Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([Cl:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[ClH:40].[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])(=[O:39])=[O:38])=[CH:35][CH:36]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
(R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) was suspended in DCM (6 ml) and treated with triethylamine (99 μl, 1.35 mmol). Then 4-methoxybenzene-1-sulfonyl chloride (112 mg, 0.54 mmol) was added, and the reaction was stirred at RT for 3 hours. Solvent was evaporated, and the crude was dissolved in EtOAc and washed with water and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was triturated with Et2O to obtain (R)-quinuclidin-3-yl 2-(4-methoxyphenylsulfonamido)-2-phenylacetate hydrochloride (105 mg; 50% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[N:13]([CH3:14])[CH3:12])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)C1CCc2ccc(Br)cc21
Yield: 80 %

Procedure:
(Method 2): 6-Bromo-indan-1-one (0.58 mmol) was dissolved in MeOH. Dimethyl-amine (3.7 mmol), acetic acid (0.059 mmol) and sodium cyanoborohydride (1.74 mmol) were added under argon atmosphere. The suspension was refluxed overnight and then cooled. The crude was evaporated to dryness and then suspended in water. The product was extracted with CH2Cl2 and washed with water. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product (6-bromo-indan-1-yl)-dimethyl-amine (80% conversion LC-MS). The crude product was used in the next synthetic step (Suzuki coupling), without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:17][CH3:18])[CH:3]=1.ClCCl>N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]([C:14]3[CH:15]=[CH:16][C:11]([CH3:8])=[CH:12][CH:13]=3)[C:6]=2[CH:5]=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: COc1cc(Br)c2nc(-c3ccccc3)[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Br)c2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2c1

Procedure:
2.5 g of 4-bromo-6-methoxy-2-phenyl-1H-benzimidazole and 2.24 g of 4-(methylbenzene)boronic acid were stirred with 1.5 g of anhydrous copper(II) acetate and about 3 g of molecular sieve in 35 ml of pyridine for 7 hours at 100° C. After dichloromethane and Celite were added, it was concentrated by evaporation and chromatographed on silica gel with a hexane/ethyl acetate mixture.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([CH3:17])[CH:9]=1.CN(C=O)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:14])=[C:10]([CH3:17])[CH:9]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.6 ml (47 mmol) oxalyl chloride in 30 ml dichloromethane is added dropwise to a iced-cooled solution of 5.21 g (23.5 mmol) 4-bromo-2-methyl-benzoic acid and 0.0087 ml DMF in 100 ml CH2Cl2. After complete addition, the cooling bath is removed and stirring maintained for 2 h at RT. The solvent is evaporated to dryness and the residue is dried in vacuo and dissolved in 100 ml dichloromethane and 8.21 ml N-ethyl-diisopropylamine is added. To this solution 2.5 ml (28 mmol) morpholine is added slowly. Stirring is continued for 0.5 h, then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford the title compound which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:13]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH2:11])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
A similar procedure starting from 5-chloroisatoic anhydride and 4-bromoaniline gave N-(4-bromophenyl)-2-amino-5-chlorobenzamide which gave the expected NMR, MS, and elemental analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3O)[N:9]=1)[CH3:2].[CH3:29][S:30]([CH2:33][CH2:34][NH2:35])(=[O:32])=[O:31]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3[NH:35][CH2:34][CH2:33][S:30]([CH3:29])(=[O:32])=[O:31])[N:9]=1)[CH3:2]
Reactant: CS(=O)(=O)CCN
Reactant: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4O)no2)cc1OCC
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4NCCS(C)(=O)=O)no2)cc1OCC

Procedure:
Prepared using General Procedure 14 from 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol 60 and 2-(methylsulfonyl)ethanamine.
Reaction SMILES: [C:1]([C:4](=[CH:10][CH2:11][CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:4](=[CH:10][CH:11]([Br:13])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC=C(C(C)=O)C(=O)OCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(=CC(C)Br)C(C)=O
Temperature: 25 °C
Yield: 98.2 %

