Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([NH:19][NH2:20])(=[O:18])[CH:15]([CH3:17])[CH3:16].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]([NH:20][NH:19][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(C)C(=O)NN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)C(=O)NNC(=O)CCNC(=O)OC(C)(C)C

Procedure:
25.00 g (132 mmol) 3-tert-butoxycarbonylamino-propionic acid, 13.50 g (132 mmol) isobutyric acid hydrazide, 50.91 g (159 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and 50 ml diisopropylethylamine are stirred in 500 ml of tetrahydrofuran/dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is extracted with ethyl acetate and 10% potassium hydrogen carbonate solution. The organic phase is dried and evaporated to dryness. The residue is crystallised from toluene/isopropylether.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:16]Br.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[Br:16][C:14]1[C:9]([O:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][C:11]([NH2:15])=[N:12][CH:13]=1
Reactant: BrBr
Reactant: Cc1ncccc1Oc1ccnc(N)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1ncccc1Oc1cc(N)ncc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.1 %

Procedure:
To 4-(2-methylpyridin-3-yloxy)pyridin-2-amine (3.67 g, 18.2 mmol) in acetic acid (50 mL) was added bromine (0.94 ml, 18.2 mmol). The reaction was stirred at ambient temperature for 5 minutes. Ammonium acetate (1.41 g, 18.2 mmol) was added. After 5 minutes, the solution was concentrated and saturated sodium bicarbonate solution was added. The reaction was extracted with ethyl acetate, dried and concentrated to give the title compound (5.0 g, 98% yield) as light yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl.Cl.[CH2:21]([N:23]([CH2:35][CH3:36])[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]Cl)[CH2:28][CH2:27]1)[CH3:22]>CN(C)C=O>[CH2:35]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:11]2[C:12]3[C:13](=[O:15])[C:14]4[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=4)[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:28][CH2:27]1)[CH3:36]
Reactant: CCN(CC)CCN1CCN(CCCl)CC1
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN1CCN(CCc2cccc3[nH]c4ccccc4c(=O)c23)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 9.75 g of 9-acridanone, 200 ml of dimethylformamide and 4.8 g sodium hydride is stirred for 0.5 hour, treated portionwise with 17.8 g of 2-[4-[2-(diethylamino)ethyl]-1-piperazinyl]ethyl chloride trihydrochloride, stirred at 70° for 18 hours, then heated to boiling under reflux for 8 hours and evaporated. The residue is treated with 100 ml of water and extracted with dichloromethane. The extract is washed with water, dried and evaporated. The product is crystallized twice from petroleum ether and there is obtained 10-[2-[4-[2-(diethylamino)ethyl]-1-piperazinyl]ethyl-9-acridanone of melting point 106°-108°.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([Mg]Br)[CH3:17]>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([C:2]1[C:3]([CH3:15])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:17]
Reactant: CC[Mg]Br
Reactant: Cc1c(Br)cccc1C1=NC(C)(C)CO1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CCc1cccc(C2=NC(C)(C)CO2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(3-bromo-2-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (3.4 g, 12.7 mmol) was dissolved in 30 mL of ethyl ether under nitrogen atmosphere in a 100 mL round bottom flask equipped with magnetic stirring, thermometer, and reflux condenser. Ni(dppp)Cl2 (100 mg) was added and the mixture was cooled to 0° C. in an ice bath. Ethyl magnesium bromide (5.5 mL, 3M in ether) was added, the reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for 2½ hours, and finally at reflux for 2 hours. The mixture was then cooled to 0° C., quenched with saturated aqueous NH4Cl. The organic layer was removed and the aqueous layer was extracted with ether. The organic phases were combined and dried over MgSO4. The solvent was removed in vacuo to give 2.84 g 2-(3-ethyl-2-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole, 1H NMR (CDCl3, 200 MHz), δ (ppm): 7.5 (d, 2H), 7.2 (m, 2H), 4.1 (s, 2H), 2.7 (m, 2H), 2.45 (s, 3H), 1.4 (s, 6H), 1.2 (t, 3H), Rf=0.25 (4:1 hexane:ether), containing ca. 5% original aryl bromide. The oxazoline was suspended in 100 mL of 6N HCl and refluxed for 5 hours with vigorous stirring. The mixture was allowed to cool to room temperature, whereupon 3-ethyl-2-methyl-benzoic acid crystallized: 1.74 g, m.p. 96-98° C., 1H NMR (CDCl3, 200 MHz), δ (ppm): 7.85 (d, 1H), 7.4 (d, 1H), 7.22 (t, 1H), 2.7 (q, 2H), 2.6 (s, 3H), 1.21 (t, 3H). An additional 110 mg was recovered by ether extraction of the aqueous phase.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:35]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:13]([S:40]([C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)(=[O:42])=[O:41])[CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1
Reactant: Cc1cc(C)c(-c2cc(C=O)c[nH]2)c(C)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2cc(C=O)cn2S(=O)(=O)c2cccnc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-mesityl-1H-pyrrole-3-carbaldehyde (0.36 g) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 0.14 g) under ice-cooling, and the mixture was stirred at room temperature for 0.5 hr. A solution of 15-crown-5 (0.75 g) in tetrahydrofuran (3 mL) was added and, after stirring for 5 min, pyridin-3-ylsulfonyl chloride (0.45 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 0.5 hr, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1→2:1) to give the title compound as a pale-brown amorphous form (yield 0.38 g, 62%).
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:17][C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][CH2:17][C:18]#[N:19])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCc1ccc(NCC#N)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 472.2 %

