Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)(O)=O.C1(P([N:43]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.O>O1CCOCC1>[NH2:43][C:4]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(C(=O)O)nccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Nc1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc12
Temperature: 100 °C
Yield: 26.9 %

Procedure:
A mixture of N-(1-carboxyisoquinolin-5-yl)-N′-[4-(trifluoromethyl)benzyl]urea (Example 117, 309 mg, 0.794 mmol), diphenylphosphoryl azide (210 μl, 0.975 mmol) and triethylamine (210 μl, 1.50 mmol) in 1,4-dioxane (25 ml) was heated at 100° C., under a nitrogen atnosphere for 1.5 h. Water (0.25 ml) was then added and the reaction mixture heated for a further 1 hour. The reaction mixture was then cooled to room temperature, filtered and the filtrate evaporated. The residue was purified using a Bond-Elut SCX ion-exchange cartridge, first eluting non-basic materials with methanol, then eluting the product with 2M methanolic ammonia. The basic fractions were evaporated and further purified by flash column chromatography (eluant 5% MeOH-95% dichloromethane increasing to 10% MeOH-90% dichloromethane). The product was then passed through a second SCX purification to give the title compound (77 mg, 27%). m/z (ES+) 361 (M+H)+.
Reaction SMILES: [I-].C[N+:3](C)(C)N.CC(C)([O-])C.[K+].[Br:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([O:21][C:22]2[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:31])[C:15]=1[Cl:32]>CN(C=O)C.[Cu]Cl>[Br:13][C:14]1[C:15]([Cl:32])=[C:16]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:21][C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[C:26]([CH:25]=[CH:24][C:23]=1[Cl:31])[NH2:3]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Oc1cc(Cl)cc(Br)c1Cl
Reactant: C[N+](C)(C)N
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2Cl)c1[N+](=O)[O-]
Temperature: -40 °C

Procedure:
1,1,1-trimethylhydrazinium iodide (14.7 g, 72.7 mmol) was added to potassium tert-butoxide (8.20 g, 72.7 mmol) and copper (I) chloride (0.180 g, 1.82 mmol) in DMF (50 mL) at 0° C. The resulting mixture was allowed to stir for several minutes at which point the mixture was cooled to −40° C. and 1-bromo-2,5-dichloro-3-(2-chloro-6-nitrophenoxy)benzene (7.23 g, 18.2 mmol) as a solution in DMF (50 mL) was added dropwise. The reaction mixture was then maintained at −40° C. for 20 minutes, at which point the reaction was quenched at −40° C. with saturated aqueous ammonium chloride (10 mL). Water (10 mL) was then added and the mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate (2×200 mL). The combined organic fractions were washed with water (3×200 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by automated column chromatography on silica gel (1.5 kg) eluting with 25% EtOAc/hexanes to give the title compound. LRMS (M+1)=412.4.
Reaction SMILES: [CH3:1][CH:2]([C:5](=O)[CH3:6])[C:3]#[N:4].C(O)C.[CH3:11][NH:12][NH2:13].[ClH:14]>O>[ClH:14].[NH2:4][C:3]1[N:12]([CH3:11])[N:13]=[C:5]([CH3:6])[C:2]=1[CH3:1]
Reactant: CNN
Reactant: CC(=O)C(C)C#N
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nn(C)c(N)c1C

Procedure:
2-Methyl-3-keto-butyronitrile (J. Am. Chem. Soc. 79, 723, 1957) (25.25 g.) in 120 ml. ethanol was treated with 15 g. methylhydrazine while cooling. The solution was refluxed 3 hours then concentrated in vacuum, benzene added and the solution concentrated again. Ether was added to give 29.12 g. mp 70-106 of base (contained H2O). This was converted to the hydrochloride with HCl in isopropyl alcohol. HCl had mp 286°-288°.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.O=[CH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34].O>O1CCCC1.CCCCCC>[CH3:2][O:3][CH:4]=[CH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)CCC=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COC=CCCC(=O)OC
Temperature: -78 °C
Yield: 607.8 %

