Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16](Cl)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CC(O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([N:22]4[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]4)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Clc1nccn2c(-c3cccc(Br)n3)cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine (from Example 38 supra) (1.44 g, 4.65 mmol), 1-methylpiperazine (2.1 g, 21 mmol), and diisopropylethylamine (2.7 g, 21 mmol) in 2-propanol (300 mL) was stirred and heated at reflux overnight. The solution was then cooled to room temperature, concentrated under reduced pressure. The resulted solid was washed with water, partitioned between CH2Cl2 and brine. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (CH2Cl2:CH3OH, 100:1) to give 3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine. (Yield 1.27 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:24]([OH:30])[CH2:25][CH2:26][CH2:27][C:28]#[CH:29]>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][CH2:24][OH:30])=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=1
Reactant: C#CCCCCO
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Product: COc1c(C)cnc(Cn2cc(C#CCCCCO)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of 4-chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (see Example 1) with 5-hexyn-1-ol according to the General Procedure A. tR: 4.92 min. 1H-NMR (DMSO-d6) δ 8.04 (s, 1H), 7.22 (s, 1H), 6.69 (br. s, 2H), 5.25 (s, 2H), 4.39 (t, 1H), 3.70 (s, 3H), 3.40 (q, 2H), 2.39 (t, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 1.55 (m, 4H).
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH2:6]([C:8]1[CH2:9][CH2:10][CH2:11][N:12]2[C:17]=1[C:16]1[NH:18][C:19]3[C:24]([C:15]=1[CH2:14][CH2:13]2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:7].[OH-:25].[Na+].[CH2:27]=O>ClCCl.O>[OH:25][CH2:27][C:8]1([CH2:6][CH3:7])[CH:17]2[N:12]([CH2:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:16]=32)[CH2:11][CH2:10][CH2:9]1
Reactant: [OH-]
Reactant: CCC1=C2c3[nH]c4ccccc4c3CCN2CCC1
Reactant: C=O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: O
Product: CCC1(CO)CCCN2CCc3c([nH]c4ccccc34)C21
Reaction time: 0.17 h

Procedure:
10.0 g. (28.5 moles) of 1-ethyl-2,3,4,6,7,12-hexahydro-indolo[2,3-a]quinolizine perchlorate are dissolved in 100 ml. of dichloromethane, and 75 ml. of distilled water and 20 ml. of a 2N sodium hydroxide solution are added to the dichloromethane solution in argon atmosphere under constant stirring. The reaction mixture is stirred for 10 minutes, thereafter the organic phase is separated, dried over anhydrous potassium carbonate, and filtered. The filtrate is concentrated in vacuo, under argon atmosphere, to a final volume of 15 ml., and 2.0 g. (66.8 mmoles) of paraformaldehyde are added to the concentrate. The solvent is evaporated in vacuo, and the residue is heated at 160°-170° C (bath temperature) for 4 hours in a closed vessel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:16]=[C:15]([C:28]([OH:30])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:50]([N:52]3[CH2:56][C:55](=[O:57])[NH:54][CH2:53]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)[N:16]=[C:15]([C:28]([N:52]3[CH2:50][CH2:53][NH:54][C:55](=[O:57])[CH2:56]3)=[O:30])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccnc(C(F)(F)F)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccnc(C(F)(F)F)c3)n2)CCN1

Procedure:
75 mg (0.15 mmol) of the compound of Example 47A is reacted analogously to the synthesis of the compound of Example 1 with 17 mg (0.17 mmol) of 2-oxopiperazine. 74 mg (84% of theory) of the title compound is obtained.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.C[Mg]Br.C1COCC1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[CH:19]=1.O>C1COCC1>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:25])[C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)[CH:19]=1
Reactant: O=Cc1cccnc1
Reactant: Ic1ncn2ccsc12
Agent: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1ncn2ccsc12
Reaction time: 0.33 h

Procedure:
A solution of 2.50 g of 7-iodoimidazo[5,1-b]thiazole in 50 ml of dry THF was cooled in ice, and 11.3 ml of a 0.93 M methylmagnesium bromide/THF solution was added to the cooled solution under an argon atmosphere. The mixture was stirred at that temperature for 20 min. Pyridine-3-aldehyde (1.04 ml) was then added thereto, and the mixture was stirred at that temperature for 40 min and then at room temperature for 4 hr. Water was added to the reaction solution, and the mixture was extracted five times with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and was then concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 1.925 g of 7-[(pyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][CH3:36].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:35][CH3:36])[CH:28]=2)[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12]
Reactant: COc1cc(B(O)O)ccc1F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F
Temperature: 25 °C
Reaction time: 168 h
Yield: 51.7 %

