Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1[N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:6]2=[C:5]([CH2:12][CH2:13][NH2:14])[CH:4]=1.[CH:15](OCC)=[O:16].C[O-].[Na+]>CO>[N:3]1[N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:6]2=[C:5]([CH2:12][CH2:13][NH:14][CH:15]=[O:16])[CH:4]=1
Reactant: CCOC=O
Reactant: NCCc1cnn2c1NCCC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=CNCCc1cnn2c1NCCC2
Yield: 62.6 %

Procedure:
To a solution of 2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)ethylamine dihydrochloride (2.36 g) and ethyl formate (40 g) in methanol (20 ml) was added 28% sodium methoxide solution in methanol (4.0 g), and the mixture was stirred under reflux for 16 hours. The insoluble materials were filtered off using Celite, and the filtrate was concentrated in vacuo. The residue was triturated with acetonitrile and dried in vacuo to give N-[2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)ethyl]formamide (1.2 g) as a solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[BrH:5].[Br:6][CH:7]1[C:12](=O)[CH2:11][CH2:10][NH:9][CH2:8]1>C(O)C>[BrH:6].[BrH:5].[N:1]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[S:3][C:2]=1[NH2:4]
Reactant: NC(N)=S
Reactant: O=C1CCNCC1Br
Agent: Br
Solvent: CCO
Product: Nc1nc2c(s1)CNCC2
Yield: 84.9 %

Procedure:
4.55 g thiourea was added to 15.2 g 3-Bromo-piperidin-4-one hydrobromide in 152 mL ethanol and refluxed for 20 h. The reaction was cooled and the solid was filtered, washed with ethanol and dried to give 15.8 g of the desired product.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][CH3:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[C:10](Cl)(Cl)=[S:11]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:8][CH3:9])[CH2:6][O:7][C:10](=[S:11])[O:5][CH2:4]1)[CH3:2]
Reactant: CCC(CC)(CO)CO
Reactant: S=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCC1(CC)COC(=S)OC1
Temperature: 25 °C

Procedure:
The thiocarbonate 1 was prepared by a variation of the thiocarbonylation procedure developed by Corey and Hopkins. To a three-necked round-bottomed flask, equipped with a mechanical stirrer and an additional funnel, was placed 2,2-diethyl-1,3-propanediol (15.86 g, 120 mmol), 4-dimethylaminopyridine (DMAP, 29.32 g, 240 mmol) and 120 mL of toluene under an atmosphere of nitrogen. The mixture was allowed to stir at room temperature until a homogeneous solution was reached. The mixture was cooled to 0-5° C. and then a solution of thiophosgene (9.43 mL, 120 mmol) in 90 mL of toluene was added dropwise via the additional funnel over a period of 90 min. This resulted in the formation of a bright orange DMAP-thiophosgene complex. After the completion of addition, the reaction mixture was allowed to stir for an hour at 0-5° C. and then slowly warmed to room temperature. The reaction mixture was allowed to stir at room temperature for an additional hour and then the precipitated DMAP-HCl salt was removed by filtration. The filtrate was concentrated under reduced pressure using a rotary evaporator. The crude material was purified by recrystallization (the crude material was dissolved in refluxing ether, allowed to cool to room temperature and slowly evaporated) or by column chromatography (silica gel, 2:1 methylene chloride/hexanes). The desired thiocarbonate 1 was obtained as white crystalline in 70% yield. Mp (DSC) 64.4° C. 1H-NMR (CDCl3, 300 MHz) δ 4.17 (s, 4H), 1.51-1.43 (q, 4H, J=7.5 Hz), 0.92-0.87 (t, 6H, J=7.5 Hz); 13C-NMR (CDCl3, 75 MHz) δ 189.53, 76.08, 33.67, 23.09, 6.97; IR (KBr pellet) (cm−1) 2960, 2920, 1455, 1395, 1380, 1290, 1240, 1200, 1180, 1060, 990, 930, 720.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14](O)=[O:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14]([NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])=[O:15]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: C[C@@H](N)c1ccccc1
Product: COc1ccc(C(=O)N[C@H](C)c2ccccc2)cc1Cl

