Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C1(O)C=CC=CC=1.[CH3:19][O:20][C:21](=[O:25])[CH:22](Br)[CH3:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:22]([CH3:23])[C:21]([O:20][CH3:19])=[O:25])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Using 4-bromo-2-nitrophenol as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a dark red oil: 1H NMR (DMSO-d6, 400 MHz): δ ppm 8.13 (d, J=2.5 Hz, 1H), 7.80 (dd, J=8.8, 2.5 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 5.29 (q, J=6.8 Hz, 1H), 3.68 (s, 3H), 1.52 (d, J=6.6 Hz, 3H). ESI-MS: m/z 305.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)OC(C)(C)C

Procedure:
Mix N-t-butyloxycarbonyl-N5 -benzyloxycarbonyl-ornithine, t-butyl ester (2.0 g, 5.0 mmol) and 10% palladium/carbon (0.5 g) in 95% ethanol (40 mL). Hydrogenate at room temperature at atmospheric pressure. Filter and evaporate the filtrate in vacuo to give N-t-butyloxycarbonyl-ornithine, t-butyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1>[OH:1][C:2]1([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 3 h
Yield: 33.2 %

Procedure:
To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (4 g, 23 mmol) in THF (100 mL) at 0° C. was added (4-methoxyphenyl)magnesium bromide (0.5 M in ether) (47 mL, 23 mmol). The reaction mixture was stirred for 3 h, and then a satd. ammonium chloride solution (200 mL) was added. The mixture was extracted with ethyl acetate (200 mL), and the organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give a crude product. The product was purified by silica gel chromatography eluting with 25% ethyl acetate in hexane to give tert-butyl 3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate (2.2 g, 7.64 mmol, 32.7% yield). LCMS (Method 107): m/z 280.7 (M+H) RT=1.929 min; 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.21 (s, 1H), 4.00 (s, 3H), 3.75 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:29][CH3:30])=[CH:9][C:10]3[C:11]4[N:19]([C@@H:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH3:21])[C:18](=[O:28])[NH:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:31])[O:4][N:3]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[CH3:50][O:51][CH2:52][CH2:53]Br>CN(C=O)C.CS(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:29][CH3:30])=[CH:9][C:10]3[C:11]4[N:19]([C@@H:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH3:21])[C:18](=[O:28])[N:17]([CH2:53][CH2:52][O:51][CH3:50])[C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1[nH]c(=O)n([C@H](C)c3ccccn3)c12
Reactant: COCCBr
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COCCn1c(=O)n([C@H](C)c2ccccn2)c2c3cc(OC)c(-c4c(C)noc4C)cc3ncc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-(3,5-Dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-(2-pyridinyl)ethyl]-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (for a preparation see Example 36, 100 mg) in DMF (5 ml) was treated with 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine, polymer bound (300 mg) and a solution of 2-bromoethyl methyl ether (40 mg) in DMF (0.5 ml). The reaction was stirred at ambient temperature, air atm for ˜3 h and then left at ambient temperature overnight. The reaction was filtered and the resin washed with methanol. The solvents were evaporated under a stream of nitrogen to leave a yellow gum which was dissolved in DMSO (1 ml) and purified by MDAP (Method formate). The product fractions were combined and reduced to dryness in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-3-[2-(methyloxy)ethyl]-1-[(1R)-1-(2-pyridinyl)ethyl]-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one as a pale yellow gum (56 mg)
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:26][NH2:27]>>[C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[N:19][C:20]([NH:26][NH2:27])=[CH:21][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)NCC(O)COc1cc(O)ccc1-c1ccc(Cl)nn1
Solvent: O
Product: CC(C)(C)NCC(O)COc1cc(O)ccc1-c1ccc(NN)nn1

Procedure:
3-[2-(3-t-Butylamino-2-hydroxypropoxy)-4-hydroxyphenyl]-6-chloropyridazine was reacted with hydrazine hydrate under similar conditions to those described in Example 7b(iii) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:35])[CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:40]3[CH2:41][CH2:42][NH:37][C:38](=[O:43])[CH2:39]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:34])[CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: O=C1CNCCN1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2C(=O)N2CCNC(=O)C2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazinone (Avocado Organics) to give the title compound. HR-MS (ES, m/z) calculated for C32H35N4O4Cl2 [(M+H)+] 609.2030, observed 609.2025.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[Si]([O:14][CH2:15][C@@H:16]([N:25]1[CH:29]=[C:28]([C:30]([O:32]C)=O)[N:27]=[CH:26]1)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C(C)(C)C)(C)C>CO>[OH:14][CH2:15][C@@H:16]([N:25]1[CH:29]=[C:28]([C:30]([NH:5][OH:6])=[O:32])[N:27]=[CH:26]1)[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NO
