Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: Fc1cccc(CBr)c1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-chloro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (100) and 3-fluorobenzyl bromide according to General Procedure B. Yield 214 mg (42%), MP 204° C.; 1H-NMR (DMSO-d6): δ 3.76 (m, 4H), 3.92 (m, 4H), 5.51 (s, 2H), 7.06 (m, 3H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.33 (m, 1H), 7.50 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=1.2, 5.2 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H); EIMS: 508 (M+1). Anal. (C25H19ClFN5O2S) C, H, N.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])(=O)[CH:2]([CH3:4])[CH3:3].[NH3:14]>CO>[NH2:14][C:1]([CH:2]([CH3:4])[CH3:3])=[CH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)C(=O)CC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)C(N)=CC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
Through a solution of 240 g of t-butyl isobutyrylacetate in 500 ml of methanol was passed 70 g of ammonia in 2 hours, maintaining the temperature at below 25° C. The resulting solution was sitrred at room temperature for 18 hours, after which the methanol was removed in vacuo. Methylene chloride was added and the suspension was filtered. The filtrate was concentrated on a rotary evaporator to give 180 g t-butyl 3-amino-4-methyl-2-pentenoate as an oil.
Reaction SMILES: C(OO)(=[O:3])C.[CH3:6][C:7]1[NH:8][C:9]([S:32][CH3:33])=[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:6][C:7]1[NH:8][C:9]([S:32]([CH3:33])=[O:3])=[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(=O)OO
Reactant: CCOC(=O)C1=C(C)NC(SC)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(S(C)=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
Peracetic acid (6.8 ml of 1M solution in methanol) was added to a solution of diethyl 1,4-dihydro-2-methyl-6-(methylthio)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (2.77 g 6.8 mmoles) in methylene chloride (150 ml) at -78°. The reaction mixture was allowed to reach room temperature and was then stirred for 30 minutes. Saturated aqueous sodium bicarbonate (150 ml) was added and the organic layer separated, dried (Na2SO4) and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with ether/petroleum ether (60°-80° ) mixtures. The two isomers were separated and recrystallised from 2-propanol.
Reaction SMILES: CN1CCOCC1.N#N.[C:10]([NH:13][C@H:14]([C:30]([OH:32])=O)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])(=[O:12])[CH3:11].C(N=C=NCCCN(C)C)C.[C:44]([O:48][C:49](=[O:73])[CH:50]([CH2:71][NH2:72])[CH2:51][C:52]1([C:57](=[O:70])[NH:58][C@H:59]2[CH2:64][CH2:63][C@@H:62]([C:65]([O:67][CH2:68][CH3:69])=[O:66])[CH2:61][CH2:60]2)[CH2:56][CH2:55][CH2:54][CH2:53]1)([CH3:47])([CH3:46])[CH3:45]>ClCCl>[C:44]([O:48][C:49](=[O:73])[CH:50]([CH:71]([C:30](=[O:32])[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[NH:13][C:10](=[O:12])[CH3:11])[NH2:72])[CH2:51][C:52]1([C:57](=[O:70])[NH:58][C@H:59]2[CH2:60][CH2:61][C@@H:62]([C:65]([O:67][CH2:68][CH3:69])=[O:66])[CH2:63][CH2:64]2)[CH2:56][CH2:55][CH2:54][CH2:53]1)([CH3:46])([CH3:45])[CH3:47]
Reactant: CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN)C(=O)OC(C)(C)C)CCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: N#N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)OC(C)(C)C)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1-Hydrobenztriazole (207 mg, 1.53 mmole) and N-methylmorpholine (235 mg, 2.36 mmole) were added to a stirred solution of N2 -acetyl-N6 -benzyloxycarbonyl-L-lysine (456 mg, 1.41 mmole) in dry dichloromethane at 0° C., followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (361 mg). The solution was stirred at 0° C. for 20 minutes and 3-{1-[(cis-4-ethoxycarbonylcyclohexyl)-carbamoyl]cyclopentyl}-2-(aminomethyl)propanoic acid t-butyl ester (500 mg, 1.18 mmole) in dichloromethane (10 ml) was added in one portion and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. The solution was concentrated under vacuum to a volume of 10 ml and partitioned between ethyl acetate and water. The organic phase was washed with water (2×50 ml), 2M hydrochloric acid (50 ml, 2×25 ml), sodium bicarbonate solution (2×25 ml) and brine and then dried (MgSO4) and the solvent evaporated. The residue was chromatographed on silica eluting with ethyl acetate to give the title compound (610 g, 71%). Found: C, 63.34; H, 8.61; N, 7.45. C39H60N4O9 (0.25 H2O) requires C, 63.48; H, 8.33; N, 7.59%.
