Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH:2]([NH2:4])[CH3:3].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:14]1[CH:19]=[C:18]([Br:20])[C:17](Br)=[CH:16][C:15]=1[Br:22].[CH:23]1[C:35]2[NH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1>[Cu](I)I.O1CCOCC1>[Br:22][C:15]1[C:14]([N:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:35]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][C:18]([Br:20])=[C:17]([N:4]2[C:2]3[CH:3]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:35]=3)[CH:16]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(N)N
Reactant: Brc1cc(Br)c(Br)cc1Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Brc1cc(-n2c3ccccc3c3ccccc32)c(Br)cc1-n1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.2 %

Procedure:
1.16 g (6.1 mmole) of copper iodide and 200 ml of anhydrous dioxane were put in a three-necked flask of 300 ml, 0.41 ml (6.1 mmole) of diaminoethane was dropped at room temperature under nitrogen flow, and the mixture was stirred for 15 minutes at room temperature and heated to 60° C. This solution was allowed to cool to room temperature, 56.8 g (244 mmole) of potassium phosphate, 12.0 g (30.5 mmole) of 1,2,4,5-tetrabromobenzene and 40.8 g (244 mmole) carbazole were added, and heated with stirring at 80° C. under nitrogen flow for 48 hours. After the reaction was completed, the reaction mixture was hot-filtered using Celite to remove insoluble matter. The filtrate was concentrated under reduced pressure. The residue was refined by NH-modified silica gel silica gel column chromatography (eluent:hexane/toluene: 1/2). The obtained crystal was repeatedly recrystallized from toluene and chloroform to give 0.90 g of a white crystal of 1,4-dibromo-3,6-di(carbazole-9-yl)benzene (yield: 5.2%). By reacting two equivalent weight of 4-(2-phenylindole-1-yl)phenyl boronic acid with this 1,4-dibromo-3,6-di(carbazole-9-yl)benzene, 1,4-di(carbazole-9-yl)-2,5-bis{4-(2-phenylindole-1-yl)phenyl}benzene was obtained. The melting point of this compound was 376° C., and the glass transition temperature was 184° C.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH:17]([CH3:19])[O:16][C:15]2[CH:20]=[C:21](Br)[CH:22]=[N:23][C:14]1=2)=[O:12])([CH3:9])([CH3:8])[CH3:7].C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C>C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH:17]([CH3:19])[O:16][C:15]2[CH:20]=[C:21]([B:29]([OH:30])[OH:28])[CH:22]=[N:23][C:14]1=2)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC1CN(C(=O)OC(C)(C)C)c2ncc(Br)cc2O1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)c2ncc(B(O)O)cc2O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Butyl lithium (2.5 M in THF, 6.08 mL, 2.5 equiv.) was added dropwise into a stirring solution of 7-bromo-2-methyl-2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (2.0 g, 6.08 mmol, 1.0 equiv.) and triisopropylborate (2.86 g, 15.19 mmol, 2.5 equiv.) in anhydrous THF (20 mL) at −78° C. under nitrogen. The reaction was stirred at −78° C. and monitored with LCMS. After 2 hr, LCMS indicated the reaction complete. The reaction was quenched with water (20 mL) and concentrated under reduced pressure. The residue was washed with ether (2×10 mL) and the aqueous layer was placed in an ice-water bath. While stirring, 10 N HCl aqueous solution was carefully added dropwise until pH˜7. Filtration and washing with ice-water (3×5 mils) gave the desired product as a white solid (923 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCCCO)cc1
Yield: 100 %

Procedure:
A mixture of 4-(4-nitro-phenyl)-butan-1-ol (2.0 g, 1.02 mmol), palladium on carbon (100 mg, 10%) and ethanol (25 ml) was treated with hydrogen gas on a Parr shaker (50 psi) for 1 hour. The mixture was filtered through a pad of celite under suction and the filtrate was concentrated under reduced pressure to afford 4-(4-amino-phenyl)-butan-1-ol (100% yield).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH2:9]=[CH:10][C:11](=[CH2:13])[CH3:12].[Cr](O)(O)(=O)=O>C(O)(=O)C.O>[CH3:13][C:11]1[CH:12]=[C:6]2[C:5](=[CH:9][CH:10]=1)[C:4](=[O:7])[CH:3]=[CH:2][C:1]2=[O:8]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=CC(=C)C
Agent: O=[Cr](=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(c1)C(=O)C=CC2=O
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A solution of 1,4-benzoquinone (13.9 g, 128 mmol) and isoprene (13.1 ml, 131 mmol) was stirred in glacial acetic acid (44 ml) for 68 hours at room temperature. The mixture was diluted with water (44 ml) and refluxed for 11/2 hours. The mixture was cooled to room temperature and acetic acid (84 ml) and chromic acid [chromium trioxide (29.4 g)] in water (30 ml)] was added sequentially, before refluxing for a further 11/2 hours. After cooling, the mixture was diluted with water (200 ml) and extracted with ether (3×50 ml). The combined ether fractions were washed with dilute sodium hydroxide solution (2M; 2×50 ml), water (2×50 ml), saturated sodium chloride solution (50 ml) and dried over magnesium sulphate. Filtration and evaporation of solvent under reduced pressure, and repeated recrystallisation from petroleum ether yielded the title compound (7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH2:9]([O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)[CH3:10].CCN(CC)CC>CC#N.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:21])=[CH:14][CH:15]=2)[N:3]=1
Reactant: C#Cc1ccc(C(=O)OCC)cc1
Reactant: Nc1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2cccc(N)n2)cc1