Reactant: COC(=O)c1cn([C@@H](CCc2ccccc2)CO[Si](C)(C)C(C)(C)C)cn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(NO)c1cn([C@H](CO)CCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A powder of NaOMe (417 mg, 7.72 mmol) was added to an ice cooled solution of hydroxylamine hydrochloride (536 mg, 7.72 mmol) in methanol (5 ml). After 30 minutes, methyl (S)-1-[1-(tert-butyldimethylsilyloxy)-4-phenyl-2-butyl]imidazole-4-carboxylate (obtained in Example 6)(389 mg, 1.0 mmol) in methanol (2 ml) was added to the mixture and the resulting mixture was stirred at reflux for 3 day. After cooling, the insoluble material was removed and then the filtrate was evaporated. The residue was diluted with water and the solution was acidified to pH 4 with 1N HClaq. The resulting mixture was washed with CHCl3. The aqueous layer was purified by HP-20 (40 cc) column chromatography eluting with water/2-propanol (9:1) and lyophilized to give (S)-1-[1-hydroxy-4-phenyl-2-butyl]-imidazole-4-carbohydroxamic acid (92.5 mg, 43.5%) as an amorphous solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:12][CH:13]=O)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:12][CH2:13][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1cc([C@H](CC=O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)c1cc([C@H](CCN2CCOCC2)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 2 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-3-oxo-propyl]-amide (40 mg, 0.09 mmol) and morpholine (15 μL, 0.17 mmol) in dichloroethane (2 mL) was stirred for 30 minutes. The mixture was then acidified (pH=4) with acetic acid (9 μL, 0.2 mmol) and then sodium triacetoxyborohydride (36 mg, 0.17 mmol) was added. After 2 hours, the reaction was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The oily residue was purified by silica gel chromatography using a gradient of 0-10% methanol in EtOAc. The solid material from the column was purified a second time by reversed-phase HPLC using a 20 minute gradient of 5-95% MeCN (0.1% TFA) in H2O (0.1% TFA) (flow rate=25 mL/minute). Desired fractions from the column was made basic with saturated aqueous sodium bicarbonate (2 mL), concentrated to half of the original volume and extracted with EtOAc (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a white solid.
Reaction SMILES: [CH:1]([CH:4]1[C:13](=O)[C:12]2[C:11]([C:15](OC)=[O:16])=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][CH:5]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:3])[CH3:2].O.[NH2:26][NH2:27]>>[CH:1]([CH:4]1[C:13]2=[N:26][NH:27][C:15](=[O:16])[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:12]=32)[NH:6][CH:5]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc2c1C(=O)C(C(C)C)C(c1ccccc1)N2
Reactant: NN
Solvent: O
Product: CC(C)C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
Methyl 3-isopropyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (35 mg, 1 mmol) and hydrazine monohydrate (20 mL) were added and the mixture was stirred under 40° C. for 3 h. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated, purified with prep-HPLC. 7 mg of solid 9-isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one was obtained (yield: 15%). 1H-NMR (400 MHz, DMSO-d6): δ 0.82-0.83 (d, J=5.2 Hz, 3H), 1.15-1.17 (d, J=5.2 Hz, 3H), 1.89-1.93 (m, 1H), 2.71-2.73 (d, J=6.0 Hz, 1H), 4.83 (s, 1H), 7.11-7.26 (m, 7H), 7.51-7.54 (m, 2H), 12.11 (s, 1H). LC-MS (ESI) m/z: 306 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O.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>[CH:16]1([CH2:15][O:14][C@@H:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][CH3:19])[CH:22]=3)=[CH:3][CH:4]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:18][CH2:17]1
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)OCC1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cccc(-c2ccc(C[C@H](OCC3CC3)C(=O)OC)cc2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
