Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[N:6]=1)=[O:4].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[S:12]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:14])=[O:13]
Reactant: COC(=O)c1ccc(C)c(S(=O)(=O)N2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)nc1S(=O)(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
5-Methyl-6-(piperidine-1-sulfonyl)-pyridine-2-carboxylic acid methyl ester (53 mg, 0.178 mmol) in dioxane (2 mL) was added to a solution of lithium hydroxide monohydrate (CAN 1310-66-3, 0.1 g, 2.38 mmol) in water (2 mL) and the mixture was stirred for 2 h at room temperature. The solvent was removed in vacuo, water (10 mL) was added, and the pH was adjusted to 3 with 1 N hydrochloric acid. The mixture was extracted by ethyl acetate (2×10 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the product (36 mg, 71%); MS (EI): m/e=285.2 [M+H]+.
Reaction SMILES: [NH4+:1].[OH-].[CH:3]1([O:9][CH2:10][C:11](Cl)=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(Cl)Cl>[CH:3]1([O:9][CH2:10][C:11]([NH2:1])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Cl)COC1CCCCC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)COC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
To 15 mL of NH4OH (25-28%) was added a solution of 2-(cyclohexyloxy)acetyl chloride (1.01 g, 5.72 mmol) in DCM (2 mL) in an ice bath and the mixture was stirred at rt for 5 min and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (0.5 g, 56%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O.[C:14]([O:17][CH2:18][CH3:19])(=[O:16])[CH3:15]>C1COCC1>[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH2:6][CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OC)cc1F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
An oven dried flask was charged with sodium hydride (60%) (389 mg, 9.73 mmol) and THF (25 mL) and cooled to 0° C. Triethyl phosphonoacetate (1.948 mL, 9.73 mmol) was added dropwise and the reaction was heated to 50° C. for 1 hr. The reaction was then cooled to 0° C., and 2-fluoro-4-methoxy-benzaldehyde (1000 mg, 6.49 mmol) was added via cannula in THF (4×5 mL). The reaction was then heated at reflux for 16 hours. Next, the reaction was cooled to room temperature and diluted with ethyl acetate (75 mL). The organic layer was washed with water (2×75 mL) and brine (75 mL), dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in ethanol (20 mL) and 10% palladium on carbon (100 mg) was added. The reaction was placed under an atmosphere of H2 (balloon) and stirred for 4 hours. The reaction was then filtered and concentrated. Purification of the residue via flash chromatography on silica gel (0 to 40% ethyl acetate/hexanes) afforded ethyl 3-(2-fluoro-4-methoxyphenyl)propanoate. 1H NMR (CDCl3, 500 MHz) δ 7.09 (t, J=8.5 Hz, 1H), 6.60 (m, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.77 (s, 3H), 2.90 (t, J=7.6 Hz, 2H), 2.58 (t, J=7.7 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:19]([O-])([O-])[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[F:1][C:2]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([C:6](=[CH:19][O:20][CH2:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(C)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(C)c1F
Reaction time: 5 h
Yield: 99.2 %

Procedure:
A mixture of ethyl 2-(2,4,5-trifluoro-3-methylbenzoyl)acetate (5.02 g), ethyl orthoformate (4.29 g) and acetic anhydride (4.93 g) was stirred at 130° to 135° C. for 5 hours and then concentrated under reduced pressure to give the title compound (6.05 g) as red oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][C:11]([CH3:17])=[CH:12][C:13](OC)=[O:14].CS(O)(=O)=O>O>[CH3:10][C:11]1([CH3:17])[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=2[CH3:8])[O:9][C:13](=[O:14])[CH2:12]1
Reactant: COC(=O)C=C(C)C
Reactant: Cc1cc(C)cc(O)c1
Agent: CS(=O)(=O)O
Solvent: O
Product: Cc1cc(C)c2c(c1)OC(=O)CC2(C)C
Yield: 92.4 %

Procedure:
3,5-Dimethylphenol (5.00 g, 0.0409 mol) and methyl 3,3-dimethylacrylate (5.14 g, 0.045 mol) were added to methanesulfonic acid (5 mL) at room temperature followed by heating at 70° for 17 hours. The reaction was cooled, diluted with water (750 mL), extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with saturated aqueous sodium hydrogencarbonate (2×100 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel flash chromatography eluting with methylene chloride afforded the title compound as a beige solid (7.73 g, 0.0378 mol, 92%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.43 (s, 6 H) 2.27 (s, 3 H) 2.46 (s, 3 H) 2.59 (s, 2 H) 6.74 (s, 2 H). MS (DCI) m/z 205 (M+H)+, 222 (M+NH4)+.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:4]=[N:5][C:6](Cl)=[CH:7][CH:8]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:6]1[N:5]=[N:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCc1ccccc1
Agent: [Na]
Product: Clc1ccc(OCc2ccccc2)nn1
Reaction time: 24 h
Yield: 90 %

Procedure:
Sodium metal (3.1 g) was added to benzyl alcohol (75 mL) and gently warmed to 50° C. for 30 minutes until all the sodium metal dissolved. A solution of 3,6-dichloropyridazine (135 mmol) in benzyl alcohol (75 mL) was added. The reaction mixture was kept at 100° C. for 24 hours. Excess benzyl alcohol was evaporated and the residue was extracted with ethyl acetate (3×100 mL) and the ethyl acetate extract was washed with water. The resulting ethyl acetate layer was collected, dried, filtered, and the filtrate was evaporated to afford the title compound (90%, 26.7 g); mp, 77-78° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-])=O)=[N:12][CH:13]=2)[CH2:4][CH2:3]1>[Pd].CCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(c2ccc(N)nc2)CC1
Reaction time: 2 h
Yield: 103.1 %

Procedure:
In a hydrogenation bottle, 130a (1.25 g, 5.73 mmol), EtOH (100 mL), 10% Pd/C (304 mmol, 0.286 mmol) were added. The mixture was hydrogenated at 55 psi for 2 hrs, filtered through celite, and washed with MeOH (20 mL). The solvent was removed in vacuo and off-white solids were obtained as 5-(1-methylpiperidin-4-yl)pyridin-2-amine 130b (1.13 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:35][NH:36][C:37](=O)[CH2:38][N:39]([CH3:41])[CH3:40])=[N:10][N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:37]([CH2:38][N:39]([CH3:41])[CH3:40])=[N:36][N:35]=3)[N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)CN(C)C)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc(CN(C)C)n21
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
To a round bottom flask was added N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)-2-(dimethylamino)acetohydrazide (25 mg, 0.0446 mmol) and toluene (3 ml). The reaction was stirred at 120° C. for 15 min. Then POCl3 (0.3 ml) was added and the reaction was stirred at 120° C. for additional 40 min. After this time, the solution was cooled to rt and the reaction mixture was concentrated. The residue was partitioned between EtOAc (30 ml) and NaHCO3 (sat, 20 ml). The organic layer was separated and washed with water (10 ml) and saturated NaCl (10 ml). The organic layer was then dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (4 g silica gel) eluting with a gradient of 0-80% EtOAc/CH2Cl2 to give product 4-(8-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as an off white solid (10 mg, 39% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[O:20][C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=1>>[NH2:18][C:19]1[O:20][C:21]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=2)[CH3:16])=[O:26])=[C:22]([CH3:24])[N:23]=1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: Cc1nc(N)oc1C(=O)O
Agent: Cl
Product: Cc1nc(N)oc1C(=O)NC(C)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 41 %

Procedure:
The title compound is prepared in 41% yield (92 mg, a white solid) from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (171 mg, 0.59 mmol, Amine-5, single enantiomer) and 2-amino-4-methyloxazole-5-carboxylic acid (100 mg, 0.70 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:28])[CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:27])=[C:5]([CH3:29])[CH:4]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)Cl>[OH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9](=[O:28])[CH2:10][N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:27])=[C:5]([CH3:29])[CH:4]=2)[CH2:33][CH2:32]1
Reactant: COc1ccc(COc2ccn(CC(=O)c3ccc(CBr)cc3C)c(=O)c2)nc1
Reactant: OC1CCNCC1
Solvent: ClCCl
Product: COc1ccc(COc2ccn(CC(=O)c3ccc(CN4CCC(O)CC4)cc3C)c(=O)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 11d, 129 mg, 0.28 mmol) in CH2Cl2 (2 mL) is added 4-hydroxypiperidine (85 mg, 0.84 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is purified via reverse phase HPLC chromatography (Waters Xbridge C18 5 μm, gradient 50%→95% methanol in water+0.1% NH4OH, 120 mL/min).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+]>CN(C=O)C>[C:19]([O:22][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1)(=[O:21])[CH3:20]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(CCl)nc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(COC(C)=O)nc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 107 %

Procedure:
To a solution of methyl 2-(chloromethyl)-6-nitro-1H-benzimidazole-4-carboxylate (Example 58, Step 1) (99 mg) in DMF (1 mL), was added sodium acetate (17 mg), and the mixture was stirred at 50° C. for 6 hours. To the reaction mixture was added ice water, and it was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified on column chromatography to obtain the titled compound (65 mg) as colorless powder.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=O)[O:10][C@@H:9]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:8]1)(=[O:5])[CH3:4].[O:29]1CCCC1>>[C:17]([O:16][CH2:14][CH2:13][CH2:12][C@H:11]1[O:10][C@@H:9]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:8][C@@H:7]1[O:6][C:3](=[O:5])[CH3:4])(=[O:29])[CH3:18]
Reactant: C1CCOC1
Reactant: CCOC(=O)CC[C@H]1O[C@@H](n2cc(CC)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Agent: [BH4-]
Agent: [Li+]
Product: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CCCOC(C)=O)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.4 g of lithium borohydride was added to a solution of 5.6 g of 3'-O-acetyl-2',5'-dideoxy-5'-(ethoxycarbonylmethyl)-5-ethyluridine in 100 ml of tetrahydrofuran and the mixture was stirred at room temperature for 4 hours. An additional 0.2 g of lithium borohydride was added and the mixture was stirred at room temperature overnight and then heated under reflux for 1 hour. The solvent was removed by evaporation in vacuo and the residue was dissolved in methanol. After standing at room temperature for a few minutes, the solvent was removed by evaporation and the residue was taken up in 40 ml of pyridine. 5 g of acetic anhydride were added and the mixture was stirred at room temperature overnight. Pyridine was removed by evaporation and the residue was partitioned between water and ethyl acetate. The aqueous solution was evaporated to dryness and the residue was subjected to flash chromatography on a column of silica gel using 10% methanol/dichloromethane for the elution to give 1.3 g of 5'-(2-acetoxyethyl)- 3'-O-acetyl-2',5'-dideoxy-5-ethyluridine in the form of a colorless oil which crystallized upon standing.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:22])[O:15][C@:14]2([CH3:21])[CH2:16][C@@H:17]([CH2:19][OH:20])[O:18][CH:13]2[O:12]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:20][CH2:19][C@H:17]1[O:18][CH:13]2[C@:14]([CH3:21])([O:15][C:11]([CH3:22])([CH3:10])[O:12]2)[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC2O[C@H](CO)C[C@@]2(C)O1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC1(C)OC2O[C@H](COC(=O)c3ccccc3)C[C@@]2(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.6 %

Procedure:
Benzoyl chloride (1.92 mL, 0.0166 mol) was added to a solution of ((5S,6aR)-2,2,6a-trimethyl-dihydro-5H-furo[3,2-d][1,3]dioxol-5-yl)methanol (from step 8) (2.72 g, 0.0138 mol) in 20 mL of anhydrous pyridine at 0° C. To this mixture 5 mol % of DMAP was added and stirred at room temperature for 3 h. Pyridine was removed under vacuum; the residue was diluted with ethyl acetate and washed with 1N HCl, saturated NaHCO3 and brine. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The compound was purified via column chromatography using hexane and ethyl acetate as a gradient mixture to give 4.1 g of the title compound (97% yield).
Reaction SMILES: [CH2:1](N1C(C)(C)C(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O)[CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=2)[C:6]1=[O:26].I[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]I>>[CH2:4]([N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:50]2[CH:55]=[CH:54][C:53]([N+:19]([O-:21])=[O:20])=[C:52]([C:22]([F:23])([F:25])[F:24])[CH:51]=2)[C:6]1=[O:26])[CH2:3][CH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([C:22]([F:24])([F:23])[F:25])[CH:14]=2)[C:6]1=[O:26]
Reactant: ICCCCCCI
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Yield: 27 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 1, 1,6-diiodohexane replacing 1,4-dibromobutane. The expected compound is obtained in the form of a light yellow solid with a yield of 27%. Melting point: 187-188° C.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:27])[C@@H:6]([N:18]1[C:24](=[O:25])[CH2:23][CH2:22][NH:21][C@H:20]([CH3:26])[CH2:19]1)[CH2:7][CH2:8][N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1.[Cl:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>>[CH3:3][O:4][C:5](=[O:27])[C@@H:6]([N:18]1[C:24](=[O:25])[CH2:23][CH2:22][N:21]([C:36](=[O:37])[NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=2)[C@H:20]([CH3:26])[CH2:19]1)[CH2:7][CH2:8][N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)NCCC1=O
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)Nc2cccc(Cl)c2)CCC1=O
Yield: 59 %