Procedure:
34.3 g (0.1 mole) methoxymethyltriphenylphosphonium chloride was suspended in 100 ml dry tetrahydrofuran and cooled to -78° C. under argon. 75 ml (0.1 mole) n-butyllithium solution in hexane was added and the solution allowed to warm to room temperature. After cooling to -78° C. 12.1 g (0.0105 moles) methyl 4-oxobutanoate was added in 50 ml tetrahydrofuran. The solution was allowed to reach room temperature then poured into water and extracted twice with ether. The ether extracts were washed with saturated sodium chloride solution dried and concentrated in vacuo. This was eluted through 250 g silica gel with 1 l ether-hexane 1:1 to give a faintly yellow liquid 9.2 g containing both (Z) and (E) enol ethers.
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18]>O=[Mn]=O.C(Cl)(Cl)Cl>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:2]=[C:3]([NH2:18])[C:4]([NH2:15])=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 100 mL round bottom flask was charged with benzyl alcohol 1 (1.38 g, 5.0 mmol), MnO2 (6.52 g, 75 mmol) and CHCl3 (20 mL). The resulting suspension stirred at rt overnight. Reaction mixture filtered through Celite, washed successively with CHCl3 and EtOH, and evaporated. Crude product absorbed onto silica gel and chromatographed using 98:2 CH2Cl2/MeOH to give 2 as an orange solid. 1H NMR (300 MHz, CDCl3) δ 10.01 (s, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.09 (br s, 1H), 7.96 (d, J=2.75 Hz, 1H), 7.37 (d, J=2.48 Hz, 1H), 7.29 (d, J=2.75 Hz, 1H), 7.08 (dd, J=2.47, 5.5 Hz, 1H), 6.94 (d, J=9.35 Hz, 1H), 3.08 (d, J=5.23 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15]Cl)([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([CH2:13][CH2:14][CH2:15][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[F:1])=[O:17])([CH3:10])([CH3:9])[CH3:8]
Reactant: Fc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)CCCCl
Product: CC(C)(C)OC(=O)CCCn1ccnc1F

Procedure:
2-Fluoroimidazole was alkylated with t-butyl-4-chlorobutyrate, using the same procedure as that for the starting material of Example 74, to give 1-(3-t-butoxycarbonylpropyl)-2-fluoroimidazole.
Reaction SMILES: O=[C:2]1[CH:8]=[CH:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH:4]=[N:3]1.COS(OC)(=O)=O.[NH3:26]>>[NH:26]=[C:2]1[CH:8]=[CH:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH:4]=[N:3]1
Reactant: O=C1C=CN(C(=O)OCc2ccccc2)CC=N1
Reactant: N
Solvent: COS(=O)(=O)OC
Product: N=C1C=CN(C(=O)OCc2ccccc2)CC=N1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1.0 g (4.0 mmol) benzyl 5-oxo-[1,4]diazepine-1-carboxylate are suspended in 1.0 ml (10.6 mmol) dimethylsulphate, stirred for two hours at 90° C. and after cooling dissolved in 10 ml (20 mmol) ammonia solution (2N in methanol). The mixture is stirred for 3.5 hours at RT and then evaporated to dryness.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[CH2:9][CH2:8][C:7](=[O:11])[C:6](=O)[C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15].CC1(C)C2CCCC(=O)C=2C(C)(C)C1C.[CH:32]([NH2:34])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[C:10]2[CH2:9][CH2:8][C:7]3[O:11][CH:32]=[N:34][C:6]=3[C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15]
Reactant: NC=O
Reactant: CC1C(C)(C)C2=C(C(=O)C(=O)CC2)C1(C)C
Agent: CC1C(C)(C)C2=C(C(=O)CCC2)C1(C)C
Solvent: Cc1ccccc1
Product: CC1C(C)(C)C2=C(c3ncoc3CC2)C1(C)C
Temperature: 200 °C
Reaction time: 24 h

