Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]([C:20]([N:22]1[CH:26]([C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:42]([NH:44][C@H:45]([C:51]([NH:53][C@H:54]([CH2:59][OH:60])[CH2:55][CH:56]([CH3:58])[CH3:57])=[O:52])[CH2:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])[CH2:25][C@H:24]([OH:61])[CH2:23]1)=[O:21])([CH3:19])[CH3:18])=[O:15].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]([C:20]([N:22]1[CH:26]([C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:42]([NH:44][C@H:45]([C:51]([NH:53][C@H:54]([CH2:59][OH:60])[CH2:55][CH:56]([CH3:58])[CH3:57])=[O:52])[CH2:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[O:28])[CH2:25][C@H:24]([OH:61])[CH2:23]1)=[O:21])([CH3:19])[CH3:18])=[O:15]
Reactant: CCCCCCCCCCCCCC(=O)NC(C)(C)C(=O)N1C[C@@H](O)CC1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CO)CC(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)NC(C)(C)C(=O)N1C[C@@H](O)CC1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CO)CC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 13.3 mg of Halovir A in 0.5 mL of pyridine was added 0.5 mL of acetic anhydride and 1.2 mg of N,N-dimethylaminopyridine. The reaction mixture was stirred under nitrogen at ambient temperature for 16 hours. The solvent was removed in vacuo, and the crude mixture was partitioned between 3 mL of saturated sodium bicarbonate and 3 mL of ethyl acetate. The layers were separated and the aqueous layer was washed with 2×3 mL of ethyl acetate. The organic layers were combined and washed with 5 mL each of 1 N HCl and brine, dried over Na2CO3, filtered, and concentrated in vacuo. The crude product was purified by C18 HPLC using 2.5% H2O in methanol. Pure Halovir D was obtained as a colorless oil and was characterized by mass spectrometry, and proton and carbon NMR spectroscopy.
Reaction SMILES: [CH2:1]([SiH](CC)CC)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH3:20][O:21][C:22]1[C:37]([O:38][CH3:39])=[C:36]([O:40][CH3:41])[C:35]([O:42][CH3:43])=[C:34]([CH3:44])[C:23]=1[CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:30][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C:23]2[C:34]([CH3:44])=[C:35]([O:42][CH3:43])[C:36]([O:40][CH3:41])=[C:37]([O:38][CH3:39])[C:22]=2[O:21][CH3:20])=[CH:33][CH:32]=1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)cc2)c(OC)c(OC)c1OC
Reactant: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
To a solution of triethylsilane (88 mg, 0.76 mmol) and TMSOTf (0.004 ml) in methylene chloride (2 ml) was added dropwise a solution of the compound (237 mg, 0.63 mmol) obtained in Step 2 in methylene chloride (2 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with saturated saline, dried, and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:6) to yield the title compound (160 mg, 0.45 mmol, yield 71%).
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:18]([O:28][CH3:29])[N:17]=3)[N:15]=[C:8]12)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:29][O:28][C:18]1[N:17]=[C:16]([C:14]2[N:15]=[C:8]3[CH:7]([C:5]4[S:45][C:2]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:3][N:4]=4)[CH2:12][CH2:11][CH2:10][N:9]3[N:13]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1nc(-c2nc3n(n2)CCCC3C(=O)NCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1nc(-c2nc3n(n2)CCCC3c2ncc(-c3ccccc3)s2)ccc1-n1cnc(C)c1
Yield: 10.6 %

Procedure:
2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (2-oxo-2-phenylethyl)amide obtained in Example 172 (26.6 mg) was dissolved in THF (1 mL). Lawesson reagent (45.6 mg) was added and the mixture was stirred with heating under reflux for 11 hours. The reaction solution was ice-cooled. Then, chloroform and a saturated sodium bicarbonate solution were added and the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (2.8 mg). The compound was further purified by CHIRALCEL™ IB (2 cm×25 cm; mobile phase:hexane:ethanol=30:70) to obtain the title compound (1.5 mg, racemate). The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[CH3:19][C:20]1[O:24][C:23]([C:25](Cl)=[O:26])=[CH:22][CH:21]=1>>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:25]([C:23]3[O:24][C:20]([CH3:19])=[CH:21][CH:22]=3)=[O:26])[S:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Reactant: Cc1ccc(C(=O)Cl)o1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(C)o3)nc12

