Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:33])[NH:7][C:8]2[CH:31]=[CH:30][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[N:26]=[C:25]([C:27]([O-:29])=O)[CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[F:32])[CH2:4][CH2:3][CH2:2]1.[Na+].C(N(CC)CC)C.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[C:42]([NH:46][C:27](=[O:29])[C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:20][N:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C:11]3[CH:30]=[CH:31][C:8]([NH:7][C:6]([NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:33])=[C:9]([F:32])[CH:10]=3)[CH2:15][CH2:16]2)[N:26]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: O=C(Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)[O-])n3)CC2)cc1F)NC1CCC1
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)c(F)c3)CC2)n1
Reaction time: 1 h
Yield: 22.5 %

Procedure:
Sodium 6-((4-(4-(3-cyclobutylureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)-picolinate (100 mg, 0.209 mmol), triethylamine (66 mg, 0.693 mmol, 0.091 mL) and tert-butylamine (32 mg, 0.435 mmol) were combined and stirred at room temperature in dichloromethane. 1-Propanephosphonic acid cyclic anhydride (208 mg, 0.326 mmol, 0.194 mL, 50% solution in ethyl acetate) was added dropwise and the reaction allowed to stir for 1 hour. The reaction mixture was concentrated at reduced pressure, the resulting residue taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated under vacuum to afford the title compound (24 mg). MS (ESI) m/z 511.6 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH2:38]([S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41])[CH3:39]>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:11]2[C@@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:9]([C:27]([N:46]3[CH2:45][CH2:44][N:43]([S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])[CH2:48][CH2:47]3)=[O:28])[C:8]([C:6]3[C:5]([O:30][CH2:31][CH3:32])=[CH:4][C:3]([C:33]([CH3:35])([CH3:34])[C:36]#[N:37])=[C:2]([Cl:1])[CH:7]=3)=[N:12]2)=[CH:18][CH:17]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)CC)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-(4-ethanesulfonyl-piperazine-1-carbonyl)-4,5-dihydro-1H-imidazol-2-yl]-2-chloro-5-ethoxy-phenyl}-2-methyl-propionitrile was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and 1-ethanesulfonyl-piperazine (example 14) in an analogous manner as described in example 25. LR-MS: 716.3 [(M+H)+]
Reaction SMILES: [OH:1][C:2]1([CH:13]([N+:15]([O-:17])=[O:16])[CH3:14])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:18]>CO.O1CCOCC1>[ClH:18].[N+:15]([CH:13]([C:2]1([OH:1])[CH2:5][NH:4][CH2:3]1)[CH3:14])([O-:17])=[O:16]
Reactant: CC([N+](=O)[O-])C1(O)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC([N+](=O)[O-])C1(O)CNC1
Yield: 96 %