Procedure:
1,1,2,3,3-Pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione is first prepared with 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-inden-4-one (Cashmeran®) (commercially available at IFF) via oxidation with (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) (prepared as described by Barton in Tetrahedron Letters, 1984, 25(6), pages: 603-606). A 100 mL reaction flask is charged with 1,1,2,3,3-pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione (10 g, 0.04 mol) and formamide (NH2CHO) (50 mL). The reaction mixture is heated to 200° C. and stirred for 24 hours. The crude mass is diluted with toluene (50 mL) and then washed once with aqueous sodium carbonate (10%, 100 mL) followed by twice with brine (30 mL). Toluene is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product of a mixture of 6,6,7,8,8-pentamethyl-5,6,7,8-tetrahydro-4H-1-oxa-3-aza-as-indacene and 6,6,7,8,8-pentamethyl-5,6,7,8-tetrahydro-4H-indeno[4,5-d]oxazole (˜10 g) is obtained.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:16][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:14]2)[CH:8]=1)C.[Li+].[OH-]>CO>[C:28]([C:15]1[CH:16]=[C:17]([NH:18][C:19](=[O:27])[C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[N:13]([C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:32])=[O:3])[CH:12]=[CH:11][CH:10]=2)[N:14]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc(Cl)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)c2ccc(Cl)cc2)n(-c2cccc(CCC(=O)O)c2)n1
Yield: 90.4 %

Procedure:
A solution of Example 158 (45 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH=4, and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-{3-[3-t-butyl-5-(4-chloro-benzoylamino)-pyrazol-1-yl]-phenyl}-propionic acid, (38.5 mg, 87%). 1H NMR (DMSO-d6): 10.38 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.39 (s, 1H), 7.32 (d, J=4.8 Hz, 2H), 7.15 (t, J=4.8 Hz, 1H), 6.38 (s, 1H), 2.80 (t, J=7.6 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 1.29 (s, 9H); MS (ESI) m/z: 426 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([NH:17][NH:18][C:19]([CH:21]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:24][CH2:23][N:22]2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:20])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]2[O:20][C:19]([CH:21]3[CH:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:25][CH2:24][CH2:23][N:22]3[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N:18][N:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)NNC(=O)C1CN(C(=O)OCc2ccccc2)C1
Agent: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1c1nnc(C2CN(C(=O)OCc3ccccc3)C2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of tert-butyl 2-{[2-({1-[(benzyloxy)carbonyl]azetidin-3-yl}carbonyl)hydrazino]carbonyl}-3-phenylpiperidine-1-carboxylate (235 mg, 0.44 mmol) in dichloromethane (4 ml) at 0° C. were added imidazole (71.6 mg, 1.05 mmol), polystyrene bound triphenyl phosphine (471 mg, 0.96 mmol, 2.04 g/mmol), and carbon tetrabromide (320 mg, 0.96 mmol). The reaction was warmed to rt and allowed to stir for 18 h. The reaction mixture was filtered and rinsed with dichloromethane. The filtrate was concentrated to give an oil. The crude material was purified via flash chromatography (silica, 0-35% EtOAc/hexanes) to yield tert-butyl 2-(5-{1-[(benzyloxy)carbonyl]azetidin-3-yl}-1,3,4-oxadiazol-2-yl)-3-phenylpiperidine-1-carboxylate (96%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][C:10](=[CH2:22])[CH:11]([OH:21])[CH:12]([NH:18][CH:19]=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2].S(Br)([Br:25])=O.O>C(Cl)Cl>[Br:25][CH2:22][CH:10]([CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]([OH:21])[CH:12]([NH:18][CH:19]=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=C(CCOCC(=O)OCC)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COCCC(CBr)C(O)C(NC=O)C(=O)OCC
Reaction time: 0.17 h

Procedure:
7.5 g (23.6 mmol) of ethyl 6-ethoxycarbonylmethoxy-2-formylamino-3-hydroxy-4-methylene-hexanoate are dissolved in 75 ml of CH2Cl2 and 2.2 ml (28.3 mmol) of thionyl bromide are then added dropwise at room temperature to this solution. After 1 hour 50 ml of water are added and the reaction mixture is stirred vigorously for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and once with brine. The aqueous phases are extracted twice with CH2Cl2. The combined organic phases are dried over Na2SO4, filtered, and concentrated by evaporation giving ethyl 4-bromomethyl-6-ethoxycarbonylmethoxy-2-formylamino-3-hydroxy-hexanoate as a yellow oil which is further reacted without purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[C:14]([O-])(=[O:16])[CH3:15].[Na+].C(C1C(=O)CC(C2C=CC(F)=CC=2)CC1=O)(=O)C>>[C:14]([CH:9]1[C:10](=[O:12])[CH2:11][CH:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:7][C:8]1=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Agent: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Agent: [Na+]
Product: CC(=O)C1C(=O)CC(c2cccs2)CC1=O

