Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CCOCC.Cl.[N:27]([O-])=[O:28].[Na+]>O>[N:27]([N:8]([CH2:7][C:6]1[CH:19]=[CH:20][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:11][CH:10]=1)=[O:28]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1ccc(NCc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(N(Cc2ccc(Cl)cc2)N=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 50 g of the hydrochloride salt from Step 1, 500 mL water, 250 mL ether and 170 mL of 1N hydrochloric acid was treated with a solution of 12.3 g sodium nitrite in 50 mL of water. After stirring for 2 h at room temperature the reaction mixture was extracted twice with ether. The combined extracts were washed with water and dried over MgSO4. Filtration and concentration gave N-nitroso-N-(p-chlorobenzyl)-4-t-butylaniline.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:31]=[C:30]([CH2:32][O:33][C:34](=[O:40])[NH:35][CH2:36][CH2:37][CH2:38][NH2:39])[O:29][N:28]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:8]([O:7][C:6](=[O:12])[NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([O:33][CH2:32][C:30]1[O:29][N:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:22][CH:23]=2)[CH:31]=1)=[O:40])([CH3:9])([CH3:11])[CH3:10].[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:31]=[C:30]([CH2:32][O:33][C:34](=[O:40])[NH:35][CH2:36][CH2:37][CH2:38][NH2:39])[O:29][N:28]=2)=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: NCCCNC(=O)OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Product: CC(C)(C)OC(=O)NCCCNC(=O)OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1

Procedure:
{3-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethoxycarbonylamino]-propyl}-carbamic acid tert-butyl ester was synthesized using t-butyl N-(3-aminopropyl)carbamate in the same manner as in Example 121, and then a boc-deprotection of the compound was performed to synthesize (3-amino-propyl)-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a desired compound.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][C:12]2=[N:11][C:10]=1[C:20]([O:22][CH3:23])=[O:21])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][C:12]2=[N:11][C:10]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCC2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc2n(c(=O)c1O)CCCC2
Reaction time: 3.5 h

Procedure:
Intermediate methyl 3-(benzyloxy)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2a]pyrimidine-2-carboxylate prepared in Step 2b was dissolved in MeOH and catalytic 10% Pd/C was added at room temperature. The mixture was stirred under H2 atmosphere for 3.5 hours. Filtration of the catalyst and evaporation of methanol gave a residue to which diethyl ether was added; filtration afforded methyl 3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate as a pale brown solid with the spectroscopical properties identical to the compound described in Step 5a.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[O:47])[NH:21][C@@H:22]([C:34]1[N:38]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:37]=[N:36][N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([NH:21][C@@H:22]([C:34]1[N:38]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:37]=[N:36][N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:47]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nnnn1CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nnnn1CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
((1R)-2-(2-Naphthyl)-1-((1R)-2-(2-naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethylcarbamoyl)ethyl)carbamic acid tert-butyl ester (215 mg; 0.34 mmol) was dissolved in a mixture of methylene chloride (4 ml) and trifluoroacetic acid (2 ml) and stirred at room temperature for 30 min. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and aqueous sodium hydrogencarbonate (10%; 10 ml). The phases were separated, the organic phase was dried (Magnesium sulfate) and the solvent removed in vacuo. The residue was chromatographed on silica (3×20 cm) using ethyl acetate as eluent to afford 152 mg of (2R)-2-amino-3-(2-naphthyl)-N-((1R)-2-(2-naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethyl)propionamide.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>>[CH3:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccc(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(N(CCC(=O)O)C(=O)c2ccc3c(c2)nc(CNc2ccc(C(=N)N)cc2)n3C)c1
Yield: 62 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 62% of theory, C27H28N6O3 (484.6) ##EQU60##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([OH:22])=[O:21].[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>C1COCC1.CS(C)=O>[C:27]([CH2:26][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([OH:22])=[O:21])([O:29][CH2:30][CH3:31])=[O:28]
Reactant: Cc1c(CC(=O)O)c2cc(O)ccc2n1Cc1ccccc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOC(=O)COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 590 mg (2.0 mmol) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (Example 2, Part C) in 30 mL of THF and 10 mL of DMSO was treated with 180 mg (4.5 mmol) of 60% NaH/mineral oil and after 10 minutes, 0.25 mL (2.25 mmol) of ethyl 2-bromoacetate was added. The mixture was stirred for 0.5 hour, acidified with 1N HCl and extracted with EtOAc. The EtOAc solution was washed with water, saturated NaCl solution, dried (Na2SO4) and concentrated at reduced pressure. After chromatography on silica (eluted with a gradient, CH2Cl2 →3% MeOH/CH2Cl2) there was obtained 590 mg (77% yield) of 5-(carbethoxymethoxy)-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid.
Reaction SMILES: [O:1]1[CH:5]2[C:6]3[C:11]([CH:2]1[CH2:3][CH2:4]2)=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH2:12]([N:14](CC)CC)C.BrB1C2CCCC1CCC2.CN.Cl>ClCCl.O1CCCC1.C(OCC)C>[CH3:12][NH:14][C@H:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C@@H:2]([OH:1])[CH2:3][CH2:4]1
Reactant: CCN(CC)CC
Reactant: c1ccc2c(c1)C1CCC2O1
Agent: BrB1C2CCCC1CCC2
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN[C@@H]1CC[C@H](O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 606.5 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-1,4-epoxynaphthalene (2.92 g, 20 mmol) and triethylamine (0.3 mL, 2 mmol) in 40 mL of dichloromethane at 0° C. was added 9-bromo-9-borabicyclo[3.3.1]nonane (1 M solution in tetrahydrofuran, 30 mL, 30 mmol). The reaction mixture was stirred at 0° C. for 20 minutes, and a 2 M solution of methylamine in tetrahydrofuran (40 mL) was then added, forming a white precipitate. The reaction mixture was stirred at room temperature for 16 h, poured into 100 mL of 1 M aqueous hydrochloric acid, and filtered. The filtered aqueous layer was washed with dichloromethane, basified with NaOH pellets to pH 13, and then extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give a gummy yellow solid. The solid was slurried in diethyl ether, filtered, washed with diethyl ether and air dried to give 2.15 g of the title compounds as white powder.
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH3:13])([O-])=O.[N+]([C:17]1[CH:22]=CC=C[C:18]=1C)([O-])=O>>[CH:9]1[C:4]2[C:5](=[CH:13][CH:18]=[CH:17][CH:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cc1ccccc1[N+](=O)[O-]
Product: c1ccc2ccccc2c1

