Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N(C(OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[CH3:46][O:47][CH2:48][CH2:49][NH2:50]>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([NH:50][CH2:49][CH2:48][O:47][CH3:46])=[O:38])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: COCCN
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: COCCNC(=O)c1cc(N2CCCC2=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (150 mg) described in Example 769 and 2-methoxyethylamine (84 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (68 mg) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][CH:29]3[CH2:31][CH2:30]3)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: BrCC1CC1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(OCC2CC2)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 90 °C
Yield: 39.7 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (26 mg, 0.19 mmol) and (bromomethyl)cyclopropane (14 μL, 0.14 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 90° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/dichlrormethane (3.5:0.5:4) followed by trituration with diethyl ether afforded 12 mg (41%) of 3-(2-pyridyl)-5-(3-cyano-5-cylopropylmethoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.91 (t, 1H), 7.50 (m, 1H), 7.40 (s, 1H), 3.95 (d, 2H), 1.21 (m, 1H), 0.72 (m, 2H), 0.41 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[S:31](Cl)(=[O:33])=[O:32].O>CN(C=O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[N:8]([S:31]([C:23]3[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=3[O:21][CH3:20])(=[O:32])=[O:33])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.13 g of sodium hydride as an 80% dispersion in oil was added in portions, with stirring, to a solution of 1 g of 5-chloro-3-cyclohexyl-1,3-dihydro-2H-benzimidazol-2-one in 10 ml of DMF at room temperature; 1.1 g of 2-methoxy-4-nitrobenzenesulfonyl chloride were then introduced and the reaction medium was stirred at room temperature for 4 hours. The solvent was then evaporated off under vacuum and the residue obtained was taken up with water. It was then extracted with DCM, washed with water and then dried over sodium sulfate and the solvent was evaporated off to dryness. The residue obtained was chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product in the form of a slightly yellow solid, which crystallized from absolute EtOH. m=1.52 g. M.p.=185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[F:8].[Si:11]([O:18][CH2:19][C:20](N(OC)C)=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1COCC1.CCCCCC>[Si:11]([O:18][CH2:19][C:20]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CON(C)C(=O)CO[Si](C)(C)C(C)(C)C
Reactant: Fc1ccc([Mg]Br)cc1Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(F)c(Cl)c1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
0.5M (3-Chloro-4-fluorophenyl)magnesium bromide in THF (27.4 mL, 13.7 mmol) was added dropwise to 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (2.00 g, 8.57 mmol) in THF (20 mL) cooled in ice. The mixture became turbid after about half of the Grignard reagent was added. This was stirred in an ice bath for 2 hours, quenched with saturated aqueous NH4Cl, and concentrated to remove the THF. The aqueous residue was extracted with 2 portions DCM. The combined DCM layers were dried over MgSO4, filtered, and evaporated to yield a crude product (3.62 g) as an oil. This was taken up in hexane and purified on a silica gel plug with hexane until product started eluting, then 15:1 hexane/EtOAc. Product-containing fractions yielded 2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanone (2.28 g, 7.53 mmol, 87.9% yield) as an oil.