Procedure:
A mixture of 8.06 g (0.047 mole) ethyl 2-acetyl-2-pentenoate and 8.43 g (0.047 mole) N-bromosuccinimide in 50 ml of carbon tetrachloride was heated at reflux for 15 minutes. The mixture was quickly cooled to room temperature, and the succinimide removed by filtration. Concentration of the solution in vacuo afforded 11.5 g (98%) of ethyl 2-acetyl-4-bromo-2-pentenoate.
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C([O-])(O)=O.[Na+]>C1COCC1>[CH:1]([N:4]1[C:8](=[O:9])[C:7]([CH3:16])([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:6]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NC(C)(c2ccccc2)C1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)N(C(C)C)C(=O)C1(C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of (t)-3-isopropyl-5-methyl-5-phenyl imidazoline-2,4-dione from Step A (1.0 g, 4.3 mmol) in THF (50 mL) at 0° C. was added NaH (220 mg of a 60% dispersion in oil, 5.6 mmol). After 5 min, methyl bromoacetate (0.69 g, 4.52 mmol) was added and the mixture was stirred for 1 h. The reaction mixture was warmed to ambient temperature and then poured into saturated aqueous NaHCO3 (200 mL) and extracted with EtOAc (2×250 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 50:50, to give racemic title compound. The enantiomers were resolved by HPLC, utilizing a ChiralPak OD column and eluting with hexane:EtOH 60:40. The first major peak to elute was methyl (3-isopropyl-5-methyl-2,4-dioxo-5-phenylimidazolin-1-yl)acetate, isomer A, and the second major peak to elute was methyl (3-isopropyl-5-methyl-2,4-dioxo-5-phenylimidazolin-1-yl)acetate, isomer B, the title compound. MS: m/z=305 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:13][C:12]3=[O:29])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH2:33][C:3]1=2.[ClH:41]>CO.CCOCC>[ClH:41].[ClH:41].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:29])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:30][NH:31][CH2:32][CH2:33][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cc5)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 38 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)benzyloxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (73 mg, 0.13 mmol) was dissolved in MeOH (0.5 mL) and 2 N HCl in Et2O (3 mL) was added. The reaction was allowed to proceed for 3 h. The mixture was concentrated and purified by preparative HPLC. Converion to the HCl salt (2 NHCl/Et2O) provided the title compound (26 mg, 38%) as a yellow solid: mp 311-315° C.; 1H NMR (500 MHz, CD3OD) δ 7.77 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.2 Hz, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.50 (s, 1H), 7.09 (dd, J=8.3, 1.8 Hz, 1H), 6.38 (dd, J=7.6, 2.7 Hz, 1H), 6.17 (d, J=2.7 Hz, 1H), 5.33 (s, 2H), 4.51 (s, 2H), 3.77 (s, 3H), 3.71 (t, J=6.2 Hz, 2H), 3.24 (t, J=6.1 Hz, 2H); ESI MS m/z 454 [M+H]+; HPLC (Method B)>99% (AUC), tR=14.2 min.
Reaction SMILES: [CH3:1][C:2]1([CH2:36][CH3:37])[CH:7]([CH3:8])[CH:6]([O:9][C:10](=[O:32])[CH:11]([CH2:28][CH2:29][CH2:30][CH3:31])[C:12]([O:14][CH:15]2[CH2:20][C:19]([CH3:23])([CH2:21][CH3:22])[NH:18][C:17]([CH3:26])([CH2:24][CH3:25])[CH:16]2[CH3:27])=[O:13])[CH2:5][C:4]([CH3:35])([CH2:33][CH3:34])[NH:3]1.[C:38]([C:42]1[CH:43]=[C:44]([CH:49]=[C:50]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:51]=1[OH:52])[CH2:45]N(C)C)([CH3:41])([CH3:40])[CH3:39].[NH2-].[Li+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:26][C:17]1([CH2:24][CH3:25])[CH:16]([CH3:27])[CH:15]([O:14][C:12](=[O:13])[C:11]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:45][C:44]2[CH:49]=[C:50]([C:53]([CH3:54])([CH3:56])[CH3:55])[C:51]([OH:52])=[C:42]([C:38]([CH3:40])([CH3:39])[CH3:41])[CH:43]=2)[C:10]([O:9][CH:6]2[CH2:5][C:4]([CH3:35])([CH2:33][CH3:34])[NH:3][C:2]([CH3:1])([CH2:36][CH3:37])[CH:7]2[CH3:8])=[O:32])[CH2:20][C:19]([CH3:23])([CH2:21][CH3:22])[NH:18]1
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCC(C(=O)OC1CC(C)(CC)NC(C)(CC)C1C)C(=O)OC1CC(C)(CC)NC(C)(CC)C1C
Agent: [Li+]
Agent: [NH2-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCCC(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)(C(=O)OC1CC(C)(CC)NC(C)(CC)C1C)C(=O)OC1CC(C)(CC)NC(C)(CC)C1C

