Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:23][NH:24][CH3:25].C(N(C(C)C)C(C)C)C>CN(C)C=O.CN(C1C=CN=CC=1)C.ClCCl>[F:18][C:19]([F:33])([F:34])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:23][N:24]([CH3:25])[C:6](=[O:8])[C:5]1[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C(O)c1cnc(Cl)cc1-c1ccccc1Cl
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of 300 mg (1.12 mmol) 6-chloro-4-(2-chloro-phenyl)-nicotinic acid (Example 24, step e)) in 12 ml dichloromethane 0.15 ml (1.7 mmol) oxalyl chloride and one drop of N,N-dimethylformamide were added at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated in vactio. The residue was redissolved in 6 ml dichloromethane and added dropwise to a solution of 432 mg (1.68 mmol) (3,5-bis-trifluoromethyl-benzyl)-methyl-amine, 0.39 ml (2.2 mmol) N-ethyldiisopropylamine and 7 mg (0.06 mmol) 4-(N,N-dimethylamino)pyridine in 6 ml dichloromethane at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was diluted with dichloromethane and washed with two portions of 1 M aqueous hydrochloric acid solution. The combined aqueous layers were extracted with dichloromethane. The combined organic extracts were washed with two portions of 1 M aqueous sodium hydroxide solution. The combined basic aqueous layers were extracted with dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 475 mg (84%) of the title compound as a light yellow amorphous mass.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH2:10][CH:9]2[C:11]3(OCC[O:12]3)[CH:6]([CH2:7][CH2:8]2)[CH2:5][C:4]=1/[CH:16]=[CH:17]/[C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:20]([CH3:30])[N:19]=1.C(=O)([O-])O.[Na+]>C1COCC1>[Cl:2][C:3]1[CH2:10][CH:9]2[C:11](=[O:12])[CH:6]([CH2:5][C:4]=1/[CH:16]=[CH:17]/[C:18]1[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[N:20]([CH3:30])[N:19]=1)[CH2:7][CH2:8]2
Reactant: Cn1nc(/C=C/C2=C(Cl)CC3CCC(C2)C32OCCO2)cc1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(/C=C/C2=C(Cl)CC3CCC(C2)C3=O)cc1-c1ccc(F)cc1
Yield: 93.8 %

Procedure:
A mixture of 2N hydrochloric acid (100 ml) and the product of Step 2 (18.0 g, 43 mmol) in THF (100 ml) was stirred at 60° C. for 2 hrs. The reaction mixture was basified with saturated sodium hydrogen carbonate and then extracted with ethyl acetate (3×200 ml). The organic extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethylacetate: hexane (1:1) to afford 3-chloro-4-{(E)-2-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]vinyl}bicyclo[4.2.1]non-3-en-9-one (14.96 g, 94%). δH (400 MHz, CDCl3) 1.59-1.71 (2H, m), 1.76-1.83 (1H, m), 2.02-2.10 (2H, m), 2.38-2.51 (2H, m), 2.58-2.62 (1H, m), 2.87-2.90 (1H, m), 2.96-3.01 (1H, m), 3.84 (3H, s), 6.49 (1H, s), 6.64 (1H, d, J 16.5), 7.14-7.18 (2H, m), 7.38-7.42 (2H, m), 7.54 (1H, d, J 16.5).
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[CH:3]1[CH:8]2[C:6](C(OC)=O)([C:7]2([CH3:10])[CH3:9])[C:5](=[O:15])[O:4]1.[Cl-].[Li+]>CN(C)P(=O)(N(C)C)N(C)C.CCOCC>[Cl:17][C:2]([Cl:1])([Cl:16])[CH:3]1[CH:8]2[CH:6]([C:7]2([CH3:10])[CH3:9])[C:5](=[O:15])[O:4]1
Reactant: COC(=O)C12C(=O)OC(C(Cl)(Cl)Cl)C1C2(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC1(C)C2C(=O)OC(C(Cl)(Cl)Cl)C21
Yield: 27.9 %

