Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]3[S:15][CH2:16][CH2:17][N:18]=3)[CH:8]=2)[CH2:5][CH:4]([C:19]([NH:21][CH:22]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][C:24]([O:26]CC)=[O:25])=[O:20])[CH2:3]1.[OH-].[Na+]>C1COCC1>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]3[S:15][CH2:16][CH2:17][N:18]=3)[CH:8]=2)[CH2:5][CH:4]([C:19]([NH:21][CH:22]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[CH2:3]1
Reactant: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(NC3=NCCS3)c2)C1)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC(NC(=O)C1CC(=O)N(c2cccc(NC3=NCCS3)c2)C1)c1cccnc1

Procedure:
A solution of ethyl 3-({5-oxo-1-(3-(1,3-thiazolin-2-ylamino)phenyl)pyrrolidin-3-yl}carbonylamino)-3-(3-pyridyl)propanoate (75 mg, 0.16 mmol, 1.0 eq), THF (1.0 mL), and 1.0 N NaOH (0.16 mL, 1.0 eq) was stirred at room temperature overnight. The solvent was removed on rotary evaporator. The title compound was abstained as an off-white solid from preparative HPLC. 1H NMR (MeOH-d4, 400 MHz): δ 2.68-2.99 (m, 4), 3.35 (m, 1), 3.67 (m, 2), 4.05 (m, 4), 5.42 (m, 1), 7.16 (m, 1), 7.52 (m, 2), 7.78 (m, 1), 7.88 (s, 1), 8.28 (m, 1), 8.62 (m, 1), 8.75 (m, 1). MS (ES+): 455 (M+H)+; (ES−): 453 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:10][C:2]1=2.[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Br:32])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25].C(N(CC)CC)C.O>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Br:32])[C:29]=1[O:30][CH3:31])[C:24]([N:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:10][C:2]1=2)=[O:25]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: CC(=O)c1ccc(-c2cnc3c(c2)NCCO3)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(C(C)=O)cc4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
In a 10 ml flask, 1-[4-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-phenyl]-ethanone (59 mg, 0.23 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (287 mg, 0.87 mmol) were dissolved in dichloromethane. Triethylamine (0.32 ml, 2.3 mmol) was added thereto and then stirred at room temperature for 12 hours. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain 1-{4-[1-(3,5-dibromo-4-methoxy-benzoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-phenyl}-ethanone as white solid (119 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:5](O)=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:5]2[S:18][C:17]([NH:19][CH:2]3[CH2:3][CH2:4][CH2:8][CH2:9][CH2:10]3)=[N:16][N:15]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NNC(N)=S
Reactant: COc1ccc(Cl)c(OC)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(OC)c1-c1nnc(NC2CCCCC2)s1
Temperature: 95 °C
Yield: 28.3 %

Procedure:
To a mixture of 3-chloro-2,6-dimethoxybenzoic acid (2.3 mmol, 500 mg), thiosemicarbazide (5b) (2.3 mmol, 399 mg) in anhydrous dioxane (10 mL) at 70° C. to 80° C., POCl3 (2.3 mmol, 215 μL) was added, and the mixture was warmed at 95° C. for 5 hours. The solvent was removed by distillation under reduced pressure to give a crude material which was basified at pH 8-7 with a saturated solution of NaHCO3. The precipitate obtained was collected by filtration, washed with water, and dried under vacuum. The solid was subjected to flash chromatography eluting with ethyl acetate/cyclohexane to give 115 mg of the title compound. Yield: 14%.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6]>O1CCCC1>[OH:6][CH2:5][C:4]1[C:3]([CH3:11])=[C:2]([OH:1])[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(O)cccc1C(=O)O
Solvent: C1CCOC1
Product: Cc1c(O)cccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
3-Hydroxy-2-methyl-benzoic acid (1.0 g, 7.2 mmol) in tetrahydrofuran (80 mL) was treated with dropwise added BH3-tetrahydrofuran (1M in tetrahydrofuran) (10 mL). The reaction mixture was stirred at rt overnight. Quenched with 10% NaOH, the mixture was adjusted pH to 7 with 10% HCl and extracted with isopropanol/dichloromethane (1:3) (2×), The organic layers were combined and washed with water, brine, dried to afford the title compound (795 mg, 80%). MS (DCI/NH3) m/z 139 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:12])=[O:4].C[Si]([C:17]#[N:18])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.[Cl-].[Na+]>[F:12][C:6]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][C:17]#[N:18]
Reactant: C[Si](C)(C)C#N
Reactant: O=C(CBr)c1ccc(O)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CC#N
Product: N#CCC(=O)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.4 %