Procedure:
1,1-Dimethylethyl 3-hydroxy-3-(1-nitroethyl)azetidine-1-carboxylate was dissolved in methanol (5 mL) and treated with 4 N HCl in dioxane. The solution was briefly heated to reflux and then was concentrated in vacuo to afford 178 mg, 0.98 mmol (96%) of 3-(1-nitroethyl)azetidin-3-ol hydrochloride as a white solid. 1H NMR (400 MHz, DMSO): 9.30 (br s, 1H), 8.96 (br s, 1H), 5.12 (q, 1H), 4.44-4.38 (m, 1H), 4.22-4.17 (m, 1H), 3.94-3.87 (m, 1H), 3.85-3.77 (m, 1H), 1.44 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[CH3:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:13](=[O:15])[CH3:14])[CH:3]=2)[N:8]=1
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2nc(C)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
6-amino-2-methylquinoline (1.02 g, 6.45 mmol) was dissolved in pyridine (30 ml), acetic anhydride (0.913 ml, 9.67 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and diisopropyl ether was added thereto for crystallization, to obtain N-(2-methyl-6-quinolinyl)acetamide (1.20 g) as white powders.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([S:19]([CH3:22])(=[O:21])=[O:20])C(C2C=CC=C(CCl)N=2)=O)=[CH:6][C:5]([C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[N:28][N:29]3S(C3C=CC=CC=3)(=O)=O)=[C:25]([NH:41][C:42]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50]Cl)[N:45]=3)=[O:43])[CH:24]=2)=[CH:4][N:3]=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[N:28][NH:29]3)=[C:25]([NH:41][C:42]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)[N:45]=3)=[O:43])[CH:24]=2)=[CH:6][C:7]=1[NH:8][S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: CS(=O)(=O)N(C(=O)c1cccc(CCl)n1)c1cc(-c2cc(NC(=O)c3cccc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Reactant: C1COCCN1
Product: CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3cccc(CN4CCOCC4)n3)c3cn[nH]c3c2)cnc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
N-{2-Chloro-5-[4-({[6-(chloromethyl)-2-pyridinyl]carbonyl}amino)-1-(phenylsulfonyl)-1H-indazol-6-yl]-3-pyridinyl}-6-(chloromethyl)-N-(methylsulfonyl)-2-pyridinecarboxamide (60 mg, 0.061 mmol) and morpholine (0.5 ml, 5.74 mmol) were placed in a vial and heated in a microwave at 90° C. for 15 min. The mixture was concentrated by blow down under a stream of nitrogen. The crude residue was suspended in IPA (2 ml) and 2M NaOH (1 ml) added. The mixture was stirred at room temperature for 2 h. The solvent was removed by blow down and the residue purified by MDAP (Method E) (3×800 μl injections in DMSO, the insoluble salt was filtered off through a filter tube). Product-containing fractions were combined and the solvent removed in vacuo. The residue was dissolved in DCM:MeOH and added to the top of a 1 g silica cartridge that was subsequently eluted with 0-5% MeOH/DCM over 5 column volumes. No separation was observed, hence all fractions were combined and the solvent removed under a stream of nitrogen. The residue was dissolved in DMF/Acetone/Water (0.2 ml:0.2 ml:20 μl) and purified by MDAP (Method E). Product-containing fractions were combined and the solvent removed in vacuo. The resulting oil was triturated with ether to give the title compound as a cream solid (8 mg).
Reaction SMILES: [CH3:1][N:2]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[NH2:3].Cl.[C:12](=[NH:17])(OCC)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:7]([O:6][C:4]([N:2]([CH3:1])[NH:3][C:12](=[NH:17])[CH3:13])=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(C)=N
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=N)NN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A solution of tert-butyl 1-methylhydrazinecarboxylate (10.0 g, 68.4 mmol), ethyl acetimidate hydrochloride (42.1 g, 342 mmol), and potassium carbonate (94.4 g, 684 mmol) in DMF (150 mL) was heated at 105° C. for 5 hours. The contents were cooled to 0° C. before the precipitated material was collected by vacuum filtration and resuspended in H2O (100 mL). After 30 minutes of vigorous stirring, the remaining precipitate was collected and dried in a 45° C. vacuum oven overnight to yield the title compound as a white solid (7.56 g, 59.0%): mp 187-189° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.28 (br s, 1H), 2.77 (s, 3H), 1.64 (s, 3H), 1.36 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4](=[O:20])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([CH3:19])=[C:14]([C:16]([OH:18])=O)[S:15][C:9]=2[N:8]=[CH:7]1)[CH3:2].CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][N:43]([C:16]([C:14]3[S:15][C:9]4[N:8]=[CH:7][N:6]([CH2:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:21][CH3:22])=[O:20])[C:11](=[O:12])[C:10]=4[C:13]=3[CH3:19])=[O:18])[CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: CCN(CC)C(=O)Cn1cnc2sc(C(=O)O)c(C)c2c1=O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)Cn1cnc2sc(C(=O)N3CCN(c4ccc(Cl)c(Cl)c4)CC3)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a mixture of 3-(2-(diethylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (0.12 g, 0.37 mmol) in DCM (5 mL) was added DIEA (0.2 mL, 1.1 mmol), 4(3,4-dichlorophenyl)piperazine (0.073 g, 0.37 mmol), and HATU (0.182 g, 0.48 mmol). The reaction mixture was stirred at RT overnight. The organic layer was diluted with CH2Cl2 and then washed with sat. NaHCO3 aq. (20 mL), dried over Na2SO4, and concentrated to give crude product as a gummy solid. Purification by flash column chromatography using a mixture of Et2O: DCM (1:1) as the eluant afforded the 0.092 g of 2-(6-(4-(3,4-dichlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxo thieno[2,3-d]pyrimidin-3(4H)-yl)-N,N-diethylacetamide, (yield: 50%).
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.C([O-])(=O)C.[Na+].[I:16]I.[OH-].[Na+]>C(O)(=O)C.O1CCCC1>[I:16][C:2]1[O:1][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=1
Reactant: Nc1nccc2occc12
Reactant: II
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1nccc2oc(I)cc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 68.1 %

