Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C.Cl.O1CCOCC1>CS(C)=O>[NH:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=2)[CH2:17][CH2:18]1
Reactant: OCCc1cc(Cl)nc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: OCCc1cc(NC2CCNCC2)nc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2.33 h

Procedure:
A mixture of 2-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]ethanol (0.085 g, 0.38 mmol, from Step 1), tert-butyl 4-aminopiperidine-1-carboxylate (0.30 g, 1.5 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) in dimethyl sulfoxide (0.86 mL) was heated in the microwave to 100° C. for one hour, then to 140° C. for 140 minutes. The reaction mixture was concentrated. The residue was dissolved in 1,4-dioxane (2.8 mL) and was treated with 4.0 M hydrogen chloride in dioxane (2.8 mL, 11 mmol). After stirring overnight, solvent was removed in vacuo. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded two major fractions, the desired product was the first eluting of the peaks having the desired mass (16 mg, 15%). LCMS (M+H)+: 290.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C.O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([CH:22]4[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2c1c(I)cn2C1CCNCC1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(Cl)Cl
Product: CN1CCC(N2CCC(n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
A mixture of 4-chloro-5-iodo-7-(4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidine (0.52 g, 1.43 mmol), 1-methyl-4-piperidone (0.178 g, 1.57 mmol), and glacial acetic acid (0.094 g, 1.57 mmol) in dichloroethane was stirred at 0° C. for 20 minutes. Sodium 15 triacetoxy borohydride (0.455 g, 2.15 mmol) was added and stirred for 15 minutes at 0° C., after which the ice bath was removed, allowed to warm to room temperature and stirred over night. Additional 1-methyl-4-piperidone (0.178 g, 1.57 mmol), glacial acetic acid (0.094 g, 1.57 mmol), and sodium triacetoxy borohydride (0.455 g, 2.15 mmol) were added and stirred at room temperature. To the reaction solution was added sodium bicarbonate (0.721 g, 8.58 mmol) in water (10 mL) and stirred for 1 hour. The organic layer was evaporated under reduced pressure. Ethyl acetate was added, the layers were partitioned, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The compound was purified by flash chromatography on silica using dichloromethane/ethyl acetate (1:1), 10% methanol in dichloromethane, and then 20% methanol in dichloromethane to give 400 mg (61%) of 4-chloro-5-iodo-7-[1-(1-methyl-4-piperidinyl)-4-piperidinyl]-7H-pyrrolo[2,3-d]pyrimidine
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[N:10][OH:11])[CH2:4][C:3]1([CH3:13])[CH3:12].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:10]([CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:13])([CH3:12])[CH2:4]1)[OH:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1C(C)(C)CC(=NO)CC1(C)C
Reactant: BrCc1ccccc1
Product: CN1C(C)(C)CC(N(O)Cc2ccccc2)CC1(C)C
Yield: 40 %

