Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC#N>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH:18]2[CH2:19][CH2:20][O:16][CH2:17]2)[CH2:12][CH2:11]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1N1CCNCC1
Reactant: O=C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnccc1N1CCN(C2CCOC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round-bottomed flask was charged with 1-(3-nitro-4-pyridyl)piperazine (prepared according to methods similar to the one depicted in Step 1 of Preparation N-1), dihydrofuran-3(2H)-one (98 mg, 1.13 mmol) and acetic acid (129 uL, 2.27 mmol) in MeCN (4 mL). Na(OAc)3BH (482.4 mg, 2.27 mmol) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was partitioned between EtOAC and an aqueous saturated solution of Na2CO3. The organic extracts were dried over MgSO4, and concentrated under reduced pressure to give 1-(3-nitropyridin-4-yl)-4-(tetrahydrofuran-3-yl)piperazine as a yellow solid. MS (ES+) 279.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.Cl.C(O)(=O)C.O>CC1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(C(=C2CCN(Cc3ccccc3)CC2)c2ccc(F)cc2)cc1

Procedure:
A mixture of 40 parts of α,α-bis(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol, 120 parts of a hydrochloric acid solution and 50 parts of acetic acid was stirred and refluxed for 2 hours. The reaction mixture was cooled and water and methylbenzene were added: three layers were obtained. The two supernatant phases were separated and treated with ammonium hydroxide. The organic phase was separated, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 26 parts of 4-[bis(4-fluorophenyl)methylene]-1-(phenylmethyl)piperidine (intermediate 13).
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:24])[CH:10]2[NH:14][C:15](=[O:23])[CH2:16][C:17]2[S:18][C:19](=[O:22])[S:20][CH:21]=2)[C:7]=1[C:25]([OH:27])=[O:26])(=O)C.C(=O)(O)[O-].[Na+].[S-][C:34]#[N:35].[K+].P(=O)(O)(O)O>O.C(C(C)=O)C(C)C.N1C=CC=CC=1>[C:25]([C:7]1[N:8]2[CH:11]([S:12][CH2:13][C:6]=1[CH2:5][N+:35]1[CH:34]=[CH:25][CH:7]=[CH:6][CH:5]=1)[CH:10]([NH:14][C:15](=[O:23])[CH2:16][C:17]1[S:18][C:19](=[O:22])[S:20][CH:21]=1)[C:9]2=[O:24])([O-:27])=[O:26]
Reactant: N#C[S-]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C(Cc1csc(=O)s1)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CSC12
Temperature: 60 °C
Yield: 101.9 %

Procedure:
Water (50 cc.) and pyridine (8.3 cc.) are added to 3-acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene (22 g.), sodium bicarbonate (4.35 g.) and potassium thiocyanate (99.5 g.). After stirring, a syrupy homogeneous medium is obtained, the pH of which is adjusted to 6.5 by adding concentrated phosphoric acid. The mixture is heated to 60° C. for 5 hours. After cooling, it is diluted with distilled water (350 cc.) and washed three times with chloroform (a total of 300 cc.). The last traces of chloroform are removed from the aqueous phase under reduced pressure (20 mm Hg), and this phase is then treated with decolourising charcoal, filtered over "Supercel" and cooled with an ice-water bath. It is acidified to pH= 2 by adding 4 N hydrochloric acid whilst maintaining the temperature below 5° C. After precipitation, the mixture is stirred for 1 hour whilst continuing to cool it with an ice-water bath, and is then washed twice by decanting, using iced water (one liter). The precipitate is isolated by filtration and washed three times with iced water (a total of 300 cc.). The moist solid obtained is suspended in water (100 cc.) and a 25% solution of Amberlite LA 2 in methyl isobutyl ketone (100 cc.) is added. The mixture is stirred until the solid has completely dissolved and the organic phase is then decanted and discarded. The aqueous phase is extracted twice with a 25% Amberlite LA 2 solution in methylisobutyl ketone (a total of 150 cc.), then with ethyl acetate (100 cc.) and finally 3 times with ethyl ether (a total of 300 cc.). The water is evaporated under reduced pressure (20 mm Hg) at 40° C. An oil is obtained which, when triturated in acetone (150 cc.), gives a white solid which is filtered off. The compound obtained is washed three times with acetone (a total of 150 cc.) and then dried under reduced pressure (0.5 mm Hg) to give 2-carboxylato-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-3-(1-pyridinio-methyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (11.7 g.).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:14][C:15]2[N:16]([CH3:21])[N:17]=[C:18]([CH3:20])[CH:19]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:21][N:16]1[C:15]([NH:14][C:7]2[C:6]([CH2:4][OH:3])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=2)=[CH:19][C:18]([CH3:20])=[N:17]1
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1cc(C)nn1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc(CO)c(Nc2cc(C)nn2C)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cold (0° C.) solution of 4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester, 16, (2.0 g, 6.5 mmol) in THF (30 mL) is added dropwise lithium aluminum hydride (10.4 mL of IM solution in THF, 10.4 mmol). The reaction is stirred at 0° C. for 5 minutes, then the ice bath is removed and the mixture allowed to stir for 45 minutes at room temperature. The reaction is re-cooled to 0° C., and H2O (0.4 mL) added dropwise to the mixture. After stirring 10 min at 0° C., NaOH solution (0.4 mL of 2N solution) is added dropwise. After stirring an additional 10 min at 0° C., H2O (1.2 mL) is added to the mixture, and the mixture stirred at room temperature for 15 minutes. The resulting mixture dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is purified over silica (5% MeOH//chloroform) to afford 1.0 g of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.22 (s, NH), 7.89 (s, 1H), 6.22 (s, 1H), 4.72 (s, 2H), 3.68 (s, 3H), 2.47 (s, 3H), 2.26 (s, 3H); ESI+ MS: m/z (rel intensity) 266.0 (100, M++H).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)=[O:7]
Reactant: CC(=O)OCC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CO)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Yield: 8.1 %