Procedure:
2-Amino-6-bromopyridine (0.38 g, 2.4 mmol), alkyne 29-2 (0.35 g, 2.0 mmol), Et3N (1.0 mL, 7.2 mmol), (Ph3P)2PdCl2 (76 mg, 0.11 mmol), an CuI (26 mg, 0.14 mmol) were combined in 5 mL CH3CN, sealed in a glass pressure tube and heated to 100° for 3 h. The mixture was diluted with EtOAc, washed with water and brine, dried (MgSO4), concentrated, and purified by flash chromatography (silica, 5% acetone/hexane), to give 29-3 as a tan solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][C:18]([C:25]([F:28])([F:27])[F:26])=[CH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])=[CH:12][CH:11]=1>O1CCCC1>[Br:1][C:19]1[C:20]([C:21]([F:22])([F:23])[F:24])=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[NH:17][C:18]=1[C:25]([F:28])([F:26])[F:27]
Reactant: FC(F)(F)c1cc(C(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: FC(F)(F)c1[nH]c(-c2ccc(Cl)cc2)c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
N-Bromosuccinimide (0.9 g, 5 mmol) is added to a solution of 2-(p-chlorophenyl)-3,5-bis(trifluoromethyl)pyrrole (0.78 g, 2.5 mmol) and tetrahydrofuran (50 mL). The reaction mixture is stirred at room temperature overnight then concentrated in vacuo to give a solid. The solid is chromatographed using silica gel and 20% ethyl acetate in hexanes as eluant to yield the title compound as a light green solid (0.376 g, mp 71°-75° C., 38%).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11](C)[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18](Cl)=[CH:17][C:16]=2[CH3:23])[C:8]=1[N+:24]([O-])=O)[CH2:4][CH3:5])[CH3:2].[CH2:27](O)C>[Pd]>[CH3:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[O:14][C:9]1[C:8]([NH2:24])=[C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:12]([CH3:27])=[CH:11][N:10]=1
Reactant: CCO
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1[N+](=O)[O-]
Agent: [Pd]
Product: CCC(CC)Nc1c(C)cnc(Oc2c(C)cccc2C)c1N

Procedure:
A mixture of (1-ethyl-propyl)-[6-methyl-3-nitro-2-(4 chloro-2,6-dimethyl-phenoxy)-pyridin-4-yl]-amine (800 mg, 2.12 mmol) and 160 mg of 10% Pd IC in 150 ml of ethanol was hydrogenated at 50 psi overnight. The mixture was filtered through Celite™ and the filtrate was concentrated to dryness to give a purple glass form (810 mg) which was purified through silica gel column chromatography using 1:1 chloroform:hexane as eluent to give the Ute compound as tan crystals (360 mg), mp 98-100° C. 1H NMR (CDCl3) δ 7.05 (m, 3H), 6.11 (s, 1H), 4.00 (brs, 1H), 3.28 (m, 1H), 3.09 (brs, 2H), 2.14 (s, 9H), 1.451.75 (m, 4H), 0.98 (t, 6H) ppm. The corresponding HCl salt was prepared as white solid, mp 158-162° C., 1H NMR(D2O) δ 7.27 (s, 3H), 6.67 (s, 1H), 3.65 (m, 1H), 2.27 (s, 3H), 2.16 (s, 6H), 1.45-1.80 (m, 4H), 0.93 (t, 6H) ppm.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:10])[NH2:9])=[CH:4][CH:3]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[N:10]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(-c2ccncc2)ns1
Temperature: 25 °C
Yield: 6 %

Procedure:
To a solution of pyridine-4-carboximidamide hydrochloride (2.00 g, 12.7 mmol) and perchloromethyl mercaptan (1.75 ml, 16.3 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (3.26 g, 81.5 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to give 150 mg (5.98%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[S:9][C:5]=2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=1.[CH3:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.[Cl-].[Na+]>N1C=CC=CC=1.O1CCCC1>[CH3:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[C:6]3[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH3:13])[S:9][C:5]=3[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2nn(C(=O)OC(C)(C)C)c3sc(C(=O)NC(C)(C)c4ccccc4)nc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.7 %

