Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[N:6]=[CH:5]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:17]3[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=3)[CH:3]=2)[N:8]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: Clc1ncc2cc(Br)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(-c2ccc3nc(Cl)ncc3c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
A mixture of 6-bromo-2-chloroquinazoline (32) (5.0 g, 20.5 mmol), 3,5-dimethoxyphenylboronic acid (33) (3.7 g, 20.5 mmol), Cs2CO3 (20.0 g, 61.5 mmol) and Pd(PPh3)2Cl2 (1.4 g, 2.1 mmol) in THF (50 mL), dioxane (50 mL) and water (10 mL) was degassed with N2 three times, and stirred at 80° C. for 3 hours. An aliquot of the reaction mixture was analyzed by both TLC and LCMS, which indicated that the reaction had proceeded to completion. The mixture was cooled to room temperature, and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=8:1) to obtain 2-chloro-6-(3,5-dimethoxyphenyl)quinazoline (34) as a light yellow solid (2.4 g, 38%). MS (ES+) C16H13ClN2O2 requires: 300. Found: 301, 303 [M+H]+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N+:7]=[N-:8]>>[CH2:9]([N:6]1[CH:3]=[C:2]([C:1]([OH:5])=[O:4])[N:8]=[N:7]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCN=[N+]=[N-]
Reactant: C#CC(=O)O
Product: CCCCCCCCCCCCn1cc(C(=O)O)nn1
Temperature: 120 °C

Procedure:
A mixture of propiolic acid (46 μL, 0.7419 mmol) and 1-azido-dodecane (156.8 mg, 0.7419 mmol) was heated to 120° C. in a capped vial for 14 h, to yield the title triazole as white, crystalline solid (189.3 mg, 91% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:8][C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH2:4][CH2:5][CH2:6][CH3:7]>CC(C)=O>[I-:2].[CH2:3]([O:8][C:9]1[C:13]([C:14]2[CH:15]=[N+:16]([CH3:1])[CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CI
Reactant: CCCCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCCCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.3 ml, 5 mmol) and 3-(3-pentyloxy-1,2,5-thiadiazol-4-yl)pyridine (620 mg, 2.5 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.81 g (84%).
Reaction SMILES: Cl.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C(N3CCCCC3)=O)SC=12.[Cl:40][C:41]1[CH:42]=[C:43]([NH:65][C:66]([NH:68][C:69](=[O:77])[CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[S:67])[CH:44]=[C:45]([Cl:64])[C:46]=1[O:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]2[CH:54]=[C:55]([C:57]([N:59]3[CH2:63][CH2:62][CH2:61][CH2:60]3)=[O:58])[S:56][C:49]=12>>[Cl-:40].[Cl:40][C:41]1[CH:42]=[C:43]([NH:65][C:66]([NH:68][C:69](=[O:77])[CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[S:67])[CH:44]=[C:45]([Cl:64])[C:46]=1[O:47][C:48]1[CH:53]=[CH:52][NH+:51]=[C:50]2[CH:54]=[C:55]([C:57]([N:59]3[CH2:60][CH2:61][CH2:62][CH2:63]3)=[O:58])[S:56][C:49]=12
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1cc(Cl)c(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(Cl)c1
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCCC4)sc23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1cc(Cl)c(Oc2cc[nH+]c3cc(C(=O)N4CCCC4)sc23)c(Cl)c1
Product: [Cl-]
Yield: 42 %

Procedure:
Following the procedure described above for the synthesis of compound 136a (Table 12, Example 93) but replacing compound 135d with compound 142, title compound 143 was obtained in 42% yield. Characterization of 143 is provided in the Table 13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[N+:13]([O-])([O-:15])=[O:14].[K+].OS(O)(=O)=O>>[CH3:1][O:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2cccnc2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1ccc2cccnc2c1[N+](=O)[O-]
Yield: 48.8 %