Procedure:
In analogy to the procedure described in example 58F, (S)-4-((S)-4-hydroxy-6-aza-spiro[2. 5]oct-6-yl)-2-((R)-3-methyl-7-oxo-[1,4]diazepan-1-yl)-butyric acid methyl ester dihydrochloride and 3-chlorophenyl isocyanate gave the title compound in 59% yield as off-white solid. MS: 506.2 (MH+, 1Cl).
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[C:8]([N:13]2[C:17]([C:18]([OH:20])=O)=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[N:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C.[NH2:32][C:33]1[C:41]([CH3:42])=[CH:40][C:39]([I:43])=[CH:38][C:34]=1[C:35](O)=[O:36]>C(#N)C>[Cl:6][C:7]1[C:8]([N:13]2[C:17]([C:18]3[O:20][C:35](=[O:36])[C:34]4[CH:38]=[C:39]([I:43])[CH:40]=[C:41]([CH3:42])[C:33]=4[N:32]=3)=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[N:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cc(I)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of methanesulfonyl chloride (2.91 mL, 37.74 mmol) in acetonitrile (50 mL) was added dropwise a mixture of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Step C) (10.0 g, 34.31 mmol) and triethylamine (4.78 mL, 34.31 mmol) in acetonitrile (50 mL) at −5° C. The reaction temperature was then maintained at 0° C. throughout successive addition of reagents. After stirring for 20 minutes, 2-amino-3-methyl-5-iodobenzoic acid (i.e. the product from Step A) (9.51 g, 34.31 mmol) was added and stirring was continued for an additional 10 minutes. A solution of triethylamine (9.56 mL, 68.62 mmol) in acetonitrile (15 mL) was then added dropwise, and the reaction mixture was stirred 30 minutes, followed by the addition of methanesulfonyl chloride (2.91 mL, 37.74 mmol). The reaction mixture was then warmed to room temperature and stirred 2 hours. The solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 8.53 g of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:24]([OH:26])=O)[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH2:36][CH:37]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[NH2:41][C:39](=[O:40])[CH2:38][CH:37]([NH:36][C:24]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][CH2:11][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:13][CH2:14]1)=[O:26])[C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(=O)CC(N)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CC(N)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 79.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluoro-phosphate (129 mg, 0.34 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (82 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.112 mL, 0.68 mmol) in DMF (4 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. 3-amino-3-(4-chlorophenyl)propanamide (Intermediate 107) (45 mg, 0.23 mmol) was then added to the reaction and stirred for 3 hours. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(3-amino-1-(4-chlorophenyl)-3-oxopropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (99 mg, 100%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=2[O:2]1.[N+:11]([O-])(O)=O.O>C(O)(=O)C>[CH2:1]1[O:2][C:3]2[CH:4]=[C:5]([CH3:10])[C:6]([NH2:11])=[CH:7][C:8]=2[O:9]1
Reactant: Cc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(cc1N)OCO2
Reaction time: 0.75 h
Yield: 87 %

Procedure:
To a solution of (3,4-methylenedioxy)toluene (5 ml) in acetic acid (20 ml) cooled with a cold water bath was added, dropwise, nitric acid (70%, 5 ml). The mixture was stirred for 45 min. To work up, water (100 ml) was added and the resulting yellow precipitate was filtered and washed with water until the aqueous filtrate was colorless. The yellow solid was dissolved in EtOAc (250 ml) and dried (MgSO4), and the solid was filtered off. The filtrate was subjected to catalytic hydrogenation (10% Pd/C, 1 atm) for 12 hours. The reaction mixture was then filtered off the catalyst and the filtrate was concentrated on a rotavap to give (3,4-methylenedioxy)-6-methylaniline as a brownish grey solid (5.49g, 87% yield).
Reaction SMILES: Cl.FC1C=CC=C(F)C=1C([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:23][C:16]=23)=[C:10]([F:30])[CH:9]=1)=O.[O:36]=[C:37]1[C:42]([C:43]([OH:45])=O)=[CH:41][CH:40]=[CH:39][N:38]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[F:30][C:10]1[CH:9]=[C:8]([NH:7][C:43]([C:42]2[C:37](=[O:36])[N:38]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:39]=[CH:40][CH:41]=2)=[O:45])[CH:13]=[CH:12][C:11]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:23][C:16]=12
Reactant: O=C(O)c1cccn(-c2ccccc2)c1=O
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1c(F)cccc1F
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1cccn(-c2ccccc2)c1=O

Procedure:
Prepared in a similar manner as Example 239 using 3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (Compound E of Example 237) and 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid. 1H NMR (DMSO-d6) δ 12.87 (s, 1H), 12.18 (s, 1H), 9.39 (s, 1H), 8.70–8.85 (m, 2H), 8.60 (d, 1H, J=7.1 Hz), 8.00–8.25 (m, 3H), 7.94 (s, 1H), 7.30–7.75 (m, 8H), 6.77 (t, 1H, J=6.6 Hz), 6.45 (d, 1H, J=4.6 Hz), 4.21 (s, 2H), 3.68 (s, 2H), 2.43 (s, 6H); LC/MS(ESI+) m/z 518 (M+H)+.