Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[C:16]1([CH:22]=[CH:23][CH2:24]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:24][CH:23]=[CH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClCC=Cc1ccccc1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Cl)c(Cl)cnn1CC=Cc1ccccc1
Yield: 88.6 %

Procedure:
To a suspension of 16.5 g (100 mmoles) of 4,5-dichloro-3(2H)-pyridazinone and 150 g (163 mmoles) of anhydrous potassium carbonate in 100 ml of anhydrous dimethylformamide a solution of 16.8 g (110 mmoles) of 3-phenyl-2-propenyl chloride in 5 ml of anhydrous dimethylformamide is dropped under stirring and cooling at a temperature below 15° C. The reaction mixture is stirred at room temperature for a day and poured onto 600 ml of water under stirring. The separated crystals are filtered, washed with water, dried and optionally purified by treating with aluminium oxide in a benzene solution. Thus 24.9 g (89%) of the desired compound are obtained. M.p.: 98°-99° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[O:7]=[C:8]1[NH:17][CH:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[C:15]2[C:14](=[O:26])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.Br[CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40].O>CN(C)C=O>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([CH:16]2[C:15]3[C:14](=[O:26])[CH2:13][CH2:12][CH2:11][C:10]=3[N:9]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)[C:8](=[O:7])[N:17]2[CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])=[CH:25][CH:24]=1)#[N:23]
Reactant: COC(=O)C(C)Br
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Cesium carbonate (713 mg, 2.19 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)1,2,3,4,5,6,7,8octahydroquinazolin-4-yl)-benzonitrile (example 1, 300 mg, 0.73 mmol) and methyl 2-bromopropanoate (244 mg, 1.46 mmol) in N,N-dimethylformamide (10 mL), and the mixture is stirred at 50° C. for 6 h and at room temperature over night. Water is added, and the mixture is extracted with dichloromethane. The organic layer is extracted with water and brine, dried over MgSO4 and concentrated under reduced pressure. Yield: 353 mg; ESI mass spectrum [M+H]+=498; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: FC1N=C(C([NH:10][NH2:11])=O)C=CC=1.[F:12][C:13]1[C:14]([C:20]([OH:22])=O)=[N:15][CH:16]=[C:17]([F:19])[CH:18]=1.FC1N=C(C(O)=O)C=CC=1>>[F:12][C:13]1[C:14]([C:20]([NH:10][NH2:11])=[O:22])=[N:15][CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: NNC(=O)c1cccc(F)n1
Agent: O=C(O)c1cccc(F)n1
Product: NNC(=O)c1ncc(F)cc1F

Procedure:
3,5-Difluoro-2-pyridinecarbohydrazide was prepared in a manner analogous to that described above for 6-fluoro-2-pyridinecarbohydrazide (I23) but using 3,5-difluoro-2-pyridinecarboxylic acid (CAS [745784-04-7], commercially available e.g. from Matrix Scientific, Alfa Aesar or Apollo Scientific) in the place of 6-fluoro-2-pyridinecarboxylic acid.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[N:24]1([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[N:24]1([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([NH:35]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:36][CH:37]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-piperidinomethyl-aniline in DMF.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2([C:44]([F:47])([F:46])[F:45])[O:30][N:29]=[C:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]([C:41]([NH2:43])=[O:42])=[CH:33][CH:32]=3)[CH2:27]2)[CH:22]=[C:23]([Cl:25])[CH:24]=1>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2([C:44]([F:46])([F:45])[F:47])[O:30][N:29]=[C:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]([C:41]([N:43]=[S:2]([CH3:4])[CH3:1])=[O:42])=[CH:33][CH:32]=3)[CH2:27]2)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: CS(C)=O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CS(C)=NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of dimethylsulfoxide (38 mg) in dichloromethane (1 mL) at −60° C. was added trifluoroacetic anhydride (105 mg). After the reaction mixture was stirred for 10 minutes at −60° C., a solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxamide (75 mg, in 1.5 mL of dichloromethane and 0.4 mL of dimethylsulfoxide) was added. The reaction mixture was allowed to warm to −20° C. over 1 h, then quenched with water and extracted with dichloromethane. The combined organic extract was washed with aqueous 1.0 N of NaOH and brine, dried with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (98:2 to 95:5) as eluent to afford the title product, a compound of the present invention, as semi-solid (70 mg, 82% yield).
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C@@H:11]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C3C=CC=CC=3)[C@@H:22]([O:23]C(=O)C3C=CC=CC=3)[C@H:12]2[O:13]C(=O)C2C=CC=CC=2)[N:10]=1)=O>CO>[C@@H:11]1([N:9]2[N:10]=[C:6]([C:4]([NH2:1])=[O:3])[CH:7]=[N:8]2)[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@H:12]1[OH:13]
Reactant: N
Reactant: COC(=O)c1cnn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Solvent: CO
Product: NC(=O)c1cnn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 96 h
Yield: 92 %