Procedure:
[BSU62430] 2,4-dinitrotoluene dioxygenase; [PSU49504] 2-nitrotoluene dioxygenase.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>C(O)C.O>[CH2:17]([N:1]([CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:4]=1)[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1c(-c2ccccc2)sc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)c2c(-c3ccccc3)sc3ccccc23)cc1

Procedure:
Preparation of the starting material a solution of 15.0 g (67 mmol) of 3-amino-2-phenyl-benzo(b)thiophene and 7.8 g (74 mmol) of benzaldehyde freshly distilled in 50 milliliters of benzene is refluxed for 10 hours with a water trap. After cooling, it is diluted with benzene, the excess benzaldehyde is eliminated by stirring with a solution of sodium bisulphite, the organic phase is dried over Na2SO4 and evaporated: 3-benzylidenamino-2-phenyl-benzo(b)thiophene in the form of a crude oily product which crystallises when it is triturated with methanol: 19.0 g (91% of theory) of yellow crystals, mp 92°-93° C. (ethanol). 9.6 g (31 mmol) of this Schiff base and 12 g (0.32 mol) of NaBH4 in 300 milliliters of absolute ethanol are refluxed with stirring for 25 hours. The cooled reaction mixture is diluted in water and extracted with ether. By evaporating the organic phase dried over K2CO3, the 3-benzylamino-2-phenyl-benzo(b)thiophene is obtained in the form of a crude oily product which crystallises when it is triturated with methanol. 9.0 g (92% of theory), colourless crystals, mp 52°-53° C. (methanol).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:27][CH:28]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[CH2:29]1.CCN(CC)CC>C(Cl)(Cl)Cl>[C:1]([NH:9][CH2:10][C:11]([NH:27][CH:28]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[CH2:29]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccc(Cl)cc2)C1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccccc1)NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Benzoylglycine (9.9 mg, 0.055 mmol), 3-ethyl-1-{3(dimethylaminopropyl}carbodiimide hydrochloride (EDCI) (10.5 mg) and 1-hydroxybenzotriazole hydrate (HOBt) (7.4 mg) were added to a solution of 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride (14.2 mg, 0.050 mmol) and Et3N (15.2 mg) in CHCl3 (2.5 mL). The reaction mixture was stirred at 25° C. for 16 h, washed with 2 N aqueous NaOH (2 mL×2) and brine (1 mL). After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to afford 3-(N-benzoylglycyl)amino-1-(4-chlorobenzyl)pyrrolidine (compound No. 1) as a pale yellow oil (17.7 mg, 95%): The purity was determined by RPLC/MS (95%); ESI/MS m/e 372.0 (M++H, C20H22ClN3O2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1([Cl:23])[CH2:19][CH:18]1[C:20](Cl)=[O:21]>O1CCCC1>[Cl:16][C:17]1([Cl:23])[CH2:19][CH:18]1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)C1CC1(Cl)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2CC2(Cl)Cl)cc1
Temperature: 60 °C
Yield: 59.7 %

