Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)=[O:3].[CH2:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1)[CH2:11][CH3:12].C(=O)(O)[O-].[K+].O>C1(C)C=CC=CC=1>[NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)=[O:3]
Reactant: NC(=O)C1CCNCC1
Reactant: CCCOc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOc1ccc(CN2CCC(C(N)=O)CC2)cc1
Yield: 79.1 %

Procedure:
The method taught by R. A. Farr et al, J. Org. Chem. 1981, 46, 1212-1215, was used in the following two-step preparation. A vigorously stirred solution of 16.5 grams (0.129 mole) of 4-aminocarbonylpiperidine, 25.0 grams (0.135 mole) of 4-propoxyphenylmethyl chloride, and 19.4 grams (0.193 mole) of potassium bicarbonate in 200 mL of toluene was heated at reflux for 6.5 hours. The reaction mixture was then cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with two portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue, which was slurried in pentane and collected by filtration, yielding 28.2 grams of 4-aminocarbonyl-N-(4-propoxyphenylmethyl)piperidine, mp 142°-146° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[CH3:20][CH:21]([SH:23])[CH3:22]>CN(C)C=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][S:23][CH:21]([CH3:22])[CH3:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)SCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To benzyl bromoacetate (100 mg, 0.437 mmol) in dimethyl formamide (2 mL) is added triethylamine (67 uL, 0.481 mmol) and 2-propanethiol (41 uL, 0.437 mmol). After stirring at rt during 2 h, the solvent is evaporated, the residue is treated with dichloromethane and water. The organic phase is dried and evaporated to give a crude compound before purification by preparative HPLC (Column Waters C18 ODB 5 μm 19×50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN, 12.5-15 min 100% ACN) to yield the title compound.
Reaction SMILES: [I:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CC(=C(C)C)C.O.P([O-])([O-])(O)=[O:20].[Na+].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[I:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([OH:20])=[O:6]
Reactant: O=P([O-])([O-])O
Reactant: COc1c(I)cccc1C=O
Agent: CC(C)=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(I)cccc1C(=O)O
Reaction time: 0.33 h

Procedure:
To a solution of 3-iodo-2-methoxy-benzaldehyde (3.68 g, 14 mmol) in tert-butanol (70 mL) was added 2,3-dimethyl-but-2-ene (7 mL) followed by a solution comprising disodium hydrogen phosphate monohydrate (7.56 g 56 mmol) and sodium chlorite (7.56 g, approx. 66 mmol, technical grade) in water (70 mL). The resulting mixture was stirred for 20 minutes then diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated. The residual solid was recrystallized from cyclohexane to give the title compound as a white solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH2:22]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(N)cc1OC
Reactant: Oc1cccc(Nc2nc(F)ncc2F)c1
Product: COc1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-fluoro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (d, 1H, J=6.6 Hz), 7.59 (bs, 1H), 7.30 (s, 1H), 7.20–7.10 (m, 2H), 7.00–6.75 (m, 4H), 6.59 (bd, 1H, J=7.8 Hz), 3.87 (s, 3H), 3.84 (s, 3H); 19F NMR (CDCl3): −47229; LCMS: ret. time: 17.77 min.; purity: 78%; MS (m/e): 357 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:6][N:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1)([OH:3])=[O:2].BrN1C(=O)C[CH2:23][C:22]1=O>CN(C=O)C.CCOC(C)=O>[CH2:22]([O:2][C:1]([C:4]1[C:5]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[N:6][N:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1)=[O:3])[CH3:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)n1cc(C(=O)O)c(-c2ccc(F)cc2)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C(C)(C)C)nc1-c1ccc(F)cc1
Yield: 75.2 %

Procedure:
Add a solution of NaOH (15%, 6 mL) to a solution of 4-ethoxycarbonyl-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole (0.350 g, 1.2 mmol) in MeOH (3 mL) and then add acetonitrile (1 mL). Stir the mixture at 50° C. for 3 h, cool to RT and add HCl (10%) until the pH=3. Extract the mixture with EtOAc (3×100 mL). Combine the organic layers and wash with brine (100 mL), dry (MgSO4) and concentrate to provide 4-carboxy-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole as a yellow solid (0.320 g), MS (ESi+): 229.1 (M+H)+. Next treat a solution of 4-carboxy-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole (0.315 g, 1.2 mmol) in DMF (15 mL) previously degassed with N-bromosuccinimide (0.235 g, 1.32 mmol) at RT for about 18 h. Dilute the mixture with EtOAc (80 mL) and wash with cooled water (5×10 mL), dry (MgSO4), and concentrate to provide the desired compound as yellow solid (0.262 g, 73% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[NH:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]([NH2:29])=[O:28])=[CH:26][C:21]=2[N:20]=[CH:19]1>>[F:17][C:13]1[CH:12]=[C:11]([CH:9]([NH:8][C:6]2[N:7]=[C:2]([N:20]3[C:21]4[CH:26]=[C:25]([C:27]([NH2:29])=[O:28])[CH:24]=[CH:23][C:22]=4[N:18]=[CH:19]3)[CH:3]=[N:4][CH:5]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: NC(=O)c1ccc2[nH]cnc2c1
Reactant: CC(Nc1cncc(Cl)n1)c1cccc(F)c1
Product: CC(Nc1cncc(-n2cnc3ccc(C(N)=O)cc32)n1)c1cccc(F)c1
Yield: 21.3 %

Procedure:
In an analogous fashion, to Example 3, 6-chloro-N-[1-(3-fluorophenyl)ethyl]pyrazin-2-amine (025 g, 1 mmol) was reacted with 1H-benzimidazole-5-carboxamide (0.2 g, 1.2 mmol) to afford the product as a mixture of isomers. These were separated by chromatography using dichloromethane-methanol (98:2-92:8) as eluant to afford from the less polar fractions 1-(6-{[1-(3-fluorophenyl)ethyl]amino}pyrazin-2-yl)-1H-benzimidazole-6-carboxamide (80 mg).
Reaction SMILES: C([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])C1C=CC=CC=1.C([Li])CCC.[C:18]1(=[O:22])[CH2:21][CH2:20][CH2:19]1.C(O)(=O)C>C1COCC1.CCCCCC>[OH:22][C:18]1([CH2:12][S:9]([NH2:8])(=[O:10])=[O:11])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC1
Reactant: CS(=O)(=O)NCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: NS(=O)(=O)CC1(O)CCC1
Reaction time: 0.08 h

Procedure:
Under inert gas, 2.00 g of N-benzylmethanesulfonamide were initially charged in 20 ml of THF, then, at a temperature of −78° C., 13.50 ml of a 1.6 N solution of butyllithium in hexane were added dropwise and the mixture was stirred at constant temperature for 5 minutes. The reaction solution was admixed with 3.23 ml of cyclobutanone and allowed to come to room temperature while stirring. After the addition of 1.24 ml of acetic acid, the volatile constituents were removed under reduced pressure. The residue was taken up in a mixture of 50 ml of ethyl acetate and 50 ml of aqueous sodium hydrogencarbonate solution, and the aqueous phase was extracted again with 50 ml of ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The crude product thus obtained was recrystallized from ethyl acetate/n-heptane, then dissolved in 20 ml of methanol and, with addition of 0.36 g of 20% Pd(OH)2/C, stirred under a hydrogen atmosphere at 60° C. for 3 hours. After filtration to remove the solid residues, the filtrate was freed of the solvent under reduced pressure. This gave the product (1.07 g) with a molecular weight of 165.2 g/mol (C5H11NO3S).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11]([N:15](C(=O)C)[C:16](=[O:18])[CH3:17])[O:12]2)=[CH:7][CH:6]=1)(=O)C.O.NN>C(O)C.C(OCC)(=O)C>[C:16]([NH:15][C:11]1[O:12][C:13]2[C:8]([CH:9]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:7][CH:6]=[C:5]([OH:4])[CH:14]=2)(=[O:18])[CH3:17]
Reactant: CCOC(=O)C1=C(N(C(C)=O)C(C)=O)Oc2cc(OC(C)=O)ccc2C1c1cccnc1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(NC(C)=O)Oc2cc(O)ccc2C1c1cccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.7 %

Procedure:
Ethyl 7-(acetyloxy)-2-(diacetylamino)-4-pyridin-3-yl-4H-chromene-3-carboxylate (6.989 g, 15.9 mmol) was dissolved in absolute ethanol (50 mL). Hydrazine hydrate (950 μL, 19.5 mmol) was added and the mixture stirred at room temperature for 6 h. The reaction mixture was evaporated to dryness to give an orange solid. The residue was dissolved in a mixture of ethyl acetate (200 mL) and ethanol (50 mL). Silica gel 60 (35 g) was added and the mixture evaporated to dryness. Purified by flash chromatography over silica gel 60, 40-63 μm (eluent: 75% ethyl acetate/petroleum spirits (54×100 mL fractions), packing height: 15 cm, column diameter: 5 cm). The fractions containing the major band (Rf 0.26, eluent: 75% ethyl acetate/petroleum spirits, fractions 15-53) were combined and evaporated to dryness to give the title compound (3.307 g, 59% yield) as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12].[Sn](Cl)(Cl)(Cl)Cl.[K+].[Br-]>ClCCl>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:11](=[O:12])[CH:10]=[C:9]([CH3:14])[CH3:8]
Reactant: COc1ccsc1
Reactant: CC(C)=CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccsc1C(=O)C=C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-methoxythiophene (21.3 g, 0.187 mol) [S. Gronowitz, Arkiv. Kemi., 1958, 12, 239] in dichloromethane (50 mL) was slowly added to a solution of 3,3-dimethylacryloyl chloride (22 mL, 0.195 mol) and tin(IV) chloride (23 mL, 0.195 mol) in dichloromethane (350 mL) at 0°-5° C. After stirring at 0°-5° C. an additional 1 h, the solution was poured into ice water (1 L). The organic layer was separated, washed with water, and dried over magnesium sulfate. The solvent was evaporated in vacuo. The resulting oil was purified by flash chromatography using dichloromethane as the eluant to give the product, 29.6 g (81%): mp 49°-51° C.; IR (KBr): 1671, 1628 and 1430 cm-1 ; MS: m/z 197 (MH+ ; 1H NMR (CDCl3): δ 1.98 (d, J=1.2 Hz, 3H), 2.23 (d, J=1.1 Hz, 3H), 3.98 (s, 3H), 6.85 (d, J=5.5 Hz, 1H), 6.89 (dd, J=1.1 Hz, J=1.2 Hz, 1H) and 7.47 (d, J=5.5 Hz, 1H).
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6](Cl)(=[O:8])[CH3:7].C1COCC1.O.[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH:27]1[CH:32]([NH:33][C:34]2[C:41]([F:42])=[CH:40][C:37]([C:38]#[N:39])=[C:36]([NH:43][C:44]3[CH:45]=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=3)[N:35]=2)[CH2:31][CH2:30][NH:29][CH2:28]1>C(OCC)(=O)C>[C:6]([N:29]1[CH2:30][CH2:31][CH:32]([NH:33][C:34]2[C:41]([F:42])=[CH:40][C:37]([C:38]#[N:39])=[C:36]([NH:43][C:44]3[CH:45]=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=3)[N:35]=2)[CH:27]([N:18]2[C:19](=[O:26])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]2=[O:16])[CH2:28]1)(=[O:8])[CH3:7]
Reactant: CC(=O)Cl
Reactant: Cc1cncc(Nc2nc(NC3CCNCC3N3C(=O)c4ccccc4C3=O)c(F)cc2C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Nc2nc(Nc3cncc(C)c3)c(C#N)cc2F)C(N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydrogen carbonate (13 mg) and acetyl chloride (0.005 ml) were added to a THF/water (0.5 ml/0.5 ml) solution containing 6-((3-(1,3-dioxoisoindolin-2-yl)piperidin-4-yl)amino)-5-fluoro-2-((5-methylpyridin-3-yl)amino)nicotinonitrile (15 mg) obtained in the 2nd step under ice cooling, followed, by stirring at room temperature for 0.5 hours. Ethyl acetate was added to the reaction solution. The obtained organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure. Yellow oily matter of 6-((1-acetyl-3-(1,3-dioxoisoindolin-2-yl)piperidin-4-yl)amino)-5-fluoro-2-((5-methylpyridin-3-yl)amino)nicotinonitrile (12 mg) was thus obtained.
Reaction SMILES: [Li+].CCC[CH2-].[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>CCCCCC.O1CCCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([S:20]([N:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: O=C1CCCN1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)N2CCCC2=O)c1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
15.75 cm3 of a 1.6M solution of N-butyllithium in hexane is added to 2.22 g of 2-pyrrolidinone in solution in 80 cm3 of tetrahydrofuran and cooled to -25° C., the temperature being maintained between -25° C. and -20° C. After agitation for 30 minutes at -25° C., a solution of 5.40 g of 3-methoxybenzene sulphonyl chloride [J. Chem. Soc. P.T.2., 579 (1982)]in 40 cm3 of tetrahydrofuran is poured drop by drop into the mixture, operating between -25° C. and -20° C. After agitation for 30 minutes at -25° C., the whole is allowed to return to ambient temperature. The solvent is evaporated under reduced pressure; the residue is taken up in water, filtered and crystallized from isopropanol. 3.5 g of expected product is obtained
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:19]=O.[ClH:21].[CH3:22][NH:23][CH3:24]>C(#N)C>[ClH:21].[CH2:11]([CH:10]([CH2:22][N:23]([CH3:19])[CH3:24])[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNC
Reactant: C=O
Reactant: COc1cccc(C(=O)CCc2ccccc2)c1
Agent: Cl
Solvent: CC#N
Product: COc1cccc(C(=O)C(Cc2ccccc2)CN(C)C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
28 g (0.12 mole) of 1-(3-methoxyphenyl)-3-phenylpropan-1-one were dissolved in 200 ml of acetonitrile, following which 11.3 g (0.12 mole) of the iminium salt of paraformaldehyde and dimethylamine hydrochloride were added under a nitrogen atmosphere. The reaction mixture was then heated for one hour at 60° C. and afterwards cooled to 20° C. The product partially precipitates on stirring overnight. The solvent was removed in vacuo and the crude product was dissolved in water. Sodium bicarbonate was added to the aqueous solution until the pH was 8 and the solution was then extracted three times with ether. The ether extracts were combined, dried over sodium sulfate and the ether was distilled off. The (2RS)-2-benzyl-3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one was dissolved in 100 ml of methyl ethyl ketone and ethereal HCl solution was added until the pH was 1. The resultant precipitate was suction filtered, washed with ether and dried in vacuo; 2-benzyl-3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one hydrochloride was obtained in a yield of 33.0 g (83%) with a melting point of 130° C.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[CH3:27])[N:11]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][CH3:28])=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:21]([CH3:27])[CH:22]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1cc(Cl)ccc1C1c2c(cc(Br)n2C(C)C)C(=O)N1C1CCOCC1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(C1CCOCC1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5-(tetrahydro-pyran-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate AK) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 7.52 min (HPLC 2); ESI-MS: tR=1.25 min, [M+H]+479/481 (LC-MS 1); TLC: Rf=0.36 (EtOAc).
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:13])=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4])[CH3:2].[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH2:21])[CH3:17]>C1COCC1>[ClH:13].[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH:21][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:8][CH:9]=1)[CH3:17]
Reactant: CCN(CC)CCN
Reactant: CCS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1ccc(NS(=O)(=O)CC)cc1
Product: Cl
Temperature: -10 °C

Procedure:
Dissolve 4.97 g (0.22 moles) 4-[(ethylsulfonyl)amino]benzoyl chloride in 25 ml THF. Stir under N2 at -10° C. To the solution add 3.0 ml (0.22 mole) N,N-diethylethylenediamine dropwise. Follow the progress of the reaction by thin layer chromatography on silica gel (acetonitrile:methanol:ammonium hydroxide, 85:10:5). When the reaction is complete, remove the solvents in vacuo. Dissolve the gummy residue in refluxing ethanol and chill to produce white crystals. Filter the precipitate to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=1[CH2:19][NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH3:33])[C:24]=1[CH3:40])=[O:22].CCN(CC)CC>CCO>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=1[CH2:19][NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH:32]([CH:34]2[CH2:35][CH2:36][N:37]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:38][CH2:39]2)[CH3:33])[C:24]=1[CH3:40])=[O:22]
Reactant: Clc1ncccn1
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(c3ncccn3)CC2)c2ccccc12
Temperature: 100 °C
Yield: 64.6 %

Procedure:
To a re-sealable vial was added 2-chloropyrimidine (185 mg, 1.611 mmol), (R or S)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide hydrochloride (508 mg, 1.074 mmol) (Compound 326), and EtOH (8 mL). To this solution was added Et3N (449 μl, 3.22 mmol). The vial was sealed and heated to 100° C. overnight. The solution was allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified via silica gel chromatography (hexanes: (3:2 DCM:IPA)) to afford the title compound as a solid (357 mg, 0.694 mmol, 64.6% yield). LCMS 515 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 11.60 (s, 1 H), 8.30 (d, J=4.7 Hz, 2 H), 7.76 (d, J=7.6 Hz, 1 H), 7.73-7.64 (m, 2 H), 7.14-7.01 (m, 2 H), 6.55 (t, J=4.7 Hz, 1 H), 6.15 (s, 1 H), 4.84-4.75 (m, 1 H), 4.57-4.47 (m, 1 H), 4.33 (d, J=4.2 Hz, 2 H), 4.22-4.11 (m, 1 H), 3.84 (s, 3 H), 2.92-2.81 (m, 1 H), 2.63-2.52 (m, 4 H), 2.20 (s, 3H), 2.05-1.94 (m, 1 H), 1.61-1.49 (m, 4 H), 1.34-1.21 (m, 1 H), 1.04-0.91 (m, 1 H), 0.83-0.75 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:32](=[O:34])[CH3:33])[CH:14]=[C:13]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1cc(N)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,4,6-triamine was dissolved in 1 ml of methylene chloride, and 43 μl of triethylamine, 22 μl of acetic anhydride and 1 mg of 4-dimethylaminopyridine were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water. The solution was subjected to extraction with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 32 mg of the objective compound as yellow powder.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[C:15]([NH:26][CH2:27][C:28]([NH:30][CH:31]2[CH2:34][N:33]([CH:35]3[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=O)[CH2:37][CH2:36]3)[CH2:32]2)=[O:29])=[N:14]1.[NH2:44][CH2:45][CH2:46][OH:47]>>[OH:47][CH2:46][CH2:45][NH:44][C:41]([CH:38]1[CH2:39][CH2:40][CH:35]([N:33]2[CH2:34][CH:31]([NH:30][C:28](=[O:29])[CH2:27][NH:26][C:15]3[C:16]4[C:21](=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=4)[N:13]([CH3:12])[N:14]=3)[CH2:32]2)[CH2:36][CH2:37]1)=[O:43]
Reactant: NCCO
Reactant: Cn1nc(NCC(=O)NC2CN(C3CCC(C(=O)O)CC3)C2)c2cc(C(F)(F)F)ccc21
Agent: CCN=C=NCCCN(C)C
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(C(=O)NCCO)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared from EDCI coupling of 4-{3-[2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetylamino]-azetidin-1-yl}-cyclohexanecarboxylic acid (as prepared in Example 39, Step A) and 2-aminoethanol using the procedure described in Example 39.
Reaction SMILES: CS[C:3](=[N:7][C:8]1C=CC=CN=1)[NH:4][C:5]#[N:6].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])C.CCOCC>N1C=CC=CC=1>[C:5]([NH:4][C:3]([NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[N:7][C:8]1[CH:27]=[CH:26][N:25]=[CH:28][CH:29]=1)#[N:6]
Reactant: CCN(CC)CC
Reactant: CSC(=Nc1ccccn1)NC#N
Reactant: NCCN1CCNCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#CNC(=Nc1ccncc1)NCCN1CCNCC1
Temperature: 25 °C

Procedure:
S-methyl-N-cyano-N′-pyridylisothiourea (3.84 g, 20 mmol) and 1-(2-aminoethyl)piperazine (2.89 ml, 22 mmol) were suspended in pyridine (8 mL) in a reaction flask equipped with magnetic stirring under nitrogen. Triethylamine (2.8 mL, 20 mmol) was added followed by (4-dimethylamino)-pyridine (cat., 100 mg). The reaction mixture became clear. It was stirred at 50-60° C. for 12 hours and cooled to room temperature. Ether (100 mL) was then added and precipitate formed. The precipitate was collected to give crude N-cyano-N′-(2-piperazin-1-yl-ethyl)-N″-pyridin-4-yl-guanidine which was used without further purification. ESMS 274.2 (M+1).