Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH3:12].[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(N(CC)CC)C>ClCCl>[CH2:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[CH3:12])[CH2:17][CH2:16]1)[CH3:14]
Reactant: CCN1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc([N+](=O)[O-])cc2C)CC1

Procedure:
A solution of 1 g (3.78 mmol) 1-bromomethyl-2-methyl-4-nitro-benzene, 0.539 ml (4.16 mmol) 1-ethylpiperazine and 0.63 ml (4.54 mmol) triethylamine in 15 ml dichloromethane is stirred at room temperature for 0.5 h. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, 100% EtOAc=>EtOAc:MeOH=7:3) to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][C:23]4[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=4)=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C[Si](I)(C)C.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][C:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=4)=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(Cl)c4)cccc3c2)cn1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cccc2cc(Oc3ccc(=O)[nH]c3)ccc12
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution/suspension of N-(3-chloro-4-fluorophenyl)-6-((6-(methoxy)-3-pyridinyl)oxy)-1-naphthalenecarboxamide (167 mg, 0.39 mmol) in chloroform (4.7 mL) was added trimethylsilyl iodide (Aldrich, 221 mg, 1.10 mmol). The reaction mixture was heated at 70° C. (oil bath) for 2.5 h, cooled to RT and MeOH (1 mL) was added. After stirring for 15 min, the dark yellow solution was concentrated in vacuo and treated with concentrated aqueous NH4OH (3 mL). The title compound was isolated by filtration and dried under high vacuum. MS (ESI, pos. ion) m/z: 409.1 (M+1). Mass Calc'd for C22H14ClFN2O3: 408.81.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:11][P:12](=[O:17])([O:15]C)[O:13]C)(O)=[O:9].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH:1]1([NH:7][C:8]([CH2:11][P:12](=[O:13])([OH:17])[OH:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: COP(=O)(CC(=O)O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CP(=O)(O)O)NC1CCCCC1
Yield: 57 %

Procedure:
Cyclohexyl amine (0.045 mole) and dimethyl (carboxymethyl)phosphonate (0.04 mole) were dissolved in 100 ml. of methylene chloride. As the solution was stirred, dicyclohexylcarbodiimide (0.045 mole) was added portionwise. The solution was stirred overnight and the mixture filtered. The filtrate was concentrated to a solid and the solid recrystallized from an appropriate solvent such as methanol. m.p. 180°-3° C.; yield 57%.
Reaction SMILES: [C:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH2:36][CH3:37])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.[Cl:42][C:43]1[CH:48]=[N:47][CH:46]=[CH:45][N:44]=1>>[ClH:27].[ClH:42].[CH2:36]([O:35][C:34]1[CH:33]=[CH:32][C:31]([C:43]2[CH:48]=[N:47][CH:46]=[CH:45][N:44]=2)=[CH:30][C:29]=1[CH2:28][N:15]([CH:12]1[CH2:11][CH2:10][CH:9]([NH:8][CH3:1])[CH2:14][CH2:13]1)[C:16]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[Cl:27])=[O:17])[CH3:37]
Reactant: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Clc1cnccn1
Product: CCOc1ccc(-c2cnccn2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(NC)CC1
Product: Cl

Procedure:
The title compound is prepared from boronic acid 12 (25 mg, 42 μmol) and 2-chloropyrazine (4.0 mg, 35 μmol) in accordance with Method L2.
Reaction SMILES: O=[C:2]1[NH:7][CH:6]=[N:5][C:4]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:3]1=2.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.P(Cl)(Cl)([Cl:41])=O>O>[Cl:41][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(=O)[nH]cnc23)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(Cl)ncnc23)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 43.1 %

Procedure:
tert-Butyl 4-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (466 mg, 1.38 mmol) was dissolved in phosphorus oxychloride (2 mL) and stirred at 100° C. for 5 hours. The reaction liquid was concentrated under a reduced pressure, a 2 N aqueous sodium hydroxide solution (pH=14) was added, and then di-tert-butyl dicarbonate (602 mg, 2.76 mmol) was added to the aqueous solution, followed by stirring at room temperature for 2 hours. The reaction liquid was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=10:1) to give tert-butyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (201 mg, 43.1%) as a pale yellow amorphous.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:38])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][N:14]2C(OC(C)(C)C)=O)[CH:2]=1>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:38])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][NH:14]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)[C@H](O)CCc2ccccc2)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Reaction time: 1 h
Yield: 71 %

Procedure:
N-tert-butoxycarbonyl-trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (1.55 g) was dissolved in trifluoroacetic acid (10 mL)-chloroform (20 mL). After stirring for 1 hr, the reaction mixture was evaporated in vacuo. The residue was diluted with chloroform, and washed with saturated sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (888 mg) as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC.[Sn](Cl)(Cl)(Cl)Cl.[CH2:39]=[O:40].Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:39]=[O:40])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Oc1ccc(Cl)cc1
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cc(Cl)ccc1O
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 30.7 %