Procedure:
In a similar fashion using route 7 general procedure 15, 7-methoxyquinoline (Intermediate 58) (400 mg, 2.51 mmol), potassium nitrate (330 mg, 3.26 mmol) and conc. H2SO4 (1.2 ml) gave the title compound (250 mg, 50%) after purification by column chromatography with n-hexane/EtOAc (3:1) as the eluent.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH2:24][C@@H:25]([CH:41]([CH3:43])[CH3:42])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C@H:22]([CH2:44][C@H:45]([C:49](=[O:57])[NH:50][C:51]([C:54](=[O:56])[NH2:55])([CH3:53])[CH3:52])[CH:46]([CH3:48])[CH3:47])[O:21]C1(C)C)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CO>[C:54]([C:51]([NH:50][C:49](=[O:57])[C@H:45]([CH:46]([CH3:48])[CH3:47])[CH2:44][C@H:22]([OH:21])[C@@H:23]([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][C@@H:25]([CH:41]([CH3:43])[CH3:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=1)([CH3:52])[CH3:53])(=[O:56])[NH2:55]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5 mg of p-toluenesulfonic acid (monohydrate) are added to 82 mg of 3-tert-butoxycarbonyl-5(S)-{2-[N-(1-carbamoyl-1-methyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine in 5 ml of methanol at 0° C. The reaction solution is stirred for a further 18 hours at room temperature. After evaporation of the solvent, 20 ml of saturated sodium hydrogen carbonate solution are added to the residue and extraction is carried out repeatedly with ethyl acetate. The organic extracts are concentrated by evaporation and purified by means of FC (35 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained:Rf (dichloromethane/methanol=9:1)=0.47.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:29][CH2:30]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4C)CC3)nc2c1
Yield: 90 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H), 2.95-3.02 (m, 4H), 3.75-3.90 (m, 6H), 4.09-4.13 (m, 4H), 6.99-7.31 (m, 7H), 7.50-7.66 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:13])=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:8]=1)#N.[F:14][C:15]1C=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.[CH:24]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH:30]2[NH:13][C:6]3[CH:5]=[CH:4][C:3]([C:1]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[F:14])=[CH:8][C:7]=3[S:9](=[O:11])(=[O:10])[NH:12]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: OB(O)c1ccccc1F
Reactant: O=CC1CCCCC1
Product: O=S1(=O)NC(C2CCCCC2)Nc2ccc(-c3ccccc3F)cc21

Procedure:
5-Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H (using 2-fluorophenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). M.p. 249–250° C.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:15]=O)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1>C(O)C>[C:21]([C:18]1[CH:17]=[C:14]([CH:15]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 42.7 %

Procedure:
To a solution of 12.5 g (107 mmol) of 2,4-thiazolidinedione and 25.0 g (107 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde in 300 ml of ethanol, 1.05 ml (10.7 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 15.23 g of the desired compound (42.8% yield, pale yellow crystals).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(CC(OC)=O)#N.C(Br)C(C1C=CC=CC=1)=O.[O-]S(C(F)(F)[F:39])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F>C(#N)C>[Cl:1][C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([F:39])[C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Agent: COC(=O)CC#N
Agent: F[n+]1c(Cl)cccc1Cl
Agent: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1c(Cl)[nH]c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
To a suspension of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (4.66 g) synthesized from methyl cyanoacetate and phenacyl bromide in the same manner as in Reference Example 95 and Reference Example 97 in acetonitrile (200 mL) was added 2,6-dichloro-N-fluoropyridinium triflate (6.26 g) over 10 min under ice-cooling. The reaction mixture was stirred at the same temperature for 2 hr and at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→7:3) to give the title compound as a pale-yellow solid (yield 815 mg, 16%). More specifically, to a solution of methyl cyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran (2600 mL) was added dropwise a solution of phenacyl bromide (75 g) in tetrahydrofuran (370 mL). The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil (yield 77.4 g, 95%). To a solution (125 mL) of ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (25 g) in ethyl acetate was added dropwise 4 mol/L hydrogen chloride-ethyl acetate solution (25 mL). The mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate as colorless crystals (yield 10.0 g, 37%). The title compound was synthesized from the thus-obtained methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([O:13]C(N(C)C)N(C)C)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1>[F:1][C:2]1[N:3]=[C:4]([CH:8]=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(F)n1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=Cc1cccc(F)n1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
30 g of 2-fluoro-6-methylpyridine (270 mmol) and 70 g of tert-butoxybis(dimethylamino)methane (405 mmol) are mixed under a nitrogen atmosphere. The mixture is heated at 140° C. for 24 hours. The mixture is diluted with 50 ml of tetrahydrofuran and the solution obtained is added dropwise to an aqueous solution of 115 g of sodium periodate (538 mmol). The mixture is stirred overnight at room temperature, the precipitate formed is removed by filtration and then the tetrahydrofuran is evaporated off. The residue is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and then the solvent is evaporated under vacuum. The title product is isolated by distillation in a bulb oven, b.p.77 : 70-80° C. 34 g of a yellow oil containing about 20% of N,N-dimethylformamide are recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([OH:14])[C:11]2[C:6](=[C:7](C)[C:8](OC)=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[Cl:18]C1C=CC=CC=1N>>[Cl:18][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[C:12]2[OH:14]
Reactant: Nc1ccccc1Cl
Reactant: CCOc1cc(O)c2ccc(OC)c(C)c2n1
Product: CCOc1cc(O)c2cccc(Cl)c2n1