Procedure:
Following the procedure of Example 1, the title compound is prepared from 1,2,2,6,6-pentamethylpiperidin-4-one oxime (5.0 g, 27 mmol) and benzyl bromide (4.6 g, 27 mmol) in a 40% yield to give 3.0 g of a white solid which melts at 107°-108° C. after recrystallization from ethanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:20]12[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:25]C(=O)O[C:21]2=[O:22]>CCO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:21](=[O:22])[C:20]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH2:25])=[CH:5][CH:4]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1C(=O)NNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
4-Chlorophenylhydrazine hydrochloride (2.105 g, 14.76 mmol) was suspended in EtOH (25 ml), treated with di-isopropylethylamine (2.253 ml, 12.93 mmol) and stirred for 30 minutes. Isatoic anhydride (1.918 g, 11.76 mmol) was added and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and stirred overnight. The material was concentrated to dryness and the resulting residue was partitioned between EtOAc (˜25 ml) and 50% saturated NaCl (3×30 ml). The organic layer (also containing a small amount of emulsion which would not dissipate over 3 extractions) was dried over MgSO4 and concentrated to an orange solid. The material was triturated with EtOAc, filtered and rinsed with additional EtOAc. The filtrate was concentrated to dryness and treated with DCM (dichloromethane). The mixture was stirred overnight. The mixture was filtered, rinsed with DCM and the solid dried to provide 1.538 g (50%) of 2-amino-benzoic acid N′-(4-chloro-phenyl)-hydrazide (Intermediate 40) as a mauve-colored solid. MS (APCI): (M+1)=262.1, (M−1)=260.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@@H:15]([CH2:21][CH3:22])[C:16](OCC)=[O:17])[C@@H:9]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:9]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:10]([C@@H:15]([CH2:21][CH3:22])[CH2:16][OH:17])[C:11](=[O:14])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](CC)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 3 g (6.9 mmol) of (S)-ethyl 242S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate (Example 9, Step A) in 45 mL of Et2O was added lithium tetrahydroborate (0.334 g, 13.81 mmol) at 0° C. After being stirred at 0° C. for 50 min, the reaction was quenched (ice cold 10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: 30% to 60% EtOAc/Hexanes, gradient elution) provided the title compound.
Reaction SMILES: ClC1C=CC(CN2CCC(NC3C=CC(C#N)=CC=3)CC2)=CC=1OCC.C(OC([N:34]1[CH2:39][CH2:38][CH:37]([N:40](C(OC(C)(C)C)=O)[C:41]2[CH:46]=[CH:45][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][N:42]=2)[CH2:36][CH2:35]1)=O)(C)(C)C.Cl>O1CCOCC1.C(O)C>[NH:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41]2[N:42]=[CH:43][C:44]([O:47][S:48]([CH3:51])(=[O:49])=[O:50])=[CH:45][CH:46]=2)[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(OS(C)(=O)=O)cn2)CC1
Agent: CCOc1cc(CN2CCC(Nc3ccc(C#N)cc3)CC2)ccc1Cl
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CS(=O)(=O)Oc1ccc(NC2CCNCC2)nc1

Procedure:
The title compound was prepared in analogy to the procedure described for (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediate B16/step 2) from 4-[tert-butoxycarbonyl-(5-methanesulfonyloxy-pyridin-2-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester by cleavage of the BOC group with 4 M HCl in dioxane and ethanol at 70° C. MS (ISP): 272.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.N(C(OCC)=O)=NC(OCC)=O>CCOC(C)=O.CCOC(C)=O.CCCCCC.C1COCC1>[N:47]1([CH2:46][CH2:45][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=4)[NH:10][N:9]=3)=[CH:4][CH:3]=2)[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: N#Cc1ccc2c(c1)c(-c1ccc(O)cc1)nn2C1CCCCO1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]nc(-c3ccc(OCCN4CCOCC4)cc3)c2c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 71.1 %

Procedure:
A mixture of 3-(4-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.25 mmol), triphenylphosphine (Ph3P, 1.31 g, 5.00 mmol, 4.00 equiv.), 4.00 mL THF, 4-(2-hydroxyethyl)morpholine (656 mg, 5.00 mmol, 4.00 equiv.), and diethyl azodicarboxylate (DEAD, 871 mg, 5.00 mmol, 4.00 equiv.) were stirred at room temperature for 5 days. The reaction was diluted with EtOAc and washed with 2×6.0 N aq. HCl. The combined aqueous layers were extracted with 2×EtOAc. The acidic aqueous layer was allowed to stand at room temperature for 5 h, and then added to enough 6.0 N aq. NaOH such that the final pH>12.0. The aqueous layer was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by silica gel chromatography using 0-5% MeOH in EtOAc as eluent afforded an oil. Sonication of the oil in 15 mL of 10% EtOAc/hexane gave a precipitate. This mixture was diluted with 18 mL of hexanes, sonicated, and filtered affording the title compound (310 mg, 71.1% yield: ES-MS (m/z) 349 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=1)=[O:13].[NH2:29][OH:30].[OH-].[Na+].Cl>CO.C1COCC1>[OH:30][NH:29][C:22](=[O:24])[C:21]1[CH:26]=[CH:27][C:18]([O:17][CH2:16][CH2:15][NH:14][C:12]([C:4]2[O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:3]=2[N:2]([CH3:1])[CH3:28])=[O:13])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2N(C)C)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1c(C(=O)NCCOc2ccc(C(=O)NO)cc2)oc2ccccc12
Reaction time: 8 h

Procedure:
To a solution of crude methyl 4-[2-(3-dimethylaminobenzofuran-2-yl-carbonylamino)-ethoxy]-benzoate in MeOH and THF was added excess aqueous hydroxylamine solution and NaOH(aq.) to give pH 10-11. The reaction mixture was stirred overnight and then neutralized to pH 7-8 with aqueous hydrochloric acid and concentrated in vacuo. The residue was dissolved in acetonitrile and water and purified with prep HPLC to give the title compound (107 mg). 1H NMR (400 MHz, DMSO-d6) δ 9.88 (m, 1H), 9.31 (t, J=6.0 Hz, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.70 (m, 3H), 7.57 (t, J=7.6 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 6.99 (d, J=9.2 Hz, 2H), 4.76 (d, J=4.8 Hz, 2H), 4.23 (t, J=6.0 Hz, 2H), 3.71 (m, 2H), 2.84 (s, 3H), 2.83 (s, 3H). EM (calc.): 397.2; MS (ESI) m/e (M+1H)+: 398.1, (M−1H)−: 396.2:
Reaction SMILES: Cl.[O:2](CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC([Cl:79])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C2C(=CC=CC=2)C=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:110][CH:111]([CH2:126][O:127][C:128]1[CH:133]=[CH:132][C:131]([O:134][CH3:135])=[CH:130][CH:129]=1)[CH2:112][NH:113][C:114]([CH3:125])([CH3:124])[CH2:115][C:116]1[CH:121]=[CH:120][C:119]([O:122][CH3:123])=[CH:118][CH:117]=1>>[ClH:79].[OH:110][CH:111]([CH2:126][O:127][C:128]1[CH:133]=[CH:132][C:131]([O:134][CH3:135])=[C:130]([O:2][CH3:3])[CH:129]=1)[CH2:112][NH:113][C:114]([CH3:125])([CH3:124])[CH2:115][C:116]1[CH:117]=[CH:118][C:119]([O:122][CH3:123])=[CH:120][CH:121]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)c(OC)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 390 (M+, 0.0), 269 (17), 268 (100), 163 (6), 153 (5), 121 (21), 114 (17), 77 (5), 71 (19), 70 (17), 58 (7).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9](/[C:19](=[N:21]/O)/[NH2:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.C([O-])=O.[NH4+].CO.C(Cl)Cl>C(O)(=O)C.[Pd]>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[NH:20])[NH2:21])[C:8]=3[CH:23]=2)[CH2:2][CH2:3]1
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(/C(N)=N/O)c2cc1C1CC1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(C(=N)N)c2cc1C1CC1)S(C)(=O)=O
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
In a 25-mL round bottom flask purged with nitrogen, (Z)-5-cyclopropyl-2-(4-fluorophenyl)-N′-hydroxy-6-(N-isopentylmethylsulfonamido)benzofuran-3-carboximidamide (200 mg, 0.422 mmol) was dissolved in glacial acetic acid (4 mL), and ammonium formate (133 mg, 2.112 mmol) and 10% Pd—C (100 mg, 0.094 mmol) were added. The mixture was heated in an oil bath at 120° C. for 2.5 hours. TLC (SiO2, 5% methanol/CH2Cl2) showed the reaction was complete. The reaction was cooled to room temperature, filtered through Celite® 545, washed with additional ethyl acetate, and concentrated the filtrate by rotary evaporation. The amidine acetic acid salt was dissolved in H2O (25 mL) and ethyl acetate (50 mL), the pH was adjusted with 1 N aqueous NaOH, and the mixture was stirred for 10 minutes, re-adjusting the aqueous pH˜12 as needed. The organic phase was washed with brine (25 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation co-evaporating with CH2Cl2/hexanes to afford the title compound as a yellow solid (175 mg). The material was 84% pure by analytical HPLC. MS (ESI+) m/z 458 (M+H)+, 915 (2M+H)+; MS (ESI−) m/z 456 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)=[N:15][N:14]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:33](=[O:37])[N:34]([CH3:36])[CH3:35].[N:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:44]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:45])=[C:3]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[CH:4]=3)[CH:9]=2)[N:14]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[N:15]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2cccc(Cl)c2)nn3COC(=O)C(C)(C)C)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2cccc(Cl)c2)nn3COC(=O)C(C)(C)C)ccc1NC(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 49.3 %