Procedure:
To a solution of 2.5 g (10.73 mmol) of 2-bromo-1-(2-fluoro-4-hydroxyphenyl)ethanone in 100 ml of acetonitrile are respectively added 1.2 g (11.8 mmol) of trimethylsilyl cyanide and 12.3 ml (12.3 mmol) of tetrabutyl-ammonium fluoride solution (1M in THF). The reaction mixture is stirred at room temperature for 16 h then diluted with an aqueous solution saturated with sodium chloride. The product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered, then evaporated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 5:5) to give 1.2 g (62%) of 3-(2-fluoro-4-hydroxyphenyl)-3-oxopropanenitrile in the form of a yellow solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH:11]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC>[CH:11]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH:15]1[CH:8]=[O:9])([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CC(C)N1CCCc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CC(C)N1c2ccccc2CCC1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
Phosphorus oxychloride (18.6 g) was added dropwise to 29.2 g of N,N-dimethylformamide under ice cooling. The resulting mixture was stirred at room temperature for 30 minutes, followed by the dropwise addition of 17.5 g of 1-isopropyl-1,2,3,4-tetrahydroquinoline slowly under ice cooling. After stirring at room temperature for one hour, the reaction mixture was poured into ice water, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 10% ethyl acetate/n-hexane), whereby 11.4 g of the title compound were obtained as a reddish brown oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:32]([N:34]([CH2:44][C:45]1[C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=2[S:48][CH:49]=1)[C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[S:48]1[CH:49]=[C:45]([CH2:44][N:34]([C@@H:35]([CH3:43])[CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[C:32](=[O:33])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:12]([CH3:13])[NH:11][C:9](=[O:10])[NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 68 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-6-oxohexylcarbamate (Compound IV-15) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[Cl:8][C:9]1[C:14]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][C:12]([N:20]=[C:21]=[S:22])=[C:11]([F:23])[CH:10]=1>O1CCOCC1>[Cl:8][C:9]1[C:14]([O:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][C:12]([N:20]=[C:21]2[N:4]3[CH2:5][CH2:6][CH2:7][CH:3]3[CH2:2][S:22]2)=[C:11]([F:23])[CH:10]=1
Reactant: OCC1CCCN1
Reactant: CS(=O)(=O)Oc1cc(N=C=S)c(F)cc1Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)Oc1cc(N=C2SCC3CCCN23)c(F)cc1Cl

Procedure:
10 g 2-(Hydroxymethyl)pyrrolidine and 27.6 g 4-chloro-2-fluoro-5-methylsulphonyloxyphenyl isothiocyanate were heated under reflux for 4 hours in 200 ml dioxane. The solvent was removed and the residue heated with 50 ml 48% hydrobromic acid. After cooling, the reaction solution was added to an ice/water mixture, neutralised with 40% caustic soda and extracted with methylene chloride. After drying and concentrating, the crude product was purified by column chromatography (silica gel, eluent; hexane/ethyl acetate).
Reaction SMILES: I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]4)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C(=O)(O)[O-].[Na+].CO>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:30][N:31]1[CH:35]=[C:34]([C:2]2[C:3]3[S:11][CH:10]=[C:9]([C:12]4[CH:13]=[C:14]5[C:18](=[CH:19][CH:20]=4)[N:17]([C:21](=[O:29])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:16][CH2:15]5)[C:4]=3[C:5]([NH2:8])=[N:6][CH:7]=2)[CH:33]=[N:32]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cnc(N)c3c(-c4ccc5c(c4)CCN5C(=O)Cc4ccccc4)csc23)cn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A mixture of 7-iodo-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine (102 mg, 0.199 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (60 mg, 0.288 mmol), and PdCl2(dppf)-CH2Cl2 adduct (8 mg, 9.80 μmol) in 1,4-Dioxane (2.0 mL) and saturated aqueous sodium bicarbonate (0.6 mL, 0.600 mmol) was degassed with Nitrogen for 10 minutes in a microwave vial. The vial was then capped and the mixture was stirred at 120° C. in the microwave for 30 min. LCMS showed complete conversion. The mixture was cooled, poured into water (15 mL), and extracted with ethyl acetate (2×15 mL). The extracts were washed with brine (1×15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g SiO2, 50%-100% EtOAc in hexanes gradient over 10 minutes, then EtOAc for 5 minutes, then 0-10% MeOH in EtOAc over 20 minutes) to give 7-(1-methyl-1H-pyrazol-4-yl)-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine (69 mg, 0.141 mmol, 70.6% yield) as a light gray solid. LC/MS (ES) m/z=466 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.24 (t, J=8.46 Hz, 2H), 3.89 (s, 2H), 3.93 (s, 3H), 4.26 (t, J=8.46 Hz, 2H), 5.41 (br. s., 2H), 7.22-7.30 (m, 2H), 7.30-7.39 (m, 5H), 7.49 (s, 1H), 7.88 (s, 1H), 8.03 (s, 1H), 8.14 (s, 1H), 8.17 (d, J=8.08 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1Oc1ccc(O)cc1
Yield: 98.2 %

