Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:27]1([CH2:33][CH:34]2[CH:39]([NH2:40])[CH:38]3[CH2:41][CH2:42][N:35]2[CH2:36][CH2:37]3)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:40][CH:39]1[CH:38]2[CH2:37][CH2:36][N:35]([CH2:42][CH2:41]2)[CH:34]1[CH2:33][N:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:9]
Reactant: NC1C2CCN(CC2)C1CN1CCCCC1
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CNc1cc(OC)c(C(=O)NC2C3CCN(CC3)C2CN2CCCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.5 %

Procedure:
A solution of 5-chloro-2-methoxy-4-(methylamino)-benzoic acid (1.95 g, 9.0 mmoles) in anhydrous tetrahydrofuran (10 ml) was treated with 1,1'-carbonyldiimidazole (1.49 g, 9.2 mmoles), stirred at room temperature for 90 minutes, then added to a cooled (0° C.) solution of 2-(1-piperidylmethyl)-1-azabicyclo[2.2.2]octan-3-amine (2.12 g, 9.5 mmoles) in anhydrous tetrahydrofuran (10 ml) under nitrogen. After 18 hours at room temperature the solution was concentrated in vacuo and partitioned between methylene chloride (100 ml) and 1.0N sodium hydroxide (40 ml). The organic solution was separated and washed with 1.0N sodium hydroxide (40 ml), saturated aqueous sodium bicarbonate (40 ml), and brine (40 ml), dried (Na2SO4), and concentrated in vacuo. Filtration through alumina (eluted with 15% methanol/ethyl acetate) provided 3.24 g (86%) of a colorless foam.
Reaction SMILES: O.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[K+]>CC1C=CC(C(C)C)=CC=1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:15][CH2:14][CH2:13][CH2:12][C:11]([OH:17])=[O:16])=[CH:3]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccc(C(C)C)cc1
Product: O=C(O)CCCCc1c[nH]c2ccccc12
Reaction time: 96 h

Procedure:
In a water separator, indole (50 g, 0.43 mol.), δ-valerolactone (tetrahydropyran-2-one, 49.2 g, 0.49 mol.), potassium hydroxide (35.9 g, 0.64 mol.) in p-cymene (1-isopropyl-4-methylbenzene, 250 ml) were heated at boiling for 4 d, with stirring. For working up, water (200 ml) was added to the mixture, the phases were separated, and the aqueous phase was adjusted to pH 4 with 2M HCl and stored for 2 d at 4° C. in a refrigerator. The resulting solid was filtered off with suction and washed with water (3×20 ml). Recrystallisation from ether (50 ml) yielded 5-(1H-indol-3-yl)pentanoic acid in the form of a white solid having a melting point of 80–83° C. in a yield of 38.8 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(C(F)(F)F)=O.N#N>CCO.C(Cl)(Cl)Cl>[C:15]1([CH:14]2[C:6]3[NH:7][C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5]=3[CH2:4][CH2:3][NH:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.1 %

Procedure:
1-Phenyl-2,3,4,9-tetrahydro-1H-beta-carboline was prepared by the addition of tryptamine-HCl (500 mg, 2.54 mmol), CHCl3 (20 mL), absolute EtOH (16 mL), benzaldehyde (520 μL, 5.08 mmol), and TFA (1.9 mL, 25.4 mmol) to a N2 purged 50 mL flask. The reaction solution was allowed to stir at ambient temperature for 18 hours and then at 60° C. for 4 hours. The solution was concentrated under reduced pressure, and the crude material was chromatographed (SiO2, 100% hexane to 25% EtOAc) to yield 95 mg of 1-phenyl-2,3,4,9-tetrahydro-1H-beta-carboline; MS (ESI): 249 (MH+).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)(C)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[NH2:18])=[N:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: Nc1ccccc1CCl
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2[nH]c(SCc3ccccc3N)nc2c1
Yield: 19.5 %

