Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[C:12]2[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[O:19])=[CH:16][C:11]=2[N:10]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:9]=1.N1C=CC=CC=1.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]([NH:7][C:8]1[C:12]2[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[O:19])=[CH:16][C:11]=2[N:10]([C:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:9]=1)=[O:5]
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: COCC(=O)Cl
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with 2-methoxyacetyl chloride (6.6 mg, 0.061 mmol) was added (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (30 mg, 0.056 mmol) in DCM (1 ml) and pyridine (0.045 ml, 0.557 mmol). The vial was capped and the contents stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (1 mL), MP-Trisamine (137 mg, 0.278 mmol) added, and the contents of the vial shaken at room temperature for 3 h. The resin was filtered, and washed through with DCM (1 mL). The volatiles were removed in vacuo to afford crude (R)-2-methoxy-N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide, which was taken forward without purification. MS ESI calc'd. For C37H35N6O3 [M+H]+ 611. found 611.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[C:7](N(OC)C)=[O:8])[CH3:2].[CH3:20][Mg]Br.Cl>C1COCC1.CC(OC)(C)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7](=[O:8])[CH3:20])[CH:13]=[CH:14][C:15]=1[C:16]([F:17])([F:18])[F:19])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCOc1cc(C(=O)N(C)OC)ccc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOc1cc(C(C)=O)ccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-ethoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide from step 7 (15.96 g, 58 mmol) in THF (182 mL) at −5° C. was added methylmagnesium bromide (3 M in Et2O, 38.37 mL, 115 mmol). The mixture was stirred at 0° C. for 15 min, then warmed up to 23° C., stirring was continued for further 3 h at 23° C. Cooled to 0° C., 1 N HCl (274 mL) was added dropwise, stirring was continued at 23° C. for 15 min, the mixture was diluted with TBME, the phases were separated, the organic layer was washed with water and brine, dried over MgSO4. Removal of the solvent in vacuum left a yellow solid (13.10 g, 98%), which was used without further purification. MS (EI) 232.2 [M].
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][CH2:11][C:12]([CH3:20])([CH3:19])[C:13]#[C:14][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O>[CH2:3]([O:10][CH2:11][C:12]([CH3:20])([CH3:19])[C:13]#[CH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C#C[Si](C)(C)C)COCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CC(C)(C)COCc1ccccc1
Temperature: 5 °C
Reaction time: 3.5 h

Procedure:
A 30 L jacketed reactor was charged with methanol (6 vol) which was then cooled to 5° C. Potassium hydroxide (85%, 1.3 equiv) was added to the reactor. A 15-20° C. exotherm was observed as the potassium hydroxide dissolved. The jacket temperature was set to 25° C. A solution of 4-benzyloxy-3,3-dimethyl-1-trimethylsilylbut-1-yne (1.0 equiv) in methanol (2 vol) was added and the resulting mixture was stirred until reaction completion, as monitored by HPLC. Typical reaction time at 25° C. is 3-4 h. The reaction mixture is diluted with water (8 vol) and then stirred for 0.5 h. Hexanes (6 vol) was added and the resulting mixture was stirred for 0.5 h. The phases were allowed to settle and then the aqueous phase (pH 10-11) was drained off and discarded. The organic phase was washed with a solution of KOH (85%, 0.4 equiv) in water (8 vol) followed by water (8 vol). The organic phase was then concentrated down using a rotary evaporator, yielding the title material as a yellow-orange oil. Typical purity of this material is in the 80% range with primarily a single impurity present. 1H NMR (400 MHz, C6D6) δ 7.28 (d, 2H, J=7.4 Hz), 7.18 (t, 2H, 1=7.2 Hz), 7.10 (d, 1H, J=7.2 Hz), 4.35 (s, 2H), 3.24 (s, 2H), 1.91 (s, 1H), 1.25 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[K+].[CH:13]([CH:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:14].CS(C)=O>O>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH:15]([CH:13]=[CH2:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: C=CC(Cl)c1ccccc1
Reactant: O=C([O-])c1ccc(O)cc1O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CC(OC(=O)c1ccc(O)cc1O)c1ccccc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 64.7 %

Procedure:
154.0 g of potassium 2,4-dihydroxybenzoate and 122.3 g of vinylbenzyl chloride were added to 500 ml of dimethylsulfoxide, and stirred at 40° C. for 3 days to react. Then, 1,000 ml of water was added thereto, and the resulting mixture was extracted with 500 ml of ethyl acetate. After distilling off ethyl acetate, recrystallization of the residue from a benzene-hexane mixture solvent yielded 140 g of vinylbenzyl 2,4-dihydroxybenzoate (m.p. 52°-54° C.).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[S:11][CH:12]=2)=[C:6]([CH3:17])[CH:5]=[N:4]1)[CH3:2].[OH-].[K+]>C1COCC1.O>[CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[S:11][CH:12]=2)=[C:6]([CH3:17])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C)c1-c1csc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc(C)c1-c1csc(C(=O)O)c1
Temperature: 50 °C
Yield: 94 %