Procedure:
8-Chloro-2-ethoxy-quinolin-4-ol was synthesized according to the method presented in the synthesis of 2-ethoxy-7-methoxy-8-methyl-quinolin-4-ol in Example 137 with the exception of utilizing 2-chloro-aniline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18].ClCCl>ClCCCl>[N+:17]([C:20]1[CH:21]=[C:22]([S:26]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: c1ccc2[nH]ccc2c1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)n2ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Indole (17.09 mmol, 2.0 grams) was taken in 1,2-dichloroethane (20 mL) in 100 mL three necked round-bottomed flask. Triethylamine (34.19 mmol, 3.45 grams) was added to it at 25° C. The above mixture was added to solution of 3-nitrobenzenesulfonyl chloride (25.64 mmol, 5.68 grams) (obtained from step (i)) and dichloromethane (25 mL), while maintaining the temperature below 10° C. The reaction mixture was then stirred for a period of 24 hours at 25° C. After the completion of reaction, the reaction mixture was poured onto ice-water mixture under stirring and the product was extracted with ethyl acetate (2×30 mL). The combined ethyl acetate extracts were then washed with water, brine and dried over anhydrous magnesium sulfate. The volatiles were removed under the reduced pressure to obtain 5.4 grams of thick syrupy mass, which was purified by column chromatography using silicagel (100-200 mesh), eluent being ethyl acetate and n-hexane (5:95),
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC=CC=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(O)C>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(Oc1ccc(OCc2ccccc2)cc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(Oc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.6 %

Procedure:
A reaction vessel was charged with 38 g of 4-benzyloxyphenyl benzoate and 500 ml of ethanol, and the air in the vessel was replaced with nitrogen. Then, 1.0 g of 10% palladium carbon was added thereto, and the nitrogen in the vessel was replaced with hydrogen, followed by vigorous stirring at room temperature for 24 hours. The hydrogen in the vessel was replaced with nitrogen, after which the reaction mixture was filtered though celite, and the filtrate was concentrated, which afforded 24.5 g of 4-hydroxyphenyl benzoate (94% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][OH:14])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][OH:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)CO)cnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)CO)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)-2-hydroxyethanone (18 mg, 0.048 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (18 mg, 0.062 mmol) followed by formation of the dihydrochloride salt to afford the desired product (9.1 mg, 33%) as an off-white solid. 1H NMR (500 MHz, CD3OD) δ 9.13 (s, 1H), 8.47 (d, J=8.9 Hz, 1H), 8.33 (d, J=8.9 Hz, 1H), 8.13 (s, 2H), 5.78-5.68 (m, 1H), 4.91 (s, 2H), 3.10 (d, J=6.7 Hz, 2H), 2.94 (s, 6H), 2.49-2.42 (m, 2H), 2.10-2.00 (m, 3H), 1.76-1.66 (m, 2H), 1.48-1.36 (m, 2H); ESI MS m/z 503 [M+H]+; HPLC>99% (AUC), tR=9.40 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.Cl[CH:16]=[C:17]1[S:21][NH:20][C:19]([O:22][CH3:23])=[CH:18]1>CN(C)C=O>[ClH:14].[CH3:23][O:22][C:19]1[CH:18]=[C:17]([CH2:16][N:3]2[C:2](=[NH:1])[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)=[N:4]2)[S:21][N:20]=1
Reactant: COC1=CC(=CCl)SN1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)nn1
Solvent: CN(C)C=O
Product: COc1cc(Cn2nc(-c3ccc(Cl)cc3)ccc2=N)sn1
Product: Cl
Temperature: 80 °C