Procedure:
Prepare in a similar manner to example 4 using (R)-1-phenylethanamine and 3-chloro-4-methoxy benzoic acid. MS (M+H, 290.0).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)(C)(C)C.[NH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28]1>>[CH3:25][CH:22]1[CH2:21][CH2:20][N:19]([C:17]([CH:8]([NH:7][S:36]([C:31]2[C:30]3[CH:29]=[CH:28][NH:27][C:35]=3[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:38])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:18])[CH2:24][CH2:23]1
Reactant: CC1CCN(C(=O)C(CCc2cccnc2)NC(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(Cl)c1cccc2[nH]ccc12
Product: CC1CCN(C(=O)C(CCc2cccnc2)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
Example 52 is prepared from 70 mg (0.19 mmol) of tert-butyl{1-[(4-methylpiperidin-1-yl)carbonyl]-3-pyridin-3-ylpropyl}carbamate and indole-4-sulfonyl chloride in the same manner as Example 49 (39 mg, 46% yield). ESI MS Calc. 440.2; Found: 441.3 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:35][C:15]=1[C:16]([NH:18][C:19]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][N:45]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:44][CH2:43]2)=[CH:35][C:15]=1[C:16]([NH:18][C:19]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCNCC2)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(S(C)(=O)=O)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, methanesulfonyl chloride (0.018 mL) was added to a solution mixture of methyl 2-(2-(benzyloxy)-5-(2-(piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.11 g) in methylene chloride (2.2 mL) and pyridine (0.024 mL), followed by stirring at room temperature for 1 hour. Pyridine (0.016 mL) and methanesulfonyl chloride (9.0 μL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 50-0% hexane/ethyl acetate] to obtain 0.085 g of methyl 2-(2-(benzyloxy)-5-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH:14]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:15][C:16]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17]>C1COCC1>[C:30]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:27]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: CCCCCCCCCCCCN
Reactant: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1

Procedure:
Dodecylamine (924 mg.) in 20 ml. THF is added dropwise to a 0° C. solution of 1.78 g. z-Gly-Phe and 1.02 g. DDC in 30 ml. THF under N2 and stirred at 0° C. for 4 hours. The reaction mixture is filtered, the filtrate evaporated in vacuo to give 3.53 g. crude product, which was chromatographed on 100 g. silica gel in CHCl3 /EtOAc (2:1) to give 890 mg. product (34%). NMR (CDCl3, δ): 7.7m (1H); 7.3 d (10 Hz); 6.6 m (1H); 6.2 (1H); 5.2 s (2H); 4.8 m (1H); 3.9 d, J=6 Hz (2H); 3.1 m (4H); 1.3 bs (20H); 0.9 m (3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](#[N:17])[CH2:14][C:15]#[N:16].[OH-].[Na+]>ClCCl>[OH:9][C:8]([C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[C:14]([C:13]#[N:17])[C:15]#[N:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: N#CCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CC(C#N)=C(O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A 0° C. solution of 4-nitrobenzoyl chloride (24.12 g, 130 mmol) and malononitrile (8.60 g, 130 mmol) in dichloromethane (200 mL) was treated with PhCH2N(CH2CH3)3Cl (3.0 g), treated dropwise with 10N NaOH (30 mL), stirred at 0° C. for 1 hour, and filtered. The filter cake was washed with dichloromethane and diethyl ether, dissolved in 5% HCl, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from ethyl acetate/hexanes to provide 23 g of the desired product. MS(ESI(−)) m/e 214 (M−H)−.
Reaction SMILES: Br.Br.[C:3]([C:7]1[N:11]=[C:10]([S:12][CH2:13][CH2:14][NH2:15])[NH:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[C:3]([C:7]1[N:11]=[C:10]([S:12][CH2:13][CH2:14][NH:15][C:32](=[O:33])[NH:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:35])[F:34])=[CH:26][CH:27]=2)[NH:9][N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1n[nH]c(SCCN)n1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1n[nH]c(SCCNC(=O)Nc2ccc(C(F)(F)F)cc2)n1
Temperature: -40 °C
Yield: 86 %

Procedure:
To 10 g (27 mmole) of 3-t-butyl-5-(2-aminoethylthio)-1H-1,2,4-triazole dihydrobromide in 100 ml of methylene chloride was added 5.5 g (54 mmole) of triethylamine. The mixture was cooled to -40° C. and a solution of 5.2 g (27 mmole) of 4-trifluoromethylphenyl isocyanate in methylene chloride was slowly added. The stirred mixture was slowly allowed to warm to room temperature and was stirred at room temperature for eighteen hours. The reaction mixture was washed twice with water, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 9 g of 3-t-butyl-5-(2-(4-trifluoromethylphenylcarbamoylamino)-ethylthio)-1H-1,2,4-triazole, m.p. 238°-240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].[CH2:27]([O:29][P:30]([C:35]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][C:39]=1[Br:46])([F:37])[F:36])(=[O:34])[O:31][CH2:32][CH3:33])[CH3:28]>CN(C=O)C>[CH2:32]([O:31][P:30]([C:35]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:40][C:39]=1[Br:46])([F:37])[F:36])(=[O:34])[O:29][CH2:27][CH3:28])[CH3:33]
Reactant: Clc1ccc(Nc2nc(-c3ccccc3)cs2)cc1Cl
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(CBr)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(CN(c2ccc(Cl)c(Cl)c2)c2nc(-c3ccccc3)cs2)cc1Br
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
To (3,4-Dichloro-phenyl)-(4-phenyl-thiazol-2-yl)-amine (0.34 g, 1.04 mmol) in DMF (5 mL) was added K2CO3 (0.23 g, 1.71 mmol). After 0.1 hour, [(2-Bromo-4-bromomethyl-phenyl)-difluoro-methyl]-phosphonic acid diethyl ester (0.15 g, 0.34 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and H2O, after which the organic layer was dried over NaSO4 and concentrated in vacuo. The resulting material was purified via column chromatography (1/1 hexanes/ethyl acetate) to yield 0.176 g (76%) of a clear, colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.84-7.22 (m, 11 H), 6.81 (s, 1 H), 5.23 (s, 2 H), 4.23 (m, 4 H), 1.31 (t, J=7.5 Hz, 6 H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH:18]([S:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[N:19]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:20]2(=[O:22])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl>CCOCC>[C:12]1([CH:18]([S:31]([C:32]2[NH:36][N:35]=[N:34][N:33]=2)=[O:9])[N:19]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:20]2(=[O:22])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2ccccc2S(=O)(=O)N1C(Sc1nnn[nH]1)c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1c2ccccc2S(=O)(=O)N1C(c1ccccc1)S(=O)c1nnn[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 199.3 %

