Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[CH3:12][CH2:13][O:14][CH2:15][CH3:16].C(OCC)=C>C(OCC)(=O)C>[CH2:13]([O:14][CH:15]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:16])[CH3:12]
Reactant: CCOCC
Reactant: CC(C)c1ccc(O)cc1
Agent: C=COCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(C)Oc1ccc(C(C)C)cc1

Procedure:
To 50 ml of dehydrated ethyl acetate (AcOEt) were added 5.0 g (36.7 mmol) of 4-isopropylphenol and 1.7 ml of hydrochloric acid/ether (HCl-Ether) solution (1.0 mol/L), and temperature of the reaction system was controlled to 40° C. Ethyl vinyl ether (7.9 g: 109.6 mmol) was added dropwise to the mixture, and the resultant mixture was stirred overnight. After the completion of the reaction, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, and washed with water to remove the solvent. Thus obtained mixture was purified by silica gel column chromatography (eluent: hexane) to provide 7.0 g (33.6 mmol) of 1-(1-ethoxy)ethoxy-4-isopropylbenzene.
Reaction SMILES: [NH2:1][C@H:2]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)[C:3]([NH:5][C@@H:6]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=1)=[O:8])=[O:4].C(N(C(C)C)CC)(C)C.[O:51]=[C:52](Cl)OC(Cl)(Cl)Cl>O1CCCC1>[N:36]1([CH2:35][CH2:34][O:33][C:30]2[CH:31]=[CH:32][C:27]([CH:2]3[C:3](=[O:4])[N:5]([C@@H:6]([C@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH3:20])[C:7]([NH:9][C:10]4[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=4)=[O:8])[C:52](=[O:51])[NH:1]3)=[CH:28][CH:29]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(OCCN3CCOCC3)cc2)[C@@H](C)c2ccccc2)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)NC(c3ccc(OCCN4CCOCC4)cc3)C2=O)n1
Reaction time: 0.33 h

Procedure:
Crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (≈0.19 mmol) was dissolved in tetrahydrofuran (10 mL) that contained diisopropylethylamine (160 μL, 122 mg, 0.94 mmol) and was transferred via cannula to a solution of diphosgene (16 μL, 26 mg, 0.13 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred for 20 minutes and then partitioned between ethyl acetate and water. The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted with 0-100% ethyl acetate in hexanes and the isolated material further purified by preparative thin layer chromatography using silica gel eluted with ethyl acetate. Precipitation of the isolated product from dichloromethane with an excess of hexanes gave (2S,3S)-2-{4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide as an off white solid (32 mg, 29%).
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].[CH3:11][S:12][C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]2[C:21]=1[C:20](=[O:22])[CH2:19][CH2:18]2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:23][C:16]1[CH:15]=[CH:14][C:13]([S:12][CH3:11])=[C:21]2[C:17]=1[CH2:18][CH2:19][C:20]2=[O:22])([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCSP(=O)(Cl)OCC
Reactant: CSc1ccc(O)c2c1C(=O)CC2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCSP(=O)(OCC)Oc1ccc(SC)c2c1CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 7-methylthio-4-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product O-ethyl S-propyl O-(7-methylthioindan-1-on-4-yl) thiophosphate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:21][CH2:20][CH2:19][C:16]3[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=3)=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: Brc1ccc(C2CC2)cc1
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(CCNc2ccc(C3CC3)cc2)nc1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-cyclopropyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 307.2 [M+H]+) was prepared from 1-bromo-4-cyclopropyl-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:21])[NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:13]([OH:20])[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].[Cl:22][C:23]1[CH:28]=[C:27]([N+]([O-])=O)[CH:26]=[CH:25][N:24]=1>CN(C=O)C.O>[C:3]([O:7][C:8](=[O:21])[NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:13]([O:20][C:27]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:22])[CH:28]=2)[CH2:12][CH2:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccnc(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.32 g, 8.00 mmol) was suspended in dry DMF (15 mL) under argon. To this was added Intermediate 10a (1.05 g, 4.00 mmol) followed by 2-chloro-4-nitropyridine (0.64 g, 4.02 mmol). The dark coloured mixture was stirred at RT under argon for 30 min. The reaction mixture was diluted with water and extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated in vacuo. Purification by FCC, eluting with 0-70% ethyl acetate in cyclohexane, gave the title compound as a white foam (1.43 g, 95%). LCMS (Method 3): Rt 4.22 min, m/z 373.1 [MH+].
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:39](=O)[CH2:40][CH2:41][CH3:42]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CCCC=O
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Product: CCCCN[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure F using butyraldehyde. The final product was obtained in 13% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[C:4]([CH3:20])[CH:3]=1.FC(F)(F)C(O)=O.ClCCl>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(F)ccc1NC1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)ccc1NC1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To an ice cooled solution of tert-butyl 3-((4-fluoro-2-methylphenyl)amino)azetidine-1-carboxylate (D30) (300 mg, 1.07 mmol) in dichloromethane (2 ml), a mixture of trifluoroacetic acid/dichloromethane (4.5 ml/1.5 ml) was added and the mixture stirred at room temperature for 1 h. Solvents were evaporated in vacuo and the resulting residue was purified by SPE-SCX cartridge (10 g). Collected ammonia fractions, after solvent evaporation afforded the title compound (D55) (0022/107/1) (190 mg)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[O:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[O:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH2:1][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[CH2:15][CH2:14]1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: NC1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CNC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a solution of methyl 3-formylbenzoate (492 mg, 3.0 mmol) in MeOH (10 mL) was added tetrahydro-2H-pyran-4-amine (303 mg, 3.0 mmol) and AcOH (0.05 mL). The mixture was stirred at 25° C. for 2 h. NaBH3CN (945 mg, 15.0 mmol) was added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated and the residue was dissolved in water and extracted with DCM. The organic layer was concentrated, and the residue was purified by prep-TLC to give the title product (500 mg, Yield 67%). LCMS (m/z): 250.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cccc5[nH]ccc45)ncnc32)CC1
Yield: 32 %