Procedure:
A mixture of 4-n-octylaniline (0.21 g; 1 mmol), BrCH2CN (0.156 mmol; 1.3 mmol) and K2CO3 (0.28 g; 2 mmol) in anhydrous CH3CN (3 ml) was stirred overnight at ˜60° C. under N2, then concentrated under reduced pressure. The residue was partitioned between CH2Cl2 (20 ml) and H2O (10 ml). The organic phase was dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by crystallization from hexane to give the title compound (0.18 g; 74%) as creamy solid. 1H-NMR (CDCl3) 7.06 (d, 2H, J=8.48 Hz); 6.63 (d, 2H, J=8.48 Hz); 4.06 (d, 2H, J=5.75 Hz); 3.83 (broad m, 1H); 2.51 (t, 2H, J=7.92 Hz); 1.55 (m, 3H); 1.27 (m, 10H); 0.86 (t, 3H, J=6.87 Hz).
Reaction SMILES: ClCCl.CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@:24]2([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][O:37][CH3:38])=[C:31]([F:39])[CH:30]=3)[CH2:26][C@H:25]2[CH2:27][OH:28])=[CH:17][N:16]=1>O.C(N(CC)CC)C>[CH3:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@:24]2([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][O:37][CH3:38])=[C:31]([F:39])[CH:30]=3)[CH2:26][C@H:25]2[CH:27]=[O:28])=[CH:17][N:16]=1
Reactant: COCOc1ccc([C@]2(COc3cnc(C)nc3C)C[C@H]2CO)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc([C@]2(COc3cnc(C)nc3C)C[C@H]2C=O)cc1F
Temperature: -78 °C
Yield: 106 %

Procedure:
A dichloromethane (20 ml) solution of dimethyl sulfoxide (5.8 ml) was added dropwise to a dichloromethane (100 ml) solution of oxalyl chloride (3.45 ml), while the solution was stirred at −78° C. The obtained mixture was stirred at −78° C. for 10 minutes, and a dichloromethane (30 ml) solution of the compound 321-6 (7.4 g) was then added dropwise to the reaction mixture. The obtained mixture was stirred at −78° C. for 30 minutes. Thereafter, triethylamine (17.1 ml) was added to the reaction mixture, and the obtained mixture was stirred for 2 hours, while it was heated to 0° C. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure, so as to obtain the title compound (7.8 g).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:24]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:23]=3[N:22]=2)=[CH:17][CH:16]=1>CN(C=O)C>[Si:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[C:24]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:23]=3[N:22]=2)=[CH:17][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(C#N)ccc3n2C2CCCCC2)cc1
Reaction time: 15 h