Procedure:
To a solution of methyl 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (270 mg, 1.08 mmol) in THF/H2O (2 mL/0.4 mL) was added KOH (303 mg, 1.79 mmol). The reaction mixture was heated to 50° C. for 4 h. After the mixture was concentrated and diluted with H2O, the pH was adjusted to 3. The mixture was extracted with DCM (5 mL×3). The collected organic layers were concentrated under vacuum to give the crude acid (240 mg), which was used directly in the next step without further purification: LC-MS m/z=237 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.CCN=C=NCCCN(C)C.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)OCc2ccccc2)C1
Reaction time: 16 h

Procedure:
2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid was mixed with EDCI and benzyl alcohol and the reaction mixture was stirred for 16 h to obtain benzyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([C@@H:6]([CH3:10])[C:7](O)=[O:8])[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.S(Cl)([Cl:19])=O>ClC1C=CC=CC=1>[C:1]1(=[O:16])[N:5]([C@@H:6]([CH3:10])[C:7]([Cl:19])=[O:8])[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12
Reactant: C[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: O=S(Cl)Cl
Solvent: Clc1ccccc1
Product: C[C@@H](C(=O)Cl)N1C(=O)c2ccccc2C1=O
Temperature: 85 °C
Reaction time: 12 h

Procedure:
To a mixture of (S)-2-phthalimidopropionic acid (25.0 g) and chlorobenzene (25 mL), thionyl chloride (9.9 mL) was added and the resulting mixture was stirred at 85° C. (external temperature) for 12 hours. (S)-2-phthalimidopropionyl chloride was obtained by removing the solvent in vacuo. To a mixture of alminium chloride (16.7 g) and chlorobenzene (150 mL), anisole (18.6 mL) was added and this mixture was stirred at 60–65° C. (internal temperature). To this mixture, the solution of (S)-2-phthalimidopropionyl chloride, mentioned above, in chlorobenzene (30 mL) was added dropwise over 20 minutes, and the resulting mixture was stirred at 60–65° C. (internal temperature) for 12 hours. After the temperature of the reaction mixture was raised to 70–75° C. (internal temperature), aluminium chloride (45.6 g) was added to this mixture, and then stirred at same temperature for 3 hours. The mixture was cooled to 50° C. (internal temperature) and ethyl acetate (50 mL) was added dropwise. The resulting mixture was added to a mixture of water (250 g), ethanol (25 mL) and ethyl acetate (100 mL) at 30–45° C. (internal temperature), and stirred at same temperature for 30 minutes. Organic layer was separated from the reaction mixture, the organic layer was washed with brine, sodium bicarbonate solution, brine, 1 mol/L hydrochloric acid and brine, and dried over anhydrous sodium sulfate. After removing the solvent in vacuo, the resulting residue was recrystallized from toluene to obtain (S)-2-[2-(4-hydroxyphenyl)-1-methyl-2-oxoethyl]-isoindol-1,3-dione (18.1 g, 53.6% yield, optical purity 99.9% e.e.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[N:7][CH:8]=1)#[N:2].[SH2:29].C(NCC)C>CN(C=O)C>[NH2:2][C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[N:7][CH:8]=1)=[S:29]
Reactant: S
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cn3)ccc21
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cn3)ccc21
Reaction time: 0.33 h
Yield: 86 %

Procedure:
Through a solution of ethyl ((1S)-5-{3-[(5-cyano-2-pyridinyl)oxy]propoxy}2,3-dihydro-1H-inden-1-yl)acetate (Example 258) (600 mg, 1.58 mmol) in DMF (8 mL) was passed H2S, gently at rt for 20 min. Diethylamine (0.24 mL, 2.37 mmol) was added in one portion and the resultant light-green solution was heated at 60° C. for 3 h (TLC in 2:1 hexanes/EtOAc indicated that the reaction was complete). The darkgreen solution was purged with a strong flow of argon, and then concentrated under reduced pressure. The product (0.56 g, 86%) was isolated by column chromatography (1:1 hexanes/EtOAc) as a bright yellow solid. 1H NMR (400 MHz, CD2Cl2) δ 8.65 (dd, 1H), 8.16 (dd, 1H), 7.56 (b, 1H), 7.19 (b, 1H), 7.04 (d, 1H), 6.80-6.72 (m, 2H), 6.69 (dd, 1H), 4.56 (t, 2H), 4.16 (q, 2H), 4.12 (t, 2H), 3.50 (qt, 1H), 2.90-2.78 (m, 2H), 2.70 (dd, 1H), 2.45-2.32 (m, 2H), 2.30-2.22 (m, 2H), 1.80-1.70 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(COC)OC>[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@H](c1ccccc1)N1C(=O)N(Cc2ccccc2)[C@@H]2C(=O)OC[C@@H]21
Reaction time: 0.5 h