53 mg (0.046 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 145 mg (0.46 mmol) of methyl (S)-3-(4-bromophenyl)-2-(cyclopropylmethoxy)propionate and 129 mg (0.55 mmol) of methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 3 ml of dimethylformamide. 0.3 ml of a 2M potassium phosphate solution is added and the reaction mixture is stirred at 90° C. for 2 hours. The reaction is halted by the addition of 10 ml of water and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 70 mg of methyl (S)-2-cyclopropylmethoxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate are obtained in the form of an oil. Yield=45%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[CH:15]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:26][NH:27][S:28](Cl)(=[O:30])=[O:29].[BH4-].[Na+]>N1C=CC=CC=1>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[C:16]1[CH:15]=[C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:28](=[O:30])(=[O:29])[N:27]2[CH3:26])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: Nc1c(C(=O)c2ccc(F)c(C3OCCO3)c2)ccc2cccnc12
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)c(C3OCCO3)c2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 71.9 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(3-[1,3]dioxolan-2-yl-4-fluoro-phenyl)-methanone 420 (500 mg, 1.48 mmol), N-methylsulfamoyl chloride 213 (574 mg, 4.43 mmol) and NaBH4 (56 mg, 1.48 mmol) in pyridine (10 ml) gave the title compound (442 mg, 72%) after purification by column chromatography with heptane/EtOAc (50:50) as the eluent.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH2:14][CH2:15][F:16])[C:7]=12.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH2:14][CH2:15][F:16])[C:7]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(C)n(CCCF)c2c(Cl)nncc12
Reactant: OCc1ccccc1
Product: Cc1c(C)n(CCCF)c2c(OCc3ccccc3)nncc12
Yield: 71.2 %

Procedure:
The title compound was prepared as white crystals in 71.2% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-(3-fluoropropyl)-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: C([O-])(=O)/C=C/C([O-])=O.C(OC([N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:17]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[N:22]1([CH:18]2[CH2:19][CH2:20][CH2:21][NH:16][CH2:17]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N2CCCC2)C1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C1CNCC(N2CCCC2)C1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
The fumarate of the title compound of Example 5 (2.00 g, 5.40 mmol) was suspended in CHCl3 (20 mL) and the solution was treated with CF3COOH (25 mL). TLC (solvent system A) indicated the reaction to be complete after 10 min at rt. The solvent was evaporated in vacuo and the residue was dissolved in cold (5° C.) 50% aqueous NaOH (100 mL) and extracted with CHCl3 (2×100 mL). The combined organic layer was dried (Na2SO4) and the solvent was evaporated in vacuo to give the title compound (0.80 g, quantitative) as a colorless oil. The HBr salt of the title compound crustallized from 2-propanol: mp 217°-218° C.; 1H-NMR (CDCl3) ∂ 3.22 (dm, Jgem +11 Hz, 1H), 2.94 (dm, Jgem +12 Hz, 1H), 2.48-2.62 (complex m, 6H), 1.98-2.11 (complex m, 2H), 1.65-1.82 (complex m, 6H), 1.30-1.54 (complex m, 2H); CIMS (calcd for C9H18N2): 155. Found (MH+): 155; Anal. (calcd for C9H20Br2N2): C, H, N.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].O.C(Cl)Cl>COC(=O)OC>[Br:9][C:5]1[N:6]=[C:7]([Br:8])[C:2]2[N:3]([CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=2)[CH:4]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ncc(Br)nc1Br
Solvent: O
Solvent: COC(=O)OC
Solvent: ClCCl
Product: CCOC(=O)c1cn2cc(Br)nc(Br)c2n1
Temperature: 110 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79 mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 110° C. for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(SO4) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6%) ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz,
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:27])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH2:57])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:57][C@@H:50]2[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@H:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]5[CH3:30])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:27])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Temperature: 70 °C
Reaction time: 6.75 h
Yield: 58.9 %

Procedure:
A solution of Intermediate 152c (59 mg, 0.13 mmol) in 1,4-dioxane (1.3 mL) was treated with Intermediate 81d (44 mg, 0.12 mmol) and DIPEA (0.025 mL, 0.14 mmol) and the mixture was stirred at 70° C. for 6.75 h then at 50° C. for 64 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. The gum was purified by FCC, using 0-10% MeOH in DCM to give the title compound as a pale yellow glass (49 mg, 61%). LCMS (Method 3): Rt 3.74 min, m/z 693.5 [MH+].