Procedure:
Furo[3,2-c]pyridin-4-ylamine (7.8 g) was dissolved in 175 mL of glacial acetic acid and sodium acetate (14.3 g) added in portions (exothermic!). Subsequently a solution of iodine (44.2 g) in 150 mL of tetrahydrofuran was added dropwise and the resulting mixture allowed to stir for 4 d at ambient temperature. The mixture was poured on ice and the pH value adjusted to pH 10 by adding 10 N sodium hydroxide solution, followed by extraction with ethyl acetate. The organic extract was washed several times with sodium thiosulfate solution and brine, dried (Na2SO4) and concentrated. The crude product was purified by silica chromatography (ethyl acetate/isohexane=5/5, 7.5/2.5, 10/0) to give 10.3 g (68%) of the title compound as a brownish solid. M.p. 170-173° C.; EI-MS: 260 (M+).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[C:6]1=[O:7])=[O:4].C1CCN2C(=NCCC2)CC1.[NH2:27][C:28]([NH2:30])=[O:29]>O1CCCC1>[CH3:1][N:2]1[C:8]([OH:9])([C:6]([NH:27][C:28]([NH2:30])=[O:29])=[O:7])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:5][C:3]1=[O:4]
Reactant: NC(N)=O
Reactant: CNC(=O)N1C(=O)C(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CN1C(=O)Nc2ccccc2C1(O)C(=O)NC(N)=O

Procedure:
1-Methylcarbamoylisatin (10.2 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.3 g) are dissolved in tetrahydrofuran (100 ml), and thereto is added urea (4.5 g), and the mixture is refluxed for 10 hours. After cooling, the precipitates are taken by filtration, washed with water and methanol and recrystallized from a mixture of dimethylsulfoxide and ethanol to give 3-methyl-4-hydroxy-4-ureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline, M.p.>280° C.,
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])C.Cl>O1CCCC1>[C:9]1(=[O:18])[N:8]([CH2:7][CH2:6][CH2:5][CH:4]=[O:3])[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]12
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCCCN1C(=O)c2ccccc2C1=O

Procedure:
A solution of 4-phthalimidobutyraldehyde diethyl acetal (125 g, 0.43 mol) in a 1:1 mixture of tetrahydrofuran and 2N hydrochloric acid (800 ml) was heated at reflux for 0.75 h. The mixture was cooled, concentrated to 400 ml and extracted into dichloromethane (3×200 ml). Combined organics were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a brown oil that solidified on standing (95 g, 100%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([NH:26][C:27]1[C:28]([O:42][CH3:43])=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[Cl:21][C:16]1[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:42][CH3:43])=[C:27]([NH:26][CH2:24][CH3:25])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])=[CH:19][N:18]([CH3:20])[N:17]=1
Reactant: CCNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Reactant: Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(Cl)n1
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2Cl)c(=O)n4C)cnc1OC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and ethyl-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (stage 90.1.1, 0.138 mmol) to give the title compound as a white solid. (HPLC: tR 2.45 min (Method A); M+H=415 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.24-8.16 (m, 2H), 8.14-8.07 (m, 1H), 8.02-7.94 (m, 1H), 7.66-7.59 (m, 1H), 7.09-7.02 (m, 1H), 6.87-6.80 (m, 1H), 4.32 (q, 2H), 3.94 (s, 3H), 3.57 (s, 3H), 1.96 (s, 3H), 1.34 (t, 3H))
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)[N:3]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1nn(C2CCCCO2)c2ccccc12
Temperature: 80 °C
Yield: 79.9 %

Procedure:
To a solution of 3-bromo-1H-indazole (500 mg) synthesized according to a method of the literature (V> Auwers, et al., J. Prakt. Chem., 1924, 314) in toluene (25 mL, manufactured by Wako Pure Chemical Industries, Ltd.), 3,4-dihydro-2H-pyrane (640 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) and p-toluenesulfonic acid monohydrate (10 mg, manufactured by Wako Pure Chemical Industries, Ltd.) were added, and the mixture was heated for one hour at 80° C. The reaction solution was cooled to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate (10 mL) was added thereto. The mixture was extracted with ethyl acetate (3×20 mL), washed with brine (40 mL), and dried (MgSO4), and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), to give 570 mg of the title compound. LC-MS: HPLC retention time 4.93 minutes, m/z 281 (M+H), condition B-1.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[CH:6][CH:5]=1.O[N:31]=[C:32]([O:34][CH2:35][CH3:36])[NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:26]3[O:27][N:33]=[C:32]([O:34][CH2:35][CH3:36])[N:31]=3)[CH2:13][N:14]([C:16]([N:18]3[CH2:19][CH2:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23]3)=[O:17])[CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1
Reactant: CCOC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1noc(C2CC(c3ccc(OC(F)F)cc3)CN(C(=O)N3CCS(=O)(=O)CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
226 mg (0.52 mmol) of the compound from Example 40A and 109 mg (1.05 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were initially charged in 2.0 ml of DMF and reacted with 298 mg (0.8 mmol) of HATU and 0.27 ml (203 mg, 1.6 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 15 minutes and then the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was taken up in 5.0 ml of dioxane and admixed with about 1 g of 4 Å molecular sieve. The mixture was heated to reflux for 16 h, and the reaction mixture was purified by means of preparative HPLC. Yield: 86 mg (30% of theory)
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH:23]4[CH2:27][CH:26]([CH2:28][OH:29])[NH:25][CH2:24]4)[CH3:22])=[N:18][C:17]3=[O:30])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:48][C:49]([NH2:51])=[O:50]>CN(C=O)C>[F:40][C:2]([F:39])([F:1])[C:3]1[CH:34]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH3:22])[CH:23]4[CH2:24][N:25]([CH2:48][C:49]([NH2:51])=[O:50])[CH:26]([CH2:28][OH:29])[CH2:27]4)=[N:18][C:17]3=[O:30])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: NC(=O)CBr
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CNC(CO)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CC(CO)N(CC(N)=O)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 110.2 %

Procedure:
To a solution of 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-hydroxymethyl-pyrrolidin-3-yl)-methyl-amino]-thiazol-4-one (20 mg, 0.034 mmol) (Example 43) (30 mg, 0.051 mmol) in DMF (1 mL) was added potassium carbonate (11 mg, 0.072 mmol) followed by 2-Bromo-acetamide (30 mg, 0.22 mmol). The reaction mixture was stirred at 70° C. for 1 hour and partitioned between water and dichloromethane. The dichloromethane layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (100% ethyl acetate) to yield the title compound (24 mg, 72%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:30]=[CH:29][C:14]2[O:15][C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C@@H:18]3[C@H:23]([NH2:24])[CH2:22][CH2:21][CH2:20][N:19]3[C:13]=2[CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:55]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][C:57](O)=[O:58]>C(Cl)Cl>[CH3:66][C:63]([O:62][C:60](=[O:61])[NH:55][CH2:56][C:57]([NH:24][C@H:23]1[C@@H:18]2[N:19]([C:13]3[CH:12]=[C:11]([Cl:10])[CH:30]=[CH:29][C:14]=3[O:15][C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=32)[CH2:20][CH2:21][CH2:22]1)=[O:58])([CH3:64])[CH3:65]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reaction time: 3 h
Yield: 104.1 %