Procedure:
5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are dissolved in 100 ml of absolute tetrahydrofuran by stirring and heating to 60° C. The solution is allowed to cool to room temperature, 5.15 g (29.7 millimoles) of 2,2-dichlorocyclopropanecarboxylic acid chloride, dissolved in 10 ml of absolute tetrahydrofuran, are added dropwise and the mixture is then stirred for 6 hours under reflux. Thereafter it is concentrated to about 50 ml and the product is filtered off at 10° C., washed with water and recrystallized from dimethylformamide/water. 5.0 g (60% of theory) of 6-[p-(2,2-dichlorocyclopropylcarbonylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals, of melting point 252°-253° C.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][N:7]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])(=[O:16])=[O:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CC([O-])(C)C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([O:26][C:24]([N:31]1[CH2:36][CH2:35][N:34]([C:2]2[C:11]3[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][N:7]([S:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[F:23])(=[O:16])=[O:15])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:33][CH2:32]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1(C)CN(S(=O)(=O)c2ccccc2F)c2cccc(Br)c2O1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OC(C)(C)CN3S(=O)(=O)c2ccccc2F)CC1
Temperature: 90 °C
Yield: 82.7 %

Procedure:
A solution of 8-bromo-4-(2-fluoro-benzenesulfonyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine (450 mg, 1.124 mmol) and 1-Boc-piperazine (209.4 mg, 1.124 mmol) in 5 mL of toluene was added to a warm, degassed mixture of Pd2(dba)3(Tris(dibenzylideneacetone)dipalladium(0), 20.59 mg, 0.022 mmol), BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 35.0 mg, 0.056 mmol) and NaOt-Bu (151.26 mg, 1.57 mmol) in 5 ml of toluene. With stirring, the solution was heated at 90° C. for 2 hours, and then allowed to cool to room temperature. Ethyl acetate was added to the reaction which was then filtered through celite. The filtrate was washed with water (2×15 ml), brine (1×15 ml), and dried over MgSO4, after which the organic fraction was concentrated in vacuo. The resulting residue was purified by flash chromatography (15%–30% Ethyl acetate/Hexane) to give 470 mg (0.93 mmol) of 4-[4-(2-fluoro-benzenesulfonyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-piperazine-1-carboxylic acid tert-butyl ester. MS: (M+H) 506.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.[Br:11][Si](C)(C)C>ClCCl>[Br:11][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CC(O)c1ccc(F)cc1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(Br)c1ccc(F)cc1