Procedure:
3-(4-(3(S)-Acetoxyacetamidopyrrolidin-1-yl)-3-fluorophenyl)-5(S)-(3-isoxazolylamino-methyl)oxazolidin-2-one (1051 mg, 0.23 mM) and potassium carbonate (300 mg, 2.2 mM) were stirred at ambient temperature under nitrogen in methanol (20 ml) for 20 minutes. The mixture was evaporated to dryness and triturated with water (10 ml) to gave the desired product (77 mg).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:9]=[C:8](I)[CH:7]=[CH:6][N:5]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([O-:13])=[O:12].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:3][C:4]1[CH:9]=[C:8]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Clc1cc(I)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(Nc2ccnc(Cl)c2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a degassed (15 min, N2) suspension of 2-chloro-4-iodopyridine (3.0 g, 12.53 mmol), 3-nitroaniline (1.82 g, 13.18 mmol), BINAP (0.39 g, 0.626 mmol) and Cs2CO3 (8.16 g, 25.04 mmol) in toluene (72 mL) was added Pd(OAc)2 (0.084 g, 0.374 mmol). The reaction tube was sealed and the mixture stirred at 90° C. for 18 h. The mixture was cooled to rt and filtered, washing with EtOAc. The orange/yellow solid collected was washed with CH2Cl2 until all the product washed through into the filtrate. The filtrate was concentrated to afford 2-Chloro-N-(3-nitrophenyl)pyridine-4-amine as a bright yellow solid. Additional product was collected from the solid collected upon concentration of the previous filtrate, after washing with CH2Cl2. No further purification. Total amount of product collected was 2.85 g (91% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution (400 mL) of 1-(2,5-dihydroxyphenyl)ethanone (25.0 g) in acetonitrile were added benzylbromide (19.6 mL) and potassium carbonate (25.0 g) at room temperature, and the mixture was heated under reflux for 2 hr. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. Saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a solid. The obtained solid was washed with ethanol-isopropyl ether to give the title object compound (31.0 g, 80%) as a yellow-green solid.
Reaction SMILES: FC(F)(F)CO[C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[C:12]([S:14]([NH:17][C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])(=[O:16])=[O:15])[N:13]=[C:7]2[N:6]=1.[CH3:28][NH:29][CH3:30].Cl>O>[CH3:28][N:29]([CH3:30])[C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[C:12]([S:14]([NH:17][C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])(=[O:16])=[O:15])[N:13]=[C:7]2[N:6]=1
Reactant: CNC
Reactant: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc2nc(OCC(F)(F)F)ccn2n1
Agent: Cl
Solvent: O
Product: CN(C)c1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
The starting 5-(2,2,2-trifluoroethoxy)-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (1.5 g, 3.4 mmol) was dissolved in 5 ml (44 mmol) of 50% aqueous dimethylamine. After stirring for 48 hours at room temperature the solution was diluted with water and acidified with 6N aqueous HCl. The solid which separated was collected by filtration and treated with 0.5N aqueous NaOH and filtered to remove insoluble material. The filtrate was acidified to precipitate a solid. The solid was collected and dried to yield 1.0 g (60%) of the desired product as a solid, mp >310° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=O)=[N:5][N:4]=1.C(N(CC)CC)C.O>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[S:7][C:6]([C:8]#[N:10])=[N:5][N:4]=1
Reactant: CSc1nnc(C(N)=O)s1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CSc1nnc(C#N)s1

Procedure:
350 ml tetrahydrofuran were added dropwise upon stirring and cooling at a temperature between 0° and 5° C. to a solution of 20 ml titanium tetrachloride in 50 ml carbon tetrachloride. There were then added at first in batches 15.3 g of 5-methylthio-1,3,4-thiadiazole-2-carboxamide as obtained in Example 11, and thereafter within a period of 1 hour 50 ml triethylamine which had been taken up in 50 ml tetrahydrofuran. After addition of 50 ml water the reaction mixture was extracted with chloroform. The extract was dried on magnesium sulfate and the solvent was removed in a vacuum. The residue was taken up in acetic acid ethylester and filtrated off from the insoluble residue. The ester phase was then treated with activated carbon and finally concentrated to dryness in a vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.O.[NH2:15][NH2:16]>C(O)C>[Cl:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][C:7]([Cl:13])([NH:15][NH2:16])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Clc1ccc2nc(Cl)c(Cl)nc2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC1(Cl)C=Cc2nc(Cl)cnc2C1

Procedure:
A mixture consisting of 23 g. (0.10 mole) of 2,3,6-trichloroquinoxaline and 11 g. (0.22 mole) of hydrazine hydrate in 500 ml. of ethanol was stirred at room temperature (~20° C.) overnight (~16 hours). The precipitate which formed was separated by filtration and washed with ethanol to ultimately afford 22.2 g. (97%) of pure 2,6-dichloro-3-hydrazinoquinoxaline, m.p. <250° C. Mass Spectrum: m/e, 228 (P).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.Cl.[F:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[NH:35][C:34](=[O:37])[C:33]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[CH:32]2.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([N:41]3[CH2:42][CH2:43][CH:38]([C:33]4[C:34](=[O:37])[NH:35][C:36]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][C:27]=5[F:26])[CH2:39][CH2:40]3)=[O:19])[CH2:15][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2CN(CC2CC2)C1=O
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2CN(CC2CC2)C1=O)N1CCC(c2cc3cccc(F)c3[nH]c2=O)CC1
Yield: 56 %

Procedure:
((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-acetic acid (90 mg, 0.23 mmol) and 8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (80 mg, 0.28 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 56% yield. High resolution MS m/e (M+H)+=620.1665.
Reaction SMILES: I[Si](C)(C)C.C(OC([NH:16][C@@H:17]([CH3:46])[CH2:18][NH:19][C:20]1[N:21]([CH2:42][C:43]#[C:44][CH3:45])[C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[N:39]=[C:38]([CH3:40])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[N:25]=[CH:24][C:23]=2[N:41]=1)=O)C1C=CC=CC=1.[CH3:47]O>ClCCl>[NH2:16][C@@H:17]([CH3:46])[CH2:18][N:19]([C:20]1[N:21]([CH2:42][C:43]#[C:44][CH3:45])[C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[N:39]=[C:38]([CH3:40])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[N:25]=[CH:24][C:23]=2[N:41]=1)[CH3:47]
Reactant: CC#CCn1c(NC[C@H](C)NC(=O)OCc2ccccc2)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Reactant: CO
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CC#CCn1c(N(C)C[C@H](C)N)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 μl iodotrimethylsilane are added to a solution of 130 mg (S)-2-[(2-benzyloxycarbonylamino-prop-1-yl)amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 3 ml dichloromethane. After stirring at ambient temperature for 1 and 3 h, a further 100 μl of iodotrimethylsilane are added on each occasion. The solution is stirred for a further 4 h at ambient temperature and then combined with 5 ml of methanol and evaporated down. Then 1 M hydrochloric acid is added and the aqueous phase is washed twice with dichloromethane. The aqueous phase is made alkaline with sodium carbonate and extracted three times with dichloromethane. The organic extracts are dried over sodium sulphate, the solvent is removed and the residue is purified through silica gel (dichloromethane/methanol 1:0->3:1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:17])[CH2:15][NH2:16])[CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:22]=1[C:23](O)=[O:24].C(N=C=NC(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(O)(C)(C)C>[NH2:20][C:21]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:22]=1[C:23]([NH:16][CH2:15][C:14]([NH:13][CH2:12][CH:9]1[CH2:10][CH2:11][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=2)[CH2:8]1)=[O:17])=[O:24]
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 1-(4-chlorobenzyl)-3-{(glycylamino)methyl}pyrrolidine (0.050 mmol) in CHCl3 (1.35 mL) and tert-butanol (0.05 mL) was treated with 2-amino-4,5-difluorobenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol), and HOBt (0.060 mmol). The reaction mixture was stirred at room temperature for 19 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH/CHCl3 1:1 (10 mL) and CH3OH (10 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 3-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compound No. 1506) (22.0 mg, quant): The purity was determined by RPLC/MS (92%); ESI/MS m/e 437 (C21H23ClF2N4O2).
Reaction SMILES: CO[C:3](=[O:26])[C:4]([OH:25])=[CH:5][C:6](=[O:24])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:35][N:36](C)[C:37](C1CN(C)C(=O)C=1O)=O>>[Cl:23][C:18]1[CH:17]=[C:16]([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:6]([C:5]2[CH2:35][N:36]([CH3:37])[C:3](=[O:26])[C:4]=2[OH:25])=[O:24])[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)c1ccc(Cl)c(Cl)c1
Agent: C=O
Agent: CN
Product: CN1CC(C(=O)N(Cc2ccc(F)cc2)c2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 68 %

Procedure:
3-[(3,4-Dichlorophenyl)-(4-fluorobenzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 78-B) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (68% yield); mp 195° C., dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.9 (3H, s, NCH3), 3.03 (2H, s, NCH2), 4.90 (2H, s, NCH2), 6.87 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.02 (2H, m, aromatics), 7.2 (2H, m, aromatics), 7.22 (1H, d, J=2.5 Hz, aromatic), 7.49 (1H, d, J=8.6 Hz, aromatic), 11.9 (1H, broad, OH). Anal. calcd for C19H15Cl2FN2O3: C, 55.76; H, 3.69; N, 6.84. Found: C, 55.53; H, 3.61; N, 6.75.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.ClCCl.[Cl:16][C:17]1[C:18]([CH:24]([C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])[S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)(=[O:27])=[O:26])=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1>CN(C)C1C=CN=CC=1.CCCCCC>[Cl:16][C:17]1[C:18]([CH:24]([C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])[S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)(=[O:26])=[O:27])=[CH:19][C:20]([N:23]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[N:21][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)c(F)c2)c(Cl)cn1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)c(F)c2)c(Cl)cn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
Under a nitrogen atmosphere, methanesulfonyl chloride (0.034 ml, 0.44 mmol), triethylamine (0.062 ml, 0.44 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol) were added to a dichloromethane (3 ml) solution of [5-chloro-4-[(2,5-difluorophenyl)(3,4-difluorophenylsulfonyl)methyl]pyridin-2-yl]amine (63 mg, 0.15 mmol) at 0° C. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (73 mg, 0.12 mmol, 85%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:29]5[CH:30]=[N:31][N:32]([CH2:34][C:35]6[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=6)[CH:33]=5)=[CH:27][N:26](C(OC(C)(C)C)=O)[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:56]>C(OCC)C>[ClH:56].[F:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][N:32]1[CH:33]=[C:29]([C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[C:15]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:16]=4)[CH:21]=3)[NH:26][CH:27]=2)[CH:30]=[N:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(Cc5cccc(F)c5)c3)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1N1CCNCC1
Yield: 57 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(methylsulfonamido)phenyl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (27 mg, mmol) was deprotected in methanol/HCl in diethyl ether (3/1 ml) to afford 12 mg (57% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 9.01-9.00 (d, 1H), 8.71-8.70 (d, 1H), 8.41 (s, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.87-7.86 (d, 1H), 7.66-7.63 (dd, 1H), 7.49-7.46 (d, 1H), 7.40-7.34 (m, 1H), 7.16-7.13 (m, 1H), 7.07-7.02 (m, 2H), 5.47 (s, 2H), 3.50-3.46 (m, 4H), 3.26-3.23 (m, 7H). MS: m/z=546.2 (M+1), HPLC: 98.49% in method B.