Procedure:
Methanol saturated with ammonia at 0° (ca 150 ml) was added to 5.71 g (0.010 mol) of 1 in a pressure bottle and kept at room temperature for 4 days. After removal of the solvent, water (30 ml) was added and the mixture was extracted with ether (six 20 ml portions). The solvent was removed and the compound crystallized from ethanol to give 2.25 g (92%) of 4: m.p. 150°-151°; [α]D25 -59.4° (c 1.00, water); nmr (DMSO-d6) δ 5.97 (d, 1, J1',2' 4.0 Hz, 1'--H).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:7]=3[C:6]=2[N:5]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:4]=1.[Cl:29]N1C(=O)CCC1=O.C(O)C>C(Cl)(Cl)Cl>[Cl:29][C:12]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:6]([N:5]([C:18]4[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=4)[N:4]=[C:3]3[CH:2]([F:1])[F:28])=[C:7]2[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)CCc1c(C(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(ccc3c(C(F)F)nn(-c4ccc(S(N)(=O)=O)cc4)c32)c1Cl
Temperature: 50 °C

Procedure:
4-[3-(Difluoromethyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide (1.0 g, 1.23 mmol) from Step 2 was suspended in chloroform (100 ml), and N-chlorosuccinimide (NCS) (329 mg, 1.23 mmol) was added. The reaction was heated to 50° C. for 16 hours. At this point, ethanol (20 ml) was added to dissolve the suspended reagents. The reaction was again heated to 50° C. for 24 hours. At this time, an additional equivalent of NCS (329 mg) was added, and the reaction was heated to 50° C. for an additional 4 days. Upon cooling, a precipitate which had formed was collected. This solid was pure 4-[6-chloro-3-(difluoromethyl)-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide (350 mg, 65%): 1H NMR (acetone d6) δ=4.0 (s, 3H), 7.2 (t, 1H, j=54.0 Hz), 7.3 (d, 1H j=9.3 Hz), 7.6 (d, 1H j=9.3 Hz), 7.9 (d, 2H j=8.7 Hz), 8.0 (d, 1H j=9.3 Hz), 8.1 (d, 1H j=9.3 Hz), 8.2 (d, 2H j=8.7 Hz); 19F NMR (acetone d6) δ-113.5 ppm (d, 2F).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1Cc2ccc(NC(=O)Nc3cccc([N+](=O)[O-])c3)cc2N1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1cccc(NC(=O)Nc2ccc3c(c2)NC(=O)C3)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-(3-nitro-phenyl)-3-(2-oxo-2,3-dihydro-1H-indol-6-yl)-urea (0.23 g, 0.74 mmol) is dissolved in a mixture of DMF-MeOH. To this solution is added Pd/C (10%, wet, 0.10 g). The reaction is placed under a hydrogen balloon and stirred for 20 hours at room temperature. The catalyst is removed and the solvent is evaporated to give 1-(3-amino-phenyl)-3-(2-oxo-2,3-dihydro-1H-indol-6-yl)-urea. LC-MS: 283.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=CC=C(F)[C:3]=1[C:9]1[C:13](C(OC)=O)=[C:12](C(C(=O)C(F)(F)F)=CN(C)C)[O:11][N:10]=1.ClC1C=C([NH:36][NH2:37])C=CC=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH:36]1[CH:7]=[CH:2][C:3]([C:9]2[CH:13]=[CH:12][O:11][N:10]=2)=[N:37]1
Reactant: COC(=O)c1c(-c2c(F)cccc2Cl)noc1C(=CN(C)C)C(=O)C(F)(F)F
Reactant: NNc1cccc(Cl)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(-c2ccon2)n[nH]1
Yield: 225.8 %