Procedure:
To a solution of methyl 4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (1.52 g, 0.005 mole) in 10 ml of hexamethylphosphoric triamide was added lithium chloride (0.42 g, 0.010 mole). After heating at 75° for two hours, the cooled reaction mixture was diluted with ether. The ethereal solution was washed with water, dried over magnesium sulfate, and the ether was removed by evaporation, yielding a residue which was purified by column chromatography on silica gel using 9/1 n-hexane/ethylacetate as the eluent to give 4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane (0.34 g, 28% yield) as an oil.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH:13]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][CH:15]=[CH2:16]>C1(C)C=CC=CC=1.C1(C=CC(O)=CC=1)O>[CH2:20]([O:19][C:18]([NH:17][CH:13]1[CH:2]2[CH:3]([C:4](=[O:11])[C:5]3[C:10]([C:1]2=[O:12])=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:16][CH:15]=[CH:14]1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: C=CC=CNC(=O)OCc1ccccc1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: O=C(NC1C=CCC2C(=O)c3ccccc3C(=O)C12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
3.16 g of 1,4-naphthoquinone, 4.48 g of benzyl N-butadienylcarbamate and 50 mg of hydroquinone were dissolved in 100 ml of toluene and stirred at 25° C. for 8 hours and the solution was then concentrated in vacuo. The residue was taken up in chloroform, the solution was filtered through silica gel and the filtrate was concentrated in vacuo. 7.12 g of 1-benzyloxycarbonylamino-1,4,4a,9a-tetrahydroanthraquinone (93% pure; 92% of theory) were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[OH:20][CH:21]([CH2:34][OH:35])[CH2:22][NH:23][C:24]1[CH:25]=[C:26]([C:30](=[N:32]O)[NH2:31])[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:32]=[C:30]([C:26]3[CH:25]=[C:24]([NH:23][CH2:22][CH:21]([OH:20])[CH2:34][OH:35])[CH:29]=[CH:28][CH:27]=3)[N:31]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: NC(=NO)c1cccc(NCC(O)CO)c1
Product: COCc1cc(-c2nc(-c3cccc(NCC(O)CO)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following the general procedure 4 starting from Intermediate 3 and Intermediate 26. It was purified by preparative HPLC affording the product as a brown powder. LC/MS (Method B): 444.4 (M−H)−, 446.3 (M+H)+. HPLC (Method A) Rt 4.71 min (Purity: 99.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=O.[NH4+].[OH-]>ClCCl>[CH3:9][C@@H:8]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]([C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[CH3:1])=[N:6][CH2:7]1
Reactant: Cc1ccccc1C(=O)NC[C@H](C)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccccc1C1=NC[C@H](C)c2ccccc21
Temperature: 140 °C
Reaction time: 1 h

Procedure:
(R)-2-Methyl-N-(2-phenyl-propyl)-benzamide (2.1 g; 8.29 mmol) is added all at once to polyphosphoric acid (pre-heated to 140°) and the resulting mixture is stirred at 140° C. for 1 hour. The mixture is poured onto ice, made basic with concentrated NH4OH, and diluted with dichloromethane (100 mL). The phases are separated, and the aqueous phase extracted with dichloromethane (3×70 mL). The combined organics are washed with water (1×50 mL) and brine (1×50 mL), dried over magnesium sulfate, and evaporated in vacuo. The residue is purified by flash chromatography over silica gel (eluting with ether) to give the product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(N(C(C)C)CC)(C)C.CN(C(O[N:44]1[N:52]=[N:51][C:46]2[CH:47]=[CH:48]C=N[C:45]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=CN=NC=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:51][C:46]1[CH:47]=[CH:48][N:52]=[N:44][CH:45]=1)=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccnnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnnc1)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 67; 90 mg, 0.24 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.48 mmol), HATU (164 mg, 0.43 mmol) and 4-aminopyridazine (26.8 mg, 0.29 mmol). The solution was stirred for 2 hours and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, Isolute, 1:1 ethyl acetate/cyclohexane) to give the title compound as a white solid. 71 mg.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[C:37]([NH2:44])=[C:36]([Cl:45])[CH:35]=3)[C:19](=[O:32])[N:20]3[CH2:25][CH2:24][N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH:57]([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59]>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:41])([F:43])[F:42])[C:37]([NH2:44])=[C:36]([Cl:45])[CH:35]=3)[C:19]([N:20]3[CH2:21][CH2:22][N:23]([CH:26]4[CH2:31][CH2:30][N:29]([CH:57]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH3:63])[CH2:28][CH2:27]4)[CH2:24][CH2:25]3)=[O:32])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1
Reactant: CCOC(=O)C(C)Br
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 140 mg (0.20 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 60.8 mg (0.44 mmol) K2CO3 and 29 μL (0.22 mmol) ethyl 2-bromopropionate in 1.8 mL DMF was shaken for 2 h at 50° C. The reaction mixture was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:6]=1[C:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=1)[CH2:3][CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>C(Cl)Cl.[Zn](N=[N+]=[N-])N=[N+]=[N-]>[OH:1][C@H:2]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:6]=1[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH:14]=1)[CH2:3][CH3:4]
Reactant: CC[C@@H](O)c1cc(C)c(C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [N-]=[N+]=N[Zn]N=[N+]=[N-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@H](O)c1cc(C)c(C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropylazidocarboxylate (2.96 mL, 15.1 mmol) was added dropwise to a stirred mixture of alcohol 109 (1.3 g, 3.76 mmol), Zn(N3)2.2Py (prepared according to the method described by Viaud, M-C; Rollin, P. in Synthesis, 1990,130), triphenylphosphine (3.95 g, 15.1 mmol) and imidazole (1.03 g, 15.1 mmol) in DCM (100 mL) at approximately 0° C. After the addition, the resulting mixture was allowed to warm to ambient temperature and stirred vigorously for 18 h. The reaction mixture was filtered through a short column of silica gel eluted with the appropriate volume of DCM to remove excess salts and polar byproducts. The filtrate was concentrated in vacuo and the crude residue purified by flash chromatography on silica gel (gradient elution; 0%-20% EtOAc/hexanes as eluent) to afford azide 110 as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH2:19][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:17])[C:15]=4[CH:16]=[C:8]3[C:6]=2[N:7]=1
Reactant: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Yield: 86.2 %