Procedure:
4-[4-(1H-Indol-4-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (25 mg, 32%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.18 mmol) with 4-hydroxyindole (TCI America, Portland, Oreg., USA; 24 mg, 0.18 mmol) in the presence of potassium carbonate (54 mg, 0.39 mmol). Mass spectrum MH+=435.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.O.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc(Br)ccc1N
Solvent: O
Product: CC(=O)Nc1ccc(Br)cc1C(C)C
Yield: 83 %

Procedure:
A solution of 4-bromo-2-iso-propyl-phenylamine (780 mg, 3.64 mmol) in acetic anhydride (4 mL) was stirred at room temperature over night. The reaction was poured into water and the resulting white precipitate was filtered off and dried under vacuum to give N-(4-bromo-2-iso-propyl-phenyl)-acetamide as a light pink solid (0.770 g, 83%); 1H NMR (300 MHz, DMSO-d6): δ 9.39 (s, 1H), 7.43 (d, 1H, J=2.4 Hz), 3.16 (m, 1H), 2.04 (s, 3H), 1.13 (d, 6H, J=7 Hz); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=dichloromethane; Rf=0.21
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:18]#N)[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.Cl.[OH2:39]>C(Cl)Cl>[Cl:21][C:6]1[C:7]([CH3:20])=[C:8]([CH:18]=[O:39])[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=1
Reactant: O
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cc(F)cc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1c(Cl)cc(C(C)O)c(-c2cc(F)cc(F)c2)c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a mixture of 6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carbonitrile (2.43 g, 7.95 mmol) in methylene chloride (50 mL) was added 1.0 M diisobutylaluminum hydride in hexane (19.9 mL, 19.9 mmol) at −78° C. The reaction was warmed to rt over 2 h with stirring. 5.0 M Hydrogen chloride in water (70 mL) was added slowly, and stirring was continued for 1 h. The resultant mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated to dry. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired product (2.4 g, 97%). LCMS calculated for C16H12ClF2O (M-OH)+: m/z=293.1; Found: 293.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:34][C:35]3[CH:36]=[N:37][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:39][CH:40]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccc(C(F)(F)F)nc3)c3cc(Cl)ccc23)c1
Temperature: 0 °C

