Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[N:8]=1)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29]N)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:25][CH:24]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(O)c2)ccc1=O
Reactant: NNc1ccc(F)cc1
Product: O=c1ccn(-c2cccc(O)c2)nc1-c1ccnn1-c1ccc(F)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-hydroxyphenyl)-1H-pyridazin-4-one (A-17) and 4-fluoro-phenylhydrazine according to the method described for example 43. MS: M=349.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.C1C(=O)N([Cl:22])C(=O)C1.C(=O)(O)[O-].[Na+]>Cl>[Cl:22][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[C:14]2=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cncc2[nH]c3ccccc3c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cncc2[nH]c3ccc(Cl)cc3c12
Temperature: 25 °C
Yield: 93.7 %

Procedure:
4-methyl-9H-β-carboline (97 mg, 0.532 mmol) was dissolved in HCl (1N, 4 ml) and stirred at RT. NCS (85 mg, 0.637 mmol) was added thereto and the reaction mixture was stirred for 5 hr. Saturated sodium bicarbonate solution (20 ml) was added thereto and the reaction mixture was extracted twice with EtOAc (100 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give 6-chloro-4-methyl-9H-β-carboline (108 mg) as an oil. 1H-NMR (300 MHz, DMSO-d6): δ 8.67 (s, 1); 8.19 (s, 1); 8.11 (s, 1); 7.57-7.54 (m, 2); 2.82 (s, 3). NH4OAc standard conditions. DAD Rf=2.48 min. M+H=217.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cccc(Cl)n2)CC1

Procedure:
TEA (0.13 ml, 0.99 mmol) and 2,6-dichloropyridine (0.14 g, 0.99 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (0.20 g, 0.99 mmol) in NMP (2 ml) at room temperature. Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 30 minutes. The mixture was diluted with EtOAc and washed with water three times. The organic phase was dried over magnesium sulfate and concentrated to give the title compound. (300 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:11]([O:14]CC)(=[O:13])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:17])[CH:3]=1.[SH-:18].[Na+]>O>[SH:18][C:2]1[N:7]2[N:8]=[C:9]([S:11]([OH:14])(=[O:13])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:17])[CH:3]=1
Reactant: [SH-]
Reactant: CCOS(=O)(=O)c1nc2nc(C)cc(Cl)n2n1
Agent: [Na+]
Solvent: O
Product: Cc1cc(S)n2nc(S(=O)(=O)O)nc2n1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
The product obtained in Step 3 (6 g) was added to a solution of 8.1 g sodium hydrosulfide in 100 ml of water all at once with stirring under a nitrogen at room temperature. The mixture was heated at 60° C. for four hours with stirring and cooled to room temperature. The resultant yellow solution was washed twice with 100 ml of ethyl acetate. The pH of the aqueous layer was lowered to 1.0 with concentrated hydrochloric acid for crystallization. The crystals were collected by filtration and washed with 20 ml of water; 3.2 g of the objective compound was obtained as yellow crystals.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[CH:5]=[N:4][CH:3]=[N:2]1.CN(C=O)C.[H-].[Na+].[CH2:28](Br)[CH3:29]>O>[CH2:28]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:19][CH:18]=2)[CH2:13][CH2:14][C:15]1=[O:20])[CH3:29]
Reactant: CCBr
Reactant: O=C1CCc2cc(OCCCn3cncn3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)CCc2cc(OCCCn3cncn3)ccc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2 g (7.35 mM) of 6-[3-(1,2,4-triazol-1-yl)propoxy]-3,4-dihydrocarbostyril with 20 ml of DMF was added 350 mg (8.8 mM) of sodium hydride (60% in oil) and the mixture was heated at 60° C. for 30 minutes. Then under ice-cooling condition, 0.6 ml (8.1 mM) of ethyl bromide was added dropwise, further the reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, then extracted with chloroform, the chloroform layer was washed with water, dried with anhydrous sodium sulfate, and concentrated by removing the solvent by evaporation. The resulting residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=30:1), then recrystallized from ethyl acetate-n-hexane to yield 1.8 g of 1-ethyl-6-[3-(1,2,4-triazol-1 -yl)propoxy]-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 97.0°-98.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:21][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:21][C:10]=3[N:9]=2)=[CH:4][CH:3]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)cc1)n2C1CCCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(NC(=O)c3ccccc3)cc1)n2C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
Ethyl 1-cyclopentyl-2-(4-aminophenyl)benzimidazole-5-carboxylate (300 mg) obtained in Example 22 was dissolved in pyridine (3 ml) and chloroform (3 ml), and benzoyl chloride (127 mg) was added. The mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated under reduced pressure and water was added to the residue to allow crystallization. The crystals were collected by filtration to give the title compound (403 mg, yield 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:13][CH2:12][N:11]3[C:5]2=[C:6]([CH:26]=1)[C:7]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[N:8][C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=13>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]2[CH:13]=[CH:12][N:11]3[C:5]2=[C:6]([CH:26]=1)[C:7]([N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)=[N:8][C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=13
Reactant: CN1CCN(C2=Nc3cc(Br)ccc3N3CCc4cc(Br)cc2c43)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2=Nc3cc(Br)ccc3-n3ccc4cc(Br)cc2c43)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture 4,9-dibromo-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]-benzodiazepine (4.5 g, 9.45 mmoles) and manganese(IV) dioxide (7.0 g) in chloroform (150 ml) was heated under reflux for 3.5 hours. An additional 4.5 g of manganese dioxide was added. The reaction mixture was stirred overnight at room temperature. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography over a silica gel column (140 gm , eluted with 2% methanol:98% dichloromethane (2 1). The appropriate fractions were collected and evaporated. Crystallization of the residue from isopropanol (10 ml) yielded
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].Cl.CN1CCOCC1.[N:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[C:29]([NH:31][C@H:32]([C:40](O)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30].C1(N=C=NC2CCCCC2)CCCCC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:40](=[O:41])[C@H:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:31][C:29]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][N:23]=1)=[O:30]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
L-phenylalanine methyl ester hydrochloride (0.8 g, 3.69 mmol) was dissolved with 20 ml of THF, then the hydrochloric acid was neutralized with NMM (0.49 ml, 4.43 mmol), cooled with an ice bath for later use. N-Pyrazineformyl-L-phenylalanine (1.0 g, 3.69 mmol) of Preparation example 3 was added to another reaction flask, dissolved with 20 ml of THF, and cooled with an ice water bath, dicyclohexylcarbodiimide (DCC) (0.76 g, 3.69 mmol), HOBt (0.60 g, 4.42 mmol) were added at 0° C. and reacted for 40 min at 0° C., then the solution of L-phenylalanine methyl ester hydrochloride in THF prepared, cooled and neutralized according to the above was added, the reaction was monitored by TLC and completed after 2 h, insoluble DCU was removed by filtration, to the filtrate was added 80 ml of ethyl acetate, washed with 5% sodium bicarbonate solution, 10% citric acid solution, 5% sodium bicarbonate solution, saturated salt solution (2×20 ml) successively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure, 1.52 g of white solid was obtained with a yield of 95.6%, m.p.: 111˜113° C. 1H-NMR (CDCl3, 300 MHz): δ 3.04 (—CH2, m, 2H), 3.18 (—CH2, d, 2H), 3.69 (—CH3, s, 3H), 4.82 (—CH, m, 2H), 6.36 (—CONH, d, 1H), 6.92˜7.30 (-Ph, m, 10H), 8.26 (—CONH, d, 1H), 8.54 (-Pyz, d, 1H), 8.76 (-Pyz, d, 1H), 9.33 (-Pyz, s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].I[CH3:18]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:13])([F:14])[F:12])=[N:8][N:9]([CH3:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)nc1C(F)(F)F
Temperature: 0 °C
Yield: 81.5 %