Procedure:
48 ml of dimethoxyethane and 0.39 g (16.2 mmol) of sodium hydride were placed in a 100-ml three-neck flask equipped with a magnetic stirrer under argon and with complete exclusion of moisture. Then 3.24 g (13.2 mmol) of (3aS,6aR)-1-[(R)-(1-phenylethyl)]-dihydro-1H-furo-[3,4-d]imidazol-2,4(3H,3aH)-dione was added. After a stirring time of 10 min., 2.76 g (16.2 mmol) of benzyl bromide was added and the suspension was stirred for 30 min. Then the reaction mixture was evaporated. The residue was dissolved with 25 ml of dichloromethane and 25 ml of water. The phases were separated and the aqueous phase was washed three times, each time with 15 ml of dichloromethane. The organic phases were combined, dried with 5 g of magnesium sulfate and evaporated. (3aS,6aR)-1-[(R)-(1-phenylethyl)]-3-benzyl-dihydro-1H-furo[3,4-d]imidazol-2,4(3H,3aH)-dione was obtained as a beige product in a yield of 3.56 g (80.5 percent). Concerning the product:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][C:31]([CH3:39])([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]4)=[N:26][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3[CH:27]=[N:26][C:25]([N:28]4[CH2:29][CH2:30][C:31]([CH3:39])([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)=[N:24][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3ccccn3)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
To an ice-cold solution of ethyl 1-[5-[2-(ethylcarbamoylamino)-7-(2-pyridyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (0.18 g, 0.33 mmol) in DMSO (2 mL) was added potassium tert-butoxide (0.184 g, 1.65 mmol) and the mixture stirred at rt for 2 h. After completion of reaction (by TLC), water (10 mL) was added followed by extraction with EtOAc (2×50 mL). The organic layer was discarded and the pH of the aqueous layer was adjusted up to 4-5 then extracted with hot EtOAc (3×100 mL). The combined organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to afford the desired product as off-white solid (0.11 g, 65% yield). 1H NMR (DMSO-d6): δ 1.10 (t, J=7.20 Hz, 3H), 1.19 (s, 3H), 1.40 (m, 2H), 2.04 (m, 2H), 3.22 (q, J=7.20, 2H), 3.39 (m, 2H), 4.30 (m, 2H), 6.87 (br s, 1H, D2O exchangeable), 7.44 (m, 1H), 7.92 (s, 1H), 7.99 (m, 1H), 8.18 (s, 1H), 8.42 (d, J=8.0 Hz, 1H), 8.78 (d, (J=4.40 Hz, 1H), 8.85 (s, 2H), 10.54 (br s, 1H, D2O exchangeable) and 12.45 (br s, 1H, D2O exchangeable). MS: 518.27 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2ccncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc3ccncc3c2)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of 7-hydroxyisoquinoline (prepared by the method of R. B. Woodward and W. D. Doering, J. Am. Chem. Soc., 1945, 67, 860) (1.45 g, 10 mmol) in DMF (20 ml) was added sodium hydride (60% dispersion in oil, 0.4 g, 10 mmol) portionwise. After stirring for 30 minutes, benzyl bromide (1.2 ml, 10 mmol) was added and the reaction mixture stirred for 2 h. The reaction mixture was poured into water and extracted with diethyl ether (3×100ml). The ether extracts were combined, washed with 2N sodium hydroxide solution (2×50 ml), brine (50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound (1.6 g, 68%); δH (CDCl3) 5.21 (2H, s, OCH2), 7.30-7.51 (7H, m, ArH), 7.59 (1H, d, J 8.3 Hz, ArH), 7.75 (1H, d, J 13 Hz, ArH), 8.42 (1H, d, J 8 Hz, ArH), and 9.14 (1H, s, ArH).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:34]=[CH:33][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=3)[S:17][C:13]=2[CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:35]I.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([CH3:35])[C:11]1[CH:34]=[CH:33][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=3)[S:17][C:13]=2[CH:12]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccc(NC(=O)OC(C)(C)C)cc3s2)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ccc2nc(-c3ccc(CNC(=O)OC(C)(C)C)nc3)sc2c1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
NaH (95%, 4.5 mg, 0.18 mmol) was added to a solution of tert-butyl (5-{6-[(tert-butoxycarbonyl)amino]-1,3-benzothiazol-2-yl}pyridin-2-yl)methylcarbamate (66 mg, 0.14 mmol) in DMF (2 mL). The mixture was cooled to 0° C. and MeI (10 μL, 0.16 mmol) was added. The reaction was stirred at rt on. Water was added and the mixture was extracted with EtOAc (3×) The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (Heptane/EtOAc gradient) gave the product (60 mg) as a white solid. MS m/z (M+H) 471.
Reaction SMILES: [C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:4])[CH:2]=[CH2:3].Cl.[NH2:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CC(O)C>[CH:15]1([CH:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][CH2:14][N:5]2[C:1](=[O:4])[CH2:2][CH2:3][NH:22][CH2:23][C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCC1(O)CCCCC1
Reactant: C=CC(=O)N1CCc2ccccc2C1C1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(CCNCC1(O)CCCCC1)N1CCc2ccccc2C1C1CCCCC1
Yield: 28 %

