Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:14]=[C:13]([CH:15]=[CH:16][NH:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[O:10][CH2:9]1)[CH:2]=[CH2:3].[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)(C)C>[CH2:1]([C:4]1[CH:14]=[C:13]([CH:15]=[CH:16][NH:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:10])[CH2:9][NH:25][CH:22]([CH3:24])[CH3:23])[CH:2]=[CH2:3]
Reactant: CC(C)N
Reactant: C=CCc1cc(C=CNC(=O)OC)ccc1OCC1CO1
Solvent: CC(C)O
Product: C=CCc1cc(C=CNC(=O)OC)ccc1OCC(O)CNC(C)C

Procedure:
4.9 g (0.017 mol) of 1-[2-allyl-4-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane are heated for 3 hours with a solution of 1.57 ml (0.018 mol) of isopropylamine in 100 ml of isopropanol to 80° C. under reflux. The mixture is then evaporated under reduced pressure and the resulting crude base is crystallised from acetone-ether. 1-[2-Allyl-4-(2-methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylamino-propane, of melting point 128°-129° C. is obtained.
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:22]=[CH:21][N:20]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:19]=3)[C:12]=2[CH:11]=[CH:10]1.O=[C:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[C:28]([CH2:27][C:23]1([N:20]2[CH:21]=[CH:22][C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:19]2)[CH2:24][N:25]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH2:26]1)#[N:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CNC4)c3)ncnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CC(CC#N)(n3ccc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)c3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of {3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (3.0 g, 7.3 mmol) in THF (30 mL) were added tert-butyl 4-oxo-1-piperidinecarboxylate (1.4 g, 7.3 mmol), N,N-diisopropylethylamine (6.4 mL, 37 mmol) and sodium triacetoxyborohydride (3.1 g, 15 mmol). The reaction mixture was stirred at room temperature overnight. Brine (20 mL) and EtOAc (20 mL) were added. The organic phase was separated and the aqueous layer was extracted with EtOAc. The combined extracts were dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was purified using combiflash column eluting with 20-50% EtOAc in hexanes to generate tert-butyl 4-{3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidine-1-carboxylate as an oil. Yield: 3.37 g (78%); LC-MS: [M+H]+=592.3.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[O:9]([C:16]([N:18]=[C:19]=[S:20])=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[NH:1]=[C:2]([CH3:8])[CH:3]([C:4]([O:6][CH3:7])=[O:5])[C:19]([NH:18][C:16]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:17])=[S:20]
Reactant: O=C(N=C=S)Oc1ccccc1
Reactant: COC(=O)/C=C(/C)N
Solvent: Cc1ccccc1
Product: COC(=O)C(C(C)=N)C(=S)NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A warm solution of methyl 3-aminocrotonate (prepared according to the method of Conrad and Epstein, Chemische Berichte, 1887, 20, 3054, 10.4 g.) in toluene (20 ml.) was added with stirring to a solution of phenoxycarbonylisothiocyanate (16 g.) in toluene (50 ml.). The temperature of the mixture rose from 20° C. to 35° C. The mixture was then stirred for 11/2 hours at ambient temperature, filtered and the solid residue washed with light petroleum (b.p. 40°-60° C.) to give 3-imino-2-methoxycarbonyl-N-phenoxycarbonylthiobutyramide (8.6 g.) in the form of an orange solid, which was then dissolved in ethyl acetate (100 ml.). To this solution, a solution of bromine (1.67 ml.) in ethyl acetate (5 ml.) was added over 15 minutes at 2°-5° C. The mixture was stirred at ambient temperature for 11/2 hours and the solid product filtered off to give 4-methoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole hydrobromide (9.6 g.) m.p. 170°- 173° C. A solution of methylamine in ethanol (30% w/v; 20 ml.) was added to 4-methoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole hydrobromide (9.0 g.). The mixture was heated under reflux for 15 minutes, diluted with water (30 ml.), filtered and the solid residue dried at 100° C., to give 1-(4-methoxycarbonyl-3-methylisothiazol-5-yl)-3-methylurea (4.1 g.), m.p. 236°-237° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[C:13]=3[C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]#[N:30].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].CN(C=O)C.Cl>O>[Br:1][C:2]1[C:3]([O:27][CH2:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C:12]1[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13]=1[C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)sc2ccccc12
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)sc2ccccc12
Temperature: 80 °C
Yield: 49.9 %