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 196, 200 mg) in CH2Cl2 (4 ml) were added 4-fluoro-3-methoxyphenylboronic acid (282 mg), copper-(II)-acetate (307 mg), molecular sieve and pyridine (219 mg). The mixture was stirred at room temperature under an air atmosphere with exclusion of moisture for 7 days. The mixture was filtered, diluted with CH2Cl2 and washed with 1 M aqueous HCl. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (139 mg) as an off-white solid. MS (m/e)=486.3 [M+H+].
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:19]([O:21]CC=C)=[O:20])=[C:8]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[CH:13][N:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[K+:56].C(OCC)C>ClCCl.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[CH:13][N:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[K+:56]
Reactant: C=CCOC(=O)C1=C(c2ncc3sccn23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ncc4sccn34)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a solution of 40 mg of allyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.8 ml of dichloromethane and 0.8 ml of ethyl acetate were added under the atmosphere of argon 3.4 mg of triphenylphosphine, 29 mg of potassium 2-ethylhexanoate, 6.4 mg of tetrakis-triphenylphosphine palladium (0), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diethyl ether, and the resulting precipitate was collected by filtration, and purified by column chromatography on COSMOSEAL 40C18-PREP (water:methanol=20:1) to give 13 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][NH:12]C(OC(C)(C)C)=O)[CH:9]=2)[NH:4][CH:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][NH2:12])[CH:9]=2)[NH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2[nH]cc(Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc2[nH]cc(Cl)c2c1

Procedure:
To a solution of 3-chloro-5-(t-butoxycarbonylaminomethyl)-indole (2.62 g, 9.33 mmol) in CH2Cl2 (25 mL), cooled to 0° C. was added trifluoroacetic acid (10 mL). After 1 h the reaction was basified with aqueous NaOH (1 N) to pH=10, extracted with CH2Cl2 (3×) and then with CH2Cl2:MeOH (3:1). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. Purification of the resulting orange residue by flash chromatography (30×150 mm column; gradient elution with MeOH:CH2Cl2:CH2Cl2 saturated with NH3, 4:66:30 to 10:60:30 500 mL each) afforded the title compound as a yellow oil:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH:10](O)[CH3:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:39]1C=CN=C1.CCOC(/[N:49]=[N:50]/C(OCC)=O)=O>C(Cl)Cl>[N:39]([CH:10]([CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])=[N+:49]=[N-:50]
Reactant: CC(O)C(Cc1ccc(Cl)cc1)c1cccc(F)c1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(N=[N+]=[N-])C(Cc1ccc(Cl)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(3-fluorophenyl)-2-butanol (Step C, 0.65 g, 2.3 mmol), triphenylphosphine (1.2 g, 4.7 mmol), imidazole (0.32 g, 4.7 mmol) and zinc azide dipyridine complex (Viaud, M. C.; Rollin, P. Synthesis 1990, 130) (0.72 g, 2.3 mmol) in 10 mL CH2Cl2 was added diethylazodicarboxylate (0.73 mL, 4.7 mmol) at 0° C. After stirring at room temperature for 30 min, the resulting mixture was concentrated with silica gel (20 g) and loaded onto a silica gel column, which was eluted with 2% ether in hexane to 2% ammonia in MeOH (2 M) in 2% ether/hexane to give the title compound. 1H NMR (400 MHz, CD3OD): δ 7.25-6.85 (m, 8H), 3.76 (m, 1H), 3.33 (m, 1H), 2.92 (m, 2H), 1.15 (d, 3H).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17]>CN(C)C=O.CO.[Cu]>[Cl:17][C:12]1[CH:13]=[CH:14][C:15]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:16][CH:11]=1
Reactant: Cc1ccc(O)cn1
Reactant: Clc1ccccc1Br
Agent: [Cu]
Agent: [K]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(Cl)cc2)cn1
Reaction time: 18 h

Procedure:
7.35 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 20 ml of dimethylformamide, and 9.6 g of bromochlorobenzene and 800 mg of a copper powder were added to the suspension. The reaction was effected at a temperature of 120° C. for a period of 18 hours in a nitrogen stream while stirring. After allowing the reaction mixture to cool, the reaction mixture was diluted with 50 ml of methanol and then filtered. The filtrate was immediately concentrated to dryness, and 200 ml of chloroform and 100 ml of water were added to the dried material, and the mixture adjusted to a pH of 9 with 5 N sodium hydroxide. The insoluble matter was again separated by filtration. The resulting chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 8.2 g of oily 5-(p-chlorophenoxy)-2-methylpyridine. Gas chromatography revealed that the thus-obtained product contained no 5-(p-bromophenoxy)-2-methylpyridine.
Reaction SMILES: [Br-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[O:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1.[CH2:31]([O:33][C:34](=[O:39])[CH:35](Cl)[NH:36]O)[CH3:32].O>CCOCC.C(Cl)Cl>[CH2:31]([O:33][C:34]([C:35]1[CH2:2][C:27]2([CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[O:30][N:36]=1)=[O:39])[CH3:32]
Reactant: O=C1CCOCC1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(Cl)NO
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=NOC2(CCOCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 281.9 %