Procedure:
0.5 g of 1-(4-fluorophenyl)ethanol is dissolved in 20 cm3 of dichloromethane, under an inert atmosphere, at a temperature close to 20° C. 1.24 cm3 of pure bromo(trimethyl)silane are introduced in two lots to the reaction mixture. The latter is stirred at a temperature close to 20° C. for 48 h, then it is washed with a saturated aqueous solution of sodium chloride, dried over a phase separation cartridge and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 700 mg of crude product obtained are purified by filtration through a silica pellet (eluent: 10% ethyl acetate/90% cyclohexane). After concentrating the fractions under reduced pressure, 439 mg of 1-(1-bromoethyl)-4-fluorobenzene are obtained in the form of a colorless thick oil.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C(N=C=NC(C)C)(C)C.Cl.Cl.[CH2:51]([NH:58][NH2:59])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C)C(=O)C.ClCCl>[NH2:8][C@H:9]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH:10]([OH:14])[C:11]([NH:59][NH:58][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)O
Reactant: NNCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: N[C@H](CC1CCCCC1)C(O)C(=O)NNCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of Example 1C (50 mg, 0.17 mmol), 1-hydroxybenzotriazole hydrate (30 mg, 0.22 mmol), and N-methylmorpholine (0.07 mL, 0.63 mmol) in 5:1/dichloromethane:N,N-dimethylacetamide (2 mL) at 0° C. was treated with 1,3-diisopropylcarbodiimide (0.03 mL, 0.21 mmol), and stirred for 5 minutes. The solution was treated with 1-benzylhydrazine dihydrochloride (0.05 g, 0.25 mmol), stirred for 2 hours, and warmed to room temperature over 44 hours. The reaction was washed with 2N HCl and saturated NaHCO3, and concentrated. The concentrate was purified by silica gel chromatography with 3:1/hexanes:ethyl acetate then 1:1/hexanes:ethyl acetate, then dissolved in 4N HCl in dioxane (1 mL), stirred for 1 hour, and concentrated, then purified by HPLC to provide the desired product.
Reaction SMILES: O=C1CCCN1C1C=C(C=C(N2CCCC2=O)C=1)C(O)=O.[CH:22]1([O:26][C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])[CH:36]=2)[C:30]([O:32]C)=[O:31])[CH2:25][CH2:24][CH2:23]1>>[CH:22]1([O:26][C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])[CH:36]=2)[C:30]([OH:32])=[O:31])[CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1cc(OC2CCC2)cc(N2CCCC2=O)c1
Agent: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Product: O=C(O)c1cc(OC2CCC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D8 from methyl 3-cyclobutyloxy-5-(2-oxopyrrolidin-1-yl)benzoate (D43).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[N:26]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH3:24])[N:26]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2nn(C)c3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1-Methyl-1H-indazole-3-carboxylic acid. LC-MS (basic): tR=0.93 min; [M+H]+=506.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:36][CH:37]([CH3:46])[C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39]>ClCCl.O.C(N(CC)CC)C>[C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[CH2:42][CH2:41]1)(=[O:39])[CH:37]([CH3:46])[CH3:36]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)C(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N2CCN(C(=O)C(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 3-(methoxycarbonyl)benzoic acid (0.9 g, 5 mmol) in dichloromethane (20 mL), 1-hydroxybenzotriazole (0.75 g, 5.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.06 g, 5.5 mmol) and triethyl amine (2 mL) was added. The mixture was stirred at room temperature for 30 min, then 2-methyl-1-(piperazin-1-yl)propan-1-one (1.0 g, 5 mmol) was added and the mixture was stirred at room temperature for 16 h. The resulting mixture was added water (50 mL) and extracted with dichloromethane (100 mL×3). The organic phase was washed with sodium bicarbonate and brine and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 20:1 to 2:1) to give 1.25 g of methyl 3-(4-isobutyrylpiperazine-1-carbonyl)benzoate as an oil. Yield 94%. 1H-NMR (400 MHz, CDCl3) 1.14-1.15 (d, J=6.4 Hz, 6H), 2.81 (brs, 1H), 3.44-3.80 (m, 8H), 3.94 (s, 3H), 7.52-7.55 (t, J=7.6 Hz, 1H), 7.62-7.64 (d, J=8.0 Hz, 1H), 8.08-8.14 (m, 2H); LC-MS (ESI) m/z: 319 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH2:13])=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH:18]=O>Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][N:13]=[CH:18][C:17]2[CH:16]=[C:15]([F:14])[CH:22]=[C:21]([F:23])[CH:20]=2)=[CH:6][C:7]=1[CH:8]1[CH2:9][CH2:10][CH2:11]1
Reactant: NNc1cc(C2CCC2)c(Cl)nn1
Reactant: O=Cc1cc(F)cc(F)c1
Agent: Cl
Product: Fc1cc(F)cc(C=NNc2cc(C3CCC3)c(Cl)nn2)c1

Procedure:
3-Chloro-4-cyclobutyl-6-hydrazinopyridazine (0.502 g, 2.53 mmol) and 3,5-difluorobenzaldehyde (285 ml, 2.78 mmol) were stirred in 0.2M hydrochloric acid (10 ml) for 2 hours. This product was then collected by filtration and dried (0.81 g, 99%). MS (ES+) 323 [MH]+, 325 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.Cl>O.CS(C)=O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][N:23]=[C:22]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 140 °C
Yield: 58.7 %

Procedure:
6-Hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 38 ml of DMSO were stirred at room temperature while cesium carbonate (7.5 g, 22.9 mmol) and 4-chloro-6,7-dimethoxy-quinazoline (2.05 g, 9.14 mmol) were added. The mixture was heated at 140° C. for 3 hours. The mixture was cooled to room temperature and diluted with 40 mL of H2O. The mixture was neutralized with 2 N HCl to 6.5. The deposited solids were collected by vacuum filtration, washed with H2O, dried under vacuum and recrystallized from methanol to give the title compound (1.68 g, 59% yield) as a brown solid. LC-MS (m/z) 377 (M+1).