Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:12])=[C:5]2[C:9](=[N:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[ClH:13]>[Pd].CO>[ClH:13].[ClH:13].[NH2:2][CH2:1][C:3]1[C:4]([CH3:12])=[C:5]2[C:9](=[N:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2
Reactant: Cc1c(C#N)cnc2[nH]ccc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1c(CN)cnc2[nH]ccc12
Reaction time: 6 h

Procedure:
A suspension of 5-cyano-4-methyl-7-azaindole (48 mg, 0.31 mmol) and 10% palladium on carbon (25 mg) in methanol (10 mL) and concentrated HCl (0.5 mL) was shaken on a Parr apparatus under hydrogen (50 psi) for 6 h. The mixture was filtered through celite and evaporated in vacuo. The residue was dissolved in a minimum volume of methanol, ether was added and the solids collected by filtration to give the title compound as a pale yellow solid:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]([NH:31][CH2:32][CH2:33]O)=[O:30])=[O:8].CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]1[O:30][CH2:33][CH2:32][N:31]=1)=[O:8]
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(=O)NCCO)n(Cc3ccccn3)c2c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C3=NCCO3)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N3-(3,4-difluorobenzyl)-N2-(2-hydroxyethyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dicarboxamide (Compound 103, 36 mg, 0.069 mmol) in CH2Cl2 (3 ml) at 0° C was added Et3N (58 μl, 0.41 mmol) and methanesulfonyl chloride (11 μl, 0.14 mmol). The reaction was stirred at room temperature for 0.5 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a yellow film.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]=[C:31]=[O:32]>C1COCC1.C(Cl)Cl>[CH3:29][NH:30][C:31]([N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:32]
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)N1CCN(Cc2ccc(-c3cc(C)ccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made in the following manner: 50 mg of 3-(S)-benzyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equiv. methylisocyanate was added. The reaction was stirred at room temperature overnight. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as the free base. Treatment with 1 equiv 1M HCl in dioxane an concentration in vacuo afforded 52 mg of the corresponding hydrochloride salt. Yield 84%, ES MS m/z 448
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:23]=[CH:22][C:10]([C:11](=[O:21])[CH2:12][CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]O)[CH2:14]2)=[CH:9][CH:8]=1.[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27].[H-].[Na+]>O1CCCC1.O>[C:26]([CH:25]([CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:13]([CH2:12][C:11]([C:10]2[CH:22]=[CH:23][C:7]([F:6])=[CH:8][CH:9]=2)=[O:21])[CH2:14]1)[C:24]([O:30][CH2:31][CH3:32])=[O:29])(=[O:27])[CH3:28]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CC1CCN(CCO)C1)c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CCN1CCC(CC(=O)c2ccc(F)cc2)C1)C(C)=O
Temperature: 15 °C
Reaction time: 3 h

Procedure:
A solution of 3.88 g of methanesulfonyl chloride is added at 0° C. to a suspension of 8.5 g of the product obtained in Stage A in 100 ml of tetrahydrofuran. The mixture is left stirring for 3 hours at 15° C., and this suspension is then added to a solution, cooled to 0° C., of 4.4 g of ethyl acetoacetate containing 1.63 g of sodium hydride in 100 ml of tetrahydrofuran. The mixture is then brought to reflux for 12 hours, hydrolyzed with 5 ml of water and concentrated, and the residue is take up in 150 ml of dichloromethane. The organic phase is washed with 50 ml of water, dried over anhydrous sodium sulfate and concentrated. The oil obtained is purified by chromatography on 600 g of 70-230 mesh silica, using a mixture of dichloromethane and methanol (99:1 V/V) as eluant.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[CH:20][N:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29]C(=O)C)=[CH:25][C:24]=3[F:33])[CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)[CH:17]=2)=[C:24]([F:33])[CH:25]=1
Reactant: CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Agent: Cl
Solvent: CO
Product: Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Yield: 89.9 %