Procedure:
26.2 g (0.05 mole) of butylmalonic acid-bis(2,3,6-trimethyl-2,6-diethyl-4-piperidinyl)ester and 13.2 g (0.05 mole) of N-(3,5-di-tert.butyl-4-hydroxybenzyl) dimethylamine are dissolved in 200 ml of toluene. After the addition of 0.25 g of lithium amide, the mixture is refluxed for 4 hours. After cooling, the mixture is neutralised with 1.5 ml of 1% acetic acid, and the organic phase is repeatedly washed with water. After drying over Na2SO4, the solution is concentrated in vacuo. As residue there is obtained butyl-(3,5-di-tert.butyl-4-hydroxybenzyl)malonic acid-bis(2,3,6-trimethyl-2,6-diethyl-4-piperidinyl) ester in the form of viscous oil (Compound No. 32).
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1.[C-:19]#[N:20].[Na+]>CN(C)C=O>[C:19]([CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1)#[N:20]
Reactant: O=C1Nc2ccccc2Sc2cc(CBr)ccc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc2c(c1)Sc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolve 6.4 gm. of the bromide of Step B in 75 cc. of dimethylformamide and add 2.95 gm. of sodium cyanide. Stir the mixture at room temperature for 1.5 hours. Dilute with 600 cc. of water and extract three times with ether. Wash the combined organics with water, dry and strip to a solid residue. Triturate in hexane and recover the solid by filtration.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][C:7]2[C:8]([N:15]=1)=[N:9][C:10]([CH3:14])=[CH:11][C:12]=2[CH3:13])[CH3:4].[CH2:16]([O:18][C:19]([C:21]1([C:26]2[S:27][C:28]([CH2:31]Cl)=[CH:29][CH:30]=2)[CH2:25][CH:24]=[CH:23][CH2:22]1)=[O:20])[CH3:17].[Na+].[Cl-]>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([C:26]2[S:27][C:28]([CH2:31][N:15]3[C:8]4=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]4[N:6]=[C:5]3[CH2:3][CH3:4])=[CH:29][CH:30]=2)[CH2:25][CH:24]=[CH:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(c2ccc(CCl)s2)CC=CC1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)s2)CC=CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of petroleum ether washed NaH (1.1 equiv.) in DMF was added 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (7) (1.1 equiv.). The reaction mixture was stirred for 15 minutes at ambient temperature and then the product of Step 4, above (5) (1 equiv.), dissolved in DMF, was cannulated into the mixture of the anion in DMF. The reaction mixture was stirred at ambient temperature for 17 hours and was then poured into saturated NaCl solution and extracted 2 times with EtOAc. The combined extracts were dried over MgSO4, filtered and concentrated to dryness. The crude material was chromatographed on silica gel with a gradient elution from 50% EtOAc in hexanes to 60% EtOAc in hexanes to yield the title compound (6).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:13][CH2:12]1)#[N:2]>Cl.O1CCOCC1.CN1CCCC1=O>[C:1]([C:3]1[CH:4]=[C:5]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:13][CH2:12]1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC5CC5)c(C#N)c4)n3)cccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: N#Cc1cc(-c2nc(-c3cccc4c(CCC(=O)O)nccc34)no2)ccc1OCC1CC1
Reaction time: 4.5 h
Yield: 33.1 %

Procedure:
1,1-Dimethylethyl 3-[5-(5-{3-cyano-4-[(cyclopropylmethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoate (D48; 36 mg, 0.072 mmol) was dissolved in 4N HCl in 1,4-dioxane (4 ml) and the mixture was allowed to stand at room temperature for 4.5 h. The solvent was evaporated in vacuo and the residue triturated with dry ether to give a white solid which was dissolved in N-methyl-2-pyrrolidinone (1 ml) and purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)). The solvent was dried under a stream of nitrogen to give the title compound as a white solid (10.5 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[C:17]([NH:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[Cl:30])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13](C)[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].N[C:32]1[CH:33]=[N:34][CH:35]=C[CH:37]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[C:17]([NH:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[Cl:30])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[CH:35]=[N:34][CH:33]=[CH:32][CH:37]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Reactant: Nc1cccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cccnc1)C(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Yield: 104.4 %