Procedure:
A mixture of [1-bromo-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetonitrile (0.576 g, 1.20 mmol), sodium azide (0.393 g, 6.05 mmol) and ammonium chloride (0.33 g, 6.2 mmol) in DMF (10 mmol) was heated at 80° C. for three hours. After cooling to ambient temperature, the reaction mixture was poured into excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate. The organic phase was washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified by HPLC using 81% acetonitrile (0.1% formic acid) in water as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 58° C. for 16 hours yielded 1-{2-[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-yl]-benzo[b]thiophen-3-yl}-pentan-1-one as a light yellow foam (0.312 g, 49.8%). Mass spectrum (+EI, [M+H]+) m/z 521/523. 1H NMR (500 MHz, DMSO-d6): δ16.6–17.3 (br, 1H), 8.24 (d, 1H, J=8.86 Hz),8.16–8.20 (m, 2H), 8.08–8.09 (m, 1H), 7.95–7.97 (m, 1H), 7.75–7.78 (m, 2H), 7.46–7.52 (m, 2H), 5.76 (s, 2H), 2.42 (t, 2H, J=7.26 Hz), 1.40–1.46 (m, 2H), 0.96–1.04 (m, 2H), 0.58 ppm (t, 3H, J=7.42 Hz). Elemental Analysis for C25H21BrN4O2S: Calcd: C, 57.59; H, 4.06; N, 10.74; Found: C, 57.42; H, 4.19; N, 10.59.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10]([CH2:18][CH2:19][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][C:22]=2[F:33])([C:13]([O:15]CC)=[O:14])[CH2:9][CH2:8]1.[OH-].[Na+]>O1CCOCC1.CO>[F:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:2]([F:1])[C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][C:10]([CH2:18][CH2:19][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][C:22]=2[F:33])([C:13]([OH:15])=[O:14])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCOc2c(F)cccc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCOc4c(F)cccc4F)CC3)c2c1
Temperature: 70 °C
Reaction time: 17 h
Yield: 81.2 %

Procedure:
A mixture of 0.39 g of ethyl 1-[2-(2,6-difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 2.2 cm3 of aqueous 5N sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 17 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45° C. The residue was taken up in 5 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and was then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200μ; mass 10 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and dried in a desiccator (10 kPa). 0.3 g of 1-[2-(2,6-difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1COCC1>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:11]1[C:6]2[CH:5]=[C:4]([C:2](=[S:30])[NH2:1])[NH:20][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: NC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 17 h

Procedure:
144 mg (0.50 mmol) of 6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine and 202 mg (0.5 mmol) of Lawesson's reagent in 5 ml of THF are heated to boiling for 17 h and the mixture is then evaporated. Column chromatography (SiO2, CH2Cl2/ethanol=15:1) of the residue and stirring in diethyl ether yields 4-(3-chloroanilino)-6-(thiocarbamoyl)-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=9.8; TLC-Rf=0.44 (CH2Cl2/methanol=10:1); FAB-MS: (M+H)+=304; IR: (KBr) inter alia 1614s, 1566s, 1506m, 1474s, 1380m, 1354m, 1294m, 1134m.
Reaction SMILES: C1COCC1.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[C:13]([O:22][CH3:23])[CH:12]=1.C([Li])CCC.[Cl:29]C(Cl)(Cl)C(Cl)(Cl)Cl>C(OCC)(=O)C.O>[Cl:29][C:18]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH:7]3[O:6][CH2:10][CH2:9][O:8]3)=[CH:12][C:13]=2[O:22][CH3:23])[CH:21]=[CH:20][N:19]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1cc(C2OCCO2)ccc1-n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C2OCCO2)ccc1-n1ccnc1Cl
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a THF (50 mL) solution of 1-(4-[1,3]dioxolan-2-yl-2-methoxyphenyl)-1H-imidazole (3.85 g), n-butyllithium (1.6M hexane solution, 12 mL) was added dropwise under nitrogen atmosphere at −78° C., and the reaction solution was agitated for 30 minutes. THF (10 mL) solution of hexachloroethane (6.1 g) was added to the reaction solution and the reaction solution was agitated at room temperature for 1 hour after agitating for 30 minutes at −78° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:hexane-ethyl acetate system), and 3.19 g of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][NH:22][CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].CCN(C(C)C)C(C)C.Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(#N)C.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][N:22]([CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCNC4)no2)cc1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCN1CCOc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2C1
Temperature: 70 °C
Yield: 70.7 %