Procedure:
64.25 g (0.5 mole) of p-chlorophenol and 55 g (0.2 mole) of trioctylamine are dissolved in 100 ml of toluene. Under N2, 13 g of tin tetrachloride are added dropwise at 0° C. After 20 min at room temperature, 33 g of dried paraformaldehyde are added, and the mixture is heated at 100° C. for 5 hours. After cooling, the mixture is poured onto 2.5 l of H2O, and the mixture is acidified to pH 2 with 2N HCl and extracted with diethyl ether. The ether phase is washed with saturated NaCl solution and dried with Na2SO4 and concentrated. Chromatography on silica gel using ethyl acetate/cyclohexane (1:6) provides 24 g of the title compound, melting point 99° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:23]1([N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[O:15])[CH2:17][CH2:18]2)[CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCNCC2)CC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCN(C3CCC3)CC2)CC1
Reaction time: 0.08 h

Procedure:
1-(1-tert-Butoxycarbonyl-piperidine-4-carbonyl)-[1,4]-diazepane (2.0 g)(D8, Step 2) was dissolved in DCM (50 ml) and cyclobutanone (0.96 ml) added and the mixture stirred for 5 min. Sodium triacetoxyborohydride (2.7 g) was then added and the reaction stirred at rt for 1.5 h. The reaction mixture was then washed with saturated potassium carbonate solution (50 ml), sodium hydrogen carbonate solution (3×50 ml) and brine (50 ml). The organic layer was dried (MgSO4) and evaporated to give the subtitled compound as a white solid (1.67 g).
Reaction SMILES: [Br:1][CH2:2][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[Br-:1].[C:8]([C:6]1[S:7][C:3]([CH2:2][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:5]=1)([OH:10])=[O:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccc(CBr)s1
Solvent: CC#N
Product: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Product: [Br-]

Procedure:
A mixture of 2.54 g. (11.5 mmoles) of 5-bromomethylthiophene-2-carboxylic acid and 3.02 g. of triphenylphosphine in 50 ml. of acetonitrile was heated at reflux for 1.5 hours then was cooled. The resultant precipitate was collected by filtration and was recrystallized from ethanol:hexane to provide the (2-carboxythiophen-5-yl-methyl)triphenylphosphonium bromide weighing 3.16 g. and melting at 273°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.Cl.[NH2:19]O.C([O-])=O.[Na+]>C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:19]
Reactant: NO
Reactant: O=Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Yield: 76 %

Procedure:
A mixture of 22 g of 5-formyl-3-phenylindazole, 8 g of hydroxylamine hydrochloride and 12.5 g of sodium formate was added to 150 ml of formic acid, and after refluxing for 2 hours, the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to give 16.5 g of 5-cyano-3-phenylindazole (m.p. 150°-151° C.).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH2:19]1[NH:24][CH2:23][CH2:22][N:21]2[CH2:25][CH2:26][CH2:27][C@@H:20]12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:24]3[CH2:23][CH2:22][N:21]4[CH2:25][CH2:26][CH2:27][C@H:20]4[CH2:19]3)=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: C1C[C@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCC[C@H]4C3)cc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.7 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (150 mg, 0.43 mmol) in DMF (4 mL) were added (S)-octahydro-pyrrolo[1,2-a]pyrazine (81 mg, 0.642 mmol) and potassium carbonate (117 mg, 0.847 mmol). The resulting mixture was stirred at RT for 17 h, then concentrated in vacuo. The resulting residue was triturated with water to give the title compound as an off-white solid (130 mg, 77%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]>C([O-])(=O)C>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CC(=O)[O-]
Product: CCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
The enzyme (100 μl)a was added to ethyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (2.5 mg in solution in acetate buffer 0.1M pH 5 (350 μl) and an organic co-solvent according to the table below) (50 μl)). The reaction mixture was shaken at room temperature and analysed at different times. The reaction mixture was analysed by the gradient HPLC method 1 and by chiral CE method 1.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:37])[CH2:33][CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.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>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][OH:37])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCCCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 4-pentyn-1-ol (0.056 mL). Anhydrous DMF (20 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H20. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (5L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 117.5 mg (43%) of the desired product as a creme solid.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]([Mg]Cl)([CH3:11])([CH3:10])[CH3:9].O>CCOCC>[CH3:9][C:8]([CH3:11])([C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6])[CH3:10]
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=C(Cl)C1CCC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)C(=O)C1CCC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Cuprous iodide (1.0 gm) was added to a solution of cyclobutane carboxylic acid chloride (15.0 gms) in dry ether (40 mls) under an argon atmosphere. The suspension was stirred and cooled to -70° C. A solution of t-butyl magnesium chloride in ether (61.4 mls of 2M solution) was then added dropwise, whilst the temperature was maintained below -70° C. After the addition was complete, stirring was continued at -70° C. for 1 hour and then for several hours whilst the temperature was allowed to reach 20° C. Water was carefully added to the mixture. The ether layer was separated, combined with an extract of the aqueous phase and washed with dilute caustic soda. Drying and evaporation gave 4.9 gms of yellow oily product. Gas chromatography showed 80% of a major component. The product was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([I:34])[CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([I:34])[CH:27]=1
Reactant: NCc1ccc(F)cc1I
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (4-fluoro-2-iodophenyl)methanamine. White solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.66 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2,), 4.57 (2H, d, J=6.6 Hz, NCH2), 7.05 (1H, m, aromatic), 7.3–7.38 (3H, m, aromatics), 7.42 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.53 (2H, m, aromatics), 7.56 (1H, dd, J=2.6 Hz and J=8.0 Hz, aromatic), 8.05 (1H, broad t, NH). HRMS (ESI+) calculated for C24H24FIN3O4 [M+H+]: 564.0796. Found: 564.0809.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[I:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(=O)=O.CC(C)=O>O.O1CCCC1>[I:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a mixture of 41.8 g of diethyl malonate and 100 ml of tetrahydrofuran, 11.0 g of 60% sodium hydride was added, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was added gradually dropwise to a mixture of 69.5 g of 4-iodobenzoyl chloride and 300 ml of tetrahydrofuran under cooling with dry ice-acetone. The reaction mixture was stirred for 3 hours, and then 300 ml of water was added. The tetrahydrofuran was removed from the reaction mixture by evaporation under reduced pressure, and the reaction mixture was extracted with diethyl ether. The extract was dried over magnesium sulfate, filtered and concentrated at atmospheric pressure. The resulting residue was recrystallized in diethyl ether-hexane to give 28.5 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:31]([OH:33])=[O:32])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[CH3:34]CN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CO>[CH3:34][O:32][C:31](=[O:33])[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[NH:18][C:1]([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Product: COC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 102.8 %

