Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)=[O:3].N1C=CC=CC=1.[CH3:15][OH:16]>C(Cl)Cl>[NH:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:2]([O:16][CH3:15])=[O:3]
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc[nH]1

Procedure:
40 ml of a solution of 45 (mmoles) of 2-chlorocarbonyl-1H-pyrrole in methylene chloride were added dropwise to a cold mixture of 4.3 ml of pyridine and 3.5 ml of methanol and the mixture was washed with water, then with 6 ml of N sodium hydroxide, and was extracted with methylene chloride. The organic phases were dried and concentrated to dryness and the residue was chromatographed over silica. Elution with a mixture of hexane and ethyl acetate (8-2) yielded 4.014 g of methyl 1H-pyrrole-2-carboxylate melting at ≃74° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][N:11]1C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][C@@H:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[NH:11]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@@H]1Cc2ccccc2CN1

Procedure:
To a solution of 21 g (53 mmol) of the compound obtained in Step D in 600 mL of ethyl acetate there are added 2.1 g of palladium-on-carbon 10%. The batch is stirred at ambient temperature under a pressure of 1.3 bars of dihydrogen for 5 hours. The reaction mixture is then filtered and then concentrated to dryness. The title product is obtained in the form of a solid.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[C:4]=1[CH3:14])=[O:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:14][C:4]1[C:5]([CH2:9][CH2:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:13])=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: CN1CCNCC1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Product: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCN(C)CC1
Yield: 72.1 %

Procedure:
3-(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (1.37 g, 6.50 mmol) reacted with 1-methylpiperazine (719.6 mg, 7.15 mmol) to give 1.3 g (72%) of 3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: CCCCCCC.[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C(C1C=CC=CC=1)C.C([N-]C(C)C)(C)C.[Li+].[CH:29]1[C:34]2([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31][C:30]=1[CH2:40][O:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=[O:47])=[CH:44][CH:43]=1.[Cl-].[NH4+].[O:52]1CCCC1>C(OCC)(=O)C>[CH2:9]([O:8][C:12](=[O:52])[CH2:11][CH:46]([OH:47])[C:45]1[CH:48]=[CH:49][C:42]([O:41][CH2:40][C:30]2[CH2:31][CH2:32][CH2:33][C:34]3([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)[CH:29]=2)=[CH:43][CH:44]=1)[CH3:10]
Reactant: C1CCOC1
Reactant: O=Cc1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCc1ccccc1
Product: CCOC(=O)CC(O)c1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl acetate (2.2 mL) in tetrahydrofuran (100 mL) was added dropwise a 2M heptane/tetrahydrofuran/ethylbenzene solution of lithium diisopropylamide (11.25 mL) at −78° C. under argon atmosphere over 15 minutes, followed by stirring the reaction mixture at −78° C. for 30 minutes. Then, to the reaction mixture was added dropwise a solution of 4-(spiro[5.5]undec-1-en-2-ylmethoxy)-benzaldehyde (4.27 g) obtained in Step 6 in tetrahydrofuran (15 mL) over 10 minutes, followed by stirring the reaction mixture at −78° C. for 40 minutes. After the temperature was raised to room temperature, saturated aqueous ammonium chloride solution (100 mL) was added carefully to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:4 to 1:3) to give 3-hydroxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acid ethyl ester (4.98 g).
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.Br[C:15]1[C:16]([CH:20]2[O:24]CCO2)=[CH:17][S:18][CH:19]=1.[Li]CCCC.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH:20]([C:16]1[C:15]([B:1]([OH:6])[OH:2])=[CH:19][S:18][CH:17]=1)=[O:24]
Reactant: Brc1cscc1C1OCCO1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=Cc1cscc1B(O)O
Temperature: -78 °C
Yield: 95 %

Procedure:
To a 0.5M solution of B(Oi-Pr)3 (1.2 eq) in toluene/THF 4:1 was added a solution of 2-(4-bromo-3-thienyl)-1,3-dioxolane in toluene/THF 4:1, and the mixture was then cooled to −78° C. BuLi (1.5M in hexanes; 1.2 eq) was then added over 1 h, and the solution kept at this temperature for an additional h, then allowed to warm to −20° C. over 3 h; aq 1N HCl was added and the mixture stirred for an additional h at this temperature. Removal of volatiles gave an aqueous solution that was extracted with DCM; the combined organic phases were then washed with brine, dried over Na2SO4 and concentrated in vacuo. Yield: 95%.
Reaction SMILES: COC1C=CC(N)=CC=1.N[C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][C:27]=1OC)[C:14]([NH:16]C1C=CC(F)=C(F)C=1)=[O:15]>>[C:14]([NH2:16])(=[O:15])[C:13]1[CH:25]=[CH:26][CH:27]=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Solvent: COc1ccc(N)cc1
Product: NC(=O)c1ccccc1
Yield: 56.3 %

Procedure:
The title compound was synthesized as in Example 1 using p-anisidine (1.0 g, 7.1 mmol), CSI (0.85 mL, 9.8 mmol), and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.75 g, 6.3 mmol) to give 0.43 g of benzamide, N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(4-methoxyphenyl)amino]-carbonyl]amino]sulfonyl]amino]-. Microanalysis: C22H20F2N4O6S; calculated: C=52.17; H=3.98; N=11.06. found: C=52.17; H=3.89; N=10.95. Mp 189-192° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[C:15][C:16]2[N:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][CH:17]=2)[CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:18]1[CH:17]=[C:16]([C:15]#[C:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[N:20]2[C:19]=1[CH:24]=[CH:23][CH:22]=[N:21]2
Reactant: CC(C)(C)OC(=O)N1CCCC(C#Cc2cnc3cccnn23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(#CC1CCCNC1)c1cnc2cccnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
To a solution of 1-BOC-3-(2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl)piperidine (0.39 g, 1.2 mmol) in CH2Cl2 (10 mL) was added TFA (1.23 g, 10.8 mmol), the mixture was stirred at rt overnight and evaporated in vacuo. To the residue was added 10 mL 10% K2CO3 solution, extracted with EtOAc (20 mL×3), dried with Na2SO4, after filtration, and the filtrate was evaporated under reduced pressure to give 0.33 g product as yellow oil (107.0%). 1H NMR (300 MHz, CDCl3) δ: 8.43 (1 H, d, J=4.5 Hz), 7.93-7.97 (1 H, dd, J=1.8 and 9.0 Hz), 7.91 (1 H, s), 7.05-7.09 (1 H, dd, J=4.5 and 9.0 Hz), 2.82-2.98 (4 H, m), 2.08-2.11 (1 H, m), 1.75-1.84 (2 H, m), 1.53-1.58 (2 H, m).
Reaction SMILES: [CH3:1][N:2]([CH2:20][C:21](=[O:39])[C@@H:22]([NH:30][C:31]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@H:6]1[C:7]([O:9]CC1C=CC=CC=1)=[O:8])=[O:4].O.O1CCOCC1>CO.[OH-].[Pd+2].[OH-]>[CH3:1][N:2]([CH2:20][C:21](=[O:39])[C@@H:22]([NH:30][C:31]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4]
Reactant: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCCCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
A suspension of the phenylmethyl ester product from part (g) (0.8 g., 1.5 mmole) in methanol and palladium hydroxide (20% on carbon) is hydrogenated at room temperature and atmospheric pressure for 30 minutes. The mixture is filtered, the solids are rinsed with methanol, and the filtrate is concentrated to give 0.42 g. of yellow oil. The residue is chromatographed on LPS-1 silica gel using an elution gradient of 3→10% acetic acid in chloroform. Fractions containing the desired material are combined and concentrated. The residue is dissolved in methanol/water, filtered, concentrated (methanol removed) and lyophilized to give a white solid. The material is rechromatographed on CC-4 silica gel using ethyl acetate as the eluant. Fractions containing the desired produced are combined and lyophilized from water/dioxane to give 1-[[methyl[(S)-2-oxo-4-phenyl-3-[(1-piperidinylcarbonyl)amino]butyl]amino]carbonyl]-L-proline as a white solid; m.p. 69°-72°; [α]D25 =-37° (c=0.2, methanol). TLC (silica gel; toluene:acetic acid, 4:1) Rf =0.18.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.[CH:17]12[CH2:24][CH2:23][CH:20]([CH:21]=[CH:22]1)[CH:19]1[C:25]([O:27][C:28](=O)[CH:18]21)=[O:26]>O>[C:12]([C:11]1[CH:15]=[CH:16][C:8]([N:7]2[C:25](=[O:26])[CH:19]3[CH:18]([CH:17]4[CH2:24][CH2:23][CH:20]3[CH:21]=[CH:22]4)[C:28]2=[O:27])=[CH:9][CH:10]=1)([OH:14])=[O:13]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1OC(=O)C2C3C=CC(CC3)C12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(N2C(=O)C3C4C=CC(CC4)C3C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of K2CO3 (5.88 g, 42.5 mmol) in H2O (100 mL) was added 4-aminobenzoic acid (5.83 g, 42.5 mmol) and bicyclo[2.2.2]oct-5-en-2,3-dicarboxylic anhydride (7.20 g, 40.4 mmol). The reaction mixture was stirred at room temperature for 18 hrs. and then washed with ethylacetate (EtOAc) (75 ml,). The aqueous phase was acidified with conc. HCl until the pH reached 1. The precipitated crystals were filtered and dried: 11.77 g (98%), mp=269° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([OH:22])=O)[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][NH:25][C:20]([C:18]2[N:17]([CH3:23])[N:16]=[C:15]([NH:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:19]=2)=[O:22])[CH2:29][CH2:28]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: NCC1CC1
Product: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)NCC2CC2)n(C)n1
Yield: 80 %

Procedure:
As described for example 163c, 3-((3-(5-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methylamino)-1-methyl-1H-pyrazole-5-carboxylic acid (92 mg, 0.28 mol) was converted, using aminomethylcyclopropane instead of isopropylamine, to the title compound (85 mg, 80%) which was obtained as a white solid. MS: m/e=385.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:46]1([NH2:51])[CH2:50][CH2:49][CH2:48][CH2:47]1>>[CH:46]1([NH:51][C:40]([CH:37]2[CH2:38][CH2:39][N:34]([C:32]([N:12]3[C@@:13]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)([CH3:24])[C@@:14]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=4)([CH3:16])[N:15]=[C:11]3[C:8]3[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=3[O:43][CH2:44][CH3:45])=[O:33])[CH2:35][CH2:36]2)=[O:41])[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Reactant: NC1CCCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)NC2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, 1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid (example 211) was reacted with cyclopentylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H49Cl2N5O3 [(M+H)+] 718.3285, observed 718.3288.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[CH:36][C:28]=2[C:25]2[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=2)[NH:32][C:31]1=[O:37]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 72 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-pyridin-4-yl-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 3-methyl-5-(2-morpholin-4-yl-ethyl)-2-(2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (54 mg, 72.0%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].[H-].[Na+]>CN(C=O)C>[CH3:24][O:23][C:21]([C:20]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:15]=1[NH2:16])=[O:22]
Reactant: COc1ccc(CNc2ccncc2C#N)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)c2cnccc2n1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A cooled (0° C.) solution of 4-(4-methoxybenzylamino)-3-cyanopyridine (800 mg, 3.34 mmol) and methyl bromoacetate (0.37 mL, 4.02 mmol) in DMF was treated with sodium hydride (60% w/w in oil, 161 mg, 4.02 mmol) portionwise over 15 minutes. The mixture was allowed to warm to ambient temperature and stirred for 15 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (10 mL) and the solvent evaporated. The resultant residue was partitioned between EtOAc (100 mL), water (50 mL) and saturated NaHCO3 solution (5 mL). The organic phase was dried (Na2SO4), filtered and evaporated to give a brown oil. The oil was purified by flash column chromatography (Si-PPC, DCM:MeOH, gradient 100:0 to 85:15) to provide the title compound as an off white solid (401 mg, 39%). LCMS (method B): RT=1.33 min, M+H+=312.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)C1C=CC=CC=1>[C].[Pd].CO>[OH:8][C:9]1[C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(-c2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc(-c2ccccc2)ccc1O

Procedure:
1.9 g of methyl 3-benzyloxy-6-phenylpicolinate was reduced with 10% palladium carbon/methanol, and the resultant product was purified by column chromatography to obtain an aimed compound.
Reaction SMILES: CNC([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.[O:15]=[C:16]1CC2[C:18](=CC(C(O)=O)=CC=2)[NH:17]1>>[CH3:18][NH:17][C:16]([C:13]1[CH:12]=[C:11]2[C:7]([CH2:8][C:9](=[O:14])[NH:10]2)=[CH:6][CH:5]=1)=[O:15]
Reactant: CNC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Product: CNC(=O)c1ccc2c(c1)NC(=O)C2
Yield: 19 %

Procedure:
The compound was synthesized according to the method described for N-methyl-2-oxoindoline-5-carboxamide except substituting 2-oxoindoline-6-carboxylic acid (89 mg, 0.500 mmol), to obtain the title compound (18 mg, 19%). 1H NMR (400 MHz, CD3OD) δ 7.52 (d, J=7.6 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.40 (d, J=7.6 Hz, 1H), 3.33 (s, 2H), 2.87 (s, 31-1); MS ESI 191.0 [M+H]+, calcd for [C10H10N2O2+H]+ 191.08.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.C1([O:19][C:20](=O)[NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[C:24]([CH2:34][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:36])[CH:23]=2)C=CC=CC=1>C1COCC1.O>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][O:10][C:20](=[O:19])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:32])[CH3:33])(=[O:29])=[O:30])=[C:24]([CH2:34][N:35]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH3:36])[CH:23]=2)=[CH:6][CH:5]=1
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1CN(C)C(=O)OC(C)(C)C
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)OCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 3 h

Procedure:
Sodium hydride (60% in oil, 60 mg, 1.5 mmol) was added portionwise to a solution of 4-bromophenethyl alcohol (0.718 g, 3.57) in THF (6 mL) at 0° C. The reaction mixture was cooled to −40° C., and a solution of 16G (0.550 g, 1.19 mmol) in THF (5 mL) was added slowly dropwise. The reaction mixture was slowly warmed to 0° C., and then stirred for 3 h at 0° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient from 0 to 50% ethyl acetate in hexanes) to give 16H (0.503 g, 74%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][OH:18])=[CH:21][CH:22]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: OCc1ccc(B(O)O)cc1
Product: Nc1ncc(-c2ccc(CO)cc2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-(hydroxymethyl)-phenylboronic acid; method 1: HPLC/MS: 1.12 min, [M+H]=321;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[C:20]([CH3:23])[CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:24]#[C:25]Br.C1COCC1.C(=O)([O-])O.[Na+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([CH3:23])=[C:21]3[N:22]=[C:25]2[NH2:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc2c1nc(N)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
A mixture of N2-[4-(benzyloxy)phenyl]-4-methylpyridine-2,3-diamine (8.70 g), cyanogen bromide (6.04 g), THF (80 ml) and water (20 ml) was stirred at room temperature for 24 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate, treated with activated carbon, and recrystallized from methanol to give the title compound (5.60 g).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[CH2:2]1.C1C=CC=CC=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>CO.O>[CH2:18]([NH:25][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]([OH:11])[CH2:2]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CC(=O)c2ccccc21
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: OC1CC(NCc2ccccc2)c2ccccc21

Procedure:
Stir indan-1,3-dione (7.31 g.), benzene (200 ml.) and benzylamine (5.90 g.) and reflux into a water separator for 6 hours. Cool, filter, and wash the dark solid with ether. Boil the solid with methylene chloride, filter and remove the solvent by boiling and replace with ether. Filter to get 4.51 g. of dark solid. Stir 4.30 g. of this solid with methanol (150 ml.) and add sodium borohydride (12.0 g.) portionwise with stirring over 4 hours. Let the reaction stand at room temperature then evaporate the solvent in vacuo and digest the residue with water and ether. Extract the mixture with ether and wash, dry and evaporate the solvent in vacuo. Recrystallize the residue from cyclohexane-ether to obtain 1.996 g. of the pure free base of the title compound, m.p. 121°-125°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7](=[O:27])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:26])[C:16]([C:18]2[CH:23]=[C:22]([Cl:24])[N:21]=[N:20][C:19]=2Cl)=[O:17])[N:13]=1.[CH3:31][OH:32].[OH-].[Na+]>O1CCOCC1>[Cl:24][C:22]1[N:21]=[N:20][C:19]([O:32][CH3:31])=[C:18]([C:16]([N:15]([CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:7]([NH:6][CH2:5][C:4]3[CH:28]=[CH:29][CH:30]=[C:2]([F:1])[CH:3]=3)=[O:27])[S:10][CH:11]=2)[CH3:26])=[O:17])[CH:23]=1
Reactant: CN(Cc1csc(NC(=O)NCc2cccc(F)c2)n1)C(=O)c1cc(Cl)nnc1Cl
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1nnc(Cl)cc1C(=O)N(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A solution of 3,6-dichloro-pyridazine-4-carboxylic acid {2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide (235 mg, 0.5 mmol) and MeOH (160 mg, 5 mmol) in 1,4-dioxane (10 mL) was added NaOH (20 mg, 0.5 mmol). The mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in CH2Cl2+5% MeOH and filtered over a small plug of silica. The volatiles were evaporated and the desired product (230 mg) was obtained as a 5:1 mixture with starting material-3,6-dichloro-pyridazine-4-carboxylic acid {2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide. This mixture was used as such in the subsequent steps.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([CH2:23][CH2:24][C:25]#[N:26])[CH2:19][CH2:20][C:21]#[N:22])[CH:12]=1)[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:5]([CH2:4][CH2:3][CH2:1][NH2:2])[CH2:6][CH2:7][CH2:8][NH2:9])[CH:12]=1)[CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: [H][H]
Reactant: N#CCCN(CCC#N)Cc1cccc(CN(CCC#N)CCC#N)c1
Solvent: C1COCCO1
Product: NCCCN(CCCN)Cc1cccc(CN(CCCN)CCCN)c1
Yield: 94.3 %

Procedure:
6.97 g of 1,3-bis(N,N-bis(2-cyanoethyl)aminomethyl)benzene, 0.70 g of Raney Co and 100 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 180° C. for 2 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 6.88 g of the title compound.