Procedure:
To a solution of 0.5047 g (1.1994 mmol) methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole-4-carboxylate in dry ethanol, 0.1790 g (0.9995 mmol) 3-Chlorophenylhydrazine and 0.17 mL (0.9995 mmol) N,N-Diisopropylethylamine (DIPEA) were added. The reaction mixture was heated under reflux for 2 h. The product was isolated by using column chromatography (Petroleum ether:Diethyl ether 80:20), and 0.305 g (yield of theory: 61%) of the pyrazolyl-isoxazole derivative were obtained. Result of LC/MS [M+H]+: 499.9; 1H NMR (DMSO-d6; CCl4): 3.66 (3H, s, CH3), 7.45-7.50 (1H, dd, CH-arom.), 7.55-7.58 (1H, d, CH-arom.), 7.65-7.77 (1H, d, CH-arom.), 7.65-7.77 (1H, dd, CH-arom phenylhydrazine), 7.65-7.77 (1H, d, CH-arom. phenylhydrazine), 7.85 (1H, s, CH-arom phenylhydrazine), 8.56 (1H, s, 1-pyrazole)
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][C:5]1(C(OC)=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16].Cl.[OH-:23].[Na+]>>[OH:23][C:5]1([CH2:4][CH2:3][CH:2]([CH3:21])[CH3:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16]
Reactant: COC(=O)C1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(C)CCC1(O)C(=O)CC(=O)c2ccccc21
Yield: 63.2 %

Procedure:
A solution of Example 2C (1 g, 3.47 mmol) in 1 N NaOH (20.8 mL) was stirred at 40° C. for 4 days. The solution was neutralized to pH 7 with 1 N HCl, extracted with ethyl acetate, and the organic layer was concentrated in vacuo. Column chromatography on silica (7% methanol/dichloromethane) afforded the title compound as a white solid (0.54 g, 63.2%).
Reaction SMILES: [C:1]1([CH:7]([NH2:11])[CH2:8][C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17].C(N(CC)CC)C>ClCCl>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]#[CH:10])=[O:17]
Reactant: C#CCC(N)c1ccccc1
Reactant: O=C=NCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCC(NC(=O)NCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 187 mg of 1-phenylbut-3-yn-1-amine (Formula 17) in 5 mL of dichloromethane was added 0.16 mL of 2-chloroethyl isocyanate and 0.26 mL of triethylamine. The mixture was stirred at room temperature for 2 hours. Then, dichloromethane was removed. Column chromatography (3% methanol/dichloromethane) followed by recrystallization from chloroform to give 25 mg of 1-(2-chloroethyl)-3-(1-phenylbut-3-ynyl)urea (Formula 18) as a white solid and 200 mg of impure material which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 2.02-2.04 (m, 1H), 2.64-2.82 (m, 2H), 3.49-3.61 (m, 4H), 4.80 (br, 1H), 4.92-5.05 (m, 2H), 7.26-7.37 (m, 5H)
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][C@@H:10]([CH2:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12].N1C=CN=C1>CN(C=O)C>[Si:5]([O:9][C@@H:10]([CH2:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: COC[C@H](O)C(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butylchlorodimethylsilane (661 mg, 4.38 mmol) in DMF (2.5 mL) was added dropwise to a stirred solution of (S)-methyl 2-hydroxy-3-methoxypropanoate C4a (490 mg, 3.65 mmol) and 1H-imidazole (497 mg, 7.31 mmol) in DMF (5 mL) at 20° C., over a period of 2 minutes. The resulting solution was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated, diluted with EtOAc (50 mL) and washed sequentially with water (4×15 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. Purification by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane afforded (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-methoxypropanoate (750 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:46]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C=O)C>[C:49]([O:48][C:46]([N:53]1[CH2:54][CH2:55][N:56]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([CH2:14][N:7]([CH2:6][C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)[CH2:8][C:9]3[NH:10][CH:11]=[CH:12][N:13]=3)=[CH:16][CH:17]=2)[CH2:57][CH2:58]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.3 %