Procedure:
The title compound was prepared from 5-thien-2-yl-cyclohexane-1,3-dione (600 mg, 3.09 mmol) and sodium acetate (253 mg, 3.09 mmol), following the procedure describing the synthesis of 2-acetyl-5-(4-fluoro-phenyl)-cyclohexane-1,3-dione (example 3/a stage 1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:26])=[C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:18]=3)[C:13](=[O:27])[C:12]([C:28]([OH:30])=[O:29])=[CH:11]2)=[C:6]([F:31])[CH:5]=1)([O-:3])=[O:2].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:35].C(=O)(O)[O-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:26])=[C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:33][C:34]([C:36]5[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=5)=[O:35])[CH2:22][CH2:21]4)[CH:18]=3)[C:13](=[O:27])[C:12]([C:28]([OH:30])=[O:29])=[CH:11]2)=[C:6]([F:31])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: O=C(O)c1cn(-c2ccc([N+](=O)[O-])cc2F)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CN2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of the 1-(4-nitro-2-fluorophenyl)-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.43 g, 1 mmol) in DMF (15 ml) was added 2-bromo-4′-methoxyacetophenone (0.29 g, 1.28 mmol) and sodium bicarbonate (0.08 g, 1 mmol). The reaction mixture was stirred for 24 hr at room temperature. After removing the solvent, the residue was taken up by CH2Cl2, solution, and after washed with water and dried with Na2SO4, was evaporated to dryness. Crystallization of the solid residue from CH2Cl2/methanol (10:1) afforded the desired 1-(4-nitro-2-fluorophenyl)-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.37 g, 86%). Mp: 136° C. (dec). 1H NMR (DMSO-d6) δ 2.63 and 3.10 (two m, 8),3.81-3.83 (m, 5H) 6.40 (d, 1H, J=6.8), 7.01 (d, 2H, J=9.0), 7.94-8.03 (m, 3H), 8.17-8.56 (m, 3H), 8.93 (s, 1H), 14.88 (br s, 1H). Anal. Calcd. for C29H24F2N4O7•H2O: C, 58.39; H, 4.39; N, 9.39. Found: C, 58.75; H, 4.42; N, 9.20.
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:15]CCC[CH2:11][C:7]3=[C:8]2[OH:10])=[CH:3][CH:2]=1.C[O:17]C(C1C(=O)COC1)=O.N1NC(N)=CC=1>C(O)(=O)C>[N:1]1[N:9]2[C:4]([N:5]=[C:6]3[C:7](=[C:8]2[OH:10])[CH2:11][O:17][CH2:15]3)=[CH:3][CH:2]=1
Reactant: COC(=O)C1COCC1=O
Reactant: Oc1c2c(nc3ccnn13)CCCCC2
Agent: Nc1ccn[nH]1
Solvent: CC(=O)O
Product: Oc1c2c(nc3ccnn13)COC2

Procedure:
Using the method described for the preparation of 6,7,8,9-Tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-ol, the reaction of 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester and 2H-pyrazol-3-ylamine in acetic acid provided the desired 5H,7H-6-Oxa-1,4,8a-triaza-s-indacen-8-ol.
Reaction SMILES: Br[C:2]1([Br:11])[C:7](=[O:8])NC(=O)NC1=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21]C(=O)C)[CH:17]=[CH:18][CH:19]=1>CCOCC>[Br:11][CH2:2][C:7](=[O:8])/[CH:21]=[CH:20]/[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=1
Reactant: COc1cccc(C=CC(C)=O)c1
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Solvent: CCOCC
Product: COc1cccc(/C=C/C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 14.3 g (50 mmol) of 5,5-dibromobarbituric acid in 300 ml of ether was treated with 17.6 g (0.1 mol) of 4-(3-methoxyphenyl)-3-buten-2-one and the mixture was stirred at room temperature for 20 hours. The separated barbituric acid was filtered off. The filtrate was washed in succession with saturated sodium bicarbonate solution and with water. The organic phase was dried over sodium sulphate and concentrated. Flash chromatography of the residue on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1) yielded (E)-1-bromo-4-(3-methoxyphenyl)-3-buten-2-one as a yellow oil.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])[NH:12][C:11]=2[CH:10]=1.[OH-].[Na+]>C(C(C)=O)C>[CH3:5][O:8][C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[S:23](=[O:28])(=[O:27])[N:24]([CH3:25])[CH3:26])[NH:12][C:11]=2[CH:10]=1
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: COc1ccc2c(c1)Nc1cccc(S(=O)(=O)N(C)C)c1S2
Yield: 45.4 %