Procedure:
To a well-vented 500 mL three-necked round-bottom flask was added methyl triphenylphosphonium bromide/sodium amide mixture (“instant ylide”, 22.9 g, 5.49 mmol) and dry ether (100 mL). The mixture was stirred at rt for 1 h and filtered through a glass-fritted funnel directly into a solution of tetrahydro-pyran-4-one (5.00 g, 4.99 mmol) in ether (20 mL). This mixture was stirred at rt for 4 h. Ethyl-2-chloro-2-(hydroxyamino)acetate (8.32 g, 5.49 mmol) in DCM (100 mL) was added dropwise via addition funnel over 3 h, and the mixture was stirred for 2.5 days. Water (100 mL) was added, and the mixture was extracted three times with DCM (200 mL, 100 mL, 100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 200-g Sepra Si 50 SPE column (Isco system: Flow rate=30 mL/min; Eluent=EtOAc/heptane, 1:9 v/v for 10 min, then 1:9 to 2:3 v/v over 40 min) to afford the title compound (3.00 g, 28%) as a tan oil. 1H-NMR (400 MHz, CDCl3) δ: 4.35 (q, J=7.2 Hz, 2H), 3.89 (ddd, J=11.8, 8.7, 3.3 Hz, 2H), 3.65-3.75 (m, 2H), 2.99 (s, 2H), 1.89-1.97 (m, 2H), 1.76-1.86 (m, 2H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f24) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(C(C)C)CC)(C)C.[Cl:22][CH2:23][C:24](Cl)=[O:25].NC1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH:5][C:24](=[O:25])[CH2:23][Cl:22]
Reactant: O=C(Cl)CCl
Reactant: COc1cc([N+](=O)[O-])ccc1N
Solvent: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)CCl
Temperature: 0 °C

Procedure:
2-Methoxy-4-nitroaniline (8.40 g, 50 mmol) was dissolved in 200 mL dichloromethane and stirred at 0° C. while adding diisopropylethylamine (6.45 g, 50 mmol) then a solution of chloroacetyl chloride (5.65 g, 50 mmol) in 50 mL dichloromethane. The mixture was stirred for 17 h at 20-25° C., evaporated and 300 mL ethyl acetate added. The solution was washed with 2×100 mL 2M hydrochloric acid then brine, dried (sodium sulphate) and evaporated. The residue dissolved in 200 mL warm toluene, charcoaled then chromatographed on 300 mL flash silica in a 10 cm sinter funnel. Elution with toluene and evaporation afforded a bright yellow oil which solidified on standing. NMR showed an 11:4 mixture of product and starting aniline—product δ 9.17(s, 1H), 8.56(m,1H), 7.94(m, 1H), 7.79(m, 1H), 4.22(s, 2H), 4.03(s, 3H). Used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=1.CI.[OH-].[Na+].[C:20](O)(=O)C>O.C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[C:9](=[O:15])[NH:10][C:11]([S:14][CH3:20])=[N:12][CH:13]=1
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1ccccn1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Solvent: CCO
Product: CSc1ncc(Cc2ccccn2)c(=O)[nH]1