Procedure:
The title compound was prepared by the method of Example 1 using 1.68 g (9.33 mMol) of 2-mercapto-5-methoxybenzimidazole instead of 2-mercaptobenzimidazole and 1.99 g (11.2 mMol) of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline in 250 ml of isopropyl alcohol. The basic extraction used 5% sodium hydroxide instead of sodium carbonate. Chromatography on silica gel, followed by crystallization from diethylether, gave 520 mg of pure title compound: m.p. 140-142° C. Anal. Calc'd. for C15H15N3OS: C, 63.14; H, 5.30; N,14.73; S, 11.23. Found: C, 63.44; H, 5.42; N, 14.43; S, 11.07.
Reaction SMILES: C([Li])CCC.[C:6](=[O:8])=O.CC(C)=O.[C:13]1([CH2:19][N:20]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21]2[C:30]3[N:31]=[CH:32][N:33]([CH2:34][O:35][CH2:36][CH3:37])[C:29]=3[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)=O.C(Cl)(Cl)(Cl)Cl.C=O>O1CCCC1>[C:39]1([CH2:38][N:20]([CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:21]2[C:30]3[N:31]=[C:32]([CH2:6][OH:8])[N:33]([CH2:34][O:35][CH2:36][CH3:37])[C:29]=3[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C=O
Reactant: CCOCn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOCn1c(CO)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C

Procedure:
Butyllithium (1.6 mL of 2.5M in hexanes, 4 mmole) was added to a chilled (dry ice/acetone bath) solution of N,N-bis(phenylmethyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.7 g, 4 mmole) in tetrahydrofuran. No color change was observed. The reaction mixture was warmed to -20° C. (dry ice/carbon tetrachloride) and the reaction turned red in color. Formaldehyde gas entrained in a flow of nitrogen was added to the reaction mixture. After several minutes the reaction turned to a solid mass and the ice bath was removed. The reaction mixture was allowed to warm to ambient temperature and the color of the reaction mixture changed from red to yellow. The reaction was diluted with diethyl ether and water. The ether layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with 10-20% ethyl acetate in hexanes v/v) to provide 1 g of 4-bis(phenylmethyl)amino-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-2-methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[C:12]([CH2:17][CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[CH2:15]([O:14][C:12](=[O:13])/[C:17](/[CH3:18])=[CH:5]/[C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([F:1])[CH:3]=1)[CH3:16]
Reactant: COc1ccc(C=O)cc1F
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1ccc(OC)c(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
After 3-fluoro-4-methoxy-benzaldehyde (0.50 g, 3.24 mmol) was dissolved in anhydrous THF (10 mL), carbethoxyethylidene triphenylphosphorane (1.75 g, 4.86 mmol) was added thereto at 0° C., and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (0.768 g, 99%).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:43]1([CH:49](O)[CH2:50][CH3:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[C:43]1([CH:49]([O:2][C:1](=[O:3])[CH2:4][N:5]2[CH2:27][CH2:26][CH2:25][C@H:6]2[C:7]([N:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:50][CH3:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: CCC(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC(OC(=O)CN1CCC[C@H]1C(=O)N(Cc1ccccc1)C(=O)[C@@H](N)[C@@H](C)CC)c1ccccc1
Yield: 40.5 %

Procedure:
A solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (59 mg, 0.16 mmol), 4-N,N-dimethylaminopyridine (7.9 mg, 0.06 mmol, 0.4 eq), 1,3-dicyclohexylcarbodiimide (49 mg, 0.23 mmol, 1.5 eq) in dichloromethane (5.0 mL) was treated with (±) 1-phenyl-1-propanol (28 uL, 0.20 mmol, 1.3 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 32 mg (41%) of L-isoleucine, N-[1-(2-(1-phenylpropoxy)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: C([C:4]1[C:12]2[CH2:11][CH2:10][N:9](C(=O)C)[CH2:8][C:7]=2[S:6][C:5]=1[CH2:16][CH2:17]Cl)(=O)C.Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1>>[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:17][CH2:16][C:5]4[S:6][C:7]5[CH2:8][NH:9][CH2:10][CH2:11][C:12]=5[CH:4]=4)[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1c(CCCl)sc2c1CCN(C(C)=O)C2
Agent: Cl
Product: Fc1ccc2c(C3CCN(CCc4cc5c(s4)CNCC5)CC3)noc2c1

