Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].N1C=CC=CC=1>COCCOC>[CH:30]([O:29][C:27](=[O:28])[NH:1][C:2]1[CH:3]=[C:4]2[O:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1)([CH3:32])[CH3:31]
Reactant: Nc1cnc2nc(-c3cc(NC(=O)N4CCCC4)ccc3Cl)oc2c1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: COCCOC
Product: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)N4CCCC4)ccc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-[6-amino-[1,3]oxazolo[4,5-b]pyridin-2-yl]-4-chlorophenyl)pyrrolidine-1-carboxamide (100 mg, 0.28 mmol, 1.00 equiv), propan-2-yl chloroformate (68.3 mg, 0.56 mmol, 1.99 equiv), pyridine (111 mg, 1.40 mmol, 5.02 equiv) in ethylene glycol dimethyl ether (15 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The collected fractions were combined and concentrated under vacuum. This resulted in 60.8 mg (49%) of propan-2-yl N-[2-(2-chloro-5-[[(pyrrolidin-1-yl)carbonyl]amino]phenyl)-[1,3]oxazolo[4,5-b]pyridin-6-yl]carbamate (75) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([O:34]CC)=O)[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:37][N:38]([CH3:44])[CH2:39][CH2:40][CH2:41][CH2:42][NH2:43]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][N:38]([CH3:44])[CH3:37])=[O:34])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CN(C)CCCCN
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 58 %

Procedure:
Intermediate A and N,N-dimethylbutane-1,4-diamine were reacted together using an analogous method to that described in Step 1 of Example 1 to afford 5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-[4-(dimethylamino)butyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (139 mg, 58%) as a white solid; 1H NMR (500 MHz, DMSO) δ 1.40 (4H, dq), 1.74 (3H, s), 2.06 (6H, s), 2.15 (2H, t), 3.24 (2H, q), 6.72 (1H, d), 7.67-7.64 (2H, m), 7.71 (1H, d), 7.88-7.81 (2H, m), 7.95-7.89 (4H, m), 8.06 (1H, s), 9.30 (1H, t); APCI-MSm/z: 563[MH+]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][N:10]=1>CC(=O)OCC>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](=[O:14])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:11][N:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Fc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)c1ccc(Cl)nc1

Procedure:
The fluorobenzene (150 ml, 1.60 mmol) and 6-chloronicotinoyl chloride (17.7 g, 100 mmol) were converted to product in a manner substantially analogous to Preparation 1 to yield 15.2 g. (66.1%). EA, MS(FD), NMR.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[N:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)n1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 100 g of dimethyl 4-hydroxypyridine-2,6-dicarboxylate hydrochloride disloved in 500 ml of N,N-dimethylformamide, 122 g of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. 52.5 ml of benzyl bromide was added to the resulting reaction mixture, and it was stirred at 50° C. overnight. The reaction mixture was poured into water; and then the resulting white solid was collected after filtration, washed with water, and dried in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: C1CNC1
Reactant: ClCc1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CN2CCC2)cn1
Temperature: 80 °C
Yield: 52.1 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (0.34 g, 2.1 mmole) in 4 mL of dry acetonitrile is 389 mg (4.14 mmol) of azetidine-hydrochloride followed by 572 mg (4.14 mmol) of potassium carbonate. The reaction is heated at 80° C. for 3 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 200 mg (53% yield) of 1-(6-Chloro-pyridin-3-ylmethyl)-azetidine. Diagnostic 1H NMR (400 MHz, CDCl3) 2.06–2.14 (m, 2H), 3.23 (t, 4H, J=7.0 Hz), 3.55 (s, 2H), 7.27 (d, 1H, J=7.9 Hz), 7.61 (dd, 1H, J=8.3 and 2.5 Hz), 8.26 (d, 1H, J=2.5 Hz); MS 183.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21](O)=O>>[Cl:17][C:18]1[CH:19]=[C:20]([C:21]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)[CH:24]=[CH:25][N:26]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccnc(Cl)c2)o1
Yield: 47 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (1.92 mg, 8.83 mmol) was converted using 2-chloroisonicotinic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 1.41 mg, 47%) which was obtained as a white solid. MS: m/e=339.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH:4]([N:6]1[CH2:11][CH2:10][NH:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=O)[CH3:5])[CH3:2].C(N(CC)C(N1CCNC(=O)C1C1C=CC=CC=1)C)C>>[CH2:19]([N:3]([CH2:1][CH3:2])[CH:4]([N:6]1[CH2:11][CH2:10][NH:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)[CH3:5])[CH3:20]
Reactant: CCN(CC)C(C)N1CCNC(c2ccccc2)C1=O
Agent: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Product: CCN(CC)C(C)N1CCNC(c2ccccc2)C1

Procedure:
1-Diethylamino ethyl-2-keto-3-phenyl piperazine prepared according to Example 1 B (a) of application Ser. No. 333,497, is reduced by following the procedure described hereinabove in Example 7 (a) whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-diethylamino ethyl-2-keto-3-phenyl piperazine is reduced. The resulting 3-phenyl piperazine compound is obtained in the form of a light yellow oil boiling at 102° C./0.02 mm. Hg.
Reaction SMILES: CI.[I:3][C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][O:14][C:7]1[CH:6]=[CH:5][C:4]([I:3])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(I)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)ccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl iodide (0.29 ml, 4.68 mmol) was added to a mixture of 1.0 g (3.60 mmol) of methyl 5-iodosalicylate, 0.50 g (3.60 mmol) of potassium carbonate and 4 ml of dimethylformamide, and they were stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite and then after-treated in by an ordinary method to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[C@@H:24]([NH2:28])[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH2:37]([S:40](Cl)(=[O:42])=[O:41])[CH2:38][CH3:39].[Cl-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[C@@H:24]([NH:28][S:40]([CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1
Reactant: COc1cc(CCNC(=O)[C@@H](N)C(C)C)ccc1OCC#Cc1ccc(Cl)cc1
Reactant: CCCS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCC#Cc2ccc(Cl)cc2)c(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g of (S)-2-amino-3-methyl-butyric acid N-[2-{3-methoxy-4-(3-(4-chlorophenyl)-2-propyn-1-yloxy)-phenyl}-ethyl]-amide and 0.5 ml of triethylamine are dissolved in 50 ml of dioxane. 0.4 ml of 1-propanesulfonyl chloride is added, and the reaction mixture is stirred overnight at room temperature. It is introduced into 200 ml of saturated sodium chloride solution. Extraction is carried out twice using 150 ml of ethyl acetate each time. The organic phases are washed once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(propylsulfonyl-amino)-3-methyl-butyric acid N-[2-{3-methoxy-4-(3-(4-chlorophenyl)-2-propyn-1-yloxy)-phenyl}-ethyl]-amide, which is chromatographed on silica gel with ethyl acetate/n-hexane (1:1) and recrystallised from ethyl acetate/n-hexane, m.p. 131-133° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:31])[CH:22]=[CH:23][C:24]=1[N:25]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]1.C(N(CC)CC)C>CO>[Cl:8][C:6]1[N:5]=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:3]=[C:2]([NH:31][C:21]2[CH:22]=[CH:23][C:24]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:19]([O:18][CH3:17])[CH:20]=2)[N:7]=1
Reactant: Clc1ccc(Cc2nc(Cl)nc(Cl)n2)cc1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(Nc2nc(Cl)nc(Cc3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
2,4-Dichloro-6-(4-chloro-benzyl)-[1,3,5]triazine (0.78 g, 2.8 mmol) was added at 5° C. to a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (0.61 g, 3.0 mmol) and triethylamine (0.36 ml, 0.26 mmol) in 15 ml of methanol. The mixture was stirred at 5° C. for 1 h and thereafter evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-100% ethyl acetate as eluent to give the title compound (0.53 g, 40%) as a yellow viscous oil.
Reaction SMILES: Cl[C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[OH-].[Na+].[H][H]>C(O)C.O.[Pd]>[CH3:21][O:20][C:19]1[CH:2]=[CH:3][C:4]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][C@@H:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]=2[CH:18]=1
Reactant: [H][H]
Reactant: COc1cc2c(cc1Cl)CCN(C)C[C@H]2c1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)[C@H](c1ccccc1)CN(C)CC2

Procedure:
Hydrogenate a solution of 21.10 g (0.07 moles) of (S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1-H-3-benzazepine (e.g. obtained as described in Example 1, step D) 3.30 g (0.0825 moles) of sodium hydroxide in 300 ml of 95% ethanol at room temperature and at 4.2 kg/cm2 (=60 psi), with 1.70 g of 20% palladium hydroxide-on-carbon until the theoretical amount of hydrogen is consumed. Remove the catalyst and concentrate the filtrate to dryness on a steam bath at about 100 mm. Stir the residue with a mixture of 100 ml of water and 150 ml of ethyl ether to total dissolution. Separate the ether layer, dry over anhydrous sodium sulfate, and evaporate to dryness. Crystallize the residue from hexane to obtain analytically pure (S)-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 50°-51° C., [α]D26 =+51.8° (c=1, ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOC(C)=O>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=2)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH:8]=[CH:7][CH:6]=1)=[O:18]
Reactant: C#Cc1cccc(NC(=O)c2ccccc2C)c1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
In a 4 mL vial, N-(3-ethynylphenyl)-2-methylbenzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) were added and dissolved into EtOAc (2 mL) The mixture was then degassed for ˜20 min after which NEt3 (0.141 mL, 1.035 mmol) was added followed by Pd(PPh3)2Cl2 (21.0 mg, 0.030 mmol) and CuI (2.9 mg, 0.016 mmol). The reaction mixture was allowed to stir at 50° C. for 4 hours after which the reaction mixture was partitioned between EtOAc (4 mL) and water (4 mL) The organic extracts were combined, dried over anhydrous Na2SO4 and concentrared. The residue as purified by chromatography (silica gel, gradient elution 25% EtOAc/Hexanes EtOAc). The product containing fractions were concentrated to give the title compound as a solid (121 mg, 83%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C1C=CC2N(O)N=NC=2C=1.[OH:22][CH2:23][C:24]([NH:26][CH2:27][CH:28]([OH:43])[CH2:29][O:30][C:31]1[C:36]([CH3:37])=[CH:35][C:34]([C:38](=[NH:41])[NH:39]O)=[CH:33][C:32]=1[CH3:42])=[O:25].CCN=C=NCCCN(C)C.Cl>C1COCC1.CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:41]=[C:38]([C:34]3[CH:33]=[C:32]([CH3:42])[C:31]([O:30][CH2:29][CH:28]([OH:43])[CH2:27][NH:26][C:24](=[O:25])[CH2:23][OH:22])=[C:36]([CH3:37])[CH:35]=3)[N:39]=2)[CH:9]=[CH:10][CH:11]=1)=[O:2]
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
A solution of 3-formyl-benzoic acid (170 mg, 1.13 mmol), HOBt (184 mg, 1.36 mmol) and rac-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide (352 mg, 1.13 mmol) in THF (4 mL) and DMF (6 mL) was cooled to 0° C. before EDC hydrochloride (239 mg, 1.24 mmol) was added in portions. The mixture was stirred at rt for 1 h before it was diluted with THF (4 mL) and heated to 80° C. for 16 h. The mixture was concentrated and then separated by prep. HPLC (Waters XBridge Prep C18, 75×30 mm ID, 5 μm, 90% to 10% water (containing 0.5% of formic acid) in MeCN) to give the title compound as a white solid (130 mg). LC-MS*: tR=0.75 min; [M+1]+=425.90, 1H NMR (D6-DMSO): δ 2.35 (s, 6H), 3.20-3.29 (m, 1H), 3.40-3.49 (m, 1H), 3.71-3.82 (m, 2H), 3.84 (d, J=5.0 Hz, 2H), 3.92-4.00 (m, 1H), 5.30 (d, J=4.8 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.70 (br t, J=4.8 Hz, 1H), 7.81 (s, 2H), 7.91 (t, J=7.8 Hz, 1H), 8.24 (d, J=7.5 Hz, 1H), 8.49 (d, J=7.8 Hz, 1H), 8.69 (s, 1H), 10.18 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:3].[NH2:12][C:13]1[CH:20]=[C:19](F)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C(N(CC)CC)C>CCO>[NH2:12][C:13]1[CH:20]=[C:19]([N:8]2[CH2:7][CH2:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])([OH:11])[CH2:10][CH2:9]2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1
Reactant: CN(C)CC1(O)CCNCC1
Reactant: N#Cc1cnc(N)cc1F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)CC1(O)CCN(c2cc(N)ncc2C#N)CC1
Temperature: 80 °C

Procedure:
A mixture of 4-[(dimethylamino)methyl]-4-piperidinol (1.0 g, 4.33 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 593 mg, 4.33 mmol) and triethylamine (3.62 ml, 26.00 mmol) was heated at 80° C. in a septum sealed reaction vessel under argon for 28 h. The reaction mixture was cooled, EtOH (5 ml) added and heated at 80° C. for 18 h. The reaction mixture was then evaporated, partitioned between aqueous NaHCO3 solution and DCM, extracted 5× with DCM containing 10% MeOH, the combined DCM layers dried over MgSO4 and evaporated. The residue was triturated with Et2O (20 ml) and DCM (1 ml) to give the title compound as a beige solid. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 5.82 (s, 1H), 4.70 (s, br, 2H), 3.65-3.58 (m, 2H), 3.27-3.20 (m, 2H), 2.38 (s, 6H), 2.26 (s, 2H), 1.68-1.62 (m, 4H). (UPLC-MS 6) tR 0.25; ESI-MS 276.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CCOC(C)=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CO)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a suspension of [4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenyl]-methanol (WO 2011/070368, which is incorporated herein by reference in its entirety; 3.05 g, 12.4 mmol) in aq. NaOH solution (1M, 31 mL, 31 mmol) and EtOAc (30 mL) at RT was added 2,2,2-trichloroethyl chloroformate (1.88 mL, 13.7 mmol) over 3 min (CARE: exotherm to 35° C.) and the mixture stirred at RT for 1 h. The aqueous layer was extracted with EtOAc (20 mL), then the combined organics washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a pale orange solid. Recrystallisation from hot cyclohexane-EtOAc (3:1, 30 mL) and drying in vacuo gave the title compound as a flocculent off-white solid (3.87 g, 74%). LCMS (Method 3): Rt 4.00 min, m/z 420, 422 [MH+].
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[CH:14]=[N:13]2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH:41][C:9](=[O:10])[CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:21]([F:27])=[CH:22][CH:23]=[CH:24][C:25]=3[F:26])[CH:14]=[N:13]2)[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:37]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C(O)C(CC1CCCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCCCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 65 %

Procedure:
Using the method described in Example 49, 3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 33) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid (1.42 g, 65%); ES+-HRMS m/e calcd for C30H41N5O4SiF2 [M+H+] 602.2969 found 602.2971. 1H NMR (300 MHz, DMSO-d6) δ ppm −0.07 (s, 6H) 0.80 (s, 9H) 0.84-1.30 (m, 6H) 1.63 (br s, 5H) 1.75-1.92 (m, 1H) 2.04-2.21 (m, 1H) 3.85 (t, J=5.1 Hz, 2H) 4.06 (t, J=5.1 Hz, 2H) 5.54 (dd, J=10.7, 4.1 Hz, 1H) 6.03 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.33-7.52 (m, 3H) 7.53 (d, J=2.1 Hz, 1H) 8.28 (d, J=2.7 Hz, 1H) 10.73-10.91 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:13])[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=2)[CH:3]=1.N12CCCN=C1CCCCC2.[Cl:33][C:34]([Cl:38])([Cl:37])[C:35]#[N:36]>ClCCl>[Cl:33][C:34]([Cl:38])([Cl:37])[C:35](=[NH:36])[O:13][CH:11]([C:9]1[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[N:7]=2)[CH:3]=[C:2]([F:1])[CH:10]=1)[CH3:12]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(F)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(5-Fluoro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (1.58 g, 5.09 mmol) was dissolved in dichloromethane (10 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (153 μL, 1.018 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (5.1 mL, 50.9 mmol) dropwise over 10 min. The reaction was stirred at room temperature for 2 h and concentrated. The resulting residue was dissolved in diethyl ether. The resulting solution was decanted to separate it from the resulting dark tar which formed. The ethereal was concentrated to give 2.247 g (97%). 1H-NMR (CDCl3, 300 MHz) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.16 (m, 1H), 6.63 (q, J=6.0 Hz, 1H), 5.68 (s, 2H), 3.62 (m, 2H), 1.78 (d, J=6.0 Hz, 3H), 0.89-0.94 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:30]2[NH:31][CH:32]=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:35])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Br)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.8 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (79 mg, 61%).