Reaction SMILES: [CH2:1]([N:8]1[CH:25]=[N:24][C:23]2[N:13]([C@@H:14]3[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:12]=[N:11][C:10]=2[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)(Cl)Cl.C(O)C>N1C=CC=CC=1>[C:27]([O:21][CH2:20][C@H:19]1[O:22][C@@H:14]([N:13]2[C:23]3[N:24]=[CH:25][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9](=[O:26])[C:10]=3[N:11]=[CH:12]2)[C@H:15]([OH:16])[C@@H:17]1[OH:18])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=c1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2ncn1Cc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=c1c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](O)[C@H]3O)c2ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 1-benzylinosine (3.58 g, 10 mmol) and trityl chloride (3.3 g, 12 mmol) in pyridine (50 mL is stirred overnight at room temperature. An additional amount of trityl chloride (3.3 g) is charged on the second and third days. The reaction is monitored by thin layer chromatography on silica gel plates using a mixture of chloroform and ethanol (10:1 v/v) as the developing solvent. After all the starting material is consumed, the mixture is concentrated in vacuo, and the residue coevaporated several times with toluene and ethanol, and then chromatographed on a silica column using chloroform-ethanol (19:1 v/v) as the eluent to give 5'-O-trityl-1-benzylinosine which is crystallized from ethanol: 5.40 g (90% yield), mp 208°-209° C. 1H NMR (Me2SO-d6) δ 3.20-3.24 (2H, m, H-5',5"), 4.10-4.29 (2H, m, H-3',4'), 4.61-4.67 (1H, m, H-2', collapsed to dd upon addition of D2O, J1',2' =5.6, J2',3' =5.0 Hz), 5.24 (2H, s, CH2Ph), 5.21-5.27 (1H, m, OH, exchangeable), 5.57 (1H, d, OH), 5.92 (1H, d, H-1'), 7.06-7.32 (2OH, m, Tr, CH2Ph), 8.23, 8.51 (1H each, H-2, H-8). Analyses: calculated for C26H32N4O5 : C, 71.98, H, 5.37, N, 9.33. Found: C, 71.86, H, 5.44, N, 9.18.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([Sn](CCCC)(CCCC)CCCC)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].Br[C:27]1[N:28]=[C:29]([N:37]2[CH2:42][CH2:41][N:40]([CH:43]=[O:44])[CH2:39][CH2:38]2)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:43]([N:40]1[CH2:39][CH2:38][N:37]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:36]=[C:27]([C:10]3[CH:9]=[CH:8][C:7]([S:4](=[O:5])(=[O:6])[NH:3][CH2:1][CH3:2])=[CH:12][CH:11]=3)[N:28]=2)[CH2:42][CH2:41]1)=[O:44]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)NCC)cc1
Reactant: O=CN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCNS(=O)(=O)c1ccc(-c2cc3ccccc3c(N3CCN(C=O)CC3)n2)cc1
Yield: 41.4 %

Procedure:
N-Ethyl-4-tributylstannylbenzenesulfonamide (1.42 g) and 3-bromo-1-(4-formylpiperazin-1-yl)isoquinoline (0.82 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.12 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 5N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 1-(4-formylpiperazin-1-yl)-3-[4-(N-ethylsulfamoyl)phenyl]isoquinoline (0.45 g).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[C:12]([CH2:19][CH3:20])[CH:11]=1)(C(C)(C)C)(C)C.