Procedure:
0.20 g (0.50 mmol) of tert-butyl 3-amino-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 5 ml of pyridine is placed in a 50 ml round-bottomed flask under argon. A solution of 0.09 g (0.53 mmol) of 4-methoxybenzoyl chloride (prepared according to J. Org. Chem. 1976, 41, 2566) in 2.0 ml of tetrahydrofuran is then added dropwise and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 30 ml of dichloromethane and 30 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.05 g of tert-butyl 3-(4-methoxy-benzoylamino)-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam. 0.16 g of an impure batch is also obtained, and is repurified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.04 g of tert-butyl 3-(4-methoxybenzoylamino)-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.61 (s, 9H); 1.71 (s, 6H); 3.86 (s, 3H); 7.10 (d, J=8.5 Hz, 2H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.40 (d, J=7.5 Hz, 2H); 8.07 (d, J=8.5 Hz, 2H); 8.71 (s, 1H); 11.25 (broad s, 1H). LC-MS-DAD-ELSD: 534(−)=(M−H)(−); 536(+)=(M+H)(+).
Reaction SMILES: [C:1]([NH:5]/[N:6]=[C:7](\[CH3:13])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[Cl-].Cl[CH:16]=[N+](C)C.[C:20](=[O:23])(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([N:5]1[CH:16]=[C:13]([CH:20]=[O:23])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCOC(=O)/C(C)=N/NC(C)(C)C
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(C(C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a yellow orange solution of (E)-ethyl 2-(2-tert-butylhydrazono)propanoate (22.9 g, 123 mmol) in toluene (300 mL) was added (chloromethylene)dimethylammonium chloride (Vilsmeier salt, 34.0 g, 252 mmol) in a single portion. The suspension was stirred 3 hours at room temperature, slowly becoming a biphasic mixture of toluene over a thick orange oil. The reaction mixture was cooled to 0° C. and slowly neutralized with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer extracted with additional ethyl acetate (2×200 mL). The organic layers were combined, washed with 200 mL brine, dried over sodium sulfate, filtered and concentrated to yield ethyl 1-tert-butyl-4-formyl-1H-pyrazole-3-carboxylate (18.6 g) as a tan-orange oil which solidified on standing. +APCI (M+H) 225.1; 1H NMR (400 MHz, CDCl3, δ): 10.37 (s, 1H), 8.14 (s, 1H), 4.48 (q, J=7.0 Hz, 2H), 1.65 (s, 9H), 1.44 (t, 3H).
Reaction SMILES: [H-].[Na+].IC.C(O[C:10](=O)[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:13]1)(C)(C)C>CC#N>[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nccs2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CI
Product: CNC1CCN(c2nccs2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
384 mg (8.0 mmol, 60% in mineral oil) sodium hydride and 500 μl (8.0 mmol) iodomethane were added in turn to a solution of 1.13 g (4.0 mmol) (1-thiazol-2-yl-piperidin-4-yl)-carbamic acid-tert-butyl ester (see example 5a) for synthesis) in MeCN (40 ml). The reaction solution was stirred for 1 h at RT. Subsequently, a further 192 mg (4.0 mmol, 60% in mineral oil) sodium hydride and 250 μl (4.0 mmol) iodomethane were added and stirring took place for a further hour. Subsequently, 25% aq. ammoniac solution (2 ml) were added and concentration took place in vacuo. The residue was extracted with chloroform. The organic solution was washed with water and brine in turn, dried over MgSO4, filtered, and concentrated in vacuo. This residue was dissolved in EtOH (10 ml) and a sat. ethereal HCl soln (20 ml) was added. After 1 h stirring at RT, concentration took place in vacuo. The residue was taken up by ether (20 ml) and water (30 ml) was added. After separation of the organic phase, the aqueous phase was made basic (pH>11) with a 20% NaOH soln. Extraction subsequently took place with chloroform. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. 786 mg (3.99 mmol, 99%) N-methyl-1-(thiazol-2-yl)piperidine-4-amine were thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([F:12])[C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][NH:14][CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([F:12])[C:9]([N:14]([CH3:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)c1cccc(Br)c1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
A mixture of (3-bromo-phenyl)-fluoro-acetic acid (436 mg, 1.9 mmol), dimethyl amine (1.9 ml, 3.7 mmol-2M solution in THF), HATU (1.1 g, 2.8 mmol), DIEA (0.7 ml, 3.7 mmol) in DMF were stirred at room temperature overnight. The reaction was diluted with ethyl acetate, washed with 1N HCl, saturated Na2HCO3, brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2-(3-bromo-phenyl)-2-fluoro-N,N-dimethyl-acetamide (212 mg, 44% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.86 (d, 6H), 6.40-6.44 (d, 1H), 7.41 (m, 1H), 7.45 (d, 1H), 7.642 (m, 2H). MS: m/z 261.1 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:5]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2][NH:20][CH:17]2[CH2:19][CH2:18]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC1CC1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(C(CCNC2CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-bromo-1,1-diphenylpropane 9 (2.06 g, 7.49 mmol) in DMF (15 mL) at room temperature was added cyclopropylamine (3.26 g, 57.1 mmol, 4.0 mL) and cesium carbonate (3.19 g, 9.79 mmol). The reaction mixture was stirred at room temperature for 20 h and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 1% to 6% MeOH (2 M NH3) in DCM) gave N-(3,3-diphenylpropyl)cyclopropanamine 10 as a colorless oil. Mass spectrum: calculated for C18H21N 251.2; found 252.2 (M++1).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)[CH2:2][CH2:3][CH3:4].O.O.O.[F:14][C:15]([F:23])([F:22])[C:16]([C:18]([F:21])([F:20])[F:19])=[O:17]>CCOC(C)=O>[CH2:1]([NH:5][C:6]1[S:7][C:8]([C:16]([OH:17])([C:18]([F:21])([F:20])[F:19])[C:15]([F:23])([F:22])[F:14])=[CH:9][N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CCCCNc1nccs1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCNc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Temperature: 100 °C