Procedure:
2-acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (516 mg) was dissolved in iPrOH (15 mL). To the reaction mixture were added 1-(aminomethyl)cyclohexanol hydrochloride (635 mg) and triethylamine (0.59 mL), followed by stirring under heating at reflux for 16 hours. Thereafter, the solvent was evaporated and water was added to the mixture, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) and then further purified by alkaline silica gel column chromatography (chloroform) to obtain 1-({[3-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl]amino}methyl)cyclohexanol (214 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:2][CH2:4][CH2:5][O:9][CH3:8])=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: COCCNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 55.9 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and 1,1-bis(methylthio)-2-nitroethene (1.65 g) were refluxed in acetonitrile for 8 hr. Solvents were removed and an ethanolic solution of 2 -methoxyethylamine (0.75 g) added. After refluxing for a further 8 hr, removal of solvents gave an oil. This was purified by column chromatography to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)-2-nitro-1,1-ethenediamine (1.0 g). NMRτ(CDCl3) 7.73 s (6H); 7-7.5 m (2H); 6.2-7 m (11H); 6.23 s (2H); 3.81 s (2H); 3.42 s (1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=O)[CH3:4].[C:20]12[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:25]C(=O)O[C:21]2=[O:22]>CC(N(C)C)=O>[CH2:3]([O:5][C:6]([C:7]1[C:21](=[O:22])[C:20]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][C:8]=1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:19])[CH3:4]
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)[nH]c2ccccc2c1=O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
Sodium hydride (0.92 g, 0.023 mol; 60% suspension in mineral oil) was added portionwise to a stirred solution of 3-(4-nitrophenyl)-3-oxopropionic acid ethyl ester (5.46 g, 0.023 mol) in dimethylacetamide (20 mL) at room temperature. A solution of isatoic anhydride (3.4 g, 0.02 mol) in dimethylacetamide (20 mL) was added to this solution. The reddish mixture was stirred at 120° C. for 30 min and then the solvent was concentrated in vacuo. The crude solid was partitioned between water and ethyl acetate and the organic phase then separated. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to leave a residue which was washed once with cold tert-butylmethyl ether to yield 2-(4-nitrophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (1.61 g, 28%) as a white solid, LCMS m/z 339.33 [M+H]+ @ RT 1.16 min, 100% purity.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1ccc2nc(Cl)oc2c1
Reactant: NCc1ccccc1Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Oc1ccc2nc(NCc3ccccc3Cl)oc2c1

Procedure:
2-Chloro-benzooxazol-6-ol (1 eq) and 2-chloro-benzylamine (2 eq) was dissolved in NMP. Using a Personal Chemistry microwave system, the mixture was reacted at 180° C. for six minutes. The crude reaction mixture was diluted with ethyl acetate and washed once with brine and once with 1N HCl, or washed twice with brine, depending on the amine used. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated. This material was purified by silica gel column using hexane and ethyl acetate. MH+=275.1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:20]=[CH:21][CH:22]=1.[Br:31]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:31])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[CH:20]=[CH:21][CH:22]=1
Reactant: CCOP(=O)(OCC)c1cccc(Cn2cnc3c(N)nc(OCCOC)nc32)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1cccc(Cn2c(Br)nc3c(N)nc(OCCOC)nc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl 3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate (30) (400 mg, 0.92 mmol) was dissolved in acetonitrile and N-bromosuccinimide (500 mg, 2.8 mmol) was added in one portion. After stirring at room temperature for 2 h, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with water, 0.2 M sodium thiosulfate solution and brine. The organic phase was dried with sodium sulfate and the solvent was removed under vacuum. The crude diethyl 3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate (450 mg, 95%) was used in the next step without further purification.