Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:16])=[C:6]([C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[CH:7]=O)(=[O:3])[CH3:2].[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:4]1[C:5]([OH:16])=[C:6]([C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[CH2:7][N:27]1[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(C(C)=O)c(O)c(C=O)c1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C(C)=O)c(O)c(CN2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
A solution of 3-acetyl-2-hydroxy-5,6-dimethoxybenzaldehyde (0.14 g, 0.63 mmol) in methylene chloride (5.0 mL) was added with N-Boc-piperazine (0.13 g, 0.70 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C., and then added portionwise with sodium triacetoxyborohydride (0.16 g, 0.76 mmol). After completion of the addition, the reaction mixture was warmed to room temperature, and stirred for 10 hours. The reaction mixture was added with methylene chloride, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (2:1→3:7)) to obtain tert-butyl 4-(3-acetyl-2-hydroxy-5,6-dimethoxybenzyl)piperazine-1-carboxylate (0.20 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1ccc(Br)cc1
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a 0° C. solution of of 4-bromophenethylamine (10.0 g, 50.0 mmol) and triethylamine (7.7 mL, 55.0 mmol) in 150 mL of dichloromethane was added dropwise methanesulfonyl chloride (4.3 mL 55.0 mmol) in 20 mL of dichloromethane. After two hours, the reaction mixture was washed once with 100 mL of 10% aqueous sodium bisulfate. The organic portion was separated and the aqueous portion was extracted three times with 50 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to afford 14.0 g (100%) of the intermediate title compound.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]#[C:10][C@@H:11]([OH:13])[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:13][C@H:11]([C:10]#[C:9]/[CH:8]=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](O)C#C/C=C/c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C)C#C/C=C/c1ccccc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of alcohol 7 (400 mg, 2.32 mmol) in pyridine (pyridine was distilled over CaH2 and stored over KOH; 4.6 mL) at 23° C. was added acetic anhydride (1.10 mL, 11.6 mmol). The resulting mixture was stirred for 2 h at 23° C. The reaction was quenched by 1 N aqueous HCl (10 mL) at 0° C. and diluted with EtOAc (5 mL). The mixture was poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (silica gel 40 mL; 5→30% EtOAc in hexanes) afforded acetate 8 (486 mg, 98%, 95% ee; the ee value was determined by HPLC ((S,S) Whelk; 25 cm, 1.0 mL/min, hexanes/iPrOH=95/5).) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1.[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]3[N:15]=[N:16][NH:17][N:14]=3)[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(-c2cc(-c3nn[nH]n3)ccn2)c1
Temperature: 90 °C
Yield: 55 %

Procedure:
To a solution of 2-(1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (50 mg, 0.36 mmol) in 2 mL of DMF was added sodium azide (65 mg, 1 mmol) and ammonium chloride (54 mg, 1 mmol). The reaction mixture was heated at 90° C. for 20 hrs with vigorous stirring. It was then purified by ISCO flash column chromatography (MeOH/DCM=0-100%) to give the title compound as light pink solid (45 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 3.73 (3H, s), 7.71 (1H, dd, J=1.5 Hz and 5.1 Hz), 7.74 (2H, s), 8.46 (1H, s), 8.51 (1H, d, J=5.0 Hz). [M+H] Calc'd for C10H9N7, 228. Found, 228.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)c(F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)c(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (309 mg, 0.77 mmol) (from example 143, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.203 mL, 0.77 mmol) in water (0.500 mL) was added and the mixture was stirred at −40° C. for 20 min. Hydroxylamine (50% in water, 0.047 mL, 0.77 mmol) was added and stirring continued at −40° C. for 3 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (3.98 mL, 23.87 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 30 minutes with a flow of 19 mL/min. Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorobenzyl)-piperidine-1-carboxylate (111 mg, 38.9%) was isolated. MS m/z 371 (M+H)+
