Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9]3=[C:10]([CH2:17][CH2:18][CH2:19][N:8]3[CH:7]=1)[CH:11]=[CH:12][CH:13]=2)=[O:5])[CH3:2].[Br:20]Br>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9]3=[C:10]([CH2:17][CH2:18][CH2:19][N:8]3[CH:7]=1)[CH:11]=[C:12]([Br:20])[CH:13]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2c3c(cccc3c1=O)CCC2
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cn2c3c(cc(Br)cc3c1=O)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 134.1 %

Procedure:
To the solution of 1-Oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid ethyl ester (7.5 g, 29 mmol) in glacial acetic acid (120 mL) was added bromine (1.6 ml, 32 mmol). The mixture was stirred over night at room temperature, and new portion of bromine (1.6 mL, 32 mmol) was added. After 24 h, reaction mixture was diluted with 100 mL of H2O and pH was adjusted to 2.9. Precipitate was filtered and dried. The crude product was precipitated from CH2Cl2/Diisoprophylether and dried in vacuum drier yielding 13.07 g of the crude title product.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[CH2:14]1[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])[S:17][S:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[S:16]1[CH2:15][CH2:14][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[O:24])[S:17]1
Reactant: COC(=O)/C=C/C(=O)NCCN
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)/C=C/C(=O)NCCNC(=O)CCCC[C@@H]1CCSS1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.6 %

Procedure:
The HCl salt of (E)-methyl 4-(2-aminoethylamino)-4-oxobut-2-enoate (0.515 mmol) was taken up in 10 mL of CH3CN along with R-lipoic acid (TCI, 106 mg, 0.515 mmol), HATU (215 mg, 0.567 mmol) and DIEA (270 μL, 1.55 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and diluted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by silica gel chromatography (95% CH2Cl2, 5% MeOH) afforded 120 mg of (R,E)-methyl 4-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethylamino)-4-oxobut-2-enoate. MS (EI) calcd for C15H24N2O4S: 360.12. found 361 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C@@H:5](/[CH:15]=[CH:16]/[C:17](=[O:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][S:3]1.C1(C)C=CC=CC=1.[B]1OC2C(=CC=CC=2)O1>C(Cl)Cl>[OH:25][CH:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)/[CH:16]=[CH:15]/[C@H:5]1[CH2:4][S:3][C:2](=[O:1])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: N#CCCCCCCN1C(=O)SC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#CCCCCCCN1C(=O)SC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 4-3 (0.15 g, 0.4 mmol) in 8 mL CH2Cl2 was added 1M (R)-CBS in toluene (0.45 mL, 0.45 mmol) and cooled to −40° C. to which a solution of catechol borane (0.13 mL, 1.2 mmol) in CH2Cl2 (1 mL) was added dropwise. The solution was stirred at −40° C. for one hour and allowed to warm up to −20° C. during the following two hours. The reaction mixture was quenched at −20° C. with 1 N HCl and was stirred for 4 hours at room temperature. The phases were separated and the organic phase was sequentially washed with 1N HCl, H2O, 1 N NaOH, brine and dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 40–50% ethyl acetate/hexanes to yield 125 mg of 4-4 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.37–7.21 (m, 5H), 5.84 (dd, 1H), 5.65 (dd, 1H), 4.46 (q, 1H), 4.22 (q, 1H), 3.86–3.35 (m, 2H), 2.97 (dd, 1H), 2.88 (m, 2H), 2.80 (m, 1H), 2.36 (t, 2H), 1.70–1.27 (m, 8H); MS (+ESI): m/z 359.0 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]2=[O:21])[S:4][C:3]=1[C:22](O)=[O:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:56][CH2:57][C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:21])[S:4][C:3]=1[C:22]([NH:56][CH2:57][C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1)=[O:23]
Reactant: NCc1cccnc1
Reactant: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid (0.08 g, 0.23 mmol), 1-hydroxybenzotriazole (0.05 g, 0.35 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.07 g, 0.35 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.12 mL, 0.70 mmol), followed by the addition of 3-(aminomethyl)pyridine (0.02 mL, 0.24 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h, and then diluted with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (3×35 mL) and water (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate in hexanes to afford the title compound as a colorless solid in 79% yield (0.08 g): mp 78-80° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.32-7.23 (m, 3H), 6.96 (t, J=7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 2H), 6.15 (t, J=5.7 Hz, 1H), 6.08 (s, 1H), 4.57 (d, J=5.7 Hz, 2H), 4.15 (t, J=4.9 Hz, 2H), 3.80 (br s, 4H), 3.69 (t, J=4.9 Hz, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5, 158.2, 156.0, 149.2, 148.8, 142.5, 141.7, 135.5, 129.6, 123.6, 121.2, 118.9, 114.3, 112.4, 66.9, 43.8, 43.0, 41.2, 16.1; MS (ES+) m/z 437.4 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[Br-].[CH3:19][O:20][N:21]1[CH2:25][CH2:24][CH:23]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:22]1=[O:45].C(N(CC)CC)C>C(O)C>[CH3:19][O:20][N:21]1[CH2:25][CH2:24][C:23](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:12]([OH:13])=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[CH:10]=2)[C:22]1=[O:45]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CON1CCC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 67.9 %

Procedure:
27.6 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 54.0 g of (N-methoxy-2-pyrrolidone-3-yl)triphenylphosphonium bromide and 33.0 ml of triethylamine were heated at 50° C. in ethanol for four hours. After distilling the ethanol off, the residue was dissolved in chloroform, washed with water and then a saturated saline solution and dried over anhydrous magnesium sulfate. After distilling the chloroform off, the residue was treated with the column chromatography, using silica gel and a carrier liquid of benzene and acetone and recrystallized with a mixture of ethyl acetate and hexane to give 26.5 g of the title compound.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[C:30]([O:34][C:35]([NH:37][CH:38]([CH3:42])[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C=O.C(OCC)(=O)C>[C:30]([O:34][C:35]([NH:37][CH:38]([CH3:42])[C:39]([NH:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)C(N)Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1)NC(=O)C(C)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
A solution of 5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzylidene]thiazolidin-2,4-dione hydrochloride (2 g, 4.6 mmol) and 2-t-butoxycarbonylamino propionic acid (0.87 g, 4.6 mmol) in dimethyl formamide (10 ml) was stirred for 1 h at 0° C. N,N′-Dicyclohexylcarbodiimide (1.139 g, 5.5 mmol) was added to this solution and stirring was continued for 2 h at ambient temperature. Water (200 ml) was added to the reaction mixture, stirred for 15 minutes, ethyl acetate (250 ml) added and stirring was continued for another 15 minutes. The organic layer was separated and washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated to furnish the crude compound which was purified by column chromatography (0.95 g, yield 36.3%).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[OH:13][C:14]([CH3:18])([CH3:17])[C:15]#[N:16].O>C(Cl)Cl>[N:3]1([C:1]([O:13][C:14]([C:15]#[N:16])([CH3:18])[CH3:17])=[O:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(O)C#N
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)OC(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
A mixture of 1,