[Cl:21][C:22]1[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=O)=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[Cl:21][C:22]1[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]2[O:18][N:17]=[C:15]([C:13]3[S:14][C:10]([CH2:9][OH:8])=[CH:11][C:12]=3[CH2:19][CH3:20])[N:16]=2)=[CH:27][CH:26]=1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Reactant: O=C(O)c1ccc(Oc2ccccc2Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3Cl)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10f) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.16 g, 0.50 mmol) that was obtained in Example 10 (10d), 4-(2-chlorophenoxy)benzoic acid (0.14 g, 0.55 mmol) that was obtained in Example 19 (19a), dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), and 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.75 mL, 0.75 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7 to 5:5) as the eluent to afford the title compound (0.19 g) in a yield of 92% as a white crystalline solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[C:13]([N:16]1[C:22]([CH3:24])([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[S:18])(=[O:15])[CH3:14].[OH-].[Na+]>O>[C:13]([N:16]1[C:22]([CH3:23])([CH3:24])[C:20](=[O:21])[N:19]=[C:17]1[S:18][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N:3]([CH3:12])[CH3:2])(=[O:15])[CH3:14]
Reactant: CN(C)c1ccccc1CCl
Reactant: CC(=O)N1C(=S)NC(=O)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1C(SCc2ccccc2N(C)C)=NC(=O)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Initially, 4.18g of 2-dimethylaminobenzylchloride hydrochloride was added to a solution of 3.43 g of 1-N-acetyl-5,5-dimethyl-2-thiohydantoin in 50 mL of N,N-dimethylsulfoxide. The reaction mixture was stirred for one hour at the room temperature and poured into 100 mL of water. The pH of the solution was adjusted to 7-8 with a diluted aqueous solution of NaOH and extracted. The precipitate was extracted with 100 mL of ethyl acetate (AcOEt). The thus obtained AcOET layer was successively washed two times with 100 mL of water and 100 mL of brine, dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The thus obtained residue was purified by column chromatography (using CHCL3 as a developing solvent). Recrystallized from diethyl ether-n-hexane gave the desired compound in the form of needle-like crystal. The yield of this compound was 3.4 g with a yield ratio of 57.6%, and the melting point was 99°-100° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.O1CCCCC1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>CN(C)C=O>[OH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH3:3])=[C:5]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: BrCCCCCCCCOC1CCCCO1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)n(CCCCCCCCO)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.9 g (0.06 mole) of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide under nitrogen at 0°-5° is added dropwise over 20 minutes a solution of 10.4 g of 3-methyl-2-(3-pyridyl)indole in 60 ml of dimethylformamide. The mixture is stirred for 0.5 hour at 0°-5° followed by the dropwise addition of 17.6 g (0.06 mole) of 1-tetrahydropyranyloxy-8-bromooctane in 50 ml of dimethylformamide. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting mixture is kept at room temperature for 0.5 hour, washed with ether, basified with aqueous with 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness to give 1-(8-hydroxyoctyl)-2-(3-pyridyl)-3-methylindole.
