Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[CH:43]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=2)[CH2:48][CH2:47]1)([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C>CC(O)C.C(OCC)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:58][C:55]2[CH:54]=[CH:53][C:52]([N:49]3[CH2:48][CH2:47][N:46]([CH:43]([CH3:45])[CH3:44])[CH2:51][CH2:50]3)=[CH:57][CH:56]=2)=[N:35][CH:34]=1
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Reactant: Brc1ncc(Br)n2ncnc12
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (2 g, 7.20 mmol), 4-(4-isopropyl-piperazin-1-yl)-phenylamine (1.89 g, 8.62 mmol) and N,N-diisopropylethylamine (1.88 mL, 10.8 mmol) in 2-propanol (30 mL) are stirred at 95° C. overnight. The title compound is isolated after trituration with diethyl ether and petroleum ether as a grey solid (2.59 g, 87%).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C[Mg]Br.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.[CH3:23]CN(C(C)C)C(C)C>C(Cl)Cl>[Cl:3][C:2]1[N:1]=[C:8]([CH3:23])[N:7]=[C:5]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Mg]Br
Solvent: ClCCl
Product: COc1ccc(CNc2nc(C)nc(Cl)n2)cc1
Temperature: -10 °C
Reaction time: 4 h

Procedure:
To a solution of cyanuric chloride (3.69 g, 20 mmol) in DCM (100 mL) at −10° C. was added methylmagnesium bromide (20 mL, 60 mmol, 3.0M solution in ether) maintaining the temperature at −10° C. The reaction was stirred for 4 h at −10° C. and then quenched with saturated ammonium chloride solution (20 mL). The organic layer was separated, dried (MgSO4) and filtered. The filtrate was cooled to 0° C. before the addition of 4-methoxybenzylamine (2.74 g, 20 mmol) and DIPEA (2.6 g, 20 mmol) took place. The reaction was stirred for 18 h at r.t. The organic layer was washed with water (2×20 mL), separated, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was crystallised from diisopropyl ether affording the title compound as a pale yellow solid (2.8 g, 51%). δH (CDCl3) 7.23 (d, J 9.2 Hz, 2H), 6.85 (d, J 9.2 Hz, 2H), 5.62 (br s, 1H), 4.56 (d, J 8.1 Hz, 2H), 3.79 (s, 3H), 2.38 (s, 3H). LCMS (ES+) 265 (M+H)+, RT 2.80 minutes (Method 5).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH3:14])[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: CNC
Product: CN(C)c1ccc(S(N)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 95 %

Procedure:
A mixture of 6-chloropyridine-3-sulfonamide (5 g, 0.0259 mol) and aqueous dimethylamine (100 ml, 40%) is stirred at rt for 13 h. The mixture is concentrated to ⅕th of its original volume and cooled. The precipitate is collected by filtration, washed with ice-cold water (10 ml) and dried under vacuum to afford 4.5 g (95%) of the title compound as a solid. mp: 133-138° C., LC/MS: (ES+) 201.9.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[C:28](#[N:31])[CH:29]=[CH2:30].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:28](/[CH:29]=[CH:30]/[C:2]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])#[N:31]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1
Reactant: C=CC#N
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(/C=C/C#N)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1
Reaction time: 2 h

Procedure:
A mixture of 0.5 mmol 4-[4-(2-Iodo-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile (Example AG), 6.3 mmol acrylonitrile, 9.0 mmol triethylamine and 0.2 mmol of bis-(triphenylphosphin)-palladium(II)-dichloride in 10 ml dimethylformamide is hold under argon for 2 hours at 80°. The reaction mixture is concentrated. Chromatography (SiO2; cyclohexane/ethyl acetate 9:1) yields the title compound as a slightly yellow solid (105 mg). ). (M+H+: 421.2)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>N1C=CC=CC=1>[S:7]([N:15]1[CH2:16][CH2:17][CH:13]([O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14]1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCNC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Para-toluenesulphonyl chloride (68.8 g) was added, in portions, to a solution of 3-(R,S)-hydroxypyrrolidine (15 g) in dry pyridine (200 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 16 hours. The solution was concentrated in vacuo to approximately half the original volume then partitioned between dichloromethane (500 ml) and water (300 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined dichloromethane extracts were washed with 2M hydrochloric acid (100 ml) and 10% aqueous sodium hydroxide (100 ml) then dried (MgSO4) and concentrated in vacuo to give an oil which was crystallised from dichloromethane/ether to give the title compound as a microcrystalline powder, yield 28.3 g, m.p. 119°-121° C.
Reaction SMILES: C[Mg]Br.C([O:6][CH2:7][CH3:8])C.C(N(CC)CC)C.C(OC(=O)[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][C:26]=1[CH3:27])[OH:22])C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[OH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:20]=1[C:7](=[O:6])[CH3:8]
Reactant: CCOCC
Reactant: CCOC(=O)c1c(C)cccc1O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)c1c(C)cccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
A solution of methyl magnesium bromide 3M in diethyl ether (18.5 mL, 55.5 mmol) and triethylamine (6.0 mL, 44.4 mmol) in anhydrous toluene (14 mL) was cooled to 0° C. 6-methylsalicylic acid ethyl ester (2.0 g, 11.1 mmol) in anhydrous toluene (14 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. A saturated solution of ammonium chloride (10 mL) was added and the mixture was filtered over Celite®. The filtrate was diluted with ethyl acetate (20 mL) and water (10 mL) and layers were separated. The organic layer was washed with brine (10 mL), dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 9/1) to provide the desired ketone (26a) (1.21 g, 8.0 mmol, 72%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][C@@H:36]([OH:37])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (1S)-2-amino-1-phenylethanol, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=458.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:32][C@@H:33]1[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1.CO>C(Cl)Cl.CN(C=O)C.CN(C=O)C>[N:35]12[CH2:40][CH2:39][CH:38]([CH2:37][CH2:36]1)[C@@H:33]([NH:32][C:12]([C:10]1[S:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][CH:9]=1)=[O:14])[CH2:34]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2ccccn2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
TEA (50 μL, 0.35 mmol) is added to a suspension of 5-(pyridin-2-yl)-2-thiophenecarboxylic acid (72 mg, 0.35 mmol) in CH2Cl2:DMF (2:1, 1.5 mL). Diphenylchlorophosphate (62 μL, 0.3 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. A solution of (R)-3-aminoquinuclidine (1M, 0.2 mmol, 0.2 mL) in DMF is added and the resulting solution is stirred overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W×2 ion exchange resin (H+ form). The resin is washed with MeOH then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness to yield the desired product (15 mg, 24%). MS for C17H19N3OS (ESI) (M+H)+ m/z 314.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15]1=[O:27]>N1C=CC=CC=1>[CH:1]([O:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15]1=[O:27])=[O:2]
Reactant: O=CO
Reactant: O=C(O)c1nc2ccccc2n(CCO)c1=O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=COCCn1c(=O)c(C(=O)O)nc2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Formic acid (3 ml., 98%) was added dropwise to acetic anhydride (6 ml) which was cooled below 5°. The mixture was heated at 50° for 15 minutes and cooled to below 5° and added slowly to a cold (5°-10°) solution of 3,4-dihydro-4(2-hydroxyethyl)-3-oxo-2-quinoxalinecarboxylic acid (3.2 g) in pyridine (40 ml). The solution was allowed to warm to room temperature, stirred for 6 hours and the pyridine was distilled off under reduced pressure. Hydrochloric acid (50 ml., 2N) was added to the residue and the solid was filtered off and dried, m.p. > 100°. Attempts to recrystallise this compound from dimethylformamide resulted in the loss of the formyl group.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[O:21]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[ClH:1].[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][C:8]=1[CH3:15])[N:5]=[CH:4][C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:2]2[NH:32][C:31]1[CH:30]=[CH:29][C:28]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:34][CH:33]=1)[CH3:14]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Cl
Product: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(Oc2ccccc2)cc1
Product: Cl

Procedure:
In a similar manner to Example 1, a mixture of ethyl 4-chloro-6-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate (1.93 g) and 4-phenoxyaniline (1.33 g) in IMS (40 ml) was boiled under reflux for 2 hours to give ethyl 6-ethoxy-7-methyl-4-(4-phenoxyanilino)-1,8-naphthyridine-3-carboxylate hydrochloride, m.p. 213°-215° C. Active (1/2) at 30 mg/kg.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[OH:11][CH2:12][CH:13]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.N1C=CC=CC=1>ClCCl>[S:2]([O:11][CH2:12][CH:13]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)(=[O:4])(=[O:3])[NH2:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(C(F)(F)F)c1
Solvent: O=CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(COS(N)(=O)=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A quantity of 171 μl (1.97 mmol) of chlorosulphonyl isocyanate was admixed under argon at 0° C., with vigorous stirring, with 74 μl (1.97 mmol) of anhydrous formic acid. Following the addition, the reaction mixture solidified within seconds. A quantity of 2 ml of dichloromethane was added. The reaction mixture was then stirred further at 0° C. for 1 h and then RT for 8 h. Thereafter it was cooled to 0° C. again and admixed with a solution of 400 mg (1.31 mmol) of the compound from Example 59A and 159 μl (1.97 mmol) of pyridine in 2 ml of dichloromethane. The cooling bath was removed and the reaction mixture was stirred overnight at RT. For work-up, 5 ml of water and 5 ml of ethyl acetate were added. After 10 min, the mixture was diluted with 100 ml of ethyl acetate, and washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was purified by preparative HPLC [Method 10]. The product fraction was freed from the solvent on a rotary evaporator. Drying in an HV gave 260 mg (52% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12](=[O:18])[C:13](=O)[CH:14](Br)[CH3:15])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[NH2:8][C:7]1[C:2]2[N:3]([C:14]([CH3:15])=[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:18])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: Nc1cccnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1nc2c(N)cccn2c1C
Yield: 33.8 %

Procedure:
A solution of 2,3-diaminopyridine (6.8 g, 62 mmol) and 3-bromo-2-oxo-butyric acid ethyl ester (13 g, 62 mmol) in 1,2-dimethoxyethane (150 ml) was refluxed for 2 h. Sodium carbonate (6.5 g, 62 mmol) was added and the mixture was refluxed for 2 h. The solids were isolated by filtration and washed with dichloromethane:methanol (10:1). The filtrate and washings were combined the solvents were removed under reduced pressure. The oily residue was washed with petroleum ether and was purified twice by column chromatography on silica gel using 1) dichloromethane:methanol (10:1) 2) ethyl acetate as eluent to give 4.6 g (34%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[N:15]=[C:16]([NH:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[N:17]=[C:18]([NH2:19])[C:13]=3[S:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[N:15]=[C:16]([NH:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[N:17]=[C:18]([NH2:19])[C:13]=3[S:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(Nc2nc(N)c3scc(-c4cccc([N+](=O)[O-])c4)c3n2)cc(OC)c1OC
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1cc(Nc2nc(N)c3scc(-c4cccc(N)c4)c3n2)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
7-(3-Nitrophenyl)-N2-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2,4-diamine (400 mg, 0.88 mmol) was dissolved in ethanol (3.0 mL) and tin(II) chloride dihydrate (996 mg, 4.41 mmol) was added. The reaction mixture was stirred at 80° C. for 2 hours. After removing ethanol by distillation under reduced pressure, ammonia water was slowly added to make pH 5. Sodium carbonate was added to thus prepared yellow precipitate until the pH reached 7. The precipitate was filtered and washed several times with ethyl acetate. Concentration of the filtrate yielded the target compound of Example 11 (320 mg, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1.C(OCC)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:9]([C:10]#[N:11])([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
3,4-Dichlorophenylacetonitrile (10 g, 53.75 mmol) was stirred mechanically in THF (50 mL) at -78° C. and treated dropwise with sodium bis-(trimethylsilyl)amide (108 mL, 1 M; 2 eq.). The reaction slurry was allowed to warm to 20° C. and stirred for 3 hours. The solution was cooled to -78° C. and the slurry was treated with ethyl bromoacetate (12 mL, 107 mmol, 2 eq.). The slurry was again allowed to warm to 20° C. and stirred 18 hours. The slurry was dissolved in ethyl ether and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (400 g) with 20% ethyl acetate to give 15.85 g (82%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1)#[N:2].[ClH:16].[H][H].[CH3:19]CO>[Pd]>[ClH:16].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:19])=[O:13])[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1cc(C#N)cnc1C(F)F
Reactant: CCO
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)c1cc(CN)cnc1C(F)F
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Purge a mixture of methyl 5-cyano-2-(difluoromethyl)pyridine-3-carboxylate (160 g, 707.4 mmol) and EtOH (2 L) with nitrogen and stir 15 min. Add hydrochloric acid (37 wt % aqueous, 273 mL, 3183.2 mmol, 4.5 equiv) and palladium (5% on carbon, 48 g, 22.5 mmol, 0.031 equiv) in EtOH (100 mL), and stir the resulting suspension under 60 psi of hydrogen at room temperature for 70 min. Remove the solids by filtration over diatomaceous earth; wash the solid cake with EtOH (1 L); and concentrate the filtrate under reduced pressure. Repeat this procedure twice; combine the solids; and slurry in Et2O:DCM [10:1, 5.5 L]. Filter the solids and dry the resulting material at 45° C. for 3 hours to give the title compound as a light brown solid (714 g, 96% yield). MS (m/z) 216 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][NH2:24]>C(O)C>[NH:23]([C:17]([C:16]1[CH:21]=[CH:22][C:13]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10]2)=[CH:14][CH:15]=1)=[O:18])[NH2:24]
Reactant: COC(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)NN)cc2)CCC1

Procedure:
To a solution of methyl 4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoate (14.8 g, 48 mmol) in ethanol (100 mL) was added hydrazine (12 mL). The reaction mixture was stirred at reflux for 48 hours. The mixture was concentrated in vacuo and the residue was suspended ether (100 mL) and hexanes (50 mL). The suspension was stirred at room temperature for 2 hours and the solid was filtered off and dried under vacuum. The tert-butyl (1-(4-(hydrazinecarbonyl)phenyl)cyclobutyl)carbamate was obtained as a white solid (13.2 g, 89%). M.p.=146-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.70 (s, 1H), 7.75 (d, J=7.6 Hz, 2H), 7.67 (br.s, 1H), 7.42 (d, J=8.4 Hz, 2H), 4.51 (br.s, 2H), 2.37 (br.s, 4H), 2.1-1.9 (m, 1H), 1.85-1.7 (m, 1H), 1.33 (br.s, 9H); LCMS [M+H]: 306.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:15][C:8]2=[CH:9][N:10]=[C:11]([O:13][CH3:14])[CH:12]=[C:7]2[C:6]=1[C:16]1[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:4].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:15]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[F:24])[C:8]2=[CH:9][N:10]=[C:11]([O:13][CH3:14])[CH:12]=[C:7]2[C:6]=1[C:16]1[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:4]
Reactant: Fc1ccccc1CCl
Reactant: COC(=O)c1[nH]c2cnc(OC)cc2c1-c1cccnc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2cccnc2OC)c2cc(OC)ncc2n1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.5 %

Procedure:
5-methoxy-3-(2-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid methyl ester C4 (0.07 g, 0.22 mmol) was diluted with DMF (2 mL) and to the resulting solution was added 2-fluorobenzyl chloride (0.048 g, 0.33 mmol) and cesium carbonate (0.107 g, 0.33 mmol). The resulting suspension was allowed to stir at room temperature for 24 hours, then ethyl acetate (50 mL) and water (20 mL) were added to the reaction mixture and the layers were separated. The organic layer was sequentially washed with aqueous saturated sodium bicarbonate solution (10 mL), water (10 mL) and saturated brine (10 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo to provide a crude residue which was purified using flash chromatography to provide 1-(2-Fluoro-benzyl)-5-methoxy-3-(2-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid methyl ester C5 (0.07 g, 75%) MS: 422.20 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=[S:6])[NH:4][NH2:5].[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=O)[CH3:18])[N:12]=1)(=O)[CH3:9].C(O)(=O)C>CCO>[CH3:1][N:2]([CH3:7])[C:3](=[S:6])[NH:4][N:5]=[C:8]([C:11]1[N:12]=[C:13]([C:17](=[N:5][NH:4][C:3]([N:2]([CH3:7])[CH3:1])=[S:6])[CH3:18])[CH:14]=[CH:15][CH:16]=1)[CH3:9]
Reactant: CN(C)C(=S)NN
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NNC(=S)N(C)C)c1cccc(C(C)=NNC(=S)N(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 4,4-dimethylthiosemicarbazide (2.70 g, 0.022 mol) and 2,6-diacetylpyridine (1.63 g, 0.10 mol) in 95% EtOH (45 ml) containing glacial acetic acid (0.5 ml) was heated by a steam bath for 1 h and 10 min and allowed to cool to ambient temperature. The yellow precipitate was collected by filtration, washed with 95% EtOH, and subsequently recrystallized from toluene: yield 2.72 g (73%); mp 215° (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[N:24][OH:25])=[CH:12][CH:13]=1)=[O:6].N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>O1CCCC1>[C:36]([O:25][N:24]=[C:19]1[C:20]2[C:16](=[C:15]([O:14][C:11]3[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:26]=[CH:27][C:28]([Cl:29])=[C:2]([Cl:1])[CH:3]=4)=[CH:13][CH:12]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:18]1)(=[O:38])[CH3:37]
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=NO)nc1)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)ON=C1CCc2c(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
650 mg of N1-{6-[(1-hydroxyimino-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl}benzamide obtained in Example 47 was dissolved in 10 ml of tetrahydrofuran. To the resulting reaction solution, 1.2 ml of pyridine and 0.7 ml of acetic anhydride were added and the mixture was stirred at room temperature. After 17 hours, the reaction solution was distilled off under reduced pressure and 15 ml of ethyl acetate and 15 ml of water were added to the resulting residue. Then, the deposited powder was isolated by filtration and washed in turn with water and ethyl acetate to obtain the titled compound (310 mg).