Procedure:
A mixture of m-chloroperbenzoic acid (0.43 g, 9,.67 mmol) and 2-(1-phenyl-1H-tetrazol-5-ylthiomethyl) saccharin (1 g, 2.67 mmol) in MDC was stirred at room temperature for 24 hours. TLC (95:5 CH2Cl2 : ether) revealed the presence of starting sulfide. Additional peracid (0.2 g) was added and the mixture stirred for an additional 2 days. The reaction mixture was washed with sodium bicarbonate solution, dried (Na2SO4) and freed of solvent under vacuum. Chromatography (silica gel-95:5 CH2Cl2 :ether) afforded a foam that was crystallized from ether to afford 0.52 g of 2-(1-phenyl-1H-tetrazol-5-ylsulfinylmethyl) saccharin as a white solid, mp 161°-162° C. 1H nmr (90 MHz, CDCl3):5.5-6.0 (2H, q). FDMS: m/e 196 (M+ -PMT), 389 (M+).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:6][N:4]([CH3:5])[CH:3]=[C:15]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:14]([C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)=[O:22]
Reactant: O=C(Cc1ccncc1)c1ccco1
Reactant: COC(OC)N(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CN(C)C=C(C(=O)c1ccco1)c1ccncc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
N,N-Dimethylformamide dimethylacetal (5 mL) was added to 1-(2-furyl)-2-(4-pyridyl)-1-ethanone (2.0 g, 10.7 mmol), followed by stirring at 100° C. for 2 hours. After cooling as it was, the reaction solution was diluted with ethyl acetate and an aqueous saturated solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate (×6). The combined organic layer was dried over anhydrous sodium sulfate and concentrated, to give the title compound (2.5 g, 97%) as a reddish brown oil.
Reaction SMILES: [CH:1]1([N:9]=[C:10]=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOC(C)=O.CCCCCC.CC#[N:26]>>[CH:1]1([NH:9][C:10]([NH2:26])=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=NC1CCCCCCC1
Reactant: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NC(=S)NC1CCCCCCC1
Reaction time: 72 h
Yield: 78.2 %

Procedure:
To a stirred solution of cyclooctyl isothiocyanate (7.26 g, 42.9 mmol) in 70 ml of CH3CN was added 8.5 ml of 15N NH4OH (130 mmol). The reaction progress was monitored by thin layer chromatography (TLC); 1/1 EtOAc/hexane. After 3 days, the reaction solution was concentrated, dissolved in 50 ml of ethyl acetate and washed with water (25 ml) and brine (aqueous saturated NaCl) (3×25 ml ea.). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica gel, 3/7 EtOAc/hexane) to yield 6.25 g (78.2%) of the desired thiourea. PMR(CDCl3)ppm 6.5 (bs, 1H), 6.00 (s, 2H), 4.35 (bs, 1/2H), 3.45 (bs, 1/2H), 2.1-1.3 (m, 14H). The melting point (MP) was 93°-95° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1)[NH2:15]
Reactant: Clc1cc(-c2ccccn2)ccn1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1cc(-c2ccccn2)ccn1