Reaction SMILES: [NH2:1][C:2]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1)=[O:5].[Cl:19]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:17]([OH:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1c(O)cccc1C(=O)Nc1ccc(Br)cn1
Solvent: CN(C)C=O
Product: Nc1c(O)cc(Cl)cc1C(=O)Nc1ccc(Br)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
2-Amino-N-(5-bromo-2-pyridyl)-3-hydroxybenzamide (1.99 g) and 990 mg of N-chlorosuccinimide were dissolved in 30 ml of N,N-dimethylformamide, the solution was stirred at 50° C. for 2 hours and the insoluble matter was filtered off. The solvent was evaporated in vacuo, water was added to the resulting residue and the precipitate was collected by filtration. This was dried in vacuo, purified by means of a silica gel column chromatography, water was added to the resulting crudely purified product and the resulting precipitate was collected by filtration and dried in vacuo to give 1.12 g of 2-amino-N-(5-bromo-2-pyridyl)-5-chloro-3-hydroxybenzamide.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][C:12]([C:16](=O)[CH2:17]Br)=[C:13]([CH3:15])[N:14]=2)=[N:5]1)(=O)C.Br.C(N1C=CC(NC2SC(C(=O)CBr)=C(C)N=2)=N1)(=O)C.[C:40]([CH2:42][C:43]([NH2:45])=[S:44])#[N:41].CCOCC>CCO>[CH3:15][C:13]1[N:14]=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][NH:4][N:5]=2)[S:11][C:12]=1[C:16]1[N:45]=[C:43]([CH2:42][C:40]#[N:41])[S:44][CH:17]=1
Reactant: N#CCC(N)=S
Reactant: CC(=O)n1ccc(Nc2nc(C)c(C(=O)CBr)s2)n1
Agent: Br
Solvent: CCOCC
Solvent: CCO
Product: Cc1nc(Nc2cc[nH]n2)sc1-c1csc(CC#N)n1
Temperature: 80 °C
Yield: 62 %

Procedure:
To a solution of 1-{2-[(1-acetyl-1H-pyrazol-3-yl)amino]-4-methyl-1,3-thiazol-5-yl}-2-bromoethanone, (Intermediate 4) (150 mg; 0.35 mmol; 1 eq.) in EtOH (5 ml) is added 2-cyanothioacetamide (35.4 mg; 0.35 mmol; 1 eq.). The resulting mixture is heated 10 min at 60° C., 10 min at 70° C. and 10 min at 80° C. under microwave action. As the reaction is complete, Et2O is added. The resulting precipitate is filtered and washed with Et2O, affording Compound (55) as beige solid (84.1 mg; 62%). 1H NMR (DMSO-d6) δ 2.46 (s, 3H), 4.61 (s, 2H), 6.01 (d, J=2 Hz, 1H), 7.65 (s, 1H), 7.72 (d, J=2 Hz, 1H), 11.26 (br s, 1H). M− (ESI): 301.13; M+ (ESI): 303.14. HPLC (method A), Rt: 1.84 min (purity: 92.7%).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.NCCC1C2C(=CC=CC=2)NC=1.CC(NCCC1C2C=C(OC)C=CC=2NC=1)=O.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.[K].[Br:51][CH2:52][CH2:53][CH2:54]Br>>[Br:51][CH2:52][CH2:53][CH2:54][C:48]1[CH:47]=[CH:46][CH:45]=[C:41]2[C:42]([NH:43][C:39](=[O:49])[C:40]=12)=[O:44]
Reactant: BrCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Agent: NCCc1c[nH]c2ccccc12
Agent: [K]
Product: O=C1NC(=O)c2c(CCCBr)cccc21

Procedure:
A method of synthesizing an indole derivative of the tryptamine type particularly .[.melatonine,.]. melatonin comprising the steps of 1) reacting potassium phthalimide and 1,3-di-bromopropane to obtain 3-bromopropylphthalimide; 2) reacting 3-bromopropylphthalimide with sodium acetoacetic ester in ethanol to obtain ethyl-2-acetyl-5-phthalimidopentanoate; 3) reacting the product from step 2) with diazo-p-anisidine to obtain 2-carboxyethyl-3-(2-phthalimidoethyl)-5-methoxy-indole; 4) reacting the 2-carboxyethyl-3-(2-phthalimidoethyl)-5-methoxy-indole with 2N/NaOH and then 20% H2SO4 to obtain impure 5-methoxytriptamine, which is purified by means of hexamethyldisilazane. The mono and disubstituted derivatives are obtained and the monosubstituted derivative is hydrolyzed with aqueous methanol and then recrystallized from ethanol. The N-acetyl derivative is prepared by reaction with acetic anhydride. .[.Melatonine.]. Melatonin of high purity is obtained for prophylaxy and also against AIDS (Acquired Immuno Deficiency Syndrome).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[Cl-].[CH3:11][C:12]12[C:18]([CH3:20])([CH3:19])[CH:15]([CH2:16][CH2:17]1)[CH2:14][C:13]2=[O:21]>>[CH3:11][C:12]12[C:18]([CH3:20])([CH3:19])[CH:15]([CH2:16][CH2:17]1)[CH2:14][C:13]2([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:21]