Procedure:
A solution of 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (2 g, 7.6 mmol) and Cs2CO3 (7.46 g, 22.89 mmol) in DMF (100 mL) was stirred at 100° C. (internal temperature) for 15 min, and then chloroiodomethane (2.85 g, 15.3 mmol) in DMF (2 mL) was added dropwise. After the reaction was completed, the mixture was filtered and concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EA=10:1) to provide 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (1.8 g, yield: 86.1%). 1H-NMR (DMSO-d6, 400 MHz) δ 7.64 (d, J=8.8 Hz, 1H), 7.39˜7.46 (m, 2H), 7.21˜7.25 (m, 1H), 7.06 (s, 1H), 6.88˜6.92 (m, 1H), 6.18 (s, 2H). MS (M+H)+: 275/277.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]([O:14][C:15](=[O:18])[CH2:16]Br)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C.Cl.CCOC(C)=O>C1COCC1.O>[C:10]([O:14][C:15](=[O:18])[CH2:16][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cc(O)ccc1S
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(O)ccc1SCC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of 10 g (71 mmol) of 4-mercapto-3-methyl-phenol (DE 2101359) and 10.5 ml (1 eq., 71 mmol) of bromo-acetic acid tert-butyl ester in 250 ml of THF was treated at room temperature with 12.2 ml (1 eq., 71 mmol) of N-ethyldiisopropylamine. The suspension was heated at reflux for 1 h, cooled to ambient temperature, and treated with water. The reaction mixture was then poured onto 0.1 M HCl/AcOEt, the organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Purification by flash chromatography (SiO2, heptane/toluene/AcOEt=10/1/1) afforded finally 5.6 g of the title product as white solid.
Reaction SMILES: [C:1]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([O:3][CH2:4][CH3:5])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:13]([O:12][C:8]1[CH2:9][CH2:10][CH2:11][C:7]=1[CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 20, treatment of 2-(carbethoxymethyl)cyclopentan-1-one (Example 19) with acetic anhydride and p-toluenesulfonic acid monohydrate gives an oil, b.p. 130°-131°C. (7 mm).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:23]=[CH:24][C:14]=23)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[C:18]([NH2:19])=[CH:17][N:16]=[C:15]3[N:22]([S:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)(=[O:27])=[O:26])[CH:23]=[CH:24][C:14]=23)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Palladium hydroxide (20% wt on carbon, 2.5 g) was added to a solution of trans 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexane carboxylic acid ethyl ester (assumed to be 44.4 mmol) in acetic acid (150 mL) under nitrogen. The reaction was evacuated and purged with hydrogen and the reaction warmed to 50° C. for 8 hours. The reaction vessel was recharged with hydrogen gas and stirred at room temperature for 18 hours. The mixture was then filtered through Celite® and the filtrate concentrated to dryness under vacuum. The resulting residue was partitioned between DCM and sodium hydrogen carbonate (sat. aq.), the organic layer dried with sodium sulphate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting: ethyl acetate) to give 16.2 g (83%) of trans 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanecarboxylic acid ethyl ester as a purple solid. 1H NMR (400 MHz, CDCl3) δ: 8.13 (m, 2H), 7.83 (s, 1H), 7.53 (m, 1H), 7.45 (m, 3H), 6.54 (d, 1H), 4.75 (br s, 1H), 4.14 (q, 2H), 3.68 (m, 1H), 2.65 (br s, 2H), 2.32 (m, 1H), 2.20 (m, 2H), 2.09 (m, 2H), 1.63 (m, 2H), 1.33-1.20 (m, 5H).
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH3:19])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]([CH3:18])[CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[Cl:21][C:22]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:23]=1[O:24][CH2:25][CH:26]1[O:28][CH2:27]1>C(O)(C)(C)C>[Cl:21][C:22]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:23]=1[O:24][CH2:25][CH:26]([OH:28])[CH2:27][NH:1][C:2]([CH3:19])([CH3:20])[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]([CH3:18])[CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:9][CH:10]=1
Reactant: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)N)cc1
Reactant: Clc1ccc(Cl)c(OCC2CO2)c1
Solvent: CC(C)(C)O
Product: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)NCC(O)COc2cc(Cl)ccc2Cl)cc1
Reaction time: 24 h
Yield: 88.4 %