Procedure:
To a solution of 4-(2-nitrophenoxy)phenol (1.00 g, 4.3 mmol) in ethanol (50 ml) were added an iron powder (1.21 g, 0.022 g-atom) and a solution of ammonium chloride (0.14 g, 2.6 mmol) in water (10 ml), followed by reflux for 2 hours. The insoluble matter was filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and after drying, the solvent was evaporated under reduced pressure to give 4-(2-aminophenoxy)phenol (0.85 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([O:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([NH2:20])[S:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25].C(=O)([O-])O.[Na+]>O1CCCC1.O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([O:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([NH:20][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:25])[S:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10]
Reactant: Nc1nc2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)cc2s1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)cc2s1)Oc1ccccc1
Yield: 94.7 %

Procedure:
A solution of 2 g of 2-amino-1,3-benzothiazol-6-yl 2,6-dichlorobenzenesulfonate, 3.34 g of phenyl chloroformate, 1.79 g of sodium hydrogen carbonate in 40 cm3 of tetrahydrofuran and 4 cm3 of water is stirred for about 60 hours at a temperature in the region of 20° C. After concentrating the reaction mixture to dryness, the residue is taken up in 20 cm3 of water. The solid is filtered off by suction and washed with twice 5 cm3 of water, and then dried in an oven at 50° C. 2.5 g of 2-[(phenoxycarbonyl)amino]-1,3-benzothiazol-6-yl 2,6-dichlorobenzenesulfonate are thus obtained in the form of a brown solid, the characteristics of which are as follows:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([O:23][CH3:24])=[N:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.N1CCCCC1>>[CH3:24][O:23][C:15]1[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][N:17]2[N:16]=1
Reactant: COc1nn2c(c1C1CCN(C(=O)OC(C)(C)C)CC1)CCCC2
Solvent: C1CCNCC1
Product: COc1nn2c(c1C1CCNCC1)CCCC2

Procedure:
The title compound was prepared from 1-(tert-butoxycarbonyl)-4-(2-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-piperidine (from Step D) using a procedure analogous to that described for Piperidine 8, Step F.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1.[O:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(=O)(O)[O-].[Na+]>O.C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:23]4[CH:24]=[CH:25][O:21][CH:22]=4)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1
Reactant: OB(O)c1ccoc1
Reactant: CON=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccoc2)c1
Temperature: 80 °C

Procedure:
A mixture of 1-(3-Bromophenyl)-5-formylbenzimidazole O-methyloxime (29a) from Example 8 (0.7 g, 2.1 mmol), 3-furanylboronic acid (0.26 g, 2.34 mmol), sodium bicarbonate (0.89 g, 10.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg) in a mixture of water (5 ml) and dimethoxyethane (10 ml) is stirred at 80° C. under nitrogen over night. After cooling water is added and the mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate and concentrated under reduced pressure. The residue is eluted through silica gel with a mixture of ethyl acetate and petroleum ether (1:1). The pure fractions are evaporated to dryness. Trituration with petroleum ether affords a white, crystalline product. Yield: 0.42 g (63%). Mp 147-148° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[CH3:21])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[C:13](=[O:14])[CH2:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=1)=[O:31]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC1CCCCN1C(=O)CN(C(=O)CN)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCCCC2C)c2ccccc2)c1
Yield: 37.8 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.45 g of (RS)-2-amino-N-[2-(2-methylpiperidino)-2-oxoethyl]-N-phenylacetamide and 0.67 g of 3-methylphenyl isocyanate used as the starting material. After recrystallization from a mixture of ethanol and diisopropyl ether (50-50 by volume), 0.80 g of (RS)-N-[2-(2-methylpiperidino)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 188° C. is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: O=C1CCC(CC(=O)OCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(C[C@H]1CC[C@@H](O)CC1)OCc1ccccc1
Reaction time: 2 h