Reaction SMILES: Cl[CH2:2][C:3]1[C:15]2[C:14]3[CH:13]=[C:12]([CH3:16])[CH:11]=[CH:10][C:9]=3[N:8]([CH3:17])[C:7]=2[C:6](=[O:18])[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.[C-:25]#[N:26].[Na+].[I-].[Na+].O>CN(C)C=O>[CH3:17][N:8]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=2[C:15]2[C:3]([CH2:2][C:25]#[N:26])=[N:4][N:5]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6](=[O:18])[C:7]1=2
Reactant: [C-]#N
Reactant: Cc1ccc2c(c1)c1c(CCl)nn(-c3ccccc3)c(=O)c1n2C
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(CC#N)nn(-c3ccccc3)c(=O)c1n2C
Yield: 61.5 %

Procedure:
A solution of 5 g (14.8 mmol) of 1-(chloromethyl)-5,8-dimethyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one, of 2.7 g (55 mmol) of sodium cyanide and of 0.5 g (3 mmol) of sodium iodide in a mixture of 50 ml of dimethylformamide and of 30 ml of water is stirred for 2 h at 50° C. The mixture is left standing at room temperature and the precipitate is collected by filtration. It is washed with water and with pentane and is dried under reduced pressure. 3 g (9.1 mmol) of product are obtained, which product is used as is in the following stage.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11](CC(OCC)=O)[O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[C:38](OCC)(=[O:40])[CH3:39].O.O.O.O.C([C@@H]([C@H](C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[C:12]([CH2:39][CH:38]=[O:40])([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(CC=O)(Cc2ccccc2)COC1(C)C
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A solution of 4-benzyl-5-ethoxycarbonylmethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (48 g, 0.12 mol) in dry toluene was stirred at −78° C. during the addition of 1M diisobutyl aluminium hydride in toluene (165 ml, 165 mmol). The resulting mixture was stirred at −78° C. for 4 hours and ethyl acetate (60 ml) was then added. After 30 minutes, the mixture was allowed to warm to room temperature and a solution of potassium sodium L-tartrate tetrahydrate (250 g, mmoL) in water (800 ml) was added. The resulting biphasic mixture was stirred until the two phases were clear. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (anhydrous magnesium sulfate) and concentrated in vacuo to provide 4-benzyl-2,2-dimethyl-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid tert-butyl ester which solidified upon standing overnight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][SH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH2:16]([C:23]1[O:24][C:25]2[CH:45]=[CH:44][CH:43]=[CH:42][C:26]=2[C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][S:14][CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:31]2[CH:30]=[CH:29][C:28]([C:27]3[C:26]4[CH:42]=[CH:43][CH:44]=[CH:45][C:25]=4[O:24][C:23]=3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:33][CH:32]=2)=[CH:39][CH:38]=1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
N-Boc-L-Cysteine methyl ester (260 mg, 0.23 mL, 1.1 mmol) was added dropwise to a stirred suspension of 2-Benzyl-3-(4′-bromomethylbiphen-4-yl)benzofuran (500 mg, 1.1 mmol) and cesium carbonate (720 mg, 2.21 mmol) in anhydrous dimethylformamide (20 mL). The reaction was stirred at room temperature for 2 hrs (TLC control) and then poured into water (100 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine (3×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification using 30% ethyl acetate in heptane as eluent afforded the title compound as a white solid (620 mg, 92%): 1H NMR (CDCl3, 300 MHz): δ 7.70 (2H, m, Ar—H), 7.64 (2H, m, Ar—H), 7.60 (3H, m, Ar—H), 7.48 (1H, m, Ar—H), 7.42 (2H, m, Ar—H), 7.26-7.36 (7H, m, Ar—H), 5.32 (1H, d, J=8 Hz, NH), 4.58 (1H, m, CHN), 4.26 (2H, PhCH2), 3.79 (2H, s, PhCH2S), 3.76 (3H, s, OMe), 2.95 (1H, dd, J=13, 5 Hz, CHHCHN), 2.84 (1H, dd, J=13, 7 Hz, CHHCHN), 1.46 (9H, s, CMe3); ESI-LCMS e/z calcd for C37H37NO5S 607.760, found 608 (M+H)+, 630 (M+Na)+.