Procedure:
The mixture of 0.500 g of 3-amino-6-(4-chlorophenyl)-pyridazine and 0.438 g of 5-chloromethylene-3-methoxy-isothiazole in 10 ml of dimethylformamide is heated under argon at 80° C. for 14 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:40]=C[C:38]([CH2:41][C:42]([NH:44][CH:45]2[CH2:47][CH2:46]2)=[O:43])=[CH:37][CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:36]2[CH:35]=[CH:40][C:41]([C:42](=[O:43])[NH:44][CH:45]3[CH2:46][CH2:47]3)=[CH:38][CH:37]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=C(Cc1ccc(Br)cc1)NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)cc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 2-(4-bromo-phenyl)-N-cyclopropyl-acetamide (41.6 mg, 0.16 mmol), and Pd[P(Ph)3]4 (12.7 mg, 6.7 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 7.1 mg. MS: 498.2 (M+H+); H1-NMR (DMSO-d6): δ (ppm) 0.37-0.44 (m, 2H), 0.58-0.66 (m, 2H), 1.80-2.04 (m, 3H), 2.14-2.36 (m, 1H), 2.55-2.68 (m, 1H), 3.36-3.57 (m, 2H), 4.32-4.43 (m, 1H), 4.91-5.14 (m, 2H), 7.00-7.65 (m, 12H), 7.87-7.95 (m, 1H), 8.12-8.18 (m, 1H), 10.08-10.14 (s, 1H).
Reaction SMILES: [CH2:1]([S:7][S:8][CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])[C@H:2]([NH2:6])[C:3]([OH:5])=[O:4].S(O)(O)(=O)=O.CO[C:22](=[NH:24])[NH2:23].[OH-].[NH4+:26]>>[NH:23]([CH:1]([S:7][S:8][CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])[C@H:2]([NH2:6])[C:3]([OH:5])=[O:4])[C:22]([NH2:24])=[NH:26]
Reactant: COC(=N)N
Reactant: N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Reactant: [NH4+]
Agent: O=S(=O)(O)O
Agent: [OH-]
Product: N=C(N)NC(SSC[C@H](N)C(=O)O)[C@H](N)C(=O)O
Temperature: 60 °C

Procedure:
To a solution of cystine (1 gm, 4.2 mmol) in ammonium hydroxide (10 mL) in a screw-capped vial was added O-methylisourea hydrogen sulfate (1.8 gm, 10 mmol). The vial was sealed and heated to 60° C. for 16 h. The solution was then cooled and the ammonium hydroxide was removed by rotary evaporation. The solid was then dissolved in water (20 mL), filtered through a cotton plug. The product was then isolated by ion exchange chromatography using Bio-Rex 70 resin and eluting with hydrochloric acid (100 mM).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:12]=[C:11](OC2C=CC=CC=2)[C:10]2[N:20]=[CH:21][N:22]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]=2[C:8]=1[CH3:32]>ClCCl>[CH3:6][C:7]1[N:12]=[C:11]([NH2:5])[C:10]2[N:20]=[CH:21][N:22]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]=2[C:8]=1[CH3:32]
Reactant: Cc1nc(Oc2ccccc2)c2ncn(CCOc3ccccc3)c2c1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Cc1nc(N)c2ncn(CCOc3ccccc3)c2c1C
Temperature: 150 °C

Procedure:
A sealed tube containing ammonium acetate (12.7 g) and 6,7-dimethyl-4-phenoxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridine (1.27 g) from Part E was heated to 150° C. for 36 hours. HPLC and TLC analysis indicated that the reaction was complete. The reaction was allowed to cool to room temperature. The resulting reaction mixture was then dissolved in dichloromethane (DCM) and washed with 20% aqueous sodium hydroxide. The basic layer was washed with DCM and the combined organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The resulting oil was passed through a silica gel column using 95/5 dichloromethane/methanol as the eluant. The product was recrystallized from isopropyl alcohol, and the resulting white solid was dried under vacuum to provide 6,7-dimethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 197.0–199.0° C.