Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1.CCN(C(C)C)C(C)C>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH:28][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH:21]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCCc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2cccnc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-pyridin-3-yl-ethylamine and DIEA to give 2-(2-pyridin-3-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 361 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].C(O[CH:17]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([F:21])([F:20])[F:19])C.Cl>O1CCCC1>[F:19][C:18]([F:20])([F:21])[CH:17]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(Nc1ccccc1)C(F)(F)F
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(Nc1ccccc1)C(F)(F)F
Yield: 54.5 %

Procedure:
A solution of diethyl malonate (1.98 mL, 13.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, over 20 min, into a dispersion of sodium hydride (60% in oil, 0.52 g, 13.0 mmol) in dry tetrahydrofuran (30 mL) at 0° C., after which compound 325 (2.6 g, 11.9 mmol) was added and the mixture was stirred vigorously at reflux for 16 h. The reaction mixture was cooled, acidified to pH 3 using a 1N HCl solution. The aqueous layer was extracted twice with EtOAc. The extracts were combined, dried over sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent dichloromethane-hexane, 0:100 to 60:40) to afford title compound 326 (2.16 g, 6.48 mmol, 54% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm: 7.21-7.16 (m, 2H), 6.81-6.76 (m, 1H), 6.75-6.71 (m, 2H), 5.06 (d, J=10.4 Hz, 1H), 4.83-4.73 (m, 1H), 4.25 (q, J=7.2 Hz, 2H), 4.18-4.05 (m, 2H), 3.85 (d, J=4.4 Hz, 1H), 1.28 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H). LRMS (M+1) 334.1 (100%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[F:31][C:32]1([F:45])[CH2:37][CH2:36][C@H:35]([OH:38])[C@@H:34]([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)[CH2:33]1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:38][C@H:35]2[CH2:36][CH2:37][C:32]([F:31])([F:45])[CH2:33][C@@H:34]2[C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 53.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (167 mg, 0.37 mmol) prepared in Example 20a, the (1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (65.9 mg, 0.30 mmol) prepared in Example 88 g, sodium hydride (63%; 23.2 mg, 0.61 mmol) and DMF (2.0 mL), to yield the title compound (104 mg, 52%) as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH:18]2[C:16]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)([CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].C(N)CN>C1(C)C=CC=CC=1.[Cu]I>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH:18]2[C:16]([C:20]3[CH:25]=[CH:24][C:23]([N:27]4[CH2:31][CH2:30][CH2:29][C:28]4=[O:32])=[CH:22][CH:21]=3)([CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C1CCCN1
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Br)cc2)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NCCN
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3CCCC3=O)cc2)C1
Yield: 51.9 %

Procedure:
To a stifling suspension of potassium carbonate (1.23 g, 8.95 mmol) and CuI (42.5 mg, 0.22 mmol) in anhydrous toluene (10 mL) were added 1-(4-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate I, 1.6 g, 4.5 mmol) dissolved in toluene (10 mL) followed by addition of pyrrolidinone (0.5 mL, 6.2 mmol) and ethylene diamine (0.03 mL, 0.45 mmol). Reaction mixture was refluxed for 16 h. Reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 4:6 EtOAc:Pet. ether) to afford the title compound as white solid (800 mg, 52%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([C:26]([OH:28])=[O:27])=[CH:20]4)=[O:15])=[CH:11][C:10]=2[CH:29]=1)=[O:4].Cl.[N:31]1([C:36](N)=[NH:37])C=CC=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH:1]([CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([C:26]([OH:28])=[O:27])=[CH:20]4)=[O:15])=[CH:11][C:10]=2[CH:29]=1)=[O:4])[C:36]([NH2:37])=[NH:31]
Reactant: NCC(=O)Nc1ccc2oc(C(=O)Nc3ccc4[nH]c(C(=O)O)cc4c3)cc2c1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCC(=O)Nc1ccc2oc(C(=O)Nc3ccc4[nH]c(C(=O)O)cc4c3)cc2c1

Procedure:
170 mg (0.05 mmol) 131 was treated overnight with 73.5 mg (0.5 mmol) pyrazole-1-carboxamidine hydrochloride and 172 μL diisopropylethylamine dissolved in 2 mL DMF. Next day the resin was drained, washed five times with DMF to give 132 which was treated immediately to cleave the compound off, as described below in Example 121.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])=[C:2]=[S:3].[CH:12]1([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][C:23]([NH:25][CH3:26])=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=2)[CH2:14][CH2:13]1>CN(C=O)C>[CH:12]1([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][C:23]([N:25]([CH3:26])[C:2]([NH:1][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[O:10][CH3:11])=[S:3])=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH3:36])=[CH:32][CH:33]=2)[CH2:14][CH2:13]1
Reactant: CCOc1ccc(Cc2nc3cc(NC)ccc3n2CC2CC2)cc1
Reactant: COc1ccccc1N=C=S
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2nc3cc(N(C)C(=S)Nc4ccccc4OC)ccc3n2CC2CC2)cc1
Temperature: 50 °C
Yield: 27.8 %