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.050 g, 0.15 mmol) was dissolved in DMF:THF (1:1, 4 mL) and cooled to 0° C. Lithium bis(trimethylsilyl)amide solution (0.375 mL, 0.375 mmol, 1.0M in hexanes) was added. 3-(Chloromethyl)-6-(trifluoromethyl)pyridine (0.044 g, 0.225 mmol) was added and the reaction was allowed to warm to room temperature. After 20 minutes the reaction was heated to 50° C. for 1 hour and then submitted to aqueous workup to provide the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15](O)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CCCCCC.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[C:15]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)c1c(C(=O)OCC)[nH]c2ccccc12

Procedure:
A mixture of 3.8 g (20 mmol) of ethyl indole-2-carboxylate, 6.0 g (30 mmol) of octadecanoic acid, 1.0 g of polyphosphoric acid, 20 ml of absol. CH2Cl2 and 4.4 ml of trifluoroacetic anhydride is stirred at room temperature for 4 h. Then 1 M NaOH is added, and the mixture is extracted with ether. The ether phase is dried over Na2SO4 and the solvent is distilled off. The product precipitates after addition of petroleum ether.
Reaction SMILES: CC[O-].[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16]([N:18]1[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21](=O)[O:20]C1=O)[CH3:17].Cl>CN(C)C=O>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:18]([CH2:16][CH3:17])[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21]=1[OH:20])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CC)c1=O

Procedure:
To a 40 ml. solution of NaOEt (1.0 g. Na-0.042 mole) was added 6.8 g. (0.042 mole) of diethyl malonate and this is stirred 10 minutes, then stripped to dryness. Dimethylformamide was added until a solution formed and to this was added 5.7 g. (0.021 mole) of 1-ethyl-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione and the mixture heated at reflux for 2 hours. The reaction was then cooled and poured into dilute HCl and the resulting precipitate filtered off and rinsed well with water. Recrystallization with hexane-ethyl acetate gave 5.1 g. of the title product--m.p. 177°-180° C.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[N:5]=[CH:4][N:3]1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CCOC(C)=O.CO.[Pt]>[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:2]([OH:1])[N:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:4]=[N:5]2
Reactant: CCCCCN1C=Nc2cccc([N+](=O)[O-])c2C1O
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCN1C=Nc2cccc(N)c2C1O
Reaction time: 2 h
Yield: 74 %