Reaction SMILES: [C:1]([C:3](=[C:9]([OH:15])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].O(C)[Na].[Na].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C(O)C.C(#N)C>[C:1]([C:3](=[C:9]([O:15][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(O)C(CC)CC
Reactant: CC(C)(C)C(=O)Cl
Agent: CO[Na]
Agent: [Na]
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)C(C#N)=C(OC(=O)C(C)(C)C)C(CC)CC
Temperature: 20 °C

Procedure:
36 g (0.17 mol) of ethyl 2-cyano-3-hydroxy-4-ethyl-2-hexenoate were dissolved in ethanol, and 31 g (0.17 mol) of 30% strength NaOCH3 solution were added. The mixture was then concentrated to dryness, and the sodium enolate was released by adding toluene and reconcentration of alcohol residues. 39.7 g (0.17 mol) of the resulting sodium salt were initially charged in acetonitrile and, at 0° C. with warming to 20° C., mixed dropwise with 27.4 g (0.23 mol) of pivaloyl chloride. After 16 g of stirring at 25° C., the reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with 2% strength NaOH. The organic phase was dried and concentrated. Customary purification gave 41.5 g (83% of theory) of the title compound (b.p. 102° C./1 mbar).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4](Cl)[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH2:20])=[O:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=2)[C:18]([NH2:20])=[O:19])=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(Br)cc1Cl
Reactant: NC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(NC(=O)COc2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
To solution of (4-bromo-2-chloro-phenoxy)-acetic acid (100 mg, 0.37 mmol), 2-amino isonicotinamide (77.89 mg, 0.56 mmol) and DMAP (92.58 mg, 0.75 mmol) in DMF 5 ml was added PyBOP (394.3 mg, 0.75 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1˜2:4:1) to afford 2-[2-(4-bromo-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.076 g, 52% yield).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Br:11][CH2:12][C:13](Br)=[O:14]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:11][CH2:12][C:13]([NH:1][CH2:2][C@@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:14]
Reactant: NC[C@@H](O)c1ccccc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CBr)NC[C@@H](O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) biphasic solution of (S)-(+)-2-amino-1-phenylethanol (6.2 g, 45.2 mmol) in EtOAc (450 mL) and saturated aqueous NaHCO3 (125 mL) was added bromoacetyl bromide (4.32 mL, 49.7 mmol) via syringe. The mixture was stirred at 0° C. for 1 h then layers were separated. The aqueous layer was extracted with EtOAc (2×100 mL) then combined organics were dried with Na2SO4, filtered, and concentrated to dryness to afford the desired product as a residue (11.6 g, quant.) that was used in the next transformation: ES MS (+) m/z 258.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCCC2=O)c1
Reactant: C1CCNC1
Agent: Cl
Product: COc1cccc([C@H]2CCCC[C@H]2N2CCCC2)c1

Procedure:
2-(3-Methoxyphenyl) cyclohexanone (30g), pyrrolidine (20g) and 98 to 100% formic acid (20g) were heated under reflux at 130° to 140° C for 18 hours. The cooled mixture was poured into dilute hydrochloric acid, washed with ether, basified and ether extracted. The dried extract was evaporated to give cis-2-(3-methoxyphenyl)-1-pyrrolidinocyclohexane (19g) as a colourless oil. A sample distilled at 150° to 154° C/1 mm gave a hydrochloride m.p. 145° to 147° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[C@H:15]12[CH2:21][C@H:18]([NH:19][CH2:20]1)[CH2:17][N:16]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[N+:12]([C:5]1[CH:4]=[C:3]([CH2:2][N:19]2[CH2:20][C@@H:15]3[CH2:21][C@H:18]2[CH2:17][N:16]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(CBr)c2occc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1cc([N+](=O)[O-])cc2ccoc12
Yield: 79 %

Procedure:
The title compound was prepared according to the procedure of Example 112, Step 1, starting from 7-(bromomethyl)-5-nitro-1-benzofuran (120 mg, 70 mol %, 0.39 mmol; Intermediate 64) and tert-butyl (1S,4S)-(−)-2,5-diazabicyclo-(2.2.1)heptane-2-carboxylate (93 mg, 0.47 mmol). The title compound (115 mg, 79%) was obtained as a light yellow sticky oil. HPLC 99%, RT=2.34 min (System A; 5-60% MeCN over 3 min), 99%, RT=2.15 min (System B; 5-60% MeCN over 3 min). MS (ESI+) for C19H23N3O5 m/z 374 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([SH:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:50]([S:57][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: SCc1ccccc1