Reactant: CC12CCC(CC1=O)C2(C)C
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Product: CC1(C)C2CCC1(C)C(O)(c1ccccc1)C2

Procedure:
According to Example 2, PhMgBr.LiCl (1.00 M in THF; 1.10 mL; 1.10 mmol; 1.10 equiv) was reacted with 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (152 mg; 1.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 3.03 mL, 1.00 mmol, 1.00 equiv). Column chromatographical purification (silica; pentane:Et2O, 9:1) afforded the desired product as white solid, mp=41−42° C. (211 mg, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.[O:14]1CCCC1.[OH-].[Na+].OO>CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:13])([CH3:12])[CH2:6][CH:5]2[OH:14]
Reactant: C1CCOC1
Reactant: CC1(C)C=Cc2cc(Br)ccc2N1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CC(O)c2cc(Br)ccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-2,2-dimethyl-1,2-dihydroquinoline (4.50 g, 18.9 mmol) in tetrahydrofuran (37.8 ml, 18.9 mmol) was added BH3DMS (3.58 ml, 37.8 mmol) dropwise at 0 deg C. The resulting solution was allowed to warm to RT and stirred for 1 hour. The temperature was returned to 0 deg C. and sodium hydroxide (6N) (30.0 ml, 18.9 mmol) followed by Hydrogen peroxide (30.0 ml, 18.9 mmol) was slowly added to the reaction mixture. The resulting solution was stirred for 45 minutes and then transferred to a sep. funnel containing water and EtOAc. The layer were separated and the aqueous layer was subsequently washed 3× with DCM. The organic layers were dried with MgSO4, filtered and concentrated. The crude mixture was then purified with the MPLC (100% DCM to 10% 90:10:1 DCM:MeOH:NH4OH) to provide the desired product. MS m/z: 257 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[F:21][C:22]1[CH:27]=[C:26](O)[CH:25]=[CH:24][C:23]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[F:21][C:22]1[CH:27]=[C:26]([O:20][CH2:19][CH2:18][C@@H:16]2[CH2:17][C@@H:15]2[CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=3)[CH2:10][CH2:11]2)[CH:25]=[CH:24][C:23]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: COC(=O)Cc1ccc(O)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(OC)cn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-{(1S,2R)-2-[1-(5-Methoxypyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (1.2 g, 4.33 mmol), methyl 2-(2-fluoro-4-hydroxyphenyl)acetate (0.956 g, 5.19 mmol) and triphenylphosphine (1.702 g, 6.49 mmol) were dissolved in dichloromethane (20 ml). The mixture was stirred at RT under N2 for 5 min and diisopropyl azodicarboxylate (1.274 ml, 6.49 mmol) was added. The mixture was stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with water, dried and evaporated. The crude material was purified by column chromatography on silica gel (50 g SNAP, 5˜30% EtOAc in hexane) to afford the desired product which contains some impurities. This material was re-purified by column chromatography on silica gel (50 g SNAP, 2˜5% EtOAc in DCM) to afford the title compound. LC/MS (m/z): 444 (M+H)+. Rf was 0.4 @ 30% EtOAc in hexanes (blue spot on CAM stain).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>C1COCC1>[CH2:20]([N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5](=[O:15])[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O=C(O)c1cccc(C(=O)NC2CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1cccc(C(=O)O)c1)C1CC1
Temperature: 25 °C

Procedure:
A solution of 0.3 g (1.37 mmol) N-cyclopropyl-isophthalamic acid in 10 ml THF is treated with 142 mg (3.55 mmol) NaH (60% suspension in mineral oil) and stirred at 25° C. After 2 h 0.27 ml (3.23 mmol) allylbromide is added and after 18 h the reaction is quenched with water. The mixture is acidified with 2N HCl and extracted with EtOAc. The organic phase is washed with brine, dried with sodium sulfate and evaporated to yield the title compound that is used in the next step without purification.