Procedure:
1-Isothiocyanato-2-methoxybenzene (100 mg, 0.61 mmol) was added to a solution of 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-N-methyl-1H-benzimidazol-5-amine (100 mmol, 0.30 mmol) in DMF (5 mL). The reaction mixture was heated at 50° C. overnight. The crude product isolated following removal of the solvent was purified by chromatography on silica gel (EtOAc/CH2Cl2 1:1) giving the desired product (85 mg, 57%) 1HNMR (CDCl3): free base δ 8.26 (dd, J=2.0, 8.4 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.20 (dd, J=1.6, 8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 7.08–7.02 (m, 1H), 6.98–6.92 (m, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.4 Hz, 1H), 4.29 (s, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.96 (d, J=6.8 Hz, 2H), 3.80 (s, 3H), 3.58 (s, 3H), 1.37 (t, J=7.0 Hz, 3H), 1.10–1.00 (m, 1H), 0.59–0.52 (m, 2H), 0.32–0.25 (m, 2H). MS (ESI) (M+H)+=501.
Reaction SMILES: [CH2:1]([N:3]([N:5]=[CH:6][N:7]1[CH2:12][CH2:11][N:10](C=O)[CH2:9][CH2:8]1)[NH2:4])[CH3:2]>Cl>[CH2:1]([N:3]([N:5]=[CH:6][N:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[NH2:4])[CH3:2]
Reactant: CCN(N)N=CN1CCN(C=O)CC1
Agent: Cl
Product: CCN(N)N=CN1CCNCC1

Procedure:
2.7 g of the benzylidene derivative of 1-[(1-ethylhydrazino)iminomethyl]4-formylpiperazine dissolved in 11.6 ml of 2N HCl are treated by steam distillation. After evaporation of the water from the mixture obtained and drying of the residue 1-[(1-ethylhydrazino)iminomethyl]piperazine in the form of a dihydrochloride is obtained in the form of a white solid.
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH2:29][OH:30])[C:24]([O:26]CC)=[O:25])=[CH:19][CH:18]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO.O.O>[F:31][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH2:29][OH:30])[C:24]([OH:26])=[O:25])=[CH:19][CH:18]=3)=[N:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(CO)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(CO)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoate 32 (1 mmol) in THF:MeOH:water (3:2:1 v/v) is added 6 N LiOH (3 mmol). The reaction mixture is stirred at rt for 1 h until complete by LC/MS and diluted with water. The aqueous layer is washed with DCM (2×30 mL) and acidified to pH=5 using aqueous 1N HCl. The resulting mixture is extracted with DCM (3×50 mL). The organic layer is separated, dried over Na2SO4 and concentrated to yield a crude product, which upon crystallization from water yield 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoic acid, 26 as off white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.65 (s, 1H), 8.79 (s, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.30 (s, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 3.60-3.70 (m, 2H), 3.50-3.58 (m, 2H), 3.20-3.26 (m, 2H). MS (m/z) (M+1)+: 402.1.
Reaction SMILES: I.[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]1=[NH:13])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](Cl)=[O:28]>C(Cl)Cl>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[N:13]\[C:27](=[O:28])[C:26]1[CH:30]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=1[O:31][CH3:32])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCn1c(C)c(C)sc1=N
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 1A (312 mg, 1 mmol) and triethylamine (0.42 mL, 3 mmol) in CH2Cl2 (15 mL) at 0° C. was added 5-chloro-2-methoxybenzoyl chloride (Waterstone, 205 mg, 1 mmol), the mixture was allowed to warm to room temperature and was stirred for 14 hours. The solution was washed sequentially with water, brine, dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 0.93 (t, J=7 Hz, 3H), 1.35 (sextet, J=7 Hz, 2H), 1.68 (quintet, J=7 Hz, 2H), 2.21 (s, 3H), 2.26 (s, 3H), 3.78 (s, 3H), 4.26 (t, J=7 Hz, 2H), 7.10 (d, J=9 Hz, 1H), 7.44 (d-d, J=9 Hz, 3 Hz, 1H), 7.70 (d, J=3 Hz, 1H); MS (ESI+) m/z 353 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:18]1([CH:25]=[CH:24][C:22]([OH:23])=[CH:21][CH:20]=1)[OH:19]>CN(C=O)C>[CH3:11][N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][O:19][C:18]1[CH:25]=[CH:24][C:22]([OH:23])=[CH:21][CH:20]=1
Reactant: Oc1ccc(O)cc1
Reactant: CN(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(O)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 20 %