Procedure:
Imidazole (2.72 g, 0.040 mol) and tert-butyldimethylchloro silane (2.89 g, 192 mmol) were added to a stirred solution of compound 6 (5.1 g, 16 mmol) in DMF (10 mL). Stirring was continued for 15 h at 100° C. Upon cooling 20 crystallized. The crystals were collected and washed with ethyl acetate followed by water. The yield of 20 (after drying) was 4.70 g (62%).
Reaction SMILES: O=[CH:2][CH2:3][N:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:5](=[O:17])[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[NH2:33][CH2:34][CH2:35][C:36]1[C:44]2[S:43][C:42](=[O:45])[NH:41][C:40]=2[C:39]([OH:46])=[CH:38][CH:37]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[OH:46][C:39]1[C:40]2[NH:41][C:42](=[O:45])[S:43][C:44]=2[C:36]([CH2:35][CH2:34][NH:33][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5](=[O:17])[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:37][CH:38]=1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: O=CCN(CCCCCOCCc1ccccc1)C(=O)CCOCCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(CCOCCc1ccccc1)N(CCCCCOCCc1ccccc1)CCNCCc1ccc(O)c2[nH]c(=O)sc12
Reaction time: 8 h

Procedure:
N-(2-Oxoethyl)-3-phenethyloxy-N-(5-phenethyloxypentyl)propanamide (Example 9c), 0.12 g) was dissolved in methanol (5 mL) and treated with 7-(2-aminoethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride (0.32 g), acetic acid (0.1 mL) and water (0.3 mL). The resultant mixture was stirred for 2 hours and then sodium cyanoborohydride (0.01 g) was added and the reaction mixture was stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in methanol (5 mL) and adsorbed onto silica gel. The product was purified by flash chromatography eluting with 5% methanol, 1% ammonia in dichloromethane. Collected fractions were concentrated and the resultant residue was taken up in dichloromethane (5 mL) and treated with 4N hydrogen chloride in dioxane (0.2 mL). The mixture was stirred vigorously and concentrated. The resulting gum was azeotroped with dichloromethane (3×5 mL) to give the titled compound (0.13 g) as a white solid.
Reaction SMILES: [S:1]([C:5]1[CH:21]=[CH:20][C:8]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl[C:23](OC)=[O:24]>>[S:1]([C:5]1[CH:6]=[CH:7][C:8]([N:9]2[CH2:10][C:11](=[O:12])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:23]2=[O:24])=[CH:20][CH:21]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1ccc(NCC(=O)Nc2ccccc2)cc1
Reactant: COC(=O)Cl
Product: NS(=O)(=O)c1ccc(N2CC(=O)N(c3ccccc3)C2=O)cc1

Procedure:
2-(4-Sulphamoylanilino)-N-phenylacetamide (1.5 g) and methyl chloroformate (15.0 ml) were heated together for 3 hours in an autoclave at 130°C. The product was filtered off as crystals; yield 500 mg, m.p. 255° - 257°C (acetone).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][N:17]=[C:18]=[S:19].CCOC(C)=O>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:18]([NH:17][CH3:16])=[S:19])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN=C=S
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=S)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 1-Boc-4-aminomethylpiperidine (642 mg, 3 mmol) in THF (8 ml), methyl isothiocyanate (241 mg, 3.3 mmol) was added and the mixture was stirred at room temperature overnight. Upon completion of the reaction, purification was performed by silica gel column chromatography (Hex/AcOEt=1/4) to obtain 4-({[(methylamino)thioxomethyl]amino}methyl)piperidine carboxylic acid tert-butyl ester. The compound was identified by LC-MS.
Reaction SMILES: [CH3:1][SH:2].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12]Cl)=[C:8]([C:14]([Cl:17])([Cl:16])[Cl:15])[CH:7]=1)([O-:5])=[O:4]>C(OCC)C>[CH3:1][S:2][S:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=1[C:14]([Cl:17])([Cl:16])[Cl:15]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: CS
Solvent: CCOCC
Product: CSSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Reaction time: 2 h
Yield: 88.1 %