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.5 g of 3,6-diacetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 1.3 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 3,6-diacetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CCC(N)CC
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(4-Chloro-2,6-dimethyl-phenoxy)-nicotinic acid methyl ester (77 mg, 0.226 mmol) and 1-ethyl-propyl-amine in DMSO was heated at 120° C. for 4 hr. The mixture was quenched with sat. ammonium chloride, water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to give 140 mg of yellow solid. 1H NMR(CDCl3) d 8.10(d, 1H), 7.03(s, 2H), 6.09(s, 1H), 3.88(s, 3H), 3.35(m, 1H), 2.10(s, 3H), 2.08(s, 6H), 1.5-1.7(m, 4H), 0.96(t, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(NCCCN2CCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc(NCCCN2CCCC2)ccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
200 mg (0.716 mmol) (3-methoxy-4-nitro-phenyl)-(3-pyrrolidin-1-yl-propyl)-amine are dissolved in 10 ml of methanol and combined with 537 μl (2.148 mmol) dioxanic hydrochloric acid and 20 mg palladium on charcoal. The reaction mixture is stirred for 1 h at ambient temperature and 5 bar H2 pressure. The catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[S:14][CH:13]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]3=[O:27])=[N:7][C:6]=2[CH:28]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[S:14][CH:13]([CH2:21][C:22]([OH:24])=[O:23])[C:12]3=[O:27])=[N:7][C:6]=2[CH:28]=1
Reactant: CCOC(=O)CC1Sc2ccccc2N(Cc2nc3cc(F)ccc3s2)C1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC1Sc2ccccc2N(Cc2nc3cc(F)ccc3s2)C1=O
Temperature: 25 °C
Yield: 76.4 %

Procedure:
The compound of Example 1 (275 mg) was dissolved in methanol-dioxane (1:2, v/v, 3 ml), and 0.7 ml of 2N sodium hydroxide solution was added dropwise to the solution with stirring at room temperature. The mixture was stirred for further 90 minutes. The solvent was distilled off and the residue was diluted with water, then the aqueous mixture was acidified with 10% hydrochloric acid. The precipitated solid was crystallized from chloroform-hexane to give 196 mg of the title compound. The structural formula and physical data of this compound are shown in Table 25.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][NH:5]2.Cl[C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1
Reactant: CN1C[C@@H]2C[C@H]1CN2
Reactant: Clc1cnccn1
Solvent: ClCCl
Product: CN1C[C@@H]2C[C@H]1CN2c1cnccn1
Temperature: 80 °C

Procedure:
A solution of 2.1 g of (S,S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane prepared by the procedure of U. Jordis et al, Synthesis, 1990, 925, and 1.8 ml of 2-chloropyrazine in 8 ml of diazabicyclo[3.6.0]undecene-5 is heated to approximately 80° C. for 2 hours. The reaction solution is cooled, diluted with 100 ml of methylene chloride and washed with 30 ml of 5N aqueous sodium hydroxide. The organic layer is dried and concentrated in vacuo to dryness. The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5; methylene chloride to 5% methyl alcohol/methylene chloride) to give 2.1 g of the desired product as a pale yellow oil:
Reaction SMILES: BrC1C=CC(C(OC)=O)=CC=1C.C(N1CCNCC1)(OC(C)(C)C)=O.C(OC([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][C:40]=2[CH3:49])[CH2:35][CH2:34]1)=O)(C)(C)C>>[CH3:49][C:40]1[CH:41]=[C:42]([CH:43]=[CH:44][C:39]=1[N:36]1[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]1)[C:45]([O:47][CH3:48])=[O:46]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: COC(=O)c1ccc(Br)c(C)c1
Product: COC(=O)c1ccc(N2CCNCC2)c(C)c1