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:7]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[C:19]=4[Cl:28])=[O:17])[CH2:12][C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:31]I>CN(C=O)C.O>[Cl:28][C:19]1[C:20]([C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([N:13]1[CH2:14][CH2:15][C:7]2[C:6]([C:5]3[CH:4]=[CH:3][N:2]([CH3:31])[N:1]=3)=[N:11][CH:10]=[N:9][C:8]=2[CH2:12]1)=[O:17]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncnc2-c2ccn[nH]2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc(-c2ncnc3c2CCN(C(=O)c2cccc(C(F)(F)F)c2Cl)C3)n1
Yield: 44 %

Procedure:
To a solution of Example 18 (137 mg, 0.33 mmol) in DMF (3 mL) was added NaH, 60% dispersion in mineral oil (16 mg, 0.40 mmol). After 30 minutes MeI (0.03 mL, 0.40 mmol) was then added. After several hours the reaction was diluted with water and then extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Purification on a Prep Agilent system with a XBridge C18 OBD 50×100 mm column eluting with 5 to 99% 0.05% NH4OH in H2O/ACN over 17 min to afforded the title compound as a white solid (61.2 mg, 43%). MS (ESI) mass calcd. C19H15ClF3N5O, 421.09. m/z found 422.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09-8.92 (m, 1H), 7.82-7.75 (m, 1H), 7.58-7.42 (m, 3H), 7.06-7.01 (m, 1H), 5.19-4.92 (m, 1H), 4.58-4.38 (m, 1H), 4.22-3.94 (m, 4H), 3.57-3.22 (m, 3H).
Reaction SMILES: [CH2:1]([P:3](Cl)([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])=[O:4])[CH3:2].[OH:27][N:28]=[C:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([P:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])([O:27][N:28]=[C:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:4])[CH3:2]
Reactant: CCOC(=O)C(C)=NO
Reactant: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C)=NOP(=O)(CC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (500 mg, 1.22 mmol) and thionyl chloride (4 ml) is heated under reflux for about 1.5 hours. The reaction mixture is then concentrated to dryness to give P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic chloride. To a solution of the phosphinic chloride and methylene chloride (10 ml) is added slowly a solution of ethyl 2-hydroxyiminopropionate (320 mg, 2 eq.) and methylene chloride (5 ml) containing triethylamine (0.2 ml, 1.2 eq.). The resulting mixture is stirred at RT for 2 hours. The reaction is then worked up in methylene chloride, washed, dried and evaporated to dryness to give an oily product. The oily product is purified by preparative thin layer chromatography (prep. TLC) in silica gel (50% ethyl acetate/hexane) to yield ethyl 2-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]propionate.
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH3:39])[C:30]=2[C:34]([F:37])([F:36])[F:35])[C:25]=1[C:40](=[S:47])[N:41]([CH3:46])[CH2:42][C:43](O)=[O:44].N>CN(C=O)C.O1CCCC1>[F:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH3:39])[C:30]=2[C:34]([F:36])([F:37])[F:35])[C:25]=1[C:40]([N:41]([CH2:42][C:43]([NH2:2])=[O:44])[CH3:46])=[S:47]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc2c(C(=S)N(C)CC(=O)O)c(F)ccc2c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2c(C(=S)N(C)CC(N)=O)c(F)ccc2c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
1-Hydroxybenzotriazole (0.84 g, 1.5 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 1.2 eq) were added to a stirred solution of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-methylglycine (1.50 g, 4.15 mmol) in anhydrous DMF (15 mL) at room temperature under a dry nitrogen atmosphere. After 13/4 hours, a saturated solution of ammonia in tetrahydrofuran (100 mL) was added to the reaction mixture at room temperature. After 1 hour, the reaction was cooled to 0° C. and ammonia gas was bubbled directly into the reaction mixture for 15 minutes. While still cool, the reaction mixture was filtered and the solid was washed with THF (2×10 mL). The solvent was removed from the filtrate and the residue was diluted with water (500 mL). The aqueous phase was extracted with ether (6×100 mL). The extracts were combined and preabsorbed onto silica gel. The absorbate was flash chromatographed (19:1 chloroform:methanol, silica) and the resulting product was re-flash chromatographed (chloroform to 49:1 chloroform:methanol, silica) to provide the title compound as a light yellow solid (0.30 g, 20%), m.p. 222°-224° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5].[C:15]([N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[C:22](Cl)[CH:21]=[N:20]1)([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[C:22]([S:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:3][CH2:4][CH3:5])=[CH:14][CH:13]=2)[CH:21]=[N:20]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCCOc1ccc(CS)cc1
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2C)cc1
Yield: 46.3 %

Procedure:
To 5 ml of dry N,N-dimethylformamide was added 0.24 g of 55% sodium hydride. The resulting mixture was kept at 0° C. and added dropwise with a solution of 0.91 g of p-propoxybenzyl mercaptan dissolved in 5 ml of N,N-dimethylformamide. After ten minutes passed, the resulting mixture was added dropwise with a solution of 1.0 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone dissolved in 5 ml of N,N-dimethylformamide. After completion of dropwise addition, the resulting mixture was reacted at room temperature for four hours. The resulting solution was poured into 50 ml of water and extracted twice with 50 ml of diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate, and freed of solvent by distillation under reduced pressure to give 1.7 g of crude product. The crude product was fractionated on thin layer chromatography to obtain 0.8 g of 2-t-butyl-4-methyl-5-(p-propoxybenzylthio)-3(2H)-pyridazinone.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([Cl:13])=[O:9]
Reactant: O=C(O)Cc1cccs1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cccs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-thiophenyl acetic acid (150 mg in 2.5 mL dry methylene chloride) at 0° C. was added 0.004 mL N,N-dimethylformamide followed by the dropwise addition of 0.097 mL of oxalyl chloride. After 15 minutes the mixture was warmed to room temperature and stirred for an additional 2.5 hours. Removal of the solvents in vacuo provided the title compound which was used without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(CC)CC)[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[N+:9]([C:5]1[C:4]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:3][C:2]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: CCB(CC)c1cccnc1
Reactant: Nc1cc(Br)cc(-n2cccn2)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cc(-c2cccnc2)cc(-n2cccn2)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 5-bromo-2-nitro-3-pyrazol-1-yl-phenylamine (200 mg, 0.71 mmol) in THF (8 mL) was added, successively, 3-pyridyl-diethyl borane (157 mg), (tetrakistriphenylphosphine) palladium(0) (84 mg), and sodium carbonate (1.1 mL, 2.2 mmom of 2M aqueous). The resulting mixture was stirred at 70° C. overnight then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL), brine (50 mL), dried (MgSO4) then concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel eluted with a gradient of ethyl acetate:hexanes (1:3, 1:2, 1:0, 2:1, 4:1, 8:1), to afford 120 mg (60%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 6.45 (br, s 2H), 6.55 (t, 1H), 7.1 (s, 1H), 7.25 (s, 1H), 7.55 (m, 1H), 7.7 (s, 1H), 8.1 (dt, 1H), 8.3 (d, 1H), 8.7 (d, 1H), 8.9 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Cl:26])[N:25]=1)[C:20]([OH:22])=O>CCOC(C)=O>[Cl:26][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([Cl:16])[N:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)nc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 2,6-dichloro-isonicotinic acid (CAS RN 5398-44-7) after a reaction time of 18 hours. The compound was purified by silica gel chromatography on a 50 g column using a MPLC system eluting with EtOAc (isocratic). The product-containing fractions were pooled and evaporated to give a colorless foam. The foam was dissolved in EtOAc and washed three times with 2M aqueous Na2CO3 solution and brine, dried over MgSO4, filtered and evaporated. Colorless foam (13%). MS (ESI): m/z=372.07 [M+H]+.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[SH:14].C(N(CC)CC)C>O1CCCC1>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[S:14][CH:3]([CH2:2][C:1]([OH:8])=[O:7])[C:4]([OH:6])=[O:5]