Procedure:
A solution of 30 mg (0.06 mmol) of ethyl 2-[2,4-dichloro-5-(2-chloro-4,6-difluorophenylamino) benzoyl]-3-dimethylaminoacrylate and 15 mg (0.16 mmol) of 3-aminopyridine in 2 ml of toluene were heated at 150° C. for 7 hours. Concentration resulted in 33 mg of the desired product, which were employed without further purification in the next stage.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][OH:15].[H-].[Na+]>O1CCOCC1>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][O:15][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CCOc1ccc(N)cn1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) in dioxane (30 mL) at room temperature was added 2-(dimethylamino)ethanol (309 mg, 3.5 mmol) and 60 wt. % NaH (0.15 g, 3.7 mmol) and the reaction mixture was stirred at room temperature until the reaction was complete by LCMS analysis. The reaction mixture was poured onto ice-cold water and the product was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (30 mL), degassed with nitrogen, charged with catalytic 10 wt. % Pd/C (0.3 g) and the reaction mixture was placed under an atmosphere of hydrogen (40 Psi) until the reduction was complete by LCMS analysis. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated to provide the desired product (340 mg, 61%) as a purple solid: ESI MS m/z 182 [C9H15N3O+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(C)(C)CCBr
Reactant: Brc1cccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCn1ncc2c(Br)cccc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
To a solution of 4-bromo-1H-indazole (commercially available from Insight Chemical Solutions Ltd., 826 mg, 4.19 mmol) in DMF (10 ml) at room temperature were added Cs2CO3 (1.37 g, 4.19 mmol) and ethyl 4-bromo-2,2-dimethylbutanoate (D99) (1.40 g, 6.29 mmol) and the resulting mixture was stirred at 80° C. for 24 h then cooled to room temperature and diluted with AcOEt. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [15-25% EtOAc/cyclohexane] gave the title compound (600 mg, 40%) as orange oil. MS (ES) C15H1981BrN2O2 requires 340, found 341 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][O:27][C:26]2=[O:30])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1OCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1OCCN1CCN1CCN(Cc2ccccc2)CC1

Procedure:
744 g of 1-benzyl-piperazine are treated, together with 590 g of powdered potassium carbonate, 10 g of potassium iodide and 5 litres of toluene, with 450 g of 3-(2-chloroethyl)-2 -oxazolidinone and the mixture is heated to reflux for 21 hours. The mixture is cooled, filtered and concentrated under reduced pressure. The residue is distilled under reduced pressure. There is obtained 3-[2-(4-benzyl-1-piperazinyl)-ethyl]-2- oxazolidinone which boils at 225° - 235° C under a pressure of 2- 2.5 mm. The compound is recrystallised from ethyl acetate; melting point 82° - 84° C. The dihydrochloride of melting point 243° - 245° C is obtained by treatment with an excess of hydrochloric acid in ethanol.
Reaction SMILES: CO[C:3](=[O:28])[CH:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][OH:7].ClC1C=C(/C=C/[C:39]([N:41]2CCC(=O)N(C3CCOC3=O)C[CH2:42]2)=O)C=CC=1Cl.N1CCCCC1>CCO>[Cl:26][C:21]1[CH:20]=[C:19](/[CH:18]=[CH:17]/[C:16]([N:11]2[CH2:12][CH2:13][C:14](=[O:15])[N:8]([CH:4]([CH2:5][CH2:6][OH:7])[C:3]([N:41]([CH3:42])[CH3:39])=[O:28])[CH2:9][CH2:10]2)=[O:27])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: O=C1OCCC1N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: COC(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)C(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Yield: 43 %

Procedure:
In analogy to the procedure described in example 3, treatment of (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-4-hydroxy-butyric acid methyl ester (with 50% of the lactone, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxo-tetrahydro-furan-3-yl)-[1,4]diazepan-5-one) (intermediate 6) in EtOH with piperidine for 1.5 days at 60° C. and 2 days at RT gave 43% of the titled compound as light yellow foam. MS: 482.2 (MH+, 2Cl).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.Cl.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.Cl>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:15]3[CH2:16][CH2:17][NH:12][CH2:13][C:14]=3[C:5]=2[CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Product: Brc1ccc2[nH]c3c(c2c1)CNCC3
Temperature: 25 °C
Yield: 101.9 %

Procedure:
To a stirred solution of 4-bromophenylhydrazine hydrochloride (5.0 g, 22.36 mmol) in ethanol (100 mL), piperidin-4-one hydrochloride (1.316 g, 8.5984 mmol) was added and the mixture was heated to reflux. The reflux was maintained for 4 hours, then cooled to room temperature and dry hydrogen chloride gas was passed for 1 hour through the reaction mixture. The mixture was then again heated to reflux and maintained for 2 h. After completion of reaction, ethanol was distilled off under vacuum and the residue was dissolved in water. The aqueous layer was neutralized with 2N sodium hydroxide solution and was extracted in dichloromethane (2×100 mL). The pH of the aqueous layer was then adjusted to 12.0 with 2N sodium hydroxide solution and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude solid was washed with diethyl ether (50 mL) to obtain 8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.2 g, 39.3%) with purity 98.82% by HPLC. 1HNMR (200 MHz, DMSO-d6) δ: 2.7 (t, 2H, CH2), 3.0 (t, 2H, CH2), 3.8 (d, 2H, CH2), 7.05 (d, 1H, Ar—H), 7.2 (d, 1H, Ar—H), 7.45 (s, 1H, Ar—H), 10.97 (bs, 1H, NH). m/e=251 (M++1).