Procedure:
A mixture of 8-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (Example 13) (0.127 g, 0.3 mmol), DIPEA (0.052 ml, 0.300 mmol) and ethyl 4-bromobutanoate (0.059 g, 0.300 mmol) in acetonitrile (5 ml) was stirred and heated at 70° C. for 15 hours. The cooled reaction mixture was diluted and dissolved in EtOAc/water (30 ml of each) and the organics dried (magnesium sulphate), evaporated and purified by flash chromatography eluting with 1:1 EtOAc/iso-hexane to give the title compound (106 mgs) as a colourless gum. MS (ES) C28H3835ClN3O5 requires 499; found 500 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][C:25](=[O:27])[CH3:26])[CH:6]=1)(=[O:3])[CH3:2].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C1COCC1>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][C:25](=[O:27])[CH3:26])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]1CC2

Procedure:
A solution of 1 g. of 1,3-diacetoxy-8α-estra-1,3,5(10)-trien-17-one in 30 ml. of absolute THF is agitated under ice cooling with 2 g. of lithium tri-tert.-butoxyaluminum hydride for 45 minutes under ice cooling. The mixture is then introduced into acetic ice water/NaCl and extracted with ether. The organic phase is washed neutral, dried, and evaporated. The residue (1 g.) is purified by layer chromatography; after recrystallization from hexane/acetone, 380 mg. of 1,3-diacetoxy-8α-estra-1,3,5(10)-trien-17β-ol is produced, m.p. 210°-211° C.
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:45][CH3:46])=[C:11]([NH:13][C:14]2[N:15]=[C:16]([NH:33][C:34]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:35]=3[C:36]([NH:38][CH3:39])=[O:37])[C:17]3[CH:22]=[CH:21][N:20](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]=3[N:19]=2)[CH:12]=1)=[O:5].[OH-].[K+].CCOC(C)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:47][N:2]([CH3:1])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:45][CH3:46])=[C:11]([NH:13][C:14]2[NH:19][C:18]3=[N:20][CH:21]=[CH:22][C:17]3=[C:16]([NH:33][C:34]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:35]=3[C:36]([NH:38][CH3:39])=[O:37])[N:15]=2)[CH:12]=1)=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc(NC(=O)CN(C)C)ccc2OC)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc(NC(=O)CN(C)C)ccc2OC)[nH]c2nccc1-2
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A mixture of 2-({2-{[5-[(N,N-dimethylglycyl)amino]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (485 mg, 0.734 mmol) and a 1M aqueous KOH solution (7.34 mL, 7.34 mmol) in dioxane (20 mL) was heated at 80° C. for 7 h. The resulting mixture was allowed to cool to rt. EtOAc (50 mL) was added, followed by a saturated NaHCO3 solution (50 mL). The organic layer was washed with a saturated NaCl solution (50 mL), concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-[(2-{[5-[(N,N-dimethylglycyl)amino]-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a white solid (220 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 6H), 2.80 (d, J=4.58 Hz, 3H), 3.03 (s, 2H), 3.82 (s, 3H), 6.31 (dd, J=3.48, 1.83 Hz, 1H), 6.89-7.03 (m, 3H), 7.33 (dd, J=8.79, 2.56 Hz, 1H), 7.36-7.45 (m, 1H), 7.57 (s, 1H), 8.21 (d, J=2.38 Hz, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.51-8.61 (m, 1H), 9.40 (s, 1H), 10.17 (s, 1H), 11.35 (s, 1H); ESIMS (M+H)+=507.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[Cl:31][C:32]1[N:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[CH:34][N:33]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:38]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([Cl:31])[N:37]=3)=[O:39])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: O=C(O)c1ccnc(Cl)n1
Product: Nc1nccn2c([C@@H]3CCCN3C(=O)c3ccnc(Cl)n3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Yield: 40.4 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 2-chloropyrimidine-4-carboxylic acid, to afford the title compound (8.3 mg, 40.4%). Data: UPLC (C) Rt: 1.64 min; m/z 540.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C@H:9]3[CH2:13][NH:12][C:11](=O)[C@@H:10]3[C:4]=2[CH:3]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[BH4-].[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCCC1.C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C@H:9]3[CH2:13][NH:12][CH2:11][C@@H:10]3[C:4]=2[CH:3]=1
Reactant: O=C1NC[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@@H]12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)[C@H]1CNC[C@@H]1c1ccccc1O2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 281.1 %

