Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[N:20]=[C:19]3[C:15]([N:16]=[CH:17][NH:18]3)=[C:14](N)[N:13]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Cl[CH2:23][CH2:24][CH2:25][S:26]([NH:29][CH:30]([CH3:32])[CH3:31])(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+].C[N:40](C=O)C>>[NH2:40][C:15]1[N:16]=[CH:17][N:18]=[C:19]2[C:14]=1[N:13]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:20]2[CH2:23][CH2:24][CH2:25][S:26]([NH:29][CH:30]([CH3:32])[CH3:31])(=[O:28])=[O:27]
Reactant: CN(C)C=O
Reactant: Nc1nc(Sc2cc3c(cc2I)OCO3)nc2[nH]cnc12
Reactant: CC(C)NS(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)NS(=O)(=O)CCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio-9H-purin-6-amine (39 mg, 0.09 mmol) in DMF (2 mL) was added 3-chloro-N-isopropylpropane-1-sulfonamide (100 mg, 0.45 mmol) and Cs2CO3 (62 mg, 0.19 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS54 as a white solid (14 mg, 26%). 1H NMR (500 MHz, CDCl3/MeOH-d4): δ 8.00 (s, 1H), 7.19 (s, 1H), 6.86 (s, 1H), 5.86 (s, 2H), 4.17 (t, J=7.3 Hz, 2H), 3.34 (septet, J=6.6 Hz, 1H), 2.89 (t, J=7.6 Hz, 2H), 2.05-2.13 (m, 2H), 0.99 (d, J=6.6 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for C15H22IN6O4S2, 577.0189. found 577.0194.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[C:19]1([CH:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>CO>[C:19]1([CH:25]([N:27]2[CH2:28][CH2:29][N:30]([CH2:1][C:3]3[CH:18]=[CH:17][C:6]([O:7][C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=4)=[CH:5][CH:4]=3)[CH2:31][CH2:32]2)[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: CC(c1ccccc1)N1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(c1ccccc1)N1CCN(Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2)CC1
Reaction time: 24 h
Yield: 23.1 %

Procedure:
Using a method similar to Example 332, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.307 g, 1.27 mmol), 1-(1-phenylethyl) piperizine (0.365 g, 1.92 mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (10 mL), after 1 d, provides 0.122 g (23%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C25H29N4O2 417.2291, found 417.2298; 1H NMR (DMSO-d6): 8.62 (d, 1H, J=2.0 Hz), 8.26 (dd, 1H, J=2.4, 8.8 Hz), 8.01 (s br, 1H), 7.46 (s br, 1H), 7.36-7.28 (m, 6H), 7.27-7.21 (m, 1H), 7.12-7.05 (m, 3H), 3.42 (s, 2H), 3.39 (q, 1H, J=6.8 Hz), 2.51-2.25 (s br, 8H), 1.29 (d, 3H, J=6.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7]([O:9]CC)=O.Cl.[CH3:17][C:18]#[N:19]>>[CH3:17][C:18]1[NH:19][C:7](=[O:9])[C:6]2[C:5]3[CH2:12][CH2:13][CH2:14][CH2:15][C:4]=3[S:3][C:2]=2[N:1]=1
Reactant: CC#N
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Agent: Cl
Product: Cc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Yield: 62 %

Procedure:
To a 25 ml flask was added 4 (225 mg, 1 mmol) and 10 ml CH3CN. HCl gas was passed through the solution for 3 h, before the solvent was evaporated under reduced pressure. The residue was dissolved in 10 mL distilled water and treated with ammonia water solution to generate a white precipitate. The precipitate was collected by filtration to afford 143 mg (62%) of 5 as a white solid: 1H NMR (DMSO-d6) δ 1.75 (m, 4H), 2.48 (s, 3H), 2.69 (m, 2H), 2.83 (m, 2H), 12.16 (s, 1H). Anal. (C11H12N2OS) m/z (ESI) 220.067811 [M]+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[Cu][C:22]#[N:23].CN1CCCC1=O.O>C(OCC)(=O)C>[C:22]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)#[N:23]
Reactant: N#C[Cu]
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3I)nc2c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 80 °C
Yield: 38 %

Procedure:
A mixture of 0.39 g of 2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of copper (I) cyanide and 2 ml of 1-methyl-2-pyrrolidinone was stirred while heating at 80° C. for 2 hours. Water and ethyl acetate were poured into the reaction mixture, which was filtered through Celite™. The resultant filtrate was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.11 g of 2-(3-cyanopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 31”).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH3:27]C(C)([O-])C.[K+].[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:43]2[CH2:48][CH2:47][CH:46]([C:49]3[CH:56]=[CH:55][C:52](C=O)=[CH:51][CH:50]=3)[CH2:45][CH2:44]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1.O>C1COCC1>[CH3:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([N:43]2[CH2:48][CH2:47][CH:46]([C:49]3[CH:56]=[CH:55][C:52]([CH2:27][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:51][CH:50]=3)[CH2:45][CH2:44]2)(=[O:41])=[O:42])=[CH:38][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(c3ccc(C=O)cc3)CC2)cc1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ccc(CCCCC(=O)O)cc3)CC2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a suspension of (3-carboxypropyl)triphenylphosphonium bromide (16.5 g) in THF (170 ml) was added at room temperature potassium t-butoxide (8.63 g), and the mixture was stirred at 60° C. for 10 minutes and then cooled to room temperature. To the mixture was added a solution of 4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]benzaldehyde (4.40 g) in THF (20 ml), and the mixture was stirred at 60° C. for 1 hour. To the mixture was added water (80 ml) and the mixture was extracted with toluene (80 ml). To the aqueous layer was added 1N hydrochloric acid to make the solution pH 3, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with 2% sodium bicarbonate solution, and then with 1N hydrochloric acid and saturated brine (×3). Under reduced pressure, the mixture was concentrated, and the residue was dissolved in THF (150 ml). To the mixture was added Pd—C (0.5 g), and the mixture was stirred under hydrogen atmosphere for 5 hours. By filtration Pd—C was removed, and the filtrate was concentrated under reduced pressure. The resulting crystals were collected by filtration, which were washed with hexane to give colorless crystals of 5-[4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]phenyl]pentanoic acid (4.63 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:17])([CH2:14][CH2:15][OH:16])[CH2:12][OH:13].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:16][CH2:15][CH2:14][C:11]([CH3:17])([CH3:10])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(CO)CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CO)CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Benzoyl chloride (3.13 mL) was added to a cooled (−78° C.) solution of 2,2-dimethylbutane-1,4-diol from Step 1 (3.18 g), triethylamine (7.5 mL) and 4-(dimethylamino)pyridine (0.05 g) in dichloromethane (100 mL). The mixture was then slowly warmed up to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and the compound was purified by silica gel chromatography (hexanes/ethyl acetate 95:5 to 60:40) to afford 3,3-dimethyl-4-hydroxy-1-butyl benzoate (2.6 g, 44% yield) as a colorless oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:49])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH2:48])[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][C@H:29]4[C:33]4[CH:34]=[N:35][CH:36]=[C:37]([C:39](=[O:47])[C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH:38]=4)=[O:27])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:50]([O:54][C:55]([N:57]([CH3:63])[C@@H:58]([CH3:62])[C:59](O)=[O:60])=[O:56])([CH3:53])([CH3:52])[CH3:51].C(N(C(C)C)C(C)C)C.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:49])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C@H:25]([NH:48][C:59](=[O:60])[C@@H:58]([N:57]([C:55]([O:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:56])[CH3:63])[CH3:62])[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][C@H:29]4[C:33]4[CH:34]=[N:35][CH:36]=[C:37]([C:39](=[O:47])[C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH:38]=4)=[O:27])=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a solution of [4-((S)-2-amino-3-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-3-oxo-propyl)-phenyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (I-2b: 2.4 g, 3.7 mmol), (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (0.89 g, 4.4 mmol) and ethyldiisopropylamine (7 mL) in DMF (20 mL) was added a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.67 g, 4.4 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (0.6 g, 4.4 mmol) in DMF (10 mL) and the reaction mixture was shaken for 16 hours. The reaction mixture was diluted with ethyl acetate (300 mL), washed sequentially with brine (2×) (300 mL), saturated aqueous bicarbonate solution (300 mL), brine (300 mL), water (300 mL), and brine (300 mL), then dried over Na2SO4/MgSO4, and concentrated in vacuo to provide crude [4-((S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-3-oxo-propyl)-phenyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a yellow foam.
Reaction SMILES: Cl[CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:12]([NH:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]1=[O:45])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:46]1([P:52]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.N1C=CC=CC=1>O1CCCC1.O1CCOCC1>[C:6]([O:5][C:3]([C:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:12]([NH:25][C:26]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]1=[O:45])=[P:52]([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:4])([CH3:7])([CH3:9])[CH3:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1-(1-Chloro-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one (570mg) was dissolved in a 1:1 mixture of dry tetrahydrofuran and dioxan (20ml) under nitrogen. Triphenylphosphine (495mg) and dry pyridine (150mg) were added and the mixture heated at 49° for 16 hours. The reaction mixture was filtered the filtrate evaporated. The residue was triturated with toluene and the soluble portion re-evaporated. Chromatography on silica afforded 1-(1-t-butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio) azetidin-2-one, as a white solid (418mg). νmax (CHCl3) 1745, 1630 (broad) cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Br:9])=[C:6]([F:8])[C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)c(Br)cc(F)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1,4-Dibromo-2,5-difluorobenzene (100 g, 0.37 mol) is dissolved in concentrated sulfuric acid (200 g) and treated with fuming nitric acid (56 g, 0.44 mol, HNO3 content >90%) by drop-wise addition at an internal temperature that is maintained between 50–60° C. After the addition is complete, the mixture is cooled to room temperature and stirred for 12 hours, then poured into ice-water (1000 mL). The suspension is extracted with EtOAc (3×500 mL). The combined organic extracts are dried (MgSO4) and concentrated by rotary evaporator to give 2,5-dibromo-3,6-difluoronitrobenzene as an oily yellow solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:20][C:12]2=[N:13][C:14](O)=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].P(Cl)(Cl)([Cl:23])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:23][C:14]1[N:13]=[C:12]2[S:20][C:9]([S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[N:10][N:11]2[C:16](=[O:17])[C:15]=1[CH3:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCSc1nn2c(=O)c(C)c(O)nc2s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCCCCCCSc1nn2c(=O)c(C)c(Cl)nc2s1
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 19.5 g of the thus obtained 2-heptylthio-7-hydroxy-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 38 g of phosphorus oxychloride and 13.6 g of phosphorus pentachloride was warmed to 77°~88° C. and was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, thereafter the residue was dissolved in toluene, and the solution was washed with a potassium carbonate aqueous solution and water respectively. After the solution was dried over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography on a silica gel column with an ethyl acetate/n-hexane (2:3) mixture as an eluent. After the solvent was distilled off, 19.0 g of 7-chloro-2-heptylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 79°~81° C. Yield 92%.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:51]([N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>CN(C=O)C.O>[C:54]([O:53][C:51]([N:58]1[CH2:63][CH2:62][N:61]([C:20](=[O:22])[CH2:19][NH:18][C:16]([C:13]2[CH:12]=[CH:11][C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[O:17])[CH2:60][CH2:59]1)=[O:52])([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 0.03 h
Yield: 35.4 %

Procedure:
DIPEA (2.928 g, 22.66 mmol) was added to a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (2.892 g, 11.33 mmol) in DMF (30 mL). HOBT (1.835 g, 13.59 mmol) and EDCI.HCl (2.532 g, 13.59 mmol) were then added at room temperature. After 2 minutes, N-Boc-piperazine (3.381 g, 24.22 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine solution, dried over sodium sulphate and concentrated in vacuo to afford 1.7 g (37.5% yield) of 4-{2-[(biphenyl-4-carbonyl)-amino]-acetyl}-piperazine-1-carboxylicacid tert-butyl ester. LC-MS purity: 82.06%
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]3[CH2:18][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:21]=[C:12]23)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:28]([O:32][C:33](=[O:46])[NH:34][CH:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH2:45])=[CH:39][CH:38]=1)[CH3:36])([CH3:31])([CH3:30])[CH3:29].O1CCOCC1>CN1CCCC1=O>[C:28]([O:32][C:33](=[O:46])[NH:34][CH:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH:45][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][C:14](=[O:17])[N:13]4[CH2:18][CH:19]=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=[C:12]34)[CH:8]=[CH:7][N:6]=2)=[CH:39][CH:38]=1)[CH3:36])([CH3:30])([CH3:29])[CH3:31]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(CCN)cc1
Reactant: CS(=O)(=O)c1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(CCNc2nccc(N3CCC(=O)N4CC=C(c5ccccc5)N=C43)n2)cc1

Procedure:
The mixture of 1-(2-methanesulfonyl-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro -pyrimido[1,2-a]pyrimidin-4-one (0.20 g, 053 mmol) and {1-[4-(2-amino -ethyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.304 g, 0.79 mmol) in 1:1 dioxane: 1-methyl -2-pyrrolidinone (6 mL) was heated to 100° C. for 17 h. The mixture was partitioned between water (10 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and chromatographed on silica gel using 0-4% MeOH/CH2Cl2to afford a white solid. M+1=568.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14](=O)([O-])[O-].[Na+].[Na+].[C:20](#N)[CH3:21]>>[CH2:14]([N:6]1[C@H:5]([CH3:8])[CH2:4][N:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:2]([CH3:1])[CH2:7]1)[CH:20]=[CH2:21]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)N1C[C@@H](C)NC[C@@H]1C
Reactant: CC#N
Agent: [Na+]
Product: C=CCN1C[C@H](C)N(C(=O)OCC)C[C@H]1C
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate (643 g, 3.45 mol), alkyl bromide (328 mL, 3.80 mol), and sodium carbonate (440 g, 4.15 mol) in 2500 mL of acetonitrile was heated at reflux for 1.5 hours. The reaction was cooled to room temperature, filtered, and the solvent removed under vacuum. The residue was dissolved in 4000 mL of dichloromethane and washed with two 500 mL portions of 1 M sodium hydroxide. The dichloromethane solution was dried over magnesium sulfate and the solvent was removed to give 630 g (81%) of ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil.
Reaction SMILES: [NH:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[N+:10]([O-:12])=[O:11])[NH2:2].[CH2:13]([O:15][C:16](=[O:27])[C:17](=[CH:23]OCC)[C:18]([C:20]([OH:22])=[O:21])=O)[CH3:14].[CH2:28](O)[CH3:29]>>[CH3:8][N:7]1[C:3]([N:1]2[C:18]([C:20]([O:22][CH2:28][CH3:29])=[O:21])=[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:27])[CH:23]=[N:2]2)=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([CH3:9])=[N:6]1
Reactant: CCO
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)O
Reactant: Cc1nn(C)c(NN)c1[N+](=O)[O-]
Product: CCOC(=O)c1cnn(-c2c([N+](=O)[O-])c(C)nn2C)c1C(=O)OCC

Procedure:
120 gms. of 5-hydrazino-1,3-dimethyl-4-nitro-1H-pyrazole are dissolved in 500 ml. of absolute ethanol and 173 gms. of ethoxymethylene oxalacetic acid ethyl ester dissolved in 300 ml. of ethanol are slowly added dropwise. After refluxing for 10 hours and distilling off the solvent, the product, 1-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-1H-pyrazole-4,5-dicarboxylic acid, diethyl ester, is obtained as a brown oil, which crystallizes on trituration with cold ether, yield 143 gms. after recrystallization from cyclohexane/benzene, yellow crystals, m.p. 70°-80°.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[CH2:16]=[C:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:18]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]1[C:17]2([CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:18]2)[CH2:16]1
Reactant: C=C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ICI
Product: O=C(OCc1ccccc1)N1CCCC2(CC2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a stirred solution of Diethyl zinc (1.38 g, 11.2 ml, 1 M solution in hexane 11.24 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (1.28 g, 0.84 ml, 11.24 mmol) drop wise manner at 0° C. Diiodomethane (3.01 g, 0.90 ml, 11.24 mmol) in dichloromethane (5 ml) was added and reaction mixture was stirred at 0° C. for 30 min. A solution of benzyl 3-methylenepiperidine-1-carboxylate (prepared according to the procedure given in European Journal of Medicinal Chemistry 1991, 26, 625-631), (1.3 g, 5.62 mmol) in dichloromethane (10 ml) was added and reaction mixture stirred at 0° C. for 30 min and then at 25° C. for 18 hr. The progress of reaction was monitored by TLC. Reaction mixture was diluted with dichloromethane (25 ml) and poured in to a saturated solution of sodium bicarbonate (50 ml). Solid precipitated out was filtered, organic layer was separated and dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography using 6% ethyl acetate in hexanes to obtain the title compound (0.95 g, 68.9%). MS: m/z 246 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[C:18]3[O:17][C:16](=O)[NH:15][C:14](=[O:20])[C:13]=3[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[OH-].[NH4+:22]>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[C:18]3[NH:22][C:16](=[O:17])[NH:15][C:14](=[O:20])[C:13]=3[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1cc(F)c(F)c(F)c1)CC2
Reactant: [NH4+]
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1cc(F)c(F)c(F)c1
Yield: 106.2 %

Procedure:
A solution of 7-(3,4,5-trifluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (1.23 g, 4.34 mmol) in concentrated ammonium hydroxide (75 mL, 1926 mmol) was heated at 100° C. in a high-pressure (350 mL) vessel overnight. The reaction mixture was cooled and concentrated in vacuum to give crude 7-(3,4,5-trifluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (1.3 g, 4.61 mmol, 106% yield). LC-MS (M+H)+=283.0.