Procedure:
A mixture of 6-[4-(2-amino-2-methylpropylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (3 g), 1-(2,5-dichlorophenoxy)-2,3-epoxypropane (2.4 g) and t-butanol (100 ml) was stirred at 65° to 70° C. for 24 hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 120 g). From the chloroform/methanol (=50/1) eluted portion, 6-[4-[2-[3-(2,5-dichlorophenoxy)-2-hydroxypropylamino]-2-methylpropylamino]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (4.77 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([N:40]1[C:44](=[O:45])[CH:43]=[C:42](Cl)[S:41]1(=[O:48])=[O:47])([CH3:39])([CH3:38])[CH3:37].ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:42]2[S:41](=[O:47])(=[O:48])[N:40]([C:36]([CH3:38])([CH3:37])[CH3:39])[C:44](=[O:45])[CH:43]=2)=[CH:25][CH:26]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 37.3 %

Procedure:
A solution of benzyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (3.33 g, 6.92 mmol), 2-tert-Butyl-5-chloro-1,1-dioxo-1,2-dihydro-1λ6-isothiazol-3-one (1.86 g, 8.31 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.68 g, 0.83 mmol), and potassium carbonate (4.78 g, 0.0346 mol) in 1,4-dioxane (25 mL) were added to a flask with a reflux condenser. The reaction atmosphere was evacuated and purged four times with dry nitrogen. The reaction was heated at 80° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. ethyl acetate extracts were washed with saturated brine and dried over anhyd. sodium sulfate, filtered and concentrated to an oil. The crude was eluted with 10%–30% ethyl acetate in hexanes to give the product (1.4 g, 37%). LCMS found for C28H35N2O7S (M+H)+: m/z=543.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(NC(C)C)(C)C.[Li].[Sn:21](Cl)([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CCCCCC.C1COCC1>[Br:1][C:2]1[S:3][C:4]([Sn:21]([CH3:24])([CH3:23])[CH3:22])=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCc1ccsc1Br
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCc1cc([Sn](C)(C)C)sc1Br
Yield: 78 %

Procedure:
3-hexylthiophene and N-bromosuccinimide (hereinafter, referred to as ‘NBS’) in the same amount were reacted in DMF at room temperature for 15 hours to obtain 2-bromo-3-hexylthiophene (d). 12.4 g (50 mmol) of the 2-bromo-3-hexylthiophene (d) was added to a solution of 28 mL (56 mmol) of lithium diisopropylamine (hereinafter, referred to as ‘LDA’, 2.0M in THF/Hexane) in 40 mL of anhydrous THF at about −80˜−90° C. with stirring. At this temperature, the reaction was allowed to proceed for 20˜30 minutes. A solution of 10.0 g (50 mmol) of Me3SnCl in THF was added to the mixture, and was then stirred at −50° C. for 1 hour. After completion of the reaction, the reaction mixture was extracted with ether and water. The obtained organic layer was concentrated, and distilled to afford the title compound (yield: 78%) as a colorless oil. The 1H-NMR spectrum (CDCl3) of the monomer (3) is shown in FIG. 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.C[CH2:15][O:16]CC.C([Li])CCC.CN(C=O)C>CCCCCC>[N:8]1([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=2)[CH:15]=[O:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCOCC
Reactant: Brc1cncc(N2CCOCC2)c1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1cncc(N2CCOCC2)c1
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 4-(5-bromopyridin-3-yl)morpholine (100 mg, 0.0004 mol) in ether (2 mL, 0.02 mol) cooled at −78° C. was treated with 2.5 M n-butyllithium in hexane (0.2 mL) and was stirred for 1 h. To this mixture was added DMF (0.5 mL, 0.006 mol) dropwise. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 5-morpholin-4-ylnicotinaldehyde (70 mg, 90%) as a crude product. 1H NMR (400 MHz, CDCl3): δ□ 10.1 (s, 1H), 8.0 (s, 2H), 7.6 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H).