Procedure:
A mixture of N-(4-(6-(4-(benzyloxy)phenylamino)pyrimidin-4-yloxy)-3-fluorophenyl)acetamide (150 mg, 0.34 mmol), 6 M HCl (0.5 mL) and MeOH (3 mL) was heated at reflux for 2 h. The mixture was concentrated to remove the MeOH and the residue treated with saturated NaHCO3 solution and extracted with EtOAc. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (123 mg, 90%) as a pink solid. 1H NMR (DMSO-d6): δ 9.37 (s, 1H), 8.24 (s, 1H), 7.46-7.31 (m, 7H), 6.99-6.92 (m, 3H), 6.48 (dd, 1H, J=12.5, 2.7 Hz), 6.39 (dd, 1H, J=8.6, 2.7 Hz), 5.97 (s, 1H), 5.39 (br s, 2H), 5.08 (s, 2H); MS(ESI+) m/z 403.09 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20]1>>[O:19]1[CH:23]=[CH:22][C:21]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:20]1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccoc1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccoc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.010 mL (0.080 mMol) 3-furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:16]4[O:17][CH2:18][CH2:19][NH:20][C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:21]=1.Cl[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1.ClC1C(Cl)=CC=CN=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([N:20]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:9]4[NH:8][C:7]5[CH:21]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=[CH:5][C:6]=5[N:10]=4)[C:16]=3[O:17][CH2:18][CH2:19]2)=[N:26][CH:27]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4)[nH]c2c1
Agent: Clc1cccnc1Cl
Product: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4c3ccc(Cl)cn3)[nH]c2c1
Yield: 92 %

Procedure:
The procedure of Example 6 was repeated except for using 8-(6-(trifloromethyl)-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine and 2,5-dichloropyridine instead of 4-(5-tert-butyl-1H-benzo[d]imidazol-2-yl)benzenamine and 2,3-dichloropyridine in Example 6 respectively to obtain the title compound (4.0 g, yield: 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.COC1C=CC(C#N)=CN=1.N>CO.[Ni].CCN(CC)CC.C(O)CCC>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:31][CH2:30][C:27]4[CH:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: COc1ccc(CN)cn1
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Agent: [Ni]
Agent: COc1ccc(C#N)cn1
Agent: N
Solvent: CCCCO
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2cc3c(NCc4ccc(OC)nc4)ncnc3[nH]2)cc1
Reaction time: 6 h

Procedure:
A mixture of 5.0 g (16.6 mMol) 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzoic acid ethyl ester (WO 97/02266) and 2.52 g (18 mMol) of 6-methoxy-pyridin-3-ylmethylamine (CAS: 262295-96-5; prepared from 6-methoxy-nicotin-nitrile by hydrogenation in the presence of Raney-Nickel in methanol containing NH3) in 3.5 ml (25 mMol) of Et3N and 100 ml n-butanol is heated for 8 h to 140° C. Then additional 0.69 g of 6-methoxy-pyridin-3-ylmethylamine and 1.2 ml of Et3N are added. Heating is continued for 6 h and the hot suspension filtrated and the residue washed with n-butanol and hexane to give the title compound; m.p. 305° C.; elemental analysis for C, H, and N, within 0.5% of calculated value.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[O:15][C:16]([S:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:17][N:18]=2)[CH:11]=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][S:19][C:16]2[O:15][C:14]([C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[CH:13]=3)=[N:18][N:17]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2nnc(SCc3ccc(F)cc3)o2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(-c2nnc(SCc3ccc(F)cc3)o2)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.4 %

Procedure:
To a solution of tert-butyl[4-[5-[(4-fluorobenzyl)thio]-1,3,4-oxadiazol-2-yl]-2-pyridyl]carbamate (138 mg, 0.343 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL), and the resulting mixture was stirred at room temperature for 5 hr. The reaction mixture was alkalified with aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5-0/100), and recrystallized from methanol/chloroform/diethyl ether to give the title compound (44 mg, yield 43%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])([F:14])[F:13])[N:8]=[C:7]([C:23]([OH:25])=O)[CH:6]=[CH:5]2.CCN=C=NCCCN(C)C.Cl.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:18]([O:17][P:15]([C:12]([C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([C:23]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:25])=[N:8]2)=[CH:3][C:2]=1[Br:1])([F:13])[F:14])(=[O:16])[O:20][CH2:21][CH3:22])[CH3:19]
Reactant: Nc1ccccc1
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)O)ccc2cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)Nc3ccccc3)ccc2cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the product of step 5 (109 mg) in 5 mL CH2Cl2 was added EDCl (96 mg), aniline (0.1 mL) and Hunig's base (0.1 mL). The solution was stirred at ambient temperature for 3 hours and after concentration and flash chromatography on silica with a gradient of 10-25% EtOAc/toluene the amide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:4][CH:3]=1.[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)OC1C=CC=CC=1)#[N:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:28]([NH:27][C:25]#[N:26])=[N:36][CH2:37][CH2:38][S:39][CH2:40][C:41]2[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=2)[CH3:18])=[CH:4][CH:3]=1
Reactant: CN(CCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: CN(CCCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.75 g (2.1 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,5-pentanediamine and 0.81 g (2.1 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=627 ([M+H]+, 3), 230 (100); IR (KBr): 2162 cm-1 (C≡N). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: 87°-90° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[CH:5]2.O.[CH3:23][N:24](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:23]#[N:24])[CH:3]=2)[N:8]=1
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1ccccc1CNc1ccc2cc(C#N)ccc2n1
Temperature: 160 °C
Yield: 95 %