Procedure:
A mixture of 5.0 g of 2'-chloro-2,4'-bipyridine, 5 ml of anhydrous hydrazine and 100 ml of pyridine was refluxed. Additional 5 ml portions of anhydrous hydrazine were added after 18, 36 and 54 hours of refluxing. The solution was then refluxed for an additional 48 hours and the solvent removed under vacuum. The solid was dissolved in methylene chloride, treated with activated carbon, filtered and the filtrate concentrated to dryness. The residue was triturated with hexane, giving crystals which were recrystallized from methylene chloride-hexane, giving 2'-hydrazino-2,4'-bipyridine as yellow crystals, mp 120°-121° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[C:12](#[N:14])[CH3:13].Cl>O1CCOCC1>[CH3:13][C:12]1[NH:14][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[N:1]=1
Reactant: CC#N
Reactant: CCOC(=O)c1ccsc1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2sccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of ethyl 2-aminothiophene-3-carboxylate (0.1 g, 0.64 mmol) and acetonitrile (50 μl, 0.95 mmol) in dioxane (3 ml) was added 4M HCl in dioxane (3 ml). The mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure. The residue was diluted with water and made alcaline with a saturated aqueous sodium bicarbonate solution. The precipitate was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (42 mg, 40%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[N:26][OH:27])[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccccc2)c2ccccc2)cc(C)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccccc2)c2ccccc2)=NO)cc(C)n1

Procedure:
In analogy to example 1, step 2, from 1-(2,6-dimethyl-pyridin-4-yl)-3,3-diphenyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a white foam, MS (ESI+): m/z=331.2 ([M+H]+).
Reaction SMILES: ClCCl.[OH:4][N:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([C:12](=[O:14])[NH2:13])[C:6]1([CH3:16])[CH3:15].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(N(CC)CC)C>[C:17]([O:4][N:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([C:12](=[O:14])[NH2:13])[C:6]1([CH3:16])[CH3:15])(=[O:19])[CH3:18]
Reactant: CC1(C)CC(C(N)=O)C(C)(C)N1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)ON1C(C)(C)CC(C(N)=O)C1(C)C
Yield: 85.2 %

Procedure:
20 ml of dichloromethane and 3 ml of triethylamine were added to 0.50 g (2.7 mmol) of 1-hydroxy-3-carbamoyl-2,2,5,5-tetramethylpyrrolidine. 0.38 ml (4.0 mmol) of acetic anhydride was added dropwise to the mixture with stirring and ice-cooling, the mixture was stirred for 3 hours. The reaction mixture was washed with water, 3% diluted hydrochloric acid, water, 5% sodium hydrogencarbonate aqueous solution, and water, in this order. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate to obtain 0.53 g (2.3 mmol) of white crystals (yield: 86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([N:25]5[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26]5)[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[C:32](OC(=O)C)(=[O:34])[CH3:33].CCOCC>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][CH:22]([N:25]5[CH2:29][CH2:28][CH:27]([NH:30][C:32](=[O:34])[CH3:33])[CH2:26]5)[CH2:23][CH2:24]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N5CCC(N)C5)CC4)n3)ccc21
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)NC1CCN(C2CCN(c3nc(-c4ccc5c(c4)C(C)(C)CCC5(C)C)cs3)CC2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
150 mg (0.32 mmol) of 1-{1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-yl}pyrrolidin-3-ylamine were dissolved in 1 ml of pyridine, and 90 μl of acetic anhydride were added. The reaction mixture was stirred at RT for 15 h and subsequently evaporated. The residue was taken up in ethyl acetate, washed with sat. NaHCO3 solution, dried over Na2SO4 and evaporated. The oil obtained in this way was stirred with ether, and the precipitate formed was filtered off with suction, washed with ether and dried.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:25][N:26]([CH3:38])[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([C:32]5[CH:33]=[CH:34][C:29]([C:27]([N:26]([CH3:38])[CH3:25])=[O:28])=[CH:30][CH:31]=5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: O=C(Nc1ccc(CO)c(Br)c1)C1(c2ccc3c(c2)OCO3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CO)cc1
Temperature: 80 °C
Yield: 34.9 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)-phenyl)cyclopropanecarboxamide (39 mg, 0.10 mmol), 4-(dimethylcarbamoyl)-phenylboronic acid (29 mg, 0.15 mmol), 1 M K2CO3 (0.3 mL, 0.3 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture was heated at 80° C. for 3 h. After cooling, the mixture was filtered and purified by reverse phase HPLC to yield 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide (16 mg, 34%). ESI-MS m/z calc. 458.5, found 459.5 (M+1)+; Retention time 2.71 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:18])[N:14]([CH2:15][CH2:16][OH:17])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH2:19](Br)[C:20]#[CH:21]>>[CH3:18][C:13]1[N:14]([CH2:15][CH2:16][O:17][CH2:21][C:20]#[CH:19])[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1
Reactant: Cc1nc2c(N)nc3c(c2n1CCO)CCCC3
Reactant: C#CCBr
Product: C#CCOCCn1c(C)nc2c(N)nc3c(c21)CCCC3
Yield: 47.7 %

Procedure:
Using the general method of Example 1 Part A, 2-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (0.763 g, 3.098 mmol) was reacted with propargyl bromide (80% in toluene, 1.1 mL, 9.29 mmol) to provide 0.42 g of 2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a brown oil.