Procedure:
Using methyl 4-bromo-3-methylbenzoate (5 g) and 1-Boc-piperazine (4.47 g) and by the reaction and treatment in the same manner as in Example 94, the title compound (1.05 g) was obtained via 4-(4-methoxycarbonyl-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N:9]2[CH2:14][CH2:13][O:12][C@H:11]([C@@H:15]([OH:19])[C:16]([OH:18])=O)[C:10]2=[O:20])[CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][O:30][C:31](=[O:33])[N:32]=2)=[CH:24][CH:23]=1.NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N:9]2[CH2:14][CH2:13][O:12][C@H:11]([C@@H:15]([OH:19])[C:16]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:26][CH:27]=3)=[O:18])[C:10]2=[O:20])[CH:3]=1
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Reactant: Cc1ccc(F)cc1N1CCO[C@H]([C@@H](O)C(=O)O)C1=O
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1N1CCO[C@H]([C@@H](O)C(=O)Nc2ccc(-c3noc(=O)[nH]3)cc2)C1=O

Procedure:
According to the Step 1-3 in synthetic method for EXAMPLE 1, a cyclic carbonate analogue (0.11 g) derived from compound 63-6 and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one with DMF were used instead of 1-2 and 6-amino-1-bis(tert-butoxycarbonyl)aminoisoquinoline to obtain compound 64-1 (43.2 mg) as a pale pink amorphous solid.
Reaction SMILES: Br[C:2]1[N:3]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:10]=[C:9]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:8]=2)=[CH:5][CH:6]=1.C([Sn](CCCC)(CCCC)[C:42]1[O:43][CH:44]=[CH:45][N:46]=1)CCC.O>C1(C)C=CC=CC=1.[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>[CH3:28][O:27][CH2:26][C@H:25]([CH3:29])[O:24][C:9]1[CH:8]=[C:7]([C:4]2[N:3]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:2]([C:42]3[O:43][CH:44]=[CH:45][N:46]=3)=[CH:6][CH:5]=2)[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(Br)n2C(=O)OC(C)(C)C)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ncco3)n2C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
t-Butyl 2-bromo-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate (102.9 mg, 0.177 mmol) synthesized in Example (13c) was dissolved in toluene (5 mL), and 2-(tri-n-butylstannyl)oxazole (133.7 mg, 0.373 mmol) and tetrakis(triphenylphosphine) palladium (20.5 mg, 0.0177 mmol) was added, followed by heating to reflux for 18 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added thereto, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=35%-55%) to afford t-butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-5-(1,3-oxazol-2-yl)-1H-pyrrole-1-carboxylate.
Reaction SMILES: [CH3:1][N:2]([C:4](=[S:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3].Cl[S:13]([CH2:16][C:17](Cl)=[O:18])(=[O:15])=[O:14].O>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]([C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[S:11])[NH:3][S:13]([CH2:16][C:17]([NH:3][N:2]([CH3:1])[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[S:11])=[O:18])(=[O:15])=[O:14]
Reactant: O=C(Cl)CS(=O)(=O)Cl
Reactant: CN(N)C(=S)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(NC(=O)CS(=O)(=O)NN(C)C(=S)c1ccccc1)C(=S)c1ccccc1
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a 0° C. solution of N-methylbenzothiohydrazide (10 mmol) in DCM (20 mL) and pyridine (1 mL) was added 2-(chlorosulfonyl)acetyl chloride (5 mmol) dropwise. The mixture was kept at rt for 2 h before it was poured into water (20 ml). The organic layer was separated, dried and evaporated and the resulting residue was purified by column chromatography to give compound 68 as yellowish solids (0.8 g). 1H-NMR (CDCl3) δ 10.5 (m, 1H), 7.4 (m, 10H), 4.4 (m, 1H), 3.4-3.8 (m, 8H) ppm; ESMS calcd for C18H20N4O3S3:436.1; found: 437.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2cc(Br)ccc12
Temperature: 190 °C