Procedure:
The compound (500 mg) obtained in Example 2-2 was dissolved in DMF (10 ml) and added with WSCI hydrochloride (257 mg), HOBt (181 mg), and 1-Boc piperazine (manufactured by Aldrich Corporation) (249 mg), followed by stirring at room temperature for 3 days. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform for extraction, followed by washing with distilled water, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution. The resulting organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (111 mg) as a yellow oily substance.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1.[SH2:17]>N1C=CC=CC=1>[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:16])=[S:17])[CH2:10][CH2:9]1
Reactant: N#CCN1CCOCC1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)CN1CCOCC1
Reaction time: 8 h

Procedure:
A reaction mixture was prepared from 203 ml. each of triethylamine and pyridine plus 63 g. of morpholinoacetonitrile. Hydrogen sulfide was bubbled through the heated, stirred reaction mixture for about 2.5 hours. Stirring was continued overnight at ambient temperature. The next day, H2S was passed through the heated, stirred reaction mixture for an additional 1.5 hours. At this point, the solvents were evaporated in vacuo and the residue triturated with ether. The ether was discarded and the residue dissolved in ethanol. Crystalline morpholinothioacetamide formed in the above reaction precipitated and was separated by filtration. Treatment of the filtrate with alcoholic hydrogen chloride yielded morpholinothioacetamide hydrochloride melting in the range 64°-80° C. See also J.A.C.S., 72, 2804 (1950).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][O:18][P:19]1(=[O:26])[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CN(C=O)C>[CH3:10][C:9]([CH3:11])([CH3:12])[C:8]#[C:7][C:5]1[S:4][C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:2]([NH:1][CH:22]2[CH2:23][CH2:24][P:19]([O:18][CH3:17])(=[O:26])[CH2:20][CH2:21]2)[CH:6]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: COP1(=O)CCC(=O)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCP(=O)(OC)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.8 %

Procedure:
A solution of methyl 3-amino-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylate (474 mg, 2 mmol) and 1-Methoxy-1-oxo-1λ5 phosphinan-4-one (390 mg, 2.4 mmol) in THF (1 mL) and DMF (1 mL) was treated with dibutyltin dichloride (60 mg, 0.2 mmol). After 5 min, phenylsilane (272 μL, 2.2 mmol) was added, and the mixture was stirred for one hour at room temperature and then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with 5% LiCl and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using EtOAc:Hexanes as eluent to provide 650 mg (85%) of title compound: MS (m/z) 384.0 [M+H]−; HPLC retention time: 4.463 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][N:6]=[C:7]=[S:8].[CH:12]([NH:14][NH2:15])=[O:13]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][NH:6][C:7](=[S:8])[NH:15][NH:14][CH:12]=[O:13]
Reactant: Fc1cccc(CN=C=S)c1
Reactant: NNC=O
Solvent: CCO
Product: O=CNNC(=S)NCc1cccc(F)c1
Yield: 22.4 %

Procedure:
3-Fluorobenzyl isothiocyanate (4.3 g, 25.5 mmole) and formyl hydrazine (1.7 g, 28.7 mole) were refluxed in ethanol (30 ml) for one hour. The reaction mixture was evaporated to dryness, triturated with hexane:ethyl acetate (1:1), filtered, and recrystallized from ethanol-hexane to yield 1.3 g (22%) of crude 4-(3'-fluorobenzyl)-1-formyl-3-thiosemicarbazide.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13](=[O:25])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[C:21]([O:20][C:18](=[O:19])[CH2:17][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:25])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CN1CCNCC1=O
Yield: 99 %