Procedure:
A mixture of (6-bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) (500 mg, 1.46 mmol), zinc cyanide (188 mg, 1.6 mmol) and tetrakis-(triphenylphosphine)-palladium (168 mg, 0.145 mmol) in DMF (5 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (30 ml) and extracted with diethyl ether (2×50 ml). The combined organic layers were washed with brine (2×30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield 2-(2-methoxy-benzylamino)-quinoline-6-carbonitrile as light red oil (400 mg, 95%).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@H:20]([C:24](O)=[O:25])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CN.C[CH2:35][N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@H:20]([C:24]([NH:36][CH3:35])=[O:25])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@H](C(=O)O)C3)n3nccc3n2)cc1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)[C@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Yield: 63.1 %

Procedure:
A solution of (S)-1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-3-carboxylic acid (Compound 86, 100 mg, 0.236 mmol), methylamine (65 μL, 0.472 mmol), EDCI (90 mg, 0.472 mmol), and HOBT (16 mg, 0.118 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC (30-40% MeCN/H2O gradient+0.01% TFA) provided the titled compound as a white solid (65 mg, 63%). 1H NMR (DMSO-d6) δ: 10.92 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 8.00 (d, J=8.8 Hz, 3H), 7.61 (d, J=8.6 Hz, 2H), 7.38 (s, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.37 (d, J=8.8 Hz, 1H), 4.30 (d, J=12.1 Hz, 1H), 3.27 (dd, J=12.4, 10.6 Hz, 1H), 3.05 (d, J=11.4 Hz, 1H), 2.54-2.63 (m, 4H), 1.65-1.99 (m, 4H), 1.46 (s, 6H). ESI-MS: m/z 437.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.Cl.O.[CH3:12]O>>[CH3:12][O:8][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9]
Reactant: CO
Reactant: O=C(O)c1csc(Br)c1
Agent: Cl
Solvent: O
Product: COC(=O)c1csc(Br)c1
Temperature: 25 °C

Procedure:
Prepare a solution of 5-bromothiophene-3-carboxylic acid (500 mg, 2.41 mmol) in methanol (5 mL). Add concentrated hydrochloric acid (0.1 mL). Reflux the mixture for 3 hours, cool to room temperature, pour into water, and extract with diethyl ether (3×10 mL). Wash the combined organic phases with water (10 mL), then saturated aqueous sodium hydrogencarbonate (10 mL). Dry (magnesium sulfate), filter and concentrate. Perform flash chromatography on silica gel eluting with 5:1 hexane/ethyl acetate to afford 409 mg of 5-bromothiophene-3-carboxylic acid methyl ester as a white solid. 1H NMR (CDCl3) δ 8.10 (d, J=1.5 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([N:6]3[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]/[C:2]/3=[N:1]\[S:30]([CH3:29])(=[O:32])=[O:31])[S:8][CH:9]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)COC(=N)N1c1nc(-c2ccc(C#N)cc2)cs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CO/C(=N\S(C)(=O)=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Reaction time: 8 h
Yield: 6.4 %