Procedure:
Using 2-amino-4-methoxy-7-phenyl-benzothiazole and freshly prepared 5-methyl-furan-2-carboxylic acid chloride the title compound was obtained crude, which was chromatographed over SiO2 (Merck 230-400 mesh) eluting with nHexane/EtOAc (4:1), to afford the pure title compound as a pale yellow solid (67% yield), MS: m/e=364.0 (M+).
Reaction SMILES: [CH:1]1([S:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:25].[Na+]>CO.O>[CH:1]1([S:6]([CH:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1nccs1)C(SC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(Nc1nccs1)C(c1ccc(Cl)c(Cl)c1)S(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.8 %

Procedure:
To a solution of rac-2-cyclopentylsulfanyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (Example 10; 34 mg, 0.088 mmol) in methanol (2 mL) was added a solution of sodium periodate (34 mg, 0.16 mmol) in water (1 mL) and the mixture was stirred at 25° C. After 6 h, the precipitate was filtered off and washed with dichloromethane (15 mL). The organic layer was set aside and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. Chromatography of the residue (Biotage Flash 12M column, 50/50 hexanes/ethyl acetate) afforded rac-2-cyclopentanesulfinyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (23 mg, 66% yield) as a colorless oil: EI-HRMS m/e calculated for C16H16N2O2S2Cl2 (M+) 402.0030, found 402.0035.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([O:31][C:32](=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[CH2:13]([O:12][CH2:11][C@H:10]([CH2:9][OH:8])[O:31][C:32](=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCC/C=C\CCCCCCCCOC[C@H](COCc1ccccc1)OC(=O)CCCCCCCCCCCCCCC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOC[C@H](CO)OC(=O)CCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 3-O-benzyl-1-O-oleyl-2-O-palmitoyl-sn-glycerol (110 mg, 0.16 mmol) in 2 mL CH2Cl2 at −78° C., boron trichloride (0.35 mL, 0.35 mmol) (1 M in CH2Cl2) was added over a period of 15 min. The reaction was stirred for 30 min under argon. The contents of the flask were then poured over ice water, the aqueous layer separated and extracted with CH2Cl2 (10 mL×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified using silica gel column chromatography (hexane:EtOAc=19:1˜7:1 (Rf=0.35) gradient) to get the alcohol (66 mg, 69%) as colorless oil. [α]D27 −3° (C=1.1, CHCl3); IR(CHCl3) cm−1 3442, 2911, 2853, 1736, 1652, 1460, 1374, 1239, 1167, 1116, 1094, 1053, 722, 700 cm−1; 1H NMR (600 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H, CH3), 1.22-1.36 (m, 44 H, CH2), 1.52 (dt, J=7.2, 14.4 Hz, 4H, CH2), 1.94 (dd, J=6.0, 12.0 Hz, 4H, CH2), 2.05 (s, 1H, OH), 2.20 (t, J=7.8 Hz, 2H, CH2), 2.24 (t, J=7.8 Hz, 2H, CH2), 3.72 (s, 2H, CH2OH), 4.25 (dd, J=6.0, 12.0 Hz, 1H, CH2O Acyl), 4.31 (dd, J=4.8, 12.0 Hz, 1H, CH2OAcyl), 4.00-4.06 (dt, J=4.8, 10.2 Hz, 1H, CH), 5.35 (ddd, J=6.0, 10.8, 16.2 Hz, 2H, CH═CH); 13C NMR (150 MHz, CDCl3) δ 14.1, 22.66, 22.67, 24.78, 24.82, 24.84, 24.91, 27.14, 27.19, 29.06, 29.08, 29.15, 29.25, 29.30, 29.46, 29.50, 29.60, 29.63, 29.66, 29.67, 29.71, 29.74, 31.83, 31.88, 31.90, 34.1, 34.3, 61.5, 62.0, 72.1, 129.7, 130.0, 173.4, 173.8; EMSI calc'd for C37H70NaO5 [M+Na]+ 617.51. found: 617.60.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([CH2:34][CH3:35])=[N:19][N:20]3[C:25]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][C:23](Cl)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([CH2:34][CH3:35])=[N:19][N:20]3[C:25]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][C:23]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCNCC1
Reactant: CCc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nn2c(N3CCN(C)CC3)cc(N3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.9 %

Procedure:
0.33 ml (3 mmol) of 1-methyl-piperazine in 5 ml of DMF was added to a solution of 0.50 g (1.2 mmol) of 3-benzenesulphonyl-5-chloro-2-ethyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine in 15 ml of DMF and stirred at 100° for 1 hr. After cooling to RT the reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) and crystallization from EtOH yielded 0.04 g (69%) of 3-benzenesulphonyl-2-ethyl-5,7-bis-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 232-235°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][CH:14]([O:19][CH2:20][CH3:21])[C:15](=[NH:18])OC)[CH3:12]>CO>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:9][C:15](=[NH:18])[CH:14]([O:19][CH2:20][CH3:21])[O:13][CH2:11][CH3:12]
Reactant: NCc1cccc(Cl)c1F
Reactant: CCOC(OCC)C(=N)OC
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1cccc(Cl)c1F
Yield: 71.8 %

Procedure:
(3-Chloro-2-fluorophenyl)methanamine (1.0 g, 6.27 mmol) was added to a solution of methyl 2,2-diethoxyacetimidate (1.12 g, 6.96 mmol) in methanol (10 ml). The mixture was heated at 70 C for 1 h. The mixture was purified by chromatography (Biotage: 100% ethyl acetate) to yield N-(3-chloro-2-fluorobenzyl)-2,2-diethoxyacetimidamide (1.3 g, 4.5 mmol, 65% yield) as a colorless viscous oil. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.23-7.40 (m, 2H), 7.07 (t, J=7.9 Hz, 1H), 4.93 (s, 1H), 4.54 (s, 2H), 3.50-3.74 (m, 4H), 1.18-1.35 (m, 6H). MS (LC/MS) R.T.=1.78; [M+H]+=289.17.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.N1C=CC=CC=1>O1CCCC1>[N:15]1([S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: c1ccc2c(c1)CCN2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C1Cc2cc(S(=O)(=O)N3CCc4ccccc43)ccc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 110.5 %

Procedure:
To a mixture of 5-chlorosulfonyl-2-oxindole (5 g, 21.6 mmol) and indoline (2.9 mL, 26 mmol) in tetrahydrofuran (20 mL) was added pyridine (3.4 g, 43 mmol). After stirring at room temperature for 1 day the precipitate was collected by vacuum filtration, washed with water in ethanol (20%), dried, washed with 60 mL of hot ethanol and dried under vacuum to give 7.5 g of 5-(2,3-dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one as a pink solid. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.76 (br s, 1H, NH), 7.62 (m, 2H), 7.43 (d, 1H), 7.13–7.18 (m, 2H), 6.95 (dt, 1H), 6.90 (d, 1H), 3.87 (t, 2H, CH2), 3.51 (s, 2H, CH2), 2.91 (t, 2H, CH2). MS m/z 315 [M+1].
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)[NH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:26]O>>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:26])=[O:19])=[CH:16][CH:17]=2)[NH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(Cc2ccc(C(=O)O)cc2)C1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCCN1C(=O)NC(Cc2ccc(C(=O)OC)cc2)C1=O

Procedure:
3-n-Butyl-5-(4-carboxybenzyl) hydantoin (7.2 g., 0.025 mole) was added to a stirred solution of thionyl chloride (1.8 ml., 0.025 mole) in methanol (100 ml) prepared at -5° to -10° C. The mixture was allowed to come to room temperature and finally heated under reflux for 1 hour. After cooling, the clear solution was evaporated in vacuo to dryness and the resultant white crystalline solid was recrystallised from ethyl acetate to give the title compound. Yield 7.1 g (94%) m.p. 144° C.
Reaction SMILES: Cl.[CH2:2]([O:6][CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:4][CH3:5].[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][N:21]([C:8](=[O:10])[CH2:7][O:6][CH2:2][CH2:3][CH2:4][CH3:5])[C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCCOCC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: CCCCOCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 30.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-butoxyacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 38, (2S,4R)-4-benzyl-1-(2-butoxyacetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (9.1 mg, 30.1%). 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 7.56 (m, 2H), 7.27 (m, 2H), 7.19 (m, 5H), 6.96 (m, 4H), 4.47 (t, 1H), 4.03 (t, 1H), 3.60 (m, 1H), 3.42 (m, 2H), 3.29 (m, 2H), 2.65 (m, 3H), 1.89 (m, 2H), 1.35 (m, 4H), 0.85 (t, 3H). MS (EI) for C30H33FN2O4: 505.4 (MH+).
Reaction SMILES: [F-].[Cs+].Cl[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][N:12]=2)[N:9]=1.[NH2:24][CH2:25][C:26]1([OH:33])[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>CS(C)=O>[CH3:32][N:29]1[CH2:30][CH2:31][C:26]([CH2:25][NH:24][C:4]2[CH:5]=[CH:6][C:7]3[N:8]([C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=4)=[CH:11][N:12]=3)[N:9]=2)([OH:33])[CH2:27][CH2:28]1
Reactant: CN1CCC(O)(CN)CC1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: CN1CCC(O)(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 120 °C
Yield: 10.9 %

Procedure:
CsF (50 mg, 0.33 mmol) was added to the mixture of 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (150 mg, 0.48 mmol) and 4-(aminomethyl)-1-methylpiperidin-4-ol (150 mg, 1.04 mmol) in DMSO (1.5 mL). The mixture was heated to 120° C. over night and partitioned with EtOAc (10 mL) and water (10 mL). The organic layer was washed with brine (8 mL×3), dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by pre-HPLC to give the product 1-methyl-4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)methyl)piperidin-4-ol (22 mg, 10%)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([NH2:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([NH:23][C:26](=[O:28])[CH3:27])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(N)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC(C)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1

Procedure:
A solution of 1-({trans-4-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]cyclohexyl}oxy)propan-2-amine (172 mg) and acetic anhydride (0.24 mL) in pyridine (4 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (NH, hexane/ethyl acetate). The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (95 mg) as white crystals.
Reaction SMILES: [C:1]([NH:5][CH:6](O)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[C:9](=[S:11])=[S:10]>>[C:1]([N:5]1[CH2:6][CH2:7][S:11][C:9]1=[S:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)NC(C)(C)C
Reactant: S=C=S
Product: CC(C)(C)N1CCSC1=S

Procedure:
Similarly to Example 1, 256 g/h of N-t-butylaminoethanol are reacted with 333 g/h of carbon disulphide to form 382 g/h of N-t-butylthiazolidine-2-thione having a melting point of from 69° to 70° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:3].C(O)(=O)C.C(O)C>[Pd].[H][H]>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:3]
Reactant: [H][H]
Reactant: CN(C)CCCOC(CCCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)CCCOC(CCCc1ccccc1)c1ccc(O)cc1

Procedure:
A mixture of 1.5 g of 1-[3-(N,N-dimethylamino)propoxy]-1-(p-benzyloxyphenyl)-4-phenylbutane obtained in Example 6, 0.5 g of 10% palladium on charcoal (50% wet reagent), 1 g of acetic acid and 50 ml of ethanol was vigorously stirred in hydrogen atmosphere at room temperature until the theoretical amount of hydrogen was consumed. The reaction mixture was poured into water, made alkaline with aqueous ammonium hydroxide and extracted. After the catalyst was filtered off, the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-[3-(N,N-dimethylamino)propoxy]-1-(p-hydroxyphenyl)-4-phenylbutane. M.P., 91.5°-94.5° C. (oxalate).
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.C([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)#N>ClCCl>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: N#Cc1ccccn1
Solvent: ClCCl
Product: c1ccc(-c2nsc3nc4ccccc4n23)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
A mixture of 2-butyl -1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (15.0 g, 60.7 mmole) and 2-cyanopyridine (13.3 g, 0.13 mole) in 150 mL of dichloromethane was stirred at room temperature for 72 h. The precipitate was filtered and washed with dichloromethane to give 10.4 g (68%) of 3-(2-pyridyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole as a white solid: mp 173°-174° C.; 1H NMR (CDCl3) δ8.90 (d, 1H), 8.70 (d, 1H), 8.30 (d, 1H), 7.99 (t, 1H), 7.80 (d, 1H), 7.57 (t, 1H), 7.47 (t, 1H), 7.37 (t, 1H) ppm; 13C NMR (CDCl3) δ166.10, 151.09, 150.11, 148.74, 147.73, 137.38, 130.50, 125.85, 125.24, 124.52, 121.41, 119.11, 116.33 ppm; IR (KBr) ν3419, 3054, 1611, 1587, 1501, 1463, 1446, 727 cm-1. HRMS calcd for C13H8N4S 252.0470, found 252.0882. Anal. Calcd for C13H8N4S: C, 61.89; H, 3.20; N, 22.21. Found: C, 61.48; H, 3.30; N, 22.24.
Reaction SMILES: CN(C=O)C.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.Cl>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(I)cc1
Reactant: C1=Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(C2C=Cc3ccccc32)cc1

Procedure:
20 ml of DMF, 2.2 g (20 mmol) of indene, 4,4 g (20 mmol) of para-amino-iodo-benzene, 2 ml of triethylamine and 0,134 (0,6 mmol) of Pd(OAc)2 were stirred under reflux for 10 h. The resulting mixture was poured into 200 ml of 15% HCl. Forming precipitate was separated and washed with dichloromethane. The resulting substance was treated with the mixture 50 ml of dichloromethane and 50 ml of 5% KOH in water. Organic layer was separated, washed twice with water, filtered and dried over Na2SO4. Dichloromethane was removed and the residue was recrystallized from 20 ml of EtOH. The yeld of product was 70%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:17]1[C:18]2[C:25]([I:26])=[CH:24][N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:19]=2[N:20]=[CH:21][N:22]=1>C(O)CCC>[I:26][C:25]1[C:18]2[C:17]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:22][CH:21]=[N:20][C:19]=2[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:24]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: C1COCCN1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(I)c2c(N3CCOCC3)ncnc21

Procedure:
Morpholine (2.45 g, 28.1 mmol) and N,N-diisopropylethylamine (6.63 g, 51.3 mmol) were added to a solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) (10.5 g, 25.6 mmol) in n-butanol (300 mL), and the reaction mixture was heated at reflux for 18 hours, then concentrated under reduced pressure. Aqueous hydrochloric acid (0.1 M, 100 mL) was added and the resulting solid was collected by filtration, washed with water (20 mL) and dried under vacuum to provide the product as a yellow solid. Yield: 8.0 g, 17 mmol, 66%. LCMS m/z 461.2 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.81 (s, 1H), 5.52 (s, 2H), 3.80-3.86 (m, 4H), 3.46-3.53 (m, 6H), 0.77-0.84 (m, 2H), −0.10 (s, 9H).