Procedure:
A mixture of compound 2b (500 mg, 2.95 mmol), K2CO3 (815 mg, 5.9 mmol), and KI (480 mg, 2.95 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (649 mg, 5.9 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with CH2Cl2 and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide compound 2 as a white solid (143 mg, 0.59 mmol, 20% yield). HRMS (ESI, positive) m/z calcd. for C15H18NO2 [M+H]+: 244.13321, found: 244.13323. 1H NMR (400 MHz, Chloroform-d) δ 7.29 (ddd, J=7.3, 5.6, 2.0 Hz, 2H), 6.84-6.72 (m, 7H), 4.98 (broad s, 1H), 4.11 (t, J=6.1 Hz, 2H), 3.76 (t, J=6.1 Hz, 2H), 3.08 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([O:8]S(C)(=O)=O)[CH2:5][O:6][CH3:7].[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([CH2:5][O:6][CH3:7])[O:8][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCC(COC)OS(C)(=O)=O
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(COC)Oc1ccccc1
Temperature: 90 °C

Procedure:
A stirred mixture of 2.0 g of methanesulfonic acid 2-methoxy-1-methoxymethyl-ethyl ester, 1.4 g of phenol and 2.8 g of powdered potassium carbonate in 50 mL of dry N,N-dimethylformamide was heated at 90° C. for 24 hours. After cooling, water was added at room temperature and the mixture extracted with diethyl ether. The combined ether extracts were washed with aqueous sodium hydroxide (2 N) and water, dried (sodium sulfate) and concentrated. The crude product (1.0 g) was used in the next step without further purification. EI-MS: 198 (M+).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][CH:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[C:10]1([C@H:9]([NH:16][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(N)c1ccccc1
Reactant: CCOC(=O)CBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
Ethyl bromoacetate (4.14 g; 24.8 mmol) was treated with (R) α-methylbenzylamine (3 g, 24.8 mmol) and ethyldiisopropylamine (3.2 g; 24.8 mmol) in toluene (100 mL). After heating at reflux for 18 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 20% ethyl acetate/pentane) to provide the title compound (3.2 g, 63% yield). MS (DCI/NH3) m/z 208 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[O:6][CH2:7][CH:8](F)[C:9]3[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=3[C:14]([F:17])([F:16])[F:15])[C:4]=2[CH:3]=1.[C:24]([C@:26]1([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32])#[CH:25]>>[OH:33][C@@:26]1([C:24]#[C:25][C:2]2[CH:23]=[CH:22][C:5]3[O:6][CH2:7][CH2:8][C:9]4[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=4[C:14]([F:17])([F:16])[F:15])[C:4]=3[CH:3]=2)[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32]
Reactant: NC(=O)c1nn2c(c1C(F)(F)F)C(F)COc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-n2nc(C(N)=O)c(C(F)(F)F)c2CCO3)C1=O
Yield: 59 %

Procedure:
Similar to as described in General Procedure G, racemic 9-bromo-4-fluoro-3-(trifluoromethyl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give the titled compound as a white solid 8.9 mg (59%).
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][C:23]([OH:25])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:26][O:27][C:28]([C:30]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][C:36]=2[N+:42]([O-:44])=[O:43])[O:32][C:31]=1[CH3:45])=[O:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][O:27][C:28]([C:30]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:23](=[O:25])[CH2:22][C:14]3[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=3)=[CH:37][C:36]=2[N+:42]([O-:44])=[O:43])[O:32][C:31]=1[CH3:45])=[O:29]
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: COC(=O)c1cc(-c2ccc(N)cc2[N+](=O)[O-])oc1C
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(NC(=O)Cc3cc(OC)c(OC)c(OC)c3)cc2[N+](=O)[O-])oc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (138 mg, 0.72 mmol) and Et3N (101 μL, 0.72) in anhydrous DCM (4.5 mL) and stir the resulting solution for 5 min at rt. Add 2-(3,4,5-Trimethoxy-phenyl)-acetic acid (163 mg, 0.72 mmol) and DMAP (8 mg, 0.07 mmol) and stir the resulting solution for 10 min. Add 5-(4-Amino-2-nitro-phenyl)-2-methyl-furan-3-carboxylic acid methyl ester (58) (100 mg, 0.36 mmol) and stir the reaction solution for 22 h at rt. Quench reaction solution with sat. aqu. NH4Cl and water, separate layers and extract aqu. layer with DCM (3 times). Wash the combined organic layer with water and brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+1) to obtain 2-Methyl-5-{2-nitro-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylic acid methyl ester (59) (96 mg, 55%) as an yellow solid. 1H NMR (400 MHz, CDCl3): 2.55 (s, 3H); 3.65 (s, 2H); 3.79 (s, 3H); 3.81 (s, 6H); 3.82 (s, 3H); 6.50 (s, 2H); 6.77 (s, 1H); 7.53 (d, 1H, J=8.6 Hz); 7.66 (dd, 1H, J1=8.6 Hz, J2=2.0 Hz); 7.93 (br.s, 1 H); 7.96 (d, 1H, J=2.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>N1C=CC=CC=1>[C:26]([N:6]([CH2:5][C:4]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:28])[CH3:27]
Reactant: COc1ccc(CNc2ccccc2Oc2ccccc2)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(CN(C(C)=O)c2ccccc2Oc2ccccc2)c(OC)c1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a solution of 1.00 g of N-(2,4-dimethoxy benzyl)-2-phenoxyaniline in 1.18 g of pyridine was added 0.76 g of acetic anhydride, followed by stirring at room temperature for a day. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:3) to give 1.09 g of N-acetyl-N-(2,4-dimethoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:17][C:16]([F:19])([F:18])[CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: FC(F)(F)CCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCC(F)(F)F)cc1
Yield: 100 %

Procedure:
First, about 1 mole of methyl 4-hydroxybenzoate and about 1 mole of 4-bromo-1,1,1-trifluorobutane were added to excess acetone which was mixed with potassium carbonate at a temperature of about 40° C. for about 90 minutes to obtain about 1 mole of methyl 4-(4,4,4-trifluorobutoxy)benzoate. About 1 mole of methyl 4-(4,4,4-trifluorobutoxy)benzoate was mixed with about 1 N (normality) of excess sodium hydroxide, and methyl 4-(4,4,4-trifluorobutoxy)benzoate and sodium hydroxide were mixed to perform reflux for about 30 minutes and then neutralized to hydrochloric acid to obtain about 1 mole of 4-(4,4,4-trifluorobutoxy)benzoic acid. About 1 mole of 4-(4,4,4-trifluorobutoxy)benzoic acid was mixed with carbon dichloride and carbonyl diimidazole (CDI). After 4-(4,4,4-trifluorobutoxy)benzoic acid, carbon dichloride, and CDI were reacted at a temperature of about 25° C. for about 2 hours. About 1 mole of 4-hydroxybenzaldehyde was mixed with the above mixture at a temperature of about 25° C. for about 12 hours and, carbon dichloride and water were added to extract about 1 mole of 4-formylphenyl 4-(4,4,4-trifluorobutoxy)benzoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:17][CH:16]2[C:18]([O:20]C)=[O:19])=[CH:11][CH:10]=1.C(O)C.C[O-].[Na+:27].O>C(OCC)C.O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[O:17][CH:16]2[C:18]([O-:20])=[O:19])=[CH:13][CH:14]=1.[Na+:27]
Reactant: COC(=O)C1OC1c1ccc(COc2ccccn2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C([O-])C1OC1c1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl 3-(4-(pyridin-2-yloxymethyl)-phenyl)-oxiran-2-carboxylate described in Preparation Example 2-1-1 (19.9 g) and ethanol (300 mL) were sequentially added sodium methoxide (14.2 mL, 28% methanol solution), water (1.3 mL), tetrahydrofuran (100 mL) at 0° C, which was stirred at room temperature for one hour. To the reaction mixture was added diethyl ether (200 mL), and the precipitated solids were filtered to obtain the title compound (14.3 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[O:24][CH2:25][CH2:26][N:27]1[C:31]([CH3:32])=[CH:30][C:29]([C:33]2[CH:34]=[CH:35][C:36]([CH3:56])=[C:37]([NH:39][C:40]([C:42]3[C@H:47]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)[CH2:46][C:45](=[O:55])[NH:44][CH:43]=3)=[O:41])[CH:38]=2)=[N:28]1)(C)(C)C>C1COCC1>[OH:24][CH2:25][CH2:26][N:27]1[C:31]([CH3:32])=[CH:30][C:29]([C:33]2[CH:34]=[CH:35][C:36]([CH3:56])=[C:37]([NH:39][C:40]([C:42]3[C@H:47]([C:48]4[CH:49]=[CH:50][C:51]([F:54])=[CH:52][CH:53]=4)[CH2:46][C:45](=[O:55])[NH:44][CH:43]=3)=[O:41])[CH:38]=2)=[N:28]1
Reactant: Cc1ccc(-c2cc(C)n(CCO[Si](C)(C)C(C)(C)C)n2)cc1NC(=O)C1=CNC(=O)C[C@H]1c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C)n(CCO)n2)cc1NC(=O)C1=CNC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
A solution tetrabutylammonium fluoride (1M in THF) was added drop wise to a 0° C. solution of (S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid (5-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenyl)-amide (66 mg) in THF. The mixture was stirred at 0° C. for five minutes and then stirred at room temperature for 18 hours. The mixture was partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (0 to 8% CH3OH in CH2Cl2) gave 24 mg of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-phenyl}-amide as a solid, MS (M+H)=419.