Procedure:
Dissolve 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.0 g, 9.61 mmol) in N,N-dimethylformamide (20 mL) and cool to 0° C. Add sodium hydride (0.58 g, 14.42 mmol, 60% dispersion in oil) and stir at 0° C. for 20 min. Add iodomethane (0.90 mL, 14.42 mmol) and allow to warm to room temperature over 18 hr. Partition between ethyl acetate (100 mL) and water (50 mL). Separate the organic layer and wash with water (5×50 mL) and saturated aqueous sodium chloride solution (50 mL). Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 90:10 hexanes:ethyl acetate), to give 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.74 g, 81.7%). 1H-NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 4.27 (q, 2H), 3.95 (s, 3H), 1.33 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.C1C(=O)N([I:18])C(=O)C1>>[Cl:1][C:2]1[C:7]([I:18])=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cc(Cl)nc(N)n1
Product: CCc1nc(N)nc(Cl)c1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 2.5 g (16 mmol) 4-chloro-6-ethyl-pyrimidin-2-ylamine and 3.7 g (16 mmol) NIS. Yield after precipitation from the reaction mixture: 3.83 g (85%).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4].[F:21][CH:22]([F:31])[O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([O:23][CH:22]([F:21])[F:31])=[CH:25][CH:26]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2cccc(Cl)c2)S1(=O)=O
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc(OC(F)F)cc2)=C(c2cccc(Cl)c2)S1(=O)=O
Temperature: 160 °C
Yield: 73 %

Procedure:
2-Butyl-4-chloro-5-(3-chlorophenyl)isothiazol-3(2H)-one 1,1-dioxide (0.250 g, 0.75 mmol) and 4-(difluoromethoxy)aniline (0.238 g, 1.50 mmol) were mixed in MeCN (2 mL) and heated in a microwave reactor at 160° C. for 60 mins. The reaction mixture was evaporated and the residue was purified on a Horizon TM flash system using Heptane and EetOAc as eluant giving the title compound (0.25 g, 72.9%). 1H-NMR (500 MHz, CDCl3): δ 7.25-7.1 (m, 4H), 7.0 (s, 1H), 6.9-6.7 (dd, 4H), 6.4 (t, 1H, J=Hz), 3.8 (t, 2H), 1.95-1.8 (m, 2H), 1.55-1.45 (m, 2H), 1.05 (t, 3H); 13C-NMR (125 MHz, CDCl3): δ179.6, 159.0, 134.4, 133.3, 132.0, 129.9, 129.6, 129.6, 127.3, 124.3, 120.4, 115.9, 40.6, 30.4, 23.6, 20.3, 13.7; Mass Spectrum: M−H+ 456.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[CH:3][C:2]=1[C:10]1[CH:11]=[C:12]([C:16]([OH:19])([CH3:18])[CH3:17])[CH:13]=[N:14][CH:15]=1.[Cl:20]N1C(=O)CCC1=O>C(#N)C>[Cl:20][C:3]1[C:2]([C:10]2[CH:11]=[C:12]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:13]=[N:14][CH:15]=2)=[N:1][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(O)c1cncc(-c2cc3ccccn3n2)c1
Solvent: CC#N
Product: CC(C)(O)c1cncc(-c2nn3ccccc3c2Cl)c1

Procedure:
A solution of the title compound from Example 2 Step A (0.099 g, 0.391 mmol) and N-chlorosuccinimide (0.063 g, 0.469 mmol) in acetonitrile (1.95 ml) was stirred at room temperature for 2 hours. The reaction was then concentrated under reduced pressure, diluted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over MgSO4, filtered and concentrated under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]2[C:3]=1[C:4](=[O:27])[C:5]1[CH:6]=[C:7]3[C:25](=[O:26])[O:24][C:22](=[O:23])[C:8]3=[CH:9][C:10]=1[C:11]2=[O:21].[CH2:28]([OH:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].S(=O)(=O)(O)O.O>CO>[CH2:28]([O:36][C:22]([C:8]1[C:7]([C:25]([O:24][CH2:18][CH2:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:10][CH3:9])=[O:26])=[CH:6][C:5]2[C:4](=[O:27])[C:3]3[C:12](=[C:13]([OH:20])[C:14]4[C:19]([C:2]=3[OH:1])=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11](=[O:21])[C:10]=2[CH:9]=1)=[O:23])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: O=c1oc(=O)c2cc3c(=O)c4c(O)c5ccccc5c(O)c4c(=O)c3cc12
Reactant: CCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CCCCCCCCOC(=O)c1cc2c(cc1C(=O)OCCCCCCCC)C(=O)c1c(c(O)c3ccccc3c1O)C2=O
Reaction time: 18 h
Yield: 164.6 %

Procedure:
1.89 g (5.2 mmoles) of 6,11-dihydroxy-naphthacene-5,12-dione-2,3-dicarboxylic acid anhydride (product of example 9), 6.77 g (52 mmoles) of 1-octanol, and 0.2 g (2.08 mmoles) of 96% sulfuric acid are refluxed for 3 h with azeotropic removal of the reaction water. The mixture is kept at 25° for 18 h, then stirred with methanol and filtered. The precipitate is washed with water and dried in vacuo to give 2.58 g (81%) of red crystals, m.p. 95-96°.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[S:18])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl[C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[O:28][CH3:29].O1CCOCC1.[I-].[Na+]>O.P([O-])([O-])([O-])=O>[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([S:18][C@H:23]2[NH:26][C:25](=[O:27])[C@@H:24]2[O:28][CH3:29])=[O:19])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=C(NCCCC([O-])=S)OCc1ccc([N+](=O)[O-])cc1
Reactant: CO[C@H]1C(=O)N[C@@H]1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CO[C@H]1C(=O)N[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 350 mg of 4-p-nitrobenzyloxycarbonylaminothiobutyric acid sodium salt in 4 ml of water is added dropwise to a solution of 135 mg of (3S,4R)-4-chloro-3-methoxy-2-oxoazetidine in 6 ml of a phosphate buffer of a pH of 7 and 0.4 ml of dioxan in the presence of 150 mg of sodium iodide.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:9][CH2:8][CH:7]([OH:10])[CH:6]([OH:11])[CH2:5][O:4]1.[CH3:12][C:13]([CH3:15])=O>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>[Br:1][CH2:2][CH:3]1[O:4][CH2:5][CH:6]2[CH:7]([O:10][C:13]([CH3:15])([CH3:12])[O:11]2)[CH2:8][O:9]1
Reactant: CC(C)=O
Reactant: OC1COC(CBr)OCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)OC2COC(CBr)OCC2O1
Reaction time: 9 h
Yield: 93 %