Procedure:
4-tert-Butoxycarbonylmethyl-3-oxopiperazine-1-carboxylic acid benzyl ester (2.0 g, 5.75 mmol) is dissolved in 20 mL of methanol and 2 mL of acetic acid. Palladium (5%) on carbon (100 mg) is added, and the reaction mixture is stirred in an atmosphere of hydrogen overnight. The mixture is filtered and concentrated. Ethyl acetate is added, and the mixture is neutralized to pH 7 using 1N NaOH. The organic layer is concentrated to give (2-oxo-piperazin-1-yl)acetic acid tert-butyl ester (1.22 g).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:11]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=1>CN(C=O)C.O>[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[S:8][CH:9]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[N:11]=3)=[N:5]2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)n[nH]1
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a stirred mixture of 2-(5-methyl-1H-1,2,4-triazol-3-yl)-4-(4-(trifluoromethoxy)phenyl)thiazole (3 g, 9.2 mmol) and Cs2CO3 (4.8 g, 13 mmol) in DMF (20 mL) was added 2-chloro-4-(chloromethyl)pyridine (2.1 g, 13 mmol). The mixture was stirred at RT for 16 h, then diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with H2O (20 mL), concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1) to afford the title compound as an oil (2.1 g, 50.6%).
Reaction SMILES: Br.[CH3:2][O:3][C:4](=[O:12])[CH2:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.CCN(C(C)C)C(C)C.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:12])[CH2:5][C:6]1[S:10][C:9]([NH:11][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=2)=[O:32])=[N:8][CH:7]=1
Reactant: COC(=O)Cc1cnc(N)s1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)Cc1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Reaction time: 8 h

Procedure:
To a solution of the HBr salt of (2-amino-thiazol-5-yl)-acetic acid methyl ester (compound 44.1; 20 mmol) in DIEA (40 mmol) and DMF (100 mL) was added 3-trifluoromethylphenyl isocyanate (20 mmol) at room temperature. After overnight stirring, the reaction mixture was concentrated and purified by flash column chromatography on silica gel to provide {2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-acetic acid methyl ester (compound 44.2) in 60% yield. EIMS (m/z): calcd. for C14H12F3N3O3S (M+)+H 360.06. found 360.10.
Reaction SMILES: [C:1]([C:3]1([O:10][CH3:11])[CH2:8][CH2:7]N(C)[CH2:5][CH2:4]1)#[CH:2].[CH:12]1(N2CCC(C#C)(OC)CC2)CCCC1>>[C:1]([C:3]1([O:10][CH3:11])[CH2:8][CH2:7][CH2:12][CH2:5][CH2:4]1)#[CH:2]
Reactant: C#CC1(OC)CCN(C)CC1
Reactant: C#CC1(OC)CCN(C2CCCC2)CC1
Product: C#CC1(OC)CCCCC1

Procedure:
4-Ethynyl-4-methoxy-1-methyl-piperidine and 1-cyclopentyl-4-ethynyl-4-methoxy-piperidine may be prepared analogously.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH:13]=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19]Br.N1(C2CCCCCCC2)CCCCCCN1>C(Cl)(Cl)(Cl)Cl.CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH:13]=[C:12]([Br:19])[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: COC(=O)C1=CC(NC(=O)OC(C)(C)C)CC=C1
Agent: C1CCCC(N2CCCCCCN2)CCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: COC(=O)C1=CC(NC(=O)OC(C)(C)C)CC=C1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2.53 g (10 m mole) of methyl 3-(tert-butoxycarbonylamino)-1,5-cyclohexadienecarboxylate in 40 ml of carbontetrachloride at 0° C. is treated dropwise with 1.60 g (10 m mole) of bromine. The solution is stirred at 25° C. for 12 hours, then evaporated under reduced pressure to afford the crude dibromide which is dissolved in 40 ml of acetone and treated with 1.2 g (10 m mole) of diazabicyclooctane for 12 hours at 25° C. The solvent is evaporated under reduced pressure, and the residue is treated with ether and water. The organic phase is dried and evaporated to afford methyl 3-tert-butoxycarbonylamino-6-bromo-1,5-cyclohexadienecarboxylate.