product as a solid residue. To a solution of 500 mg of the preceding compound in 4 ml methanol and 4 ml of tetrahydrofuran is added 1.51 ml of 1N NaOH. The reactants are stirred at room temperature for 18 hours. The reaction mixture is neutralized with 1N HCl and evaporated in vacuo to a residue which is diluted with 50 ml of chloroform and washed with water, brine and dried (Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is crystallized from ethyl acetate containing ethyl alcohol. The collected solid is dried to give 215 mg of the desired product as an off white solid, m.p. 282°-288° C.
Reaction SMILES: C([NH:20][C@H:21](/[CH:34]=[CH:35]/[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(/C=C/[C@@H](N)CC1C=CC(CNC(=O)OC(C)(C)C)=CC=1)(=O)=O>>[NH2:20][C@H:21](/[CH:34]=[CH:35]/[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](/C=C/S(C)(=O)=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)NCc1ccc(C[C@H](N)/C=C/S(C)(=O)=O)cc1
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)/C=C/S(C)(=O)=O

Procedure:
This compound was prepared from trityl protected amine 73 in a synthetic procedure similar to that for compound 18. The purity was checked by LC-MS analysis and the amine was subjected to the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6]=[C:7]([CH2:17]Br)[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[P:23]([O:32]C(C)C)([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6]=[C:7]([CH2:17][P:23]([O:28][CH:29]([CH3:31])[CH3:30])([O:24][CH:25]([CH3:27])[CH3:26])=[O:32])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C=C(CBr)COCc1ccccc1)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)C(C=C(COCc1ccccc1)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 2 h

Procedure:
1.0 g (3.25 mmol) of 5-benzyloxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are suspended in 30 ml of 1,2-dichloroethane, and 0.38 ml (4.9 mmol) of thionyl chloride is added dropwise at room temperature. After 45 minutes, 20 ml of water are added to the yellow solution, and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed with saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated by evaporation. 5-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil which is reacted further in the crude state. 1.14 g (3.1 mmol) of 5-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester and 10 ml (38.5 mmol) of triisopropyl phosphite (95%) are heated to 80° C. and stirred under a pressure of approximately 130 mbar for 31/2 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. 5-benzyloxy-4-diisopropylphosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C(Cl)(=O)C(Cl)=O.[CH2:21]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1)[CH2:22][CH2:23][CH3:24]>C(N(CC)CC)C>[CH2:21]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:12]([C:4]2[C:5]3[O:9][C:8]([CH3:10])=[N:7][C:6]=3[CH:11]=[C:2]([Cl:1])[CH:3]=2)=[O:14])[CH2:27][CH2:26]1)[CH2:22][CH2:23][CH3:24]
Reactant: Cc1nc2cc(Cl)cc(C(=O)O)c2o1
Reactant: CCCCN1CCC(CN)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)cc3nc(C)oc23)CC1

Procedure:
5-Chloro-2-methylbenzoxazole-7-carboxylic acid (Ger. Offen. 2,225,544) is converted to its acid chloride by treatment with oxalyl chloride. The acid chloride is treated with N-(1-butyl-4-piperidinyl)methylamine in the presence of triethylamine to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[N:5]=[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[N:5]=[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1cc(F)c(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1cc(F)c(F)cc1F
Yield: 3.1 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-2-(piperidin-1-yl)-6-(2,4,5-trifluorophenyl)pyrimidin-5-yl)pentanoate (0.080 g; 0.190 mmol), sodium hydroxide 10N (0.200 mL; 2.00 mmol) in methanol (2 mL) at 60° C. for 18 h. Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane and then by preperative HPLC (HPLC method 1) furnished 0.0024 g (31%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:6])([CH3:5])[CH2:3][OH:4].[CH3:7][S:8](Cl)(=[O:10])=[O:9].O>C(Cl)Cl>[CH3:7][S:8]([O:4][CH2:3][C:2]([F:6])([F:1])[CH3:5])(=[O:10])=[O:9]
Reactant: CC(F)(F)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(F)(F)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.6 %

Procedure:
To a mixture of 2,2-difluoropropan-1-ol (2.00 g, 20.8 mmol) and TEA (3.16 g, 31.25 mmol) in dry DCM (20 mL) was added methanesulfonyl chloride (2.84 g, 24.96 mmol) at 0° C. The resulting reaction mixture was stirred at rt for 1.5 h. Water was added and the mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to give the title product (2.70 g, 15.52 mmol, 75% yield), which was used directly in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([Br:15])=[CH:8][N:7]=1.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>Cl>[Br:15][C:9]1[CH:8]=[N:7][C:6]2[O:5][CH2:4][C:3](=[O:2])[NH:12][C:11]=2[CH:10]=1
Reactant: COC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: O=C1COc2ncc(Br)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
In a 10 ml round flask, (5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester (144 mg, 0.49 mmol) and tin tetrachloride (375 mg, 1.96 mmol) were dissolved in 3 ml of concentrated hydrochloric acid, and then stirred at 80□ for 1 hour. The reaction mixture was cooled to room temperature, neutralized with 10% sodium hydroxide solution, and extracted with dichloromethane. The combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The resulting solid was recrystallized from tetrahydrofuran and methanol to obtain 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2-one as white solid (59 mg, 52%).