Procedure:
Benzyl 2-(4-oxocyclohexyl)acetate (5.0 g, 20.3 mmol) was dissolved in methanol (150 ml), NaBH4 (770 mg, 20.3 mmol) was added by portions to the solution at 0° C., and the mixture was stirred for 2 hr. The mixture was concentrated under reduced pressure, followed by separation with ethyl acetate and water. The organic layer was washed with saturated brine and was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=85:15) to give the title compound as an oil (900 mg, yield 18%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[N:13][C:14]=2[C:15]2[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[O:17][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(Cl)Cl.[NH3:26]>C(O)C>[NH2:26][C:2]1[C:3]2[N:4]([CH:12]=[N:13][C:14]=2[C:15]2[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[O:17][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: N
Reactant: Clc1nc2ccccc2n2cnc(-c3noc(C4CC4)n3)c12
Solvent: CCO
Solvent: ClCCl
Product: Nc1nc2ccccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
A stirred solution of 4-chloro-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-imidazo[1,5-a]quinoxaline (0.15 g) in 10 ml of a 1:1 mixture of CH2Cl2 and ethanol was saturated with ammonia. The reaction was monitored by t.l.c. (silica gel/CH2Cl2 -acetone 4:1) and ammonia was bubbled through the solution in between. When the reaction was completed, the solvent was evaporated in vacuo and the residue was triturated with 10 ml of water. The precipitate was filtered off, rinsed with water and dried to give 0.12 g of the title compound as white needles, m.p. 305°-310° C. (Compound 3).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.N([O-])=[O:13].[Na+]>O>[OH:13][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(O)ccc1[N+](=O)[O-]
Yield: 79.4 %

Procedure:
A suspension of 3.0 gm (19.6 mMol) 6-amino-3-nitro-2-picoline in 50 mL water containing 3.5 mL concentrated sulfuric acid was heated to effect solution. The resultant solution was cooled to 0° C. and a solution of 2.0 gm (29.4 mMol) sodium nitrite in 10 mL water was added with vigorous stirring at a rate to maintain the reaction mixture ≤10° C. After 4 hours the reaction mixture was filtered. The solid was washed with water and dried under reduced pressure to provide 2.4 gm (80%) of the desired compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C@@H:13]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[C:29]([CH3:31])=[CH2:30])[O:25][CH2:24][C:23]2[N:18]3[C@H:19]([CH3:33])[C:20](=[O:32])[NH:21][N:22]=2)[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C@@H:13]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[CH:29]([CH3:31])[CH3:30])[O:25][CH2:24][C:23]2[N:18]3[C@H:19]([CH3:33])[C:20](=[O:32])[NH:21][N:22]=2)[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)c1cc2c(cc1[C@@H](C)C1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A mixture of 3-[(R)-1-((R)-7-isopropenyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.0795 g, 0.175 mmol) and 10% Pd/C (0.037 g, 0.035 mmol) in MeOH (10 mL) was stirred under H2 for 1 h at rt. The reaction mixture was filtered, the filtrate was evaporated to dryness and the residue was purified by prep-TLC (eluting with 50% EtOAc in petroleum ether) to give 3-[(R)-1-((R)-7-isopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.061 g, 76%) as a solid. LC/MS (Table 1, Method 4) Rt=2.972 min.; MS m/z: 457 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 8.03 (brs, 1H), 7.00-6.92 (m, 1H), 6.64 (brs, 1H), 4.77-4.70 (m, 1H), 4.65-4.52 (m, 2H), 3.92-3.79 (m, 2H), 3.57-3.51 (m, 1H), 3.45 (m, 1H), 3.30 (m, 1H), 3.23-3.14 (m, 1H), 1.55-1.45 (m, 12H), 1.34-1.24 (m, 12H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]([CH3:17])(O)[CH3:15])=[CH:8][CH:7]=1>C(=S)=S>[Br:5][C:6]1[CH:11]=[CH:10][C:9]2[S:12][CH2:13][C:14]([CH3:17])([CH3:15])[C:8]=2[CH:7]=1
Reactant: CC(C)(O)CSc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1(C)CSc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a suspension of aluminum chloride (10.7 g, 80.0 mmol) in carbon disulfide (80 mL) was added dropwise a solution of 1-[(4-bromophenyl)thio]-2-methylpropan-2-ol (5.22 g, 20.0 mmol) in carbon disulfide (20 mL) at 0° C., and the resulting mixture was stirred at room temperature for 30 min, and heated under reflux for 3 hr. After cooling, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane) to give the title compound (1.64 g, yield 34%) as a colorless oil.