Procedure:
At 5° C., 7.2 g of methyl mercaptan is passed over a period of 20 minutes into a solution of 46 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 750 ml of diethyl ether. The reaction mixture is kept at 5° to 10° C. for 2 hours. After the solvent has been distilled off, the residue is recrystallized from ligroin. There is obtained 42 g (88% of theory) of methyldithio-4-nitro-2-trichloromethylbenzene; m.p.: 76° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]([NH2:19])=[S:18])=[N:11][CH:12]=[C:13]([Br:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22](=O)[CH3:23].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:21]=[C:22]([CH3:23])[N:19]=2)=[N:11][CH:12]=[C:13]([Br:15])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)nc1OCc1ccccc1
Reactant: CC(=O)CCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2ncc(Br)nc2OCc2ccccc2)n1
Yield: 30.7 %

Procedure:
Following the method of Example 1, Step D, 1-(3-(benzyloxy)-5-bromopyrazin-2-yl)thiourea (952 mg, 2.81 mmol), 1-chloropropan-2-one (364 mg, 3.93 mmol) and triethylamine (0.655 mL, 4.77 mmol) were reacted in ethanol (10 mL) to provide N-(3-(benzyloxy)-5-bromopyrazin-2-yl)-4-methylthiazol-2-amine (325 mg, 31%) as a light tan powder. 1H NMR (d6-DMSO) δ 8.01 (s, 1H), 7.57 (d, 2H), 7.35-7.43 (m, 3H), 6.62 (s, 1H), 5.42 (s, 2H), 2.32 (s, 3H). Mass spectrum (apci) m/z=377 (100), 379 (97) (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:37])[C:19]([C:32]([O:34]CC)=[O:33])=[CH:20][N:21]3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])=[CH:16][C:15]=2[F:38])[CH2:9]1)=O)(C)(C)C.[ClH:39]>C(O)(=O)C>[ClH:39].[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:37])[C:19]([C:32]([OH:34])=[O:33])=[CH:20][N:21]3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])=[CH:16][C:15]=2[F:38])[CH2:9]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(OC3CCNC3)c(F)cc2c1=O

Procedure:
Ethyl 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (220 mg), 0.7 ml of concentrated hydrochloric acid and 2.8 ml of acetic acid were used. The ester was treated in a similar manner to Example 1-(2) and recrystallized from ethanol, whereby 80 mg of the title compound was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])#[N:2].Cl.C(O)(=[O:26])C>>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])(=[O:26])[NH2:2]
Reactant: CN(C)CCC=C1c2ccccc2C=Cn2cc(C#N)cc21
Reactant: CC(=O)O
Agent: Cl
Product: CN(C)CCC=C1c2ccccc2C=Cn2cc(C(N)=O)cc21
Temperature: 25 °C