Procedure:
DIPEA was added (pH=9) to trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) in 1 mL of CH2Cl2 with HATU (12.5 mg, 0.03 mmol) and Boc-Gly-OH (10.3 mg, 0.03 mmol). The resulting mixture was stirred for 3 h, washed with 5% aqueous sodium bicarbonate and H2O, dried (Na2SO4) and evaporated to give [[[(trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)amino]carbonyl]methyl]carbamic Acid 1,1-dimethylethyl Ester (14.3 mg, 100%). Data: (m/z)=405 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH2:9][C:10]([O:12]CC)=O)[N:3]=1.[NH3:15]>C(O)C>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH2:9][C:10]([NH2:15])=[O:12])[N:3]=1
Reactant: CCOC(=O)Cn1nc(Br)c(Br)c1Br
Reactant: N
Solvent: CCO
Product: NC(=O)Cn1nc(Br)c(Br)c1Br
Reaction time: 72 h

Procedure:
A solution consisting of 9.7 gm. (0.025 mole) ethyl 3,4,5-tribromopyrazole-1-acetate in 250 ml. ethanol was saturated with gaseous ammonia and held at about 25° C. for 3 days. After removing most of the ethanol by evaporation under reduced pressure, the solids that formed were collected on a filter and recrystallized from a mixture of ethanol and water. There was thus obtained 5.8 gm. of 3,4,5-tribromopyrazole-1-acetamide having a melting point at 234° to 236° C.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[CH:34][N:35]=2)[N:32]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([N:33]=[CH:34][N:35]=4)[N:32]=3)[CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(C(OC2CCN(CCCCNc3ccc4ncnn4n3)CC2)c2ccccc2)cc1
Yield: 9.1 %

Procedure:
4-(Diphenylmethoxy)-1-piperidinebutanamine (1.83 g) and 6-chloro[1,2,4]triazolo[1,5-b]pyridazine (557 mg) were dissolved in 1-butanol (30 ml), followed by addition of N-ethyldiisopropylamine (931 mg). The mixture was refluxed under heating for 14 hours. After being cooled, the mixture was concentrated under reduced pressure, followed by addition of ice-water and extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with a mixture of ethyl acetate, methanol and triethylamine (45:5:1). Fractions containing the objective compound were collected and concentrated. The resulting crystals were collected, washed with ethyl ether and dried to yield the title compound (149 mg).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](=[S:16])[NH:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:21]I.O>CN(C=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([S:16][CH3:21])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: CCc1[nH]n(C2CCCC2)c2nc(=S)[nH]c(=O)c1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1[nH]n(C2CCCC2)c2nc(SC)nc(=O)c1-2
Reaction time: 3 h
Yield: 74.2 %

Procedure:
Alternatively, the product can be prepared as follows: To a stirred mixture of 1-cyclopentyl-3-ethyl-6-(thioxo) pyrazolo[3,4-d]pyrimidin-4-one (23.4 g, 0.09 mol) in DMF (250 mL) was added NaH (4.0 g, 0.1 mol., 60% dispersion in mineral oil) over 15 minutes. The resulting mixture was cooled in an ice bath, then methyl iodide (6.3 mL, 0.1 mol) was added over 20 minutes and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into water (400 mL) and the precipitate which formed was collected by filtration, washed with water, then hexane and then was dried at 80-85° C. in a vacuum oven to afford 18.6 g (74%) of 1-cyclopentyl-3-ethyl-6-(methylthio)pyrazolo[3,4-d]pyrimidin-4-one, m.p.203-205° C.