Procedure:
4-hydroxy-5-nitro-3-pentyl-3,4-dihydroquinazoline (6a, 10.0 g, 38.0 mmol) was dissolved in EtOAc-MeOH mixed solvent (2:1, 150 ml) and 3% Pt—C (1.0 g) was added. Hydrogenation was carried out at room temperature under H2 atmosphere using a balloon. After 2 h, the reaction was stopped and the mixture was filtered. The filtrated was concentrated under reduced pressure and the obtaining residual oil was purified by a short silica gel (100 g) column chromatography (eluent: EtOAc/MeOH=20/1) to give 5-amino-4-hydroxy-3-pentyl-3,4-dihydroquinazoline (2a, 6.56 g, 74%); 1H NMR (270 MHz) δ (CD3OD) 0.88 (t, J=6.9 Hz, 3H), 1.23-1.41 (m, 4H), 1.63-1.74 (m, 2H), 3.26-3.35 (m, 1H), 3.51-3.62 (m, 1H), 6.15 (s, 1H), 6.47-6.51 (m, 1H), 6.55 (dd, J=1.0 and 7.9 Hz, 1H), 7.06 (t, J=7.9 Hz, 1H), 7.43 (s, 1H); MS (ES) m/z 234 (M+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]2[S:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].I[CH3:19]>C1COCC1.CO>[CH3:19][NH:3][C:4]1[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][C:7]2[CH:12]=[CH:11][S:10][C:8]=2[N:9]=1
Reactant: CI
Reactant: CCOC(=O)c1nc2ccsc2nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2ccsc2nc1NC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a stirred suspension of neat NaH (0.82 g, 3.40 mmol) in 10 ml THF at -78° C. was canulated a cold (-78° C.) 20 ml THF solution of ethyl 3-aminothieno[2,3-b]pyrazine-2-carboxylate (0.690 g, 3.09 mmol). The reaction mixture was allowed to warm to rt, stir for 2 h and was then treated with iodomethane (0.460 g, 3.24 mmol). After stirring for 12 h at rt, the mixture was diluted with 5 ml MeOH and concentrated. Purification by column chromatography on silica gel eluting first with 10:1 then 5:1 hexanes:ethyl acetate gave the title compound (0.610 g, 84%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ1.40 (t, 3H), 3.60 (d, 3H), 4.36 (q, 2H), 7.48 (br s, 2H), 8.54 (d, 1H), 8.57 (d, 1H). MS (DCI/NH3) m/e 238 (M+H)+.
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[CH3:7][C:8]([CH3:10])=O>Cl.C1CCCCC1>[CH3:7][C:8]1([CH3:10])[S:1][CH:2]([CH2:3][OH:4])[CH2:5][S:6]1
Reactant: OCC(S)CS
Reactant: CC(C)=O
Agent: Cl
Solvent: C1CCCCC1
Product: CC1(C)SCC(CO)S1
Yield: 29.4 %

Procedure:
To a mixture of 10.18 g (0.082 mole) of 2,3-dimercapto-1-propanol, 20 mL of cyclohexane, and 5.0 g (0.086 mole) of acetone was added 4 drops of concentrated hydrochloric acid, and the mixture was stirred at reflux temperature for 3.5 hours to give, after fractional distillation of the reaction mixture, 5.85 g of a colorless oil, bp 96°-106° C./1.2-1.5 mm Hg, which solidified on standing. Recrystallization from toluene-hexane gave 3.96 g of product, mp 45°-50° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:17]([NH:19][NH2:20])=[O:18]>C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:17]([NH:19][N:20]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:18]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1cc(Cl)cc(Cl)c1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3,5-dichlorobenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 159 mg of the title compound (69%) as a orange solid in 90% purity by HPLC (Rt: 5.86, 6.66, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2nc(Cl)[nH]c2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
2-Chlorobenzimidazole (1.05 g) was dissolved in DMF (10 mL), and N-chlorosuccinimide (1.01 g) was added thereto. The mixture was stirred at 60° C. for 30 min and the reaction mixture was added to water. The precipitated solid was collected by filtration to give 2,5-dichlorobenzimidazole (0.480 g) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17]([NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:23]([O:30][C:31]3[CH:32]=[CH:33][C:34]4[N:35]([C:37]([N:40]5[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]5)=[N:38][N:39]=4)[CH:36]=3)[CH2:22][CH2:21]2)=[O:18])[N:13]([CH3:15])[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:18])[NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:23]([O:30][C:31]3[CH:32]=[CH:33][C:34]4[N:35]([C:37]([N:40]5[CH2:45][CH2:44][CH:43]([CH2:46][O:47][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:42][CH2:41]5)=[N:38][N:39]=4)[CH:36]=3)[CH2:22][CH2:21]2)[N:13]([CH3:15])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCC(CO)CC4)n3c2)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCC(COS(C)(=O)=O)CC4)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Methanesulfonyl chloride (8.8 μL, 0.13 mmol) was added to a solution of Intermediate 14g (50 mg, 0.08 mmol) and DIPEA (46 μL, 0.26 mmol) in DCM (1.5 mL) and the reaction mixture was stirred at RT for 1 h. The mixture was diluted with DCM (5 mL) and washed with water (3×5 mL). The organic layer was passed through a phase separator and concentrated in vacuo to afford the title compound (57 mg, 100%). LCMS (Method 3): Rt: 3.21 min, m/z 651 [MH+].