Procedure:
0.526 g (1.84 mmol) of trans-11-chloro-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (compound trans-XVIIa) and 17.5 mL of toluene were charged to a 50 mL round-bottomed flask equipped with a Dean-Stark distillation setup. The mixture was heated to reflux and stirred for about 10 min before it was cooled to 0° C. Then trifluoromethanesulfonic anhydride (0.32 mL, 1.9 mmol) was added dropwise and the mixture stirred for about 30 minutes. Sodium borohydride (100 mg, 2.6 mmol) was then added followed by anhydrous tetrahydrofuran (8.6 mL). The obtained solution was allowed to heat to room temperature and stirred over about 20 h. Water (8.6 mL) and 1M hydrochloric acid (0.1 mL) were added, and the mixture heated to reflux, stirred for 2 h and allowed to cool down to room temperature. 6 mL of saturated sodium carbonate solution were added, and the obtained layers were separated. The aqueous layer was extracted with diethyl ether (26 mL) three times, and the obtained organic layers were dried with sodium sulfate, filtered, rotary evaporated and dried in the vacuum oven to yield 0.797 g of a crude oil.
Reaction SMILES: C[N:2]1C(N)=NC(=O)C1.N.O=[C:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13]>>[NH2:2][C@H:11]([C:12]([OH:14])=[O:13])[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: CN1CC(=O)N=C1N
Agent: N
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Creatinine is catalytically hydrolyzed to ammonia by the enzymatic activity of an unknown creatinine iminohydrolase enzyme sample, and the resultant ammonia reacts with the reagent α-ketoglutaric acid in the presence of GDH as catalyst to produce glutamic acid. The latter reaction catalyzed by GDH concomitantly converts NADPH to NADP, the disappearance of the NADPH absorption peak at 340 nm providing the spectroscopically detectable means for monitoring the assay. That is, the NADPH disappearance rate measures the rate of glutamic acid production which, in turn, measures the rate of ammonia production. The reaction mixture employed in the GDH assay method contained, in a total volume of one milliliter of 0.1 M N,N-bis(2-hydroxyethyl)-glycine-KOH buffer solution having a pH of 7.5: 0.4 mg (ethylenedinitrilo) tetraacetic acid, disodium salt (Na2EDTA), 1.6 mg α-ketoglutaric acid, 0.24 mg NADPH, 15 units GDH (ammonia free), and 4.52 mg creatinine. One unit of L-glutamic dehydrogenase is defined as that amount of enzyme which catalyzes the reduction of 1 micromole of α-ketoglutarate to glutamate per minute at pH 7.6 and 37° C. Reaction was initiated in the above-noted reaction mixture by addition of a small sample (about 2-10 milliunits) of the desired creatinine iminohydrolase enzyme preparation after equilibration of the reaction mixture at 37° C. Creatinine iminohydrolase activity was calculated by measuring the rate of NADPH disappearance at 340 nm (the molar extinction coefficient of NADPH at 340 nm being 6.22×103) in a Beckman Model 25 spectophotometer. One unit of enzyme activity was defined as that amount of enzyme necessary to catalyze the conversion of 1 micromole of creatinine to 1 micromole of ammonia per minute under the above-noted GDH assay reaction conditions.
Reaction SMILES: CN(C)C=O.[C:6]([C@@H:9]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]=2[S:21][CH2:20]1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:8])=[O:7].C(=O)(O)[O-].[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O>[CH2:44]([O:7][C:6]([C@@H:9]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]=2[S:21][CH2:20]1)[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)O)CSc2ccccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)CSc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A mixture of 10 ml of N,N-dimethylformamide, 0.3 g of tert-butyl 3(R)-[1(S)-carboxy-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate obtained in Example 43, 0.5 g of sodium bicarbonate and 0.15 g of benzyl bromide is stirred at room temperature overnight. The mixture is diluted with water (100 ml) and extracted with ethyl acetate (200 ml). The extract is washed successively with 0.1N hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.35 g of tert-butyl 3(R)-[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1([C:7]2[N:12]([CH3:13])[C:11](=[O:14])[N:10]([CH3:15])[C:9](=[O:16])[CH:8]=2)[CH2:6][CH2:5]1>>[CH3:13][N:12]1[C:7]([NH:4][CH2:6][CH2:5][NH:3][CH2:1][CH3:2])=[CH:8][C:9](=[O:16])[N:10]([CH3:15])[C:11]1=[O:14]
Reactant: Cn1c(N2CC2)cc(=O)n(C)c1=O
Reactant: CCN
Product: CCNCCNc1cc(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 7.6 g of a 70% aqueous ethylamine solution was added 0.91 g of the previously obtained Compound 12, followed by stirring at room temperature for 3 hours. After completion of the stirring treatment, the reaction solution was concentrated under reduced pressure, and 80 ml of ethanol were added to the resultant residue. Then, the ethanol solution was further concentrated under reduced pressure. Ether was added to the resultant residue, and crystallization was then effected. Afterward, a mixed solution of ether and hexane in a ratio of 1:1 (volume ratio) was added thereto. The crystals were then collected by filtration to obtain 1.07 g of N-(1,3-dimethyl-2,4-dioxopyrimidine-6-yl)-N'-ethylethylene-diamine (Compound 13).