Procedure:
Commercially available Nα-Fmoc-Nδ-Boc-L-ornithine (1.00 g), WSCI hydrochloride (0.633 g), and HOBt (0.446 g) were reacted in methanol (20 ml) for 23 hours at room temperature. After the reaction, methanol was removed and the residue was extracted with chloroform. The extract was washed with water, saturated aqueous solution of sodium hydrogencarbonate, and saturated brine, and dried over anhydrous sodium sulfate to remove water. Syrup obtained by removing the solvent was purified by silica gel column chromatography (50 g, chloroform/ethyl acetate=5/1) to obtain the title compound (1.06 g) as a white solid.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([C:11]1[S:45][C:14]2[N:15]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)[C:16](=[O:29])[C:17]([CH3:28])([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18](=[O:19])[C:13]=2[CH:12]=1)[CH3:10].[N:46]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH2:9]([C:11]1[S:45][C:14]2[N:15]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:46][C:4](=[O:7])[O:5][N:44]=4)=[CH:35][CH:36]=3)[C:16](=[O:29])[C:17]([CH3:28])([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18](=[O:19])[C:13]=2[CH:12]=1)[CH3:10]
Reactant: O=C([O-])O
Reactant: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)C(C)(CCc1ccccc1)C2=O
Reactant: C1CCC2=NCCCN2CC1
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3-c3noc(=O)[nH]3)cc1)C(=O)C(C)(CCc1ccccc1)C2=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of hydroxylammonium chloride (0.36 g), sodium hydrogencarbonate (0.53 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[2-ethyl-5-methyl-4,6-dioxo-5-(2-phenylethyl)-5,6-dihydrothieno[2,3-b]pyridin-7(4H)-yl]methyl}biphenyl-2-carbonitrile (0.32 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.095 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.17 g, 48%).
Reaction SMILES: N1([CH2:6][CH:7](Cl)[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)CCCC1.[C:17]1([C:23]([OH:27])([C:25]#[CH:26])[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].C1C=CC=CC=1.[CH2:36]([N+:43]([CH2:48][CH3:49])(CC)CC)[C:37]1C=CC=CC=1>O>[CH3:24][C:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:27][CH2:6][CH:7]([N:43]1[CH2:36][CH2:37][CH2:49][CH2:48]1)[CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:25]#[CH:26]
Reactant: C#CC(C)(O)c1ccccc1
Reactant: CC[N+](CC)(CC)Cc1ccccc1
Reactant: ClC(COc1ccccc1)CN1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: C#CC(C)(OCC(COc1ccccc1)N1CCCC1)c1ccccc1

Procedure:
27.5 g of 1-pyrrolidinyl-2-chloro-3-phenoxy propane were gradually introduced into a reactor containing 29.2 g of 2-phenyl-3-butyne-2-ol, 20 g of sodium hydroxide in 20 ml of water and 2.27 g of benzyl triethylammonium, while stirring well. When the addition ended, the reaction medium was very thick and 20 ml of benzene were added before refluxing for 5 hours. The product was then extracted with ether, filtered, washed and dried as indicated in Example 1.