Procedure:
2,2-Dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(3-chloro-benzyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (300 mg, 0.577 mmol), chloroform (50 ml), 4-morpholinecarbonyl chloride (1.2 ml, 10.45 mmol), and di-iso-propyl ethyl amine (2.4 ml, 13.78 mmol) were combined and stirred for 48 hours at 50° C. The reaction was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 180 mg (49%) of 2,2-dimethyl-propionic acid 3-(3-chloro-benzyl)-5-{3-dimethylcarbamoyl-4-[(morpholine-4-carbonyl)-amino]-phenyl}-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. MS: m/z 633.5 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=O.[ClH:6].[F:7][C:8]([F:19])([F:18])[C:9]1[N:13]2[CH2:14][CH2:15][NH:16][CH2:17][C:12]2=[N:11][N:10]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:6][CH2:2][C:3]([N:16]1[CH2:15][CH2:14][N:13]2[C:9]([C:8]([F:18])([F:7])[F:19])=[N:10][N:11]=[C:12]2[CH2:17]1)=[O:5]
Reactant: O=C(O)CBr
Reactant: Cl
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCl)N1CCn2c(nnc2C(F)(F)F)C1
Yield: 33 %

Procedure:
Bromoacetic acid (300 mg, 2.2 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (490 mg, 2.2 mmol) were stirred in dichloromethane (5 mL) with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (412 mg, 2.2 mmol) and N,N-diisopropylethylamine (560 mL, 3.2 μmol) for 3 hours at rt. The mixture was washed with water, dried over sodium sulfate and evaporated to give the desired compound in 33% yield. LCMS for C8H8ClF3N4O (M+H)+: m/z=269.0.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH:16]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18][CH2:17]2.CCN(C(C)C)C(C)C>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([N:18]2[CH2:19][CH:20]3[CH2:23][CH2:24][CH:16]([CH2:22][CH2:21]3)[CH2:17]2)(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: C1CC2CCC1CNC2
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CC3CCC(CC3)C2)c2ccccc12

Procedure:
The title compound was prepared by reacting 4-methyl-1-naphthalenesulfonyl chloride (0.69 g) with 3-azabicyclo[3.2.2]nonane (0.43 g) in the presence of DIEA using a procedure similar to that of Example 5. Yield 1.00 g of a grey solid, mp: 143.3°-147.2° C.
Reaction SMILES: C(Cl)(Cl)Cl.C1(C)C=CC(S(O[CH2:15][CH:16]2[S:28][C:20]3=[N:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[N:19]3[CH2:18][CH2:17]2)(=O)=O)=CC=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O>[N:30]1([CH2:15][CH:16]2[S:28][C:20]3=[N:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[N:19]3[CH2:18][CH2:17]2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: C1CNCCN1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: c1ccc2c(c1)nc1n2CCC(CN2CCNCC2)S1
Yield: 51.9 %