Procedure:
A catalytic amount of molecular sieves powder (4A) was added to the mixture of 2-butylaminothiazole (1 g 6.41 mmol) prepared above and hexafluoroacetone trihydrate (2.86 g 13 mmol). The mixture was heated to gently reflux at 100° C. overnight. EtOAc is added and the mixture was filtered. Solvent was evaporated under reduced pressure. The residue was recrystallized in THF and hexanes to afford the title compound as a white solid. (1.68 g). 1H NMR δ0.95 (t, 3H), 1.40 (m, 2H), 1.6 (m, 2H), 3.20 (t, 2H), 7.3 (s, 1H); ESIMS: m/z 323 (M+H).
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4])[NH2:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([C:24](=O)[CH3:25])[CH:23]=1>CO.C(O)(=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([OH:27])=[C:22](/[C:24](=[N:2]/[NH:1][C:3]([C:5]2[CH:6]=[C:7]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)=[O:4])/[CH3:25])[CH:23]=1
Reactant: CN(C)S(=O)(=O)c1cccc(C(=O)NN)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N(C)C)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 18.4 %

Procedure:
3-(Hydrazinecarbonyl)-N,N-dimethylbenzenesulfonamide (50 mg, 0.0.206 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (35.1 mg, 0.206 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (15 mg). 1H NMR (400 MHz, acetone-d6): δ 8.29 (m, 2H), 8.01 (d, 1H, J=8.4 Hz), 7.83 (t, 1H, J=8.4 Hz), 7.62 (d, 1H, J=2.4 Hz), 7.32 (dd, 1H, J=2.4 & 8.8 Hz), 6.96 (d, 1H, J=8.8 Hz), 2.73 (s, 6H), 2.58 (s, 3H). ESI-MS: 396.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:22][C:23](O)=[O:24])[CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[CH2:34]([O:41][NH:42][C:23](=[O:24])[CH2:22][N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)N2CCOCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(CC(=O)NOCc2ccccc2)CC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetic acid (0.33 grams, 0.89 mmol) in methylene chloride (10 mL) were added sequentially triethylamine (0.43 mL, 3.1 mmol), O-benzylhydroxylamine hydrochloride (0.15 grams, 0.94 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.43 grams, 0.97 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed sequentially with 0.5 N hydrochloric acid solution, water and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was chromatorgraphed on silica gel using ethyl acetate to afford N-benzyloxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide as a white solid, 0.33 grams (78%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[CH:3][N:2]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccnnc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccnnc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 4.4 %

Procedure:
To a solution of pyridazine-4-amine (1.73 g, 18.2 mmol) and pyridine (4.41 ml, 54.6 mmol) in tetrahydrofuran (100 ml) was added 2,2,2-trichloroethyl chloroformate (3.76 ml, 27.3 mmol) was added, the mixture was stirred for 1.5 hours with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (218 mg, 4.4%) as a solid.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1)SC)#[N:5]>>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1)#[N:5]
Reactant: CCN
Reactant: CSC(=NCCSCc1cccnn1)NC#N
Product: CCNC(=NCCSCc1cccnn1)NC#N

Procedure:
Anhydrous ethylamine is reacted with N-cyano-N'-[2(3-pyridazinylmethylthio)ethyl]-S-methylisothiourea by the procedure of Example 4 to give N-cyano-N'-ethyl-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.