Procedure:
2-Methoxy-6-dimethylsulphamoylphenothiazine (m.p. 196°-198°C.; 79.6 g.) is prepared by methylation, using dimethyl sulphate (74.5 g.), of 2-hydroxy-6-dimethylsulphamoylphenothiazine (168 g.) in the presence of powdered sodium hydroxide (30.8 g.) suspended in methyl ethyl ketone (1,820 cc.).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH2:25][OH:26])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:25]=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21
Reactant: COc1ccc(N2CCCCn3c2nc2c(Cl)ccc(CO)c23)c(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(N2CCCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
To a stirred suspension of [10-chloro-1-(2-chloro-4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-yl]methanol (313 mg, 0.798 mmol) in acetonitrile (8 mL) was added Dess-Martin reagent (406 mg, 0.958 mmol) at room temperature. After 15 min, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a pale brown solid (267 mg, 0.684 mmol, 85%).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]3[CH2:17][C@H:16]([S:18][C:19]4[C@H:20]([CH3:43])[C@@H:21]5[C@@H:38]([C@H:39]([OH:41])[CH3:40])[C:37](=[O:42])[N:22]5[C:23]=4[C:24]([O:26]CC4C=CC([N+]([O-])=O)=CC=4)=[O:25])[CH2:15][N:14]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:12])[CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.[ClH:57]>O1CCCC1.O>[ClH:57].[N:1]1([C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]3[CH2:17][C@H:16]([S:18][C:19]4[C@H:20]([CH3:43])[C@@H:21]5[C@@H:38]([C@H:39]([OH:41])[CH3:40])[C:37](=[O:42])[N:22]5[C:23]=4[C:24]([OH:26])=[O:25])[CH2:15][NH:14]3)=[O:12])[CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](n5cncn5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC[C@H](n5cncn5)C4)C3)[C@H](C)[C@H]12

Procedure:
528 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3S)-3-(1,2,4-triazol-1-yl)pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 10 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.63 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 18(b), to give 85 m of the title compound, as a powder.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:32]=[CH:31][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=[CH:21][N:20]=3)[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[CH2:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:34]>C(O)C>[CH2:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:3][C:4]2[CH:32]=[CH:31][C:7]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:22]=[CH:21][N:20]=4)[CH:12]=3)=[O:9])=[CH:6][CH:5]=2)[CH2:37][CH2:36]1)[CH3:34]
Reactant: CCN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Agent: Cl
Solvent: CCO
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1
Temperature: 25 °C

Procedure:
A suspension of 466 mg (1 mmol) of 4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide hydrochloride in 25 ml of dry ethanol is treated with 381 μl (3 mmol) N-ethylpiperazine and then heated under reflux for 16 hours. The yellow solution is cooled to room temperature and decanted from a small amount of a brown insoluble residue which forms on the wall of the flask. The solvent is evaporated and the residue taken up in citric acid solution (10% w/w) and washed with dichloromethane. The aqueous layer is made basic by addition of sodium bicarbonate and sodium carbonate solution and extracted three times with 150 ml of dichloromethane containing 2 ml of ethanol. The combined organic extracts are washed with conc. sodium chloride solution, dried over sodium sulfate, and evaporated. The residue was stirred with 3 ml of ethyl acetate and the crystalline product filtered and washed with a small amount of ethyl acetate to obtain 4-(4-ethyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; m.p. 209.5–210.5° C.; tR (HPLC) 1) 6.62 min.