Reactant: Sc1cccs1
Reactant: O=C(O)/C=C\C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CC(Sc1cccs1)C(=O)O
Yield: 93 %

Procedure:
To a stirred solution of maleic acid (6.38 g, 0.055 mol) in tetrahydrofuran (50 ml) under nitrogen atmosphere was added 2-thiophenethiol (5.0 ml, 0.055 mol) and triethylamine (14.2 g, 0.14 mol). The mixture was stirred at gentle reflux for 16 hours overnight. The solvent was removed in vacuo and the residual oil was poured into 3NHCl (200 ml). The product was extracted into ethyl acetate (125 ml) in three portions, washed with saturated NaCl solution and dried over Na2SO4. The solution was filtered and concentrated in vacuo. This procedure gave the product as a light beige solid, 11.9 g, m.p. 136°-138.5° C. of 95% purity by HPLC. Yield was 93%.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[NH2:13][C:11]([C@H:10]([NH:9][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH3:15])=[O:12]
Reactant: CC[C@@H](N)C(N)=O
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN[C@H](CC)C(N)=O
Temperature: 80 °C

Procedure:
143.6 ml (1.035 mole) of triethylamine are added to a suspension of 47.75 g (0.345 mole) of (R)-2-amino-butanamide hydrochloride ([alpha]D25 : -26.1°; c=1, methanol) in 400 ml of toluene. The mixture is heated to 80° C. and 67.2 g (0.345 mole) of ethyl 4-bromobutyrate are introduced dropwise.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:4][C:3]=1[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)ccc1Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
A 12 L flask was charged with 4-bromo-3-methyl phenol (428 g, 2.29 mol), CH2Cl2 (7.5 L), triethylamine (480 mL, 3.45 mol), and tert-butyldimethylsilyl chloride (324 g, 2.15 mol). To the solution was added 4-dimethylaminopyridine (15.0 g, 0.123 mol). The reaction mixture was stirred at ambient temperature overnight. The reaction was washed with saturated ammonium chloride (2.2 L) and then DI water (0.9 L). The organic layer was dried (Na2SO4), filtered, and concentrated to crude product (699 g). This material was purified by silica gel chromatography (heptane) to give the title compound (637 g, 98.5%).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:15]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (63 mg) in 1-methyl-2-pyrrolidone (0.8 mL), was added 3-chloro-4-(pyridin-2-ylmethoxy)aniline (149 mg), and the mixture was heated to 140° C. and stirred for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with a mixed solvent (25 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (1/9) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (112 mg) as pale-yellow powder crystals.
Reaction SMILES: [I:1][C:2]1[C:10]([C:11]([Cl:13])=[O:12])=[C:9]([I:14])[C:8]([NH:15][CH3:16])=[C:7]([I:17])[C:3]=1[C:4]([Cl:6])=[O:5].[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:13][C:11]([C:10]1[C:9]([I:14])=[C:8]([N:15]([CH3:16])[C:23]([CH2:22][O:21][C:18](=[O:20])[CH3:19])=[O:24])[C:7]([I:17])=[C:3]([C:4]([Cl:6])=[O:5])[C:2]=1[I:1])=[O:12]
Reactant: CNc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)OCC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)N(C)c1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
2,4,6-Triiodo-5-methylamino-isophthaloyl dichloride (20 g, 32.8 mmol) was dissolved in DMA (60 ml) and acetoxyacetyl chloride (15.32 ml, 142 mmol) was added. The reaction was stirred overnight at room temperature with nitrogen bubbling through the reaction mixture. The reaction mixture was poured slowly onto ice-water (300 ml) and a white solid was isolated by filtration. The solid was dissolved in ethyl acetate and washed with water. The ethyl acetate was collected, dried over MgSO4, filtered and evaporated to give a white solid. This was purified by silica column chromatography eluting with petrol:ethyl acetate to give acetic acid [(3,5-bis-chlorocarbonyl-2,4,6-triiodo-phenyl)-methyl-carbamoyl]-methyl ester (16.25 g, 22.9 mmol).