Procedure:
To 30 ml of chloroform were dissolved 3 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole and 10 g of piperazine. The resultant solution was refluxed for 18 hours. The reaction mixture was cooled, added with water and then extracted with chloroform, followed by washing the chloroform layer and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure and the residue was chromatographed on silica gel and eluted with chloroform to obtain 1.2 g (Yield: 51%) of the intended product, m.p. 151°-153° C.; IR νmaxKBr cm-1 : 3600-3000, 3100-2800, 1420; Anal. Calcd. for C15H20N4S: C, 62.47; L H, 6.99; N, 19.43; S, 11.11; Found: C, 62.41; H, 7.01; N, 19.70; S, 10.88.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[S:16]([O-:19])(=O)=[O:17])[CH2:3][CH2:2]1.[Na+].P(Cl)(Cl)([Cl:23])=O>C(#N)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[S:16]([Cl:23])(=[O:19])=[O:17])[CH2:3][CH2:2]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(S(=O)(=O)Cl)c1
Temperature: 0 °C

Procedure:
31 g (0.1 mol) of sodium 2-morpholino-5-nitrobenzenesulfonate obtained in Step (a) above and 60 ml (0.67 mol) of phosphorus oxychloride were added to 300 ml of acetonitrile and the mixture was refluxed by heating for 2 hours. After cooling, the reaction mixture was added to 600 ml of ice water. The crystals thus-precipitated were collected by filtration. Yield: 18.5 g (60%).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[CH3:32].[CH:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[CH3:32])=[CH:41]/[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1C)P(=O)(OC)OC
Reactant: O=Cc1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Product: COC(=O)/C(=C/c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1C
Yield: 75 %

Procedure:
1,1,3,3-Tetramethylguanidine (0.20 g, 1.7 inmol) was added to a solution of rac.-N-[4-[[(3-hydroxybenzyl)anlino]carbonyl]-2-methylbenzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 140; 0.40 g, 0.9 mmol) and benzaldehyde (0.10 g, 0.9 mmol) in dichloromethane (50 mL) at room temperature and the reaction was stirred at ambient temperature over the weekend. The solution was diluted with dichloromethane (200 mL) and washed in turn with 1N hydrochloric acid solution, water and brine (200 mL each), dried (MgSO4) and evaporated to give (Z)-2-[[4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoyl]amino]-3-phenylpropenoic acid methyl ester (300 mg, 78% yield) which was used directly in a subsequent step.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[Na].[C:11]([C:13]1[N:17]([CH3:18])[C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)#N.C1([O:29]C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:18][N:17]1[C:13]([C:11]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)=[O:29])=[CH:14][CH:15]=[C:16]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: Cc1ccc(Br)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: Cn1c(C#N)ccc1CC(=O)O
Agent: [Mg]
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Temperature: 110 °C
Yield: 75 %

Procedure:
To a solution of the Grignard reagent prepared from 0.46 g. (20 mmol) of magnesium and 3.4 g. (20 mmol) of 4-bromotoluene in 15 ml. of anhydrous tetrahydrofuran was added under an atmosphere of nitrogen 1.12 g. (6.0 mmol) of the sodium salt of 5-cyano-1-methylpyrrole-2-acetic acid. To the resulting suspension was added 20 g. of diphenyl ether, and the reaction mixture was heated to remove tetrahydrofuran by distillation until the temperature reached 110° C. The reaction mixture was then successively heated under reflux at 110° C. for two hours, cooled, and partitioned between ether and dilute aqueous hydrochloric acid. The ether phase was worked up in the manner described in Example 1 to give 100 mg. (9%) of purple solid that contained mainly 5-cyano-1-methylpyrrole-2-acetic acid by nmr analysis. The aqueous phase was heated in a steam bath for 7 hours and the product was isolated after extraction with methylene chloride to give 1.15 g. (yield: 75%, 83% based on unrecovered cyanoacid) of 1-methyl-5-p-toluoylpyrrole-2-acetic acid as a brown solid.