Procedure:
A solution of 5-(2-pyridylmethyl)-2-thiouracil (6.6 g), methyl iodide (4.3 g) and sodium hydroxide (2.5 g) in water (100 ml) and ethanol (100 ml) was stirred at 70° for 30 minutes, allowed to cool and glacial acetic acid added to pH5. The solution was partially evaporated and cooled in an ice-bath. The precipitate was filtered off and recrystalled from ethanol to give 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone, m.p. 195°-197.5°.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[C:30]5[C:25](=[N:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[CH:24]=[CH:23][C:22]4=[O:33])[CH2:15][CH2:14]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[C:34]([O:37]Br)(=[O:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+].[C:45](#N)[CH3:46]>>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:35][C:34]([O:37][CH2:45][CH3:46])=[O:36])[CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[C:30]5[C:25](=[N:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[CH:24]=[CH:23][C:22]4=[O:33])[CH2:15][CH2:14]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Reactant: CC(=O)OBr
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CN(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(OC)cc32)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 150 mg of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one and 85 mg of bromo acetate in 15 mL of acetonitrile, 100 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 18 hours, and stirred at 40° C. for 4 hours. The solvent was distilled off under reduced pressure, thereto were added chloroform and water, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC., and an eluent of chloroform:methanol=20:1 to obtain 90 mg of ethyl ((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)acetate as an brown oily substance.
Reaction SMILES: [N:1]#[N:2].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([NH:16][C@H:17]([C:25]([N:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][C:29]([OH:31])=[O:30])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14].S(Cl)([Cl:38])=O.[CH2:40](O)[CH3:41]>>[N:1]#[N:2].[ClH:38].[CH2:40]([O:30][C:29](=[O:31])[CH2:28][N:27]([C:25](=[O:26])[C@H:17]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])[NH:16][S:13]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)(=[O:14])=[O:15])[CH2:32][CH2:33][CH2:34][CH3:35])[CH3:41]
Reactant: CCO
Reactant: CCCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=S(Cl)Cl
Agent: N#N
Product: CCCCN(CC(=O)OCC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2ccccc2c1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To an ice-cooled suspension of 1.0 g of N2 -(2-naphthalenesulfonyl)-L-arginyl-N-butylglycine in 15 ml of ethanol was added dropwise 0.5 ml of thionyl chloride with vigorous stirring. The reaction mixture was allowed to stand for 2 hours at room temperature and then refluxed for 2 hours. At the end of this period, the reaction mixture was evaporated to dryness, and the residual syrup was treated with cold ethyl ether to give 1.02 g (90%) of N2 -(2-naphthalenesulfonyl)-L-arginyl-N-butylglycine ethyl ester hydrochloride in the form of a powder.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.O[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=1.[CH:26]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][S:1][C:2]2[O:3][C:4]3[C:9]([C:10](=[O:12])[C:11]=2[CH3:26])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:16][CH:17]=1
Reactant: OCCCCc1ccc(CO)cc1
Reactant: O=c1cc(S)oc2ccccc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(SCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.1 %

Procedure:
To solution of 2-mercapto-chromen-4-one (1.52 g, 7.90 mmol) and 4-(4-hydroxymethyl-phenyl)-butan-1-ol (1.90 g, 9.90 mmol) dissolved in anhydrous THF (80 mL) was added solid PPh3 (3.11 g, 11.90 mmol) and DIAD (2.30 mL, 11.90 mmol). After completion of addition the reaction mixture continued to stir at room temperature. After 20 hours, the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material was purified using silica gel chromatography (1:1 pentane:ethyl acetate) to yield 2-[4-(4-hydroxy-butyl)-benzylsulfanyl]-3-methyl-chromen-4-one (1.29 g, 3.64 mmol) in moderate yield (46%). 1H (CDCl3, 600 MHz): δ 8.18 (1H, dd, J=7.9,1.3 Hz), 7.60 (1H, ddd, J=8.6, 7.2, 1.7 Hz), 7.31 (2H, t, J=8.5 Hz), 7.29 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 4.36 (2H, s), 3.62 (2H, m), 2.61 (2H, t, J=7.5 Hz), 2.00 (3H, s), 1.67 (2H, m), 1.56 (2H, m); 13C(CDCl3, 150 MHz): δ 174.9, 161.3, 156.0, 141.5, 133.2, 132.3, 128.3, 128.2, 125.7, 124.5, 122.2, 117.2, 116.3, 62.3, 34.7, 31.8, 29.2, 26.9, 10.1.; HRMS calcd for C21H22O3S 355.1363. found 355.1364.
Reaction SMILES: [CH2:1]([Br:3])[CH3:2].[CH3:4][N:5]([CH3:33])[CH2:6][CH2:7][CH2:8][O:9][N:10]=[C:11]1[CH2:16][C:15]([CH2:18][CH3:19])([CH3:17])[N:14]([O:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[C:13]([CH2:30][CH3:31])([CH3:29])[CH:12]1[CH3:32]>C(#N)C>[Br-:3].[CH2:30]([C:13]1([CH3:29])[CH:12]([CH3:32])[C:11](=[N:10][O:9][CH2:8][CH2:7][CH2:6][N+:5]([CH2:1][CH3:2])([CH3:4])[CH3:33])[CH2:16][C:15]([CH2:18][CH3:19])([CH3:17])[N:14]1[O:20][CH:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])[CH3:31]
Reactant: CCC1(C)CC(=NOCCCN(C)C)C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: CCBr
Solvent: CC#N
Product: CCC1(C)CC(=NOCCC[N+](C)(C)CC)C(C)C(C)(CC)N1OC(C)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethylbromide (7.5 ml) is added to a solution of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidine-4-one-O-(3-dimethylamino-propyl)-oxime (10.2 g, 0.0244 mol) in acetonitrile (12 ml). The solution is stirred 24 h at room temperature and is then evaporated. The residue is dissolved in dichloromethane, dried over MgSO4 and evaporated to afford 11.5 g of the title compound as a white powder.