Procedure:
2-Amino-4-bromobenzoic acid (15.5 g) was dissolved in 100 mL of formamide and the solution was heated at 190° C. for 10 h. After the reaction was cooled to room temperature, the solid was collected via filtration, rinsed with water, and dried to give 10.5 g of 7-bromo-4-quinazolinone, LCMS ESI(+) m/z: 225/227 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[CH:8][C:9](=O)[O:10][C:11]=1[CH3:12])=[O:5])[CH3:2].Cl.[NH2:16][NH2:17].CO>C([O-])([O-])=O.[K+].[K+]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[CH:8][C:9](=[O:10])[N:16]([NH2:17])[C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1c(C)cc(=O)oc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)c1c(C)cc(=O)n(N)c1C
Temperature: 150 °C
Yield: 7 %

Procedure:
A mixture of 4,6-dimethyl-2-oxo-2H-pyran-5-carboxylic acid ethyl ester (3.2 mL, 19 mmol) and hydrazine monohydrochloride (1.4 g, 20 mmol) in methanol (16 mL, 0.39 mmol) was heated under microwave irradiation for 2.5 hrs at 150° C. Reaction was taken up in sat. aq. K2CO3 (40 mL) and extracted with ethyl acetate (3×40 mL). The combined organic phases were washed with brine, dried over MgSO4, evaporated and purified by flash chromatography. Yield 7%. 1H NMR (500 MHz, CDCl3): 6.35 (s, 1H), 5.12 (s, 2H), 4.35 (q, J=7.1 Hz, 2H), 2.53 (s, 3H), 2.21 (s, 3H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11]3[C:12]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]4)=[N:13][C:14]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:16]=3[O:17]C)[N:10]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].[I-].[Si](Cl)(C)(C)C>CC#N>[N:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11]3[C:16](=[O:17])[NH:15][C:14]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:13][C:12]=3[NH:25][C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[N:10]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1csc(-n2cccc2)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1[nH]c(N2CCOCC2)nc(N[C@@H]2CCCNC2)c1-c1csc(-n2cccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (R)-tert-butyl 3-((5-(2-(1H-pyrrol-1-yl)thiazol-4-yl)-6-methoxy-2-morpholinopyrimidin-4-yl)amino)piperidine-1-carboxylate (xx) (0.08 g, 0.148 mmol) in MeCN (2.95 ml) was added NaI (0.033 g, 0.222 mmol) followed by TMS-Cl (0.028 ml, 0.222 mmol) under argon. The reaction was stirred at room temperature for 15 min., then heated to 50° C. for 2 h until the reaction was complete, monitored by LCMS. The solvent was removed and the reaction material was purified by preparative HPLC to give the title compound. MS (m/z)=428 (M+H). IRAK4 IC50=12 nM
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[NH:15][C:14](=[S:16])[NH:13][C:12]2=[O:17])=[CH:2]1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[OH-].[Na+].CO>[CH2:18]([S:16][C:14]1[NH:13][C:12](=[O:17])/[C:11](=[CH:10]/[C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)/[N:15]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(=S)NC1=Cc1c[nH]c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1NC(SCc2ccccc2)=N/C1=C\c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-2-thioxoimidazolidin-4-one (500 mg, 2.05 mmol) in 12.6% aq. NaOH (1 mL) and methanol (5 mL), benzyl bromide (430 mg, 2.5 mmol) was added and the reaction mixture stirred at RT for 18 h. Most of the solvent was distilled out and the precipitate was filtered and washed first with water, then with diethylether and dried. The crude material was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 15:1). Obtained the desired (5Z)-2-(benzylthio)-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,5-dihydro-4H-imidazol-4-one, as a yellow solid (700 mg, 2 mmol).