Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:24])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C@H:8]([OH:13])[C@@H:7]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH:25]([CH:27]=O)=O.C(OCC)(=O)C>C(O)C>[CH3:12][C:9]1([CH3:11])[O:10][C:5]2[CH:4]=[C:3]3[C:2](=[CH:23][C:6]=2[C@H:7]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:8]1[OH:13])[N:1]=[CH:27][CH:25]=[N:24]3
Reactant: CC1(C)Oc2cc(N)c(N)cc2[C@H](NCCc2ccccc2)[C@H]1O
Reactant: O=CC=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)Oc2cc3nccnc3cc2[C@H](NCCc2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of (3R*,4S*)-6,7-diamino-3,4-dihydro-2,2-dimethyl-4-(2-phenylethylamino)-2H-benzopyran-3-ol (1.5 g, 4.58 mmol) in ethanol (30 mL), 40% aqueous glyoxal solution (997 mg, 6.87 mmol) was added, and the resulting mixture was stirred at room temperature for 30 minutes. Upon the completion of the reaction, ethyl acetate was added thereto, the resulting solution was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated sodium chloride solution, and then dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/1) to obtain the aimed product (yield: 74%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][OH:21]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:21][CH2:20][C:19]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=3[Cl:17])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1ccc(Cl)cc1Cl
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(Cl)cc3Cl)c21
Yield: 72.4 %

Procedure:
The title compound (cis/trans=25/75) was prepared as white crystals in 72.4% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=21/79) and 2,4-dichlorobenzyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3Cl)[CH:16]=2)=[O:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([NH2:36])=[CH:31][CH:30]=2>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[NH:36][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:26])=[CH:35]4)[CH:16]=2)=[O:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(NC(=O)OC(C)(C)C)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-[1-(7-chloro-thieno[3,2-b]pyridine-2-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 492 (MH+); HPLC Rf: 5.23 min.; HPLC purity 96%.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[N:38]1[C:42]([CH2:43][O:44][C:45]2[CH:50]=[CH:49][C:48]([C:51](=O)[CH3:52])=[C:47]([CH3:54])[CH:46]=2)=[C:41]([CH:55]([CH3:57])[CH3:56])[CH:40]=[N:39]1>C1COCC1>[Cl:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[C:32]=1[N:38]1[C:42]([CH2:43][O:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]([CH3:52])=[CH:8][O:9][CH3:10])=[C:47]([CH3:54])[CH:46]=2)=[C:41]([CH:55]([CH3:57])[CH3:56])[CH:40]=[N:39]1
Reactant: CC(=O)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C(C)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
To a room temperature suspension of potassium tert-butoxide (1.36 g, 12.12 mmol) in THF (30 mL) is added (methoxymethyl)triphenyl phosphonium chloride (4.14 g, 12.12 mmol). The reaction mixture is stirred at room temperature for 20 minutes. Solid 1-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-ethanone (843 mg, 2.02 mmol) is added and the reaction is stirred at room temperature overnight. The reaction is quenched with saturated aqueous NH4Cl and is concentrated under reduced pressure. The residue is partitioned between Et2O and water. The aqueous layer is extracted with Et2O and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (0% to 30% EtOAc/Hex) to yield the title compound (836 mg, 93%) as a mix of E/Z isomers. (Major Isomer) 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.41 (d, 2H, J=7.9 Hz), 7.33-7.28 (m, 1H), 6.93 (d, 1H, J=8.4 Hz), 6.64-6.52 (m, 2H), 5.83 (q, 1H, J=1.3 Hz), 4.78 (s, 2H), 3.63 (s, 3H), 3.00 (sept, 1H, J=7.0 Hz), 2.22 (s, 3H), 1.83 (d, 3H, J=1.3 Hz), 1.30 (d, 6H, J=7.0 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.N>C(Cl)Cl>[Cl:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC4CCOCC4)c23)c1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OC4CCOCC4)c23)c1
Yield: 73.8 %

Procedure:
Using an analogous procedure to that described in Example 20, 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-tetrahydropyran-4-yloxyquinazoline (0.78 g) was reacted with trifluoroacetic acid (5 ml). The reaction mixture was evaporated and the residue was triturated under diethyl ether. The precipitate was isolated and the solid was dissolved in a mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was evaporated and the residue was purified by column chromatography on silica using a 97:3 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.47 g); NMR Spectrum: (DMSOd6) 1.8–1.9 (m, 2H), 2.2 (d, 2H), 3.52 (t, 2H), 3.8 (s, 3H), 3.92 (m, 2H), 4.95 (m, 1H), 6.7 (s, 1H), 6.75–6.85 (m, 2H), 7.5 (d, 1H), 8.12 (d, 1H), 8.4 (s, 1H), 9.85 (s, 1H); Mass Spectrum: M+H+ 402 and 404.