Procedure:
A mixture of 0.93 mol (211 g) of 2-bromomethyl-5,6-dihydroxy-1,3-dioxepane, 5.75 mol (422 ml) of acetone, 1.8 g of p-toluenesulphonic acid and 750 ml of methylene chloride was heated under reflux and the water formed was separated by means of a water separator. After about 9 h, the methylene chloride was drawn off in the rotary evaporator (filter pump), and the residue underwent fractional distillation under a medium high vacuum. At 89°-92° C. (0.5 mbar), 231 g of 4-bromomethyl-9,9-dimethyl-3,5,8,10-tetraoxabicyclo[5,3,0]decane (93% yield) were obtained as a colourless liquid which exhibited crystalline deposits in some cases at room temperature and was a mixture of isomers.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:32][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:31]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(N2CCCCC2)n1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(N2CCCCC2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 6-(piperidin-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 410.42 g/mol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1>CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=S(=O)(CCCCl)NC1CCN(Cc2ccccc2)CC1
Reaction time: 3 h

Procedure:
3-Chloropropanesulfonyl chloride (0.26 mL) was added to the ether solution (10 mL) containing 4-amino-1-benzylpiperidine (400 mg) at 0° C., followed by stirring for 3 hrs. The reaction mixture was concentrated under reduced pressure to give the title compound (678 mg).
Reaction SMILES: N1C=CC=C(OC#CC2C=CC=CC=2)[CH:2]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[C:25]([O:31][CH3:32])[CH:24]=2)[CH:17]=1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([O:22][C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)=[CH:24][C:25]=1[O:31][CH3:32])#[CH:2]
Reactant: COc1cc(Oc2cccnc2)ccc1C=O
Reactant: C(#Cc1ccccc1)Oc1cccnc1
Product: C#Cc1ccc(Oc2cccnc2)cc1OC

Procedure:
3-(4-ethynyl-3-methoxyphenoxy)pyridine was prepared as for 4-(pyridine-3-yloxy)ethynylbenzene, using 4-(pyridine-3-yloxy)-2-methoxybenzaldehyde.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:28]N>C(O)C>[C:6]1([C:5]2[C:4]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:3][NH:2][N:28]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C=C(C(=O)c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To the compound tert-butyl 4-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)piperazine-1-carboxylate (4 g) dissolved in ethanol (40 ml), and hydrazine hydrate (1.17 g) was added and the reaction mixture was refluxed for 6 hrs with vigorous stirring. The progress of reaction was monitored by TLC. After consumption of starting material, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford tert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:20]([O:22]C)=[O:21])[C:12](=[O:19])[N:13](CC(C)C)[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:24]C1C=C(F)C=CC=1C(=O)CC(C(OCC)=O)(O)C(OCC)=O>>[C:20]([C:11]1[C:12](=[O:19])[NH:13][N:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[CH:2][C:3]=2[F:24])[CH:10]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1cc(-c2ccc(F)c(F)c2)nn(CC(C)C)c1=O
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(F)cc1F)C(=O)OCC
Product: O=C(O)c1cc(-c2ccc(F)cc2F)n[nH]c1=O
Yield: 95.2 %

Procedure:
Following the procedure of Example 1 (4), ethyl 4-(2,4-difluorophenyl)-2-ethoxycarbonyl-2-hydroxy-4-oxo-butanoate was reacted to yield the title compound as a pale yellow crystalline powder (yield: 95.2%).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:19][CH:18]=[CH:17][N:7]2[C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3].[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[C:23](Br)[N:22]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][NH:27]2)=[C:23]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:19][CH:18]=[CH:17][N:7]3[C:8](=[O:16])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:3])[N:22]=1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1ccccc1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.092 mmol), 2-amino-6-bromopurine (0.035 g, 0.16 mmol), and N,N-diisopropylethylamine (0.029 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H17N8OS (M+H)+: m/z=405.1. Found: 405.1. 1H NMR (DMSO-d6, 400 MHz) δ 80.1 (1H, d, J=4.8 Hz), 7.65 (1H, s), 7.55 (1H, d, J=4.8 Hz), 7.47 (2H, m), 7.40 (3H, m), 6.79 (1H, br s), 5.48 (2H, br s), 5.13 (1H, m), 1.29 (3H, d, J=6.8 Hz) ppm.