Procedure:
2-Cyano-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine (0.135 mole) in 100 ml. of concentrated hydrochloric acid and 100 ml. of acetic acid is refluxed for 2 hours. It is then poured onto 500 ml. of water and continuously extracted with methylene chloride. The solution is left to cool to room temperature and filtered to afford 2-carbamoyl-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:11][CH2:12][CH3:13])(=[O:10])[CH3:9].[CH2:14]([O:21][C:22](=[O:34])[NH:23][C@H:24]([C:27](N1C=CN=C1)=[O:28])[CH2:25][CH3:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OC(N[C@@H](CC)C(O)=O)=O)C1C=CC=CC=1>O1CCCC1.O.C(O)(=O)C>[CH2:14]([O:21][C:22]([NH:23][C@@H:24]([CH2:25][CH3:26])[C:27](=[O:28])[CH2:9][C:8]([O:11][CH2:12][CH3:13])=[O:10])=[O:34])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(C)=O
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)n1ccnc1
Agent: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@H](CC)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of diisopropylamine (74.5 mL) in tetrahydrofuran (1 L) was cooled to −78° C., n-butyllithium-hexane solution (329 mL, 1.6 mol/L) was added dropwise, and the mixture was stirred for 1 hr. Ethyl acetate (51.6 mL) was added dropwise and the mixture was stirred at −78° C. for 1 hr. Then, a solution of benzyl[(1S)-1-(1H-imidazol-1-ylcarbonyl)propyl]carbamate prepared from (2S)-2-{[(benzyloxy)carbonyl]amino}butanoic acid (50 g) and N,N′-carbonyldiimidazole (39.5 g) in tetrahydrofuran (300 mL) was added dropwise at −78° C. After stirring at −78° C. for 1 hr, acetic acid was added to the reaction mixture. Water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→2/1) to give ethyl(4S)-4-{[(benzyloxy)carbonyl]amino}-3-oxohexanoate as a colorless oil (yield: 36.7 g, 57%).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1.Cl.C[CH:25]([NH2:40])[C:26]1C=CC(CCC2C=CC=CC=2)=[CH:28][CH:27]=1.COC1CCCN=1.COC1CCCCCN=1>>[ClH:1].[CH3:2][CH:3]([N:22]=[C:25]1[CH2:26][CH2:27][CH2:28][NH:40]1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:5]=1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1cccc(OCCCCOc2ccccc2)c1
Agent: COC1=NCCC1
Agent: COC1=NCCCCC1
Agent: Cl
Product: CC(N=C1CCCN1)c1cccc(OCCCCOc2ccccc2)c1

Procedure:
Substituting this amine for the α-methyl-ρ-phenethylbenzylamine hydrochloride, and substituting O-methylbutyrolactim for the O-methylcaprolactim results in the formation of 2-[α-methyl-m-(4-phenoxybutoxy)benzylimino]pyrrolidine hydrochloride, having a M.P. of 136°-8° C. (dec.)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:12]([CH2:14][C:15]([NH2:17])=[S:16])#[N:13]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:15]([CH2:14][C:12]#[N:13])[S:16][CH:2]=2)=[CH:6][CH:7]=1
Reactant: N#CCC(N)=S
Reactant: O=C(CBr)c1ccc(F)cc1
Product: N#CCc1nc(-c2ccc(F)cc2)cs1
Yield: 72 %

Procedure:
This compound was synthesized from 2-bromo-1-(4-fluorophenyl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (3.2 g, yield 72%). MS (ESI) m/z: Calculated for C11H7FN2S: 218.03. found: 219.0 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.O.O.Cl>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=5[O:26][N:25]=4)[CH2:32][CH2:31]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCc1c(CCCl)sc2c1CCN(C(C)=O)C2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Solvent: O
Product: CCc1c(CCN2CCC(c3noc4cc(F)ccc34)CC2)sc2c1CCN(C(C)=O)C2
Yield: 42.6 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.7 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 0.67 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.5 g of 6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 165°-167° C. (decomposition) as hydrochloride dihydrate thereof.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH:23]2[CH2:25][CH2:24]2)[N:18]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH:23]4[CH2:25][CH2:24]4)[N:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Clc1ccnc(C2CC2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1N(c2ccnc(C3CC3)n2)CCN1c1cnccc1C1CC1
Yield: 15.8 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 11 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 4-chloro-2-cyclopropylpyrimidine (I-43a: 92 mg, 0.591 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (24 mg, 0.0492 mmol), Pd2(dba)3 (23 mg, 0.0246 mmol), cesium carbonate (400 mg, 1.23 mmol) and toluene (5 mL) in seal tube at 110° C. for 14 hours. Purification by column chromatography on silica gel (2% methanol in chloroform), followed by preparative HPLC afforded 25 mg of the product (% yield).