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)cc(SCc2ccccc2)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Yield: 67 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g), benzylmercaptan (0.11 ml) and potassium carbonate (0.13 g) in acetonitrile (10 ml) was heated under reflux for 4 hours with stirring. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (1.5 ml) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.26 g, 67%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9]([O:14][CH:15]3[CH2:18][N:17]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[CH2:16]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[C:36](Cl)(=[O:39])[O:37][CH3:38]>C(Cl)Cl>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[N:17]1[CH2:18][CH:15]([O:14][C:9]2[C:8]([CH:5]3[CH2:6][CH2:7][N:2]([C:36]([O:37][CH3:38])=[O:39])[CH2:3][CH2:4]3)=[N:13][CH:12]=[CH:11][N:10]=2)[CH2:16]1
Reactant: c1ccc2nc(N3CC(Oc4nccnc4C4CCNCC4)C3)ccc2c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCC(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of 2-(3-((3-(piperidin-4-yl)pyrazin-2-yl)oxy)azetidin-1-yl)quinoline hydrochloride (see PREPARATION P4.1; 100 mg, 0.29 mmol) in dry DCM (10 mL) was added Et3N (1 mL). The reaction mixture was cooled to 0° C. with an ice bath, and methyl carbonochloridate (54 mg, 0.58 mmol) was added dropped to the reaction mixture. After 1 hour, the reaction mixture was warmed to RT, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified via flash chromatography on silica gel (20% to 45% EtOAc in petroleum ether) to give methyl 4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)piperidine-1-carboxylate (93 mg, 0.23 mmol, 79% yield) as a white solid. ESI-MS (M+1): 404 calc. for C23H25N5O2 403.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:33]6[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=6)[C:27]#[N:28])=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
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: COCCOC
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(-c6cccc(C#N)c6)n5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 80 mg, 0.196 mmol) was dissolved in DME (0.653 mL) with 3-cyanophenylboronic acid (28.2 mg, 0.196 mmol), 2 M Na2CO3 solution (0.353 mL, 0.705 mmol) and tetrakis(triphenylphosphine)palladium (11.3 mg, 0.010 mmol). The RM was heated at 150° C. 5 min under microwave irradiations. It was taken up with EtOAc and washed with 10% Na2CO3 solution and brine. The precipitate from the aqueous layer was filtered off and dried to afford the title compound as a grey solid (tR 0.8 min (conditions 2), MH+=431).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1.C(Cl)Cl>OS(O)(=O)=O>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=Cc1cc(Br)cs1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: O=Cc1cc(Br)c([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution of potassium nitrate (110 g, 1.09 mol) in H2SO4 (550 mL, conc.) was added to a solution of 4-bromo-thiophene-2-carbaldehyde (207.6 g, 1.08 mol) in H2SO4 (1.1 L, conc.) at CH2Cl2 (5 mL, anhydrous) at 0° C. over a 45 minute period. The reaction mixture was stirred 0° C. for 2 hrs, then stirred overnight at rt. The reaction mixture was poured over ice, filtered, and washed with water and hexanes. The yellow solid was dried overnight to afford the title compound (251.4 g, 98.6%). 1H-NMR (DMSO-d6): δ 9.90 (s, 1H), 8.56 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([C:32](O)=[O:33])[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18]>>[CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:32]([C:22]3[CH:21]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:25]=[CH:24][C:23]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:33])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CN(C)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3-c3ccccc3)CC2)cc1

Procedure:
The tide compound was prepared according to the procedure E described for Example 9 from Dimethyl-(4-piperazin-1-yl-phenyl)-amine [91703-23-0] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 464.3 MH+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH2:19][CH2:20][C:21]([OH:23])=O)[C:7]=1[CH2:24][N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35])[CH2:2][CH2:3][CH3:4].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH2:19][CH2:20][C:21](=[O:23])[N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:7]=1[CH2:24][N:25]1[C:26](=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]1=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNC1
Reactant: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CCC(=O)O)c(=O)c2cc(Cl)c(Cl)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CCC(=O)N2CCCC2)c(=O)c2cc(Cl)c(Cl)cc12
Yield: 52.6 %

Procedure:
A solution of 3-[4-butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)isoquinolinyl]propionic acid (1.03 g, 2.4 mmol), pyrrolidine (0.20 ml, 2.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.37 g, 2.4 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-diisopropyl ether to give 2-[[4-butoxy-6,7-dichloro-1-oxo-2-[3-oxo-3-(1-pyrrolidinyl)propyl]-1,2-dihydro-3-isoquinolinyl]-methyl]-1H-isoindole-1,3(2H)-dione (0.72 g, 66.1%) as crystals.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:21])[CH2:6][CH2:7][O:8][CH2:9][CH:10]([NH2:20])[CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:3].[C:22]([NH:32][CH2:33][CH2:34][C:35](O)=[O:36])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(N=C=NCCCN(C)C)C.CCN(CC)CC>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH:10]([NH:20][C:35](=[O:36])[CH2:34][CH2:33][NH:32][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:9][O:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:21])[CH3:19]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)CCOCC(N)COCCC(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCOCC(COCCC(=O)OCC)NC(=O)CCNC(=O)OCc1ccccc1
Yield: 91.5 %

Procedure:
The compound 29 was prepared using General Procedure B with the ester hydrochloride salt (28) (1.53 g, 5.26 mmol), N-Cbz-β-alanine (1.41 g, 6.31 mmol), 1-hydrobenzotriazole (HOBt) (0.99 g, 7.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.41 g, 7.36 mmol) and Et3N (1.02 mL, 7.36 mmol) in CH2Cl2 (30 mL). Purification by flash column chromatography (on silica gel, EtOAc:n-hexane=3:1) afforded 2.39 g (92%) of the desired product (29) as a colorless liquid. 1H NMR (CDCl3): δ 7.33 (m, 5H, ArH), 6.33 (d, J=8.0 Hz, 1H, NH), 5.57 (s, 1H, NM, 5.08 (s, 2H, OCH2Ar), 4.18 (m, 1H, CH), 4.13 (q, J=7.2 Hz, 4H, CH2O), 3.70 (m, 4H, CH2O), 3.56 (m, 2H, CH2O), 3.48 (d, J=6.0, 12.0 Hz, 2H, CH2NHCO), 3.40 (m, 2H, CH2O), 2.53 (m, 4H, CH2CO), 2.42 (t, J=6.0 Hz, 2H, CH2CO), 1.25 (t, J=7.2 Hz, 6H, CH3).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@H:4]([CH:16]([CH3:18])[CH3:17])[NH:5]C(OCC1C=CC=CC=1)=O.[CH2:21]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33]([OH:35])=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>CO.[Pd]>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@H:4]([CH:16]([CH3:18])[CH3:17])[NH:5][C:33](=[O:35])[C@@H:32]1[CH2:36][CH2:37][CH2:38][N:31]1[C:29]([O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:30]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(OC)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: COC(OC)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(C)C
Temperature: -20 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
24.5 g (0.087 mol) of N-benzyloxycarbonyl-L-valinal dimethyl acetal were dissolved in 200 ml of methanol and the solution was hydrogenated for 2 hours in the presence of 0.5 g of 5% palladium/carbon. After removal of the catalyst by filtration, the solvent was removed by evaporation and the residue was dissolved in 250 ml of dichloromethane. The solution was washed with brine and dried over magnesium sulphate. The solution was then cooled to -20° C. and there were then added 21.8 g (0.087 mol) of N-benzyloxycarbonyl-L-proline followed by 19.8 g (0.096 mol) of N,N'-dicyclohexylcarbodiimide. The solution was stirred at -20° C. for 2 hours and left to stand at 4° C. for 64 hours. The separated N,N'-dicyclohexylurea was removed by filtration and the filtrate was evaporated. The residue was taken up in ethyl acetate, the solution was washed with sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to give an oil. The product was purified by chromatography on 250 g of silica gel using ethyl acetate/hexane (1:1) for the elution. Evaporation of the solution yielded 21.9 g (67%) of N-benzyloxycarbonyl-L-prolyl-L-valinal dimethyl acetal; Rf-value (ethyl acetate): 0.63.