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]1[C:23]2[CH:24]=[CH:25][C:26]([O:28]C(=O)C)=[CH:27][C:22]=2[O:21][CH:20]=1>CC#N>[OH:28][C:26]1[CH:25]=[CH:24][C:23]2[C:19]([CH2:18][N:8]3[CH2:9][CH2:10][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]3)=[CH:20][O:21][C:22]=2[CH:27]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: CC(=O)Oc1ccc2c(CCl)coc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)NC1CCN(Cc2coc3cc(O)ccc23)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-acetamidopiperidine (429 mg, 3.00 mmol) and K2CO3 (1.14 g, 8.25 mmol) in MeCN (5 mL) was added a solution of acetic acid 3-chloromethyl-benzofuran-6-yl ester (450 mg, 2.0 mmol) in MeCN (5 mL). The reaction mixture was further diluted with MeCN (10 mL) and heated (50° C., 15 h). The solvent was removed in vacuo and the remaining residue was suspended in 5-10% CH3OH in water and enough concentrated acetic acid was added until all solids were dissolved (pH ˜7-8). The solution was slowly basified using 4 N KOH until precipitate was observed. The precipitate was filtered and rinsed with water. The pH of the mother liquor was further adjusted (4 N KOH and concentrated acetic acid) to produce additional precipitate, which was filtered and rinsed with water. This process of pH adjustment and solid filtration was repeated until no additional precipitate was observed. The precipitate was combined and dried in vacuo to provide the title compound as an off white solid (419 mg, 73%). MS (ESI): mass calcd. for C16H20N2O3, 288.15; m/z found, 289.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.44 (s, 1H), 7.69 (d, J=7.6, 1H), 7.63 (s, 1H), 7.47 (d, J=8.4, 1H), 6.86 (d, J=2.0, 1H), 6.72 (dd, J=8.4, 2.1, 1H), 3.56-3.44 (m, 3H), 2.86-2.74 (m, 2H), 1.99 (t, J=10.6, 2H), 1.76 (s, 3H), 1.74-1.62 (m, 2H), 1.43-1.27 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[C:20]1(=[O:24])[CH2:23][CH2:22][CH2:21]1>CCOCC>[OH:24][C:20]1([C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Reactant: O=C1CCC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccccc1C1(O)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
To phenyl-carbamic acid tert-butyl ester (2 g, 10.4 mmol) in ether (30 mL) at 0° C. was added t-BuLi (15 mL, 26 mmol, 1.7 M) and the reaction solution stirred for 3 hours prior to the addition of cyclobutanone (1.2 mL, 15.6 mmol). The reaction mixture was allowed to warm to room temperature. Upon completion by thin-layer chromatography (TLC), the reaction was poured into ice-cold saturated ammonium chloride (100 mL) and extracted with ethyl acetate (50 mL). The organics were dried over sodium sulfate, concentrated, and purified on a silica gel column (10% ethyl acetate/hexane) to give tert-butyl [2-(1-hydroxycyclobutyl)-phenyl]carbamate (0.86 g, 32%) as a white solid. 1H NMR (DMSO-d6): δ 8.48 (s, 1H), 7.8 (d, 1H, J=7.92 Hz ), 7.35 (dd, 1H, J=7.7, 1.4 Hz), 7.25 (td, 1H, J=7.5, 1.6 Hz), 7.03 (td, 1H, J=7.5, 1.3 Hz), 2.51-2.49 (m, 2H), 2.43-2.39 (m, 2H), 2.28-2.25 (m, 2H), 1.45 (s, 9H). MS (ESI) m/z 190 ([M+H]+); MS (ESI) m/z 188 ([M−H]−);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([O:12][CH2:15][CH2:16][CH2:17][OH:18])[CH:5]=1
Reactant: OCCCBr
Reactant: CCc1ccc(C(=O)OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCc1ccc(C(=O)OC)cc1OCCCO

Procedure:
To a solution of 4-ethyl-3-hydroxy-benzoic acid methyl ester (3.21 g, 17.81 mmol) in acetonitrile (35 mL) are added 3-bromo-1-propanol (1.85 mL, 21.37 mmol) and K2CO3 (3.69 g, 26.7 mmol). The solution is refluxed for 4 h, then poured into water and extracted three times with AcOEt. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated to give the title product. TLC, Rf (c-hexane/AcOEt 8:2)=0.15, MS (LC-MS): 239.2 [M+H]+, tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, flow: 1.5 ml/min): 5.10 min.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=O)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](=[NH:17])(OCC)[CH3:13].C(N(CC)CC)C>C(O)C>[CH3:13][C:12]1[NH:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([CH3:10])[N:17]=1
Reactant: CCOC(=O)C(N)C(C)=O
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c(C)nc1C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
Ethyl 2-amino-3-oxobutanoate hydrochloride (5 g) was added portionwise to a solution of ethyl ethaneimidate (34.0 g) and triethylamine (42 ml) in ethanol (500 ml), and the resulting yellow solution was stirred overnight. Solvent was removed in vacuo and the residue partitioned between water (200 ml) and ether (200 ml). The organic layer was separated and the aqueous phase further extracted with ether (2×200 ml). The dried organic extracts were evaporated in vacuo and the residue washed with cold ether and filtered to give the title compound as a white solid (1.1 g). m.p. 165-166° C.
Reaction SMILES: Cl.[O:2]1[C@:14]2([CH3:20])[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:22][CH2:23][CH2:24][CH3:25])[CH2:11][CH2:12][C:13]2=[O:21])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:26][CH3:27])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[CH:34]1([CH2:37][Cl:38])[CH2:36][CH2:35]1>CN(C)C=O>[ClH:38].[CH:34]1([CH2:37][N:19]2[CH2:18][CH2:17][C@:15]34[C:16]5[C:3]6[O:2][C@@:14]3([CH3:20])[C:13](=[O:21])[CH2:12][CH2:11][C@@:10]4([O:22][CH2:23][CH2:24][CH3:25])[C@H:9]2[CH2:8][C:7]=5[CH:6]=[CH:5][C:4]=6[O:26][CH3:27])[CH2:36][CH2:35]1
Reactant: ClCC1CC1
Reactant: CCCO[C@@]12CCC(=O)[C@]3(C)Oc4c(OC)ccc5c4[C@@]31CCN[C@@H]2C5
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCO[C@@]12CCC(=O)[C@]3(C)Oc4c(OC)ccc5c4[C@@]31CCN(CC1CC1)[C@@H]2C5
Temperature: 85 °C
Reaction time: 36 h
Yield: 55.4 %

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-5-methyl-14-n-propyloxymorphinan-6-one hydrochloride (compound 12 of Example 7) (1.46 g, 3.71 mmol), potassium carbonate (2.24 g, 16.24 mmol), cyclopropylmethyl chloride (0.43 ml, 4.44 mmol), and 15 ml of anhydrous N,N-dimethyl formamide was stirred at 85° C. (bath temperature) for 36 h. The inorganic solid was filtered off and the filtrate evaporated. A solution of the residue in 30 ml of CH2Cl2 was washed with H2O (3×30 ml), dried over Na2SO4 and evaporated. The residue (1,69 g orange-yellow oil) was dissolved in diethyl ether and treated with ethereal HCl to give 920 mg (55%) of 17-(cydopropylmethyl)-4,5α-epoxy-3-methoxy-5-methyl-14-n-propyloxymorphinan-6-one hydrochloride (compound 16) as colorless powder. M.p. 156-158° C. IR (KBr): 3400 (+NH), 1723 (CO) cm-1. CI-MS: m/z 412 (M+ +1). 1H-MR (DMSO-d6): δ 8.57 (s, +NH), 6,85 (d, J=8.2 Hz, 1 arom. H), 6.75 (d, J=8.2 Hz, 1 rom. H), 3.79 (s, OCH3), 1.51 (s, CH3 --C(5)), 0.97 (t, J=7.4 Hz, CH3). Analysis calculated for C25H33NO4HCl. 0.6 H2O(458.81): C 65.45, H 7.73, N 3.05, Cl 7.73; found: C 65.45, H 7.85, N 3.08, Cl 7.84.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:32])=[C:21]([C@@:23]2([CH3:31])[NH:29][C:28](=[O:30])[CH2:27][CH2:26][O:25][CH2:24]2)[CH:22]=1>>[F:32][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=2)=[O:14])=[CH:22][C:21]=1[C@@:23]1([CH3:31])[NH:29][C:28](=[O:30])[CH2:27][CH2:26][O:25][CH2:24]1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reactant: C[C@@]1(c2cc(N)ccc2F)COCCC(=O)N1
Agent: Cl
Product: C[C@@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)COCCC(=O)N1

Procedure:
Starting from 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid and (R) -3-(5-amino-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one hydrochloride, the 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [4-fluoro-3-((R)-3-methyl-5-oxo-[1,4]oxazepan-3-yl)-phenyl]-amide was obtained as a light yellow foam. MS (ISP): m/z=446.1 [M+H]+.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9](=[O:23])[C@@H:10]([NH2:22])[C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])[CH3:12].[OH:24][CH2:25][C@@H:26]1[CH2:28][C@H:27]1[C:29]#[C:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([C:39](O)=[O:40])[S:36][C:35]=2[CH:42]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:18]([O:17][C:15]([NH:14][C:11]([CH3:13])([CH3:12])[C@H:10]([NH:22][C:39]([C:37]1[S:36][C:35]2[CH:42]=[C:31]([C:30]#[C:29][C@@H:27]3[CH2:28][C@H:26]3[CH2:25][OH:24])[CH:32]=[CH:33][C:34]=2[CH:38]=1)=[O:40])[C:9]([O:8][CH3:7])=[O:23])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1cc2ccc(C#C[C@@H]3C[C@H]3CO)cc2s1
Reactant: COC(=O)[C@@H](N)C(C)(C)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)c1cc2ccc(C#C[C@@H]3C[C@H]3CO)cc2s1)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
To a stirring solution of (S)-methyl 2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate oxalate 6.3 (1.4 g, 4.3 mmol), 6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxylic acid (7.2, 900 mg, 3.3 mmol) in ACN (10 mL) at 0° C. was added triethylamine (1.8 mL, 13 mmol), followed by the portionwise addition of a suspension of HATU (2.6 g, 6.9 mmol) in ACN (10 mL), and the reaction mixture was stirred at 0° C. for 105 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between MTBE and water. The organic layer was washed with 1M citric acid, water, saturated sodium bicarbonate (2×), saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamido)-3-methylbutanoate (7.3), which was carried through to the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=S)[N:19]([CH:24]([C:26]([O:28]CC)=O)[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:33][NH2:34]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([CH3:12])([O:13][C:14]2[CH:31]=[C:18]3[C:17](=[CH:16][CH:15]=2)[O:22][CH2:21][C:20]2[N:19]3[CH:24]([CH3:25])[C:26](=[O:28])[NH:33][N:34]=2)[CH2:11]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(OC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.095 g, 0.211 mmol) in EtOH (5 mL) was added hydrazine hydrate (0.105 g, 2.109 mmol) and the mixture was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by preparative TLC (eluting with 30% EtOAc in petroleum ether) to give 3-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.064 g, 75%) as a white solid. LC/MS (Table 1, Method 2) Rt=1.143 min.; MS m/z: 403 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:13]=[C:12]([C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=1)[N:11]=2>CS(C)=O>[NH2:29][C:26]1[N:25]=[CH:24][C:23]([C:12]2[N:11]=[C:10]3[C:15]([N:16]=[C:8]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[N:9]3[CH2:30][CH:31]3[CH2:33][CH2:32]3)=[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:13]=2)=[CH:28][N:27]=1
Reactant: CN(C)CCN
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: CS(C)=O
Product: CN(C)CCNc1nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc2n1CC1CC1
Temperature: 150 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
N,N-Dimethylethylenediamine (113 mg, 1.3 mmol) and dimethyl sulfoxide (1 ml) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.26 mmol) and the resulting mixture was stirred at 150° C. for 4 hours. The reaction mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (85 mg, 68%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]([OH:16])=[CH:9][CH:8]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:14]
Reactant: CCNCC
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(Br)ccc1O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Diethylamine (2.39 mL, 23.0 mmol) was added to a solution of 5-bromosalicylic acid (1.000 g, 4.61 mmol), EDC (1.33 g, 6.91 mmol), HOAt (0.627 g, 4.61 mmol) and DMF (20.0 mL) and the system was flushed with argon. The tube was sealed and the mixture stirred at 50° C. for 12 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown oil. This oil was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford 5-bromo-N,N-diethyl-2-hydroxybenzamide as an off-white solid. MS m/z=272.1, 274.1 [M+H]+. Calcd for C11H14BrNO2: 272.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.Cl>CO>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of serine methyl ester hydrochloride (0.12 g, 0.78 mmol) in 1.6 ml of dry MeOH, at room temperature, under argon, were added successively triethylamine (10% solution, 0.16 ml) and (BOC)2O (0.19 g, 1.1 eq.) and the solution was stirred for 60 minutes. It was then poured in cold 2% HCl and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, the solids were filtered and the solvents evaporated to give 0.17 g (100%) of the titled compound as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=S)[CH2:15][C:16](=O)[CH3:17])=[O:4].[C:20]1([CH2:26][CH2:27][NH:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:28]([CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:29]=[C:16]([CH3:17])[CH:15]=1)=[O:4]
Reactant: NNCCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1CCc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-methanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with 1-(2-phenylethyl)hydrazine (CAS Reg. No. 51-71-8) to give the title compound as brown solid. MS (ESI): m/z=392.6 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=1.[H-].[Na+]>CN(C)C=O>[CH3:24][N:16]([C:14]1[CH:15]=[C:10]([S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:11]=[CH:12][C:13]=1[N+:25]([O-:27])=[O:26])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 98 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-methylthiophenol (0.98 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.00 g), sodium hydride (55 wt. %, 0.31 g) and anhydrous N,N-dimethylformamide (60 ml) and the reaction mixture was purified to give the title compound (2.56 g).