Procedure:
4-[2-(2-Imino-4,4-dimethyl-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzonitrile (0.250 g, 0.83 mmol), prepared in Example 63, was dissolved in tetrahydrofuran (2 mL), followed by triethylamine (0.139 mL, 1 mmol) and methanesulfonyl chloride (0.154 mL, 2 mmol). The mixture was stirred overnight, filtered and the tetrahydrofuran was removed in vacuo. Purification by normal phase HPLC on a phenomenex cyano column and eluting with hexane/1,2-dimethoxyethane (9:1 to 1:9) gave the title compound (0.020 g, 6%). HRMS: calcd for C16H16N4O3S2+H+, 377.07366; found (ESI, [M+H]+), 377.0722. HPLC purity 97.0% at 210-370 nm, 8.5 min; 97.1% at 244 nm, 8.5 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH:8]=O.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH:8]=[C:21]1[S:17][C:18](=[O:23])[NH:19][C:20]1=[O:22]
Reactant: COCOc1ccc(C=O)cc1OCOC
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCNCC1
Product: COCOc1ccc(C=C2SC(=O)NC2=O)cc1OCOC
Reaction time: 0.03 h

Procedure:
A mixture of 3,4-Bis-methoxymethoxy-benzaldehyde (5 mmol), thiazolidine-2,4-dione (5 mmol), benzoic acid (0.5 mmol), and piperidine (0.5 mmol) in toluene (150 mL) was heated to reflux for 15 h. Upon cooling, to the reaction mixture was added hexane (50 mL). The resulting suspension was gently stirred for 2 min and then allowed to settle. It was then filtrated and the solid was washed with cold benzene. 5-(3,4-Bis-methoxymethoxy-benzylidene)-thiazolidine-2,4-dione was obtained as a yellow solid (yield 92%). 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.81 (s, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.28-7.25(m, 1H), 7.18-7.15 (m, 1H), 5.32 (s, 2H), 5.63 (s, 2H), 3.57 (s, 3H), 3.54 (s, 3H). 13C-NMR (75 MHz) δ (ppm) 168.1, 167.6, 149.8, 147.9, 134.6, 127.7, 126.1, 121.0, 118.8, 116.8, 96.0, 95.5, 56.9, 56.8.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:19][CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][O:10]1.NN>C(O)C.C(OCC)C>[F:37][C:35]([F:36])([F:38])[C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([C:2]([F:40])([F:39])[F:1])[CH:34]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:19][CH2:20][NH2:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][O:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Agent: NN
Solvent: CCOCC
Solvent: CCO
Product: NCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)isochroman-1-yl)ethyl)isoindoline-1,3-dione (100 mg, 0.177 mmol) in ethanol (1 mL) at room temperature was added hydrazine (0.039 mL, 1.24 mmol). The flask was sealed, heated to 45° C., and held there for 3 h. The reaction was cooled to room temperature, diluted with diethyl ether, and filtered to remove the precipitate which was discarded. The mother liquor was concentrated to give 78 mg (quant.) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.75 (s, 1H), 7.69 (s, 2H), 7.05-7.20 (m, 2H), 4.64 (qAB, JAB=13.1 Hz, 2H), 3.99 (m, 2H), 3.71 (qAB, JAB=10.1 Hz, 2H), 2.91 (m, 1H), 2.76 (m, 1H), 2.68 (m, 1H), 2.50 (m, 1H), 2.16 (m, 1H), 2.02 (m, 1H), 1.79 (bs, 2H); 13C-NMR (CDCl3, 126 MHz) δ 141.3, 137.3, 135.0, 131.7 (q, J=33.6 Hz), 129.1, 127.3, 126.8, 126.5, 125.6, 123.4 (q, J=273 Hz), 121.5, 78.4, 76.7, 72.1, 60.7, 41.9, 37.3, 29.6. Mass spec.: 434.37 (MH)+. Accurate mass spec.: m/z 434.1547 [MH]+, Δ=1.8 ppm.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][NH:16]O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.N1C=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][OH:40]>CO>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][NH:16][CH2:37][CH2:36][CH2:35][CH2:34][CH2:39][OH:40])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: ONCc1c2ccccc2cc2ccccc12
Reactant: OCc1ccccn1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Product: OCCCCCNCc1c2ccccc2cc2ccccc12
Reaction time: 8 h

Procedure:
The General Procedure for the N-Boc protection of N-(Anthracen-9-ylmethyl)amino alcohols 4 to give 5. The solution of N-(anthracen-9-ylmethyl)-amino alcohol (5 mmol) in 20 mL of pyridine-methanol (1:5 v/v) was stirred at 0° C. for 10 min. A solution of di-tert-butyl dicarbonate (7.5 mmol) in methanol (5 mL) was added dropwise over ten minutes. The temperature was allowed to rise to room temperature and the reaction was stirred overnight. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride, and washed with deionized water several times. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel.