Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Br:20])[CH:15]=O.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:21][C:22]3=[CH:26][CH:25]=[N:24][N:23]23)[CH:17]=[CH:18][C:19]=1[Br:20]
Reactant: O=Cc1ccc(Br)c(Br)c1
Reactant: Nc1cc[nH]n1
Reactant: CC1(C)CCC(=O)CC1=O
Product: CC1(C)CCC2=C(C1=O)C(c1ccc(Br)c(Br)c1)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 3,4-dibromobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([NH2:29])[N:28]=4)[N:25]=3)[CH3:19])=[N:16][N:17]=2)[CH:14]=1.CCN(C(C)C)C(C)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([NH:29][C:42]([CH:39]5[CH2:41][CH2:40]5)=[O:43])[N:28]=4)[N:25]=3)[CH3:19])=[N:16][N:17]=2)[CH:14]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(c1ccc2nc(N)cn2n1)c1nnc2ccc(Br)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc2nc(NC(=O)C3CC3)cn2n1)c1nnc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)imidazo[1,2-b]pyridazin-2-amine TFA salt (250 mg, 0.52 mmol) in CH2Cl2 was added DIEA (0.65 g, 5.0 mmol) followed by cyclopropanecarbonyl chloride (0.16 g, 1.5 mmol). The reaction was stirred at ambient temperature for 30 min. Solvent was removed via rotary evaporation and the resulting residue was reconstituted in MeOH (10 mL). NH4OH (0.5 mL) was added and the reaction was stirred at ambient temperature for 1 hr. The reaction was then concentrated to dryness and the resulting material was dissolved in EtOAc, washed with saturated NaHCO3, dried with MgSO4, filtered and concentrated to dryness. The crude material was purified via MPLC (5% MeOH/0.1% NH4OH/EA) to provide the title compound, N-(6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide 48 (0.22 g, 0.52 mmol, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73-0.87 (m, 4 H) 1.83-1.99 (m, 4 H) 5.17 (d, J=7.07 Hz, 1 H) 7.38-7.57 (m, 3 H) 7.80 (d, J=9.60 Hz, 1 H) 7.99 (d, J=9.09 Hz, 1 H) 8.78 (s, 1 H) 11.14 (s, 1 H). ESI-MS:m/z 426.2 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([CH2:12][C:13]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[N:26][N:25]4[C:28]([C:31]5[CH:32]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42]([F:45])([F:44])[F:43])=[O:39])[CH:34]=[CH:35][CH:36]=5)=[CH:29][N:30]=[C:24]4[CH:23]=3)[CH:19]=[N:18]2)[CH2:16][NH:15][CH2:14]1)#[N:11].C(N(CC)CC)C>CN(C)C=O.CO>[C:10]([CH2:12][C:13]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[N:26][N:25]4[C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42]([F:44])([F:45])[F:43])=[O:39])[CH:32]=5)=[CH:29][N:30]=[C:24]4[CH:23]=3)[CH:19]=[N:18]2)[CH2:14][N:15]([C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:16]1)#[N:11]
Reactant: O=C=Nc1ccccc1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phenyl isocyanate (5.4 mg, 0.045 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (15.0 mg, 0.0303 mmol) and triethylamine (13 μL, 0.093 mmol) in N,N-dimethylformamide (0.5 mL) and methanol (0.1 mL). The reaction mixture was stirred at r.t. for 2 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=615.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:19][C:9]2=[CH:10][N:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CN(C=O)C.Br[CH2:26][C:27]1[S:31][C:30]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:29]=2[CH:28]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:19]([CH2:26][C:27]2[S:31][C:30]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:29]=3[CH:28]=2)[C:9]2=[CH:10][N:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2[nH]1
Reactant: Clc1ccc2cc(CBr)sc2c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCCOC)ncc2n1Cc1cc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 660 mg (2.497 mmol) 5-(2-Methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester in 15 mL absolute DMF 24 mg (2.497 mmol) NaH (96%) were added in an argon atmosphere. The mixture was stirred for 30 min. at room temperature. 623 mg (2.497 mmol) 2-Bromomethyl-6-chloro-benzo[b]thiophene [prepared by adopting a procedure described by Ewing, William R. et al. in; PCT Int. Appl. (1999), 300 pp. WO 9937304 A1; and Ewing, William R. et al. PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture stirred for 1 h at room temperature. The solvent was removed in vacuo and the residue purified by preparative HPLC (eluent: CH3CN/H2O/0.1% CF3COOH). The fractions containing the product were combined, concentrated in vacuo and lyophilized. Yield: 900 mg.
Reaction SMILES: CC1(C)CCC[C:4](C)(C)[NH:3]1.C([Li])CCC.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][N:18]=1.Cl.[NH2:27]N>C1COCC1.CN(C=O)C>[Br:16][C:17]1[N:18]=[CH:19][C:20]2[C:21](=[O:23])[NH:27][N:3]=[CH:4][C:24]=2[CH:25]=1
Reactant: NN
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1[nH]ncc2cc(Br)ncc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
2,2,6,6-Tetramethylpiperidine (9.58 mL, 56.4 mmol) was dissolved in dry THF (100 mL), and cooled to 0° C., whilst n-butyllithium (1.6M in hexanes, 35.2 mL, 56.43 mmol) was added over 15 min. The resulting solution was cooled to −78° C., and 6-bromonicotinic acid (3.8 g, 18.8 mmol.) was added as a solid in four equal portions, with stirring over 10 min. Stirring was continued at this temperature for 1.5 h, and the resulting deep-red solution was treated with dry DMF (10 mL) and allowed to warm to room temperature overnight. The mixture was poured onto water (200 mL) and acidified with 1M HCl, and the aqueous phase was extracted with EtOAc (×4). The combined organic phases were washed (brine), dried (sodium sulfate) and concentrated to give a yellow oil, which was dissolved in THF (25 mL) and treated with hydrazine (1M in THF, 19 mL). The precipitate was filtered, and dissolved in ethanol (50 mL) and heated to reflux in the presence of potassium acetate (5 g). The mixture was concentrated under reduced pressure and the brown oily solid was triturated with diethyl ether and the ethereal solution was subjected to flash chromatography (50% ethyl acetate/isohexane) to give a white solid (0.5 g, 12%). 1H NMR (400 MHz) DMSO-d6 δ: 8.21 (1H, s), 8.36 (1H, s), 9.20 (1H, s), 13.09, (1H, s). MS (ES M+1) 226/228.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[OH:30][C:31]1([C:38]2[S:42][CH:41]=[N:40][CH:39]=2)[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1>>[OH:30][C:31]1([C:38]2[S:42][CH:41]=[N:40][CH:39]=2)[CH2:32][CH2:33][CH:34]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:35][CH2:36]1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(O)(c3cncs3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1NC.C[CH2:31][N:32](C(C)C)C(C)C>C(O)CCC>[C:11]1([C:10]2[C:3]3[C:2]([NH:32][CH2:31][C@@H:24]4[CH2:25][CH2:26][CH2:27][O:23]4)=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN[C@@H]1CCCO1
Reactant: Brc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Solvent: CCCCO
Product: c1ccc(-c2oc3ncnc(NC[C@@H]4CCCO4)c3c2-c2ccccc2)cc1
Temperature: 120 °C
Yield: 95 %

Procedure:
Compound 69 (60 mg, 0.17 mmol), (S)-tetrahydrofuran-2-yl-methylamine (36 μL, 0.34 mmol), and DIEA 150 μL (0.86 mmol) were mixed in 1-butanol (2 mL) and heated to 120° C. for 1.5 h. The reaction mixture was concentrated, and the residue was purified by flash chromatography to yield a white solid (60 mg). MS: 372.1 (M+1). 1HNMR (DMSO-d6) ppm 8.36 (s, 1H), 7.61-7.34 (m, 10H), 5.11 (t, 1H), 3.89-3.85 (m, 1H), 3.58-3.48 (m, 4H), 1.84-1.64 (m, 3H), 1.40-1.38 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH2:20][S:21]([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:23])=[O:22])[C:8]([N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([OH:14])=O)=[O:9])=[O:4].Cl.[CH3:35][NH:36][CH3:37].C(P(=O)(OCC)OCC)#N.Cl>CN(C)C=O.C(N(CC)CC)C>[CH3:35][N:36]([CH3:37])[C:12]([CH2:11][N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([CH:7]([CH2:20][S:21]([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:22])=[O:23])[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:9])=[O:14]
Reactant: CCCCCN(CC(=O)O)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Reactant: CNC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCN(CC(=O)N(C)C)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a solution of N-[2-(2-methoxycarbonylethyl)-3-(2-naphthylsulfonyl)propionyl]-N-pentylglycine (100 mg), dimethylamine hydrochloride (21 mg), and triethylamine (70 μl) in N,N-dimethylformamide (1 ml) was added diethyl cyanophosphonate (42 μl) at 0° C. After stirring at room temperature for 16 hours, a dilute hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and evaporated at reduced pressure. The residue was purified by flash column chromatography on silica eluting with chloroform/methanol (15:1) to give 95 mg of methyl 4-[N-(N,N-dimethylcarbamoylmethyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl)pentanoate as oil. ##STR19##
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:18])[C:11]=2[N:10]([CH3:31])[C:9]1=[O:32])(=O)C.O[Li].O>C1COCC1.O.C(Cl)Cl>[OH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:18])[C:11]=2[N:10]([CH3:31])[C:9]1=[O:32]
Reactant: CC(=O)OCCCn1c(=O)c2c(c(C)c(-c3cccc(OC(F)(F)F)c3)n2C)n(C)c1=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2cccc(OC(F)(F)F)c2)n(C)c2c(=O)n(CCCO)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of 3-(1,5,7-trimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (20 mg, 0.044 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (3.70 mg, 0.088 mmol). The reaction was stirred at RT for 30 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1,5,7-trimethyl-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (5 mg, 27.6% yield) as a white solid. 1H NMR (CDCl3) δ: 7.56 (t, J=8.0 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.16 (s, 1H), 4.33-4.14 (m, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 3.52 (dd, J=12.8, 7.5 Hz, 2H), 2.21 (s, 3H), 2.03-1.83 (m, 2H). LCMS: MH+ 412 and TR=2.613 min.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:21]=[C:22]=[O:23])[CH:18]([CH3:20])[CH3:19].C(OCC)C.C1CCCCC1>O1CCCC1>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([NH:11][NH:12][C:22]([NH:21][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:23])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)CN=C=O
Reactant: NNC(=O)c1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CC(C)CNC(=O)NNC(=O)c1ccccc1-c1ccccc1
Reaction time: 8 h

Procedure:
1.00 g (4.71 mmol) of 2-phenylbenzoic acid hydrazide are placed in 10 ml tetrahydrofuran at room temperature. 0.51 g (5.15 mmol) of isobutyl isocyanate, dissolved in 2 ml tetrahydrofuran, are rapidly added dropwise with stirring. The mixture is firstly stirred further at room temperature and then allowed to stand overnight. Addition of an equal volume of diethyl ether and 10 ml of cyclohexane results in separation of a small quantity of a solid, which is filtered off and discarded. Concentration of the filtrate yields 1.53 g (ca. 100% of theory) of a slightly THF-moist product, which is used further as such.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:37]=[CH:38][CH:39]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:16](=[O:25])[CH:15]2[CH2:26][CH2:27][CH:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[OH:29])=[CH:10][CH:9]=1.[CH2:40]1[N:45]2[CH2:46][CH2:47][N:42]([CH2:43][CH2:44]2)[CH2:41]1>C1(C)C=CC=CC=1>[Br-:1].[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:17]2[C:16](=[O:25])[CH:15]([CH2:26][CH2:27][CH:28]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[OH:29])[CH:14]2[C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]3[CH:4]=[C:3]([CH:39]=[CH:38][CH:37]=3)[CH2:2][N+:42]34[CH2:47][CH2:46][N:45]([CH2:44][CH2:43]3)[CH2:40][CH2:41]4)=[CH:9][CH:10]=2)=[CH:23][CH:22]=1
Reactant: C1CN2CCN1CC2
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3cccc(CBr)c3)cc2)N1c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3cccc(C[N+]45CCN(CC4)CC5)c3)cc2)N1c1ccc(F)cc1
Product: [Br-]

Procedure:
Compound (18) and DABCO were dissolved in toluene and reacted analogously to Example IV, giving the product (19) as a colorless solid of molecular weight 704.66 (C38H40BrF2N3O3); MS (ESI): 624.30 (MH+).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:18]1=[O:36].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>C1(C)C=CC=CC=1.[Pd]>[C:32]([O:31][C:29]([CH2:28][N:19]1[C:18](=[O:36])[CH:17]([N:16]2[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8][C:37]2=[O:38])[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]1=2)=[O:30])([CH3:33])([CH3:35])[CH3:34]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C=CC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC(c2ccccc2)OC(=O)N1C1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 18 h

Procedure:
Ethyl 3-benzoylacrylate (13a) (55.6 g, 250 mmoles) is dropped into a solution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11) (66.2 g, 227 mmoles) in 200 ml of toluene, at room temperature in 1 h. The resulting mixture is left under stirring for 18 h, then added with 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h at room temperature. The catalyst is filtered off and carbonyldiimidazole (272.4 mmoles, 44.16 g) is added. After reacting for 4 h the mixture is washed 3 times with 100 ml of water. After completion of the reaction the solvent is evaporated off and the residue is purified by chromatography (eluent: hexane-ethyl acetate 7:3). A mixture of isomeric products is isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]([CH3:27])([O-])[CH3:25].[K+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([O:9][C:24]([CH3:27])([CH3:25])[CH3:23])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-bromo-2-chlorobenzoic acid (1 eq.) and anhydrous DMF (1.2 eq.) was taken up in toluene (0.9 M). To this was then added, dropwise over 5 min, oxalyl chloride (1.2 eq.) and the reaction mixture was stirred at RT for 1 h. The volatiles were then removed in vacuo and the resulting residue was taken up in toluene (0.9 M). At 0° C., potassium tert-butoxide (2.5 eq.) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into H2O and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→85:15 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c(C(F)(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1C(F)(F)F
Yield: 157.1 %

Procedure:
To a refluxing mixture of 5.0 g 4-Methyl-2-(trifluoromethyl)benzonitrile in 50 ml tetrachloromethane were added a mixture of 5.77 g N-bromosuccinimide and 1.77 g 2,2′-azobis(2-methylpropionitrile). The reaction mixture was heated under reflux for three hours. The reaction mixture was filtered through a pad of celite and the solvent was removed in vacuo to obtain 11.2 g crude 4-Bromomethyl-2-trifluoromethyl-benzonitrile (impurified with the dibromo product) as a white solid. This material was used without further purification.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([CH2:28][O:29][C:30](N=[N+]=[N-])=[O:31])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH:7][C:30]([O:29][CH2:28][C:27]1[CH:35]=[CH:36][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)=[O:31]
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To a suspension of 10.0 g of L-histidine methyl ester dihydrochloride in 200 ml of dry chloroform were added 18.4 ml of a triethylamine and 10.2 g of 4-methoxybenzyloxycarbonylazide under cooling, and the mixture was stirred for 16 hours at 0° C. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=10/1 by volume) to obtain 11.0 g of N-(4-methoxybenzyloxycarbonyl)-L-histidine methyl ester as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([CH2:23][CH2:24][O:25][CH3:26])[CH2:14][CH:13]2[C:27]([O:29]C)=[O:28])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([CH2:23][CH2:24][O:25][CH3:26])[CH2:14][CH:13]2[C:27]([OH:29])=[O:28])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(OC)cc2)Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCN1CC(C(=O)O)N(S(=O)(=O)c2ccc(OC)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
A mixture of 1.0 g (2.3 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate and 3.0 ml of 1N NaOH in 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours and the solvent removed. To the residue was added water and the mixture acidified with 1N HCl. The mixture was extracted with ethyl acetate and the extract was washed with brine and dried with Na2SO4. The solvent was removed and the residue triturated with ethyl acetate-hexane, cooled and filtered to give 0.65 g of white crystals, m.p. 164°-165° C.,; Mass spectrum (ES) 421.4 (M+H). Anal. for C20H24N2O6S: Calc'd: C,57.1; H,5.8; N,6.7; Found: C,57.3; H,5.7; N,6.4.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24]O)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[BrH:26].C1COCC1.[OH-].[Na+]>CC(O)=O>[Br:26][CH2:24][C:20]1[CH:19]=[C:18]([C:16]2[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)[CH:23]=[CH:22][CH:21]=1
Reactant: Br
Reactant: CC(C)(c1cc(-c2cccc(CO)c2)c2ncccc2c1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(c1cc(-c2cccc(CBr)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 0 °C

Procedure:
A suspension of the {3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-methanol compound from Step 3 above (30 g, 85 mmol) in AcOH (140 mL) and HBr (48 mL, 48% aq) was stirred for 18 h at 80° C. The resulting mixture was cooled to 0° C. and poured into 2L of cold NaOH (0.3N). The pH of the resulting solution was adjusted to 5 and filtered. The resulting solid was dissolved in EtOAc, washed with saturated NaHCO3 solution, brine, dried (MgSO4), filtered and concentrated. Stirring the solid in ether/EtOAc, followed by filtration gave desired 8-(3-Bromomethyl-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline as a pale brown solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[CH2:13][CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26](Br)=[O:27].[NH2:29][CH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1>>[CH2:1]([O:8][CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[CH2:13][CH2:12][N:11]1[CH2:25][C:26]([NH:29][CH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)C(COCc1ccccc1)NCC2
Reactant: O=C(Br)CBr
Reactant: NC1CCc2ccccc21
Product: COc1cc2c(cc1OC)C(COCc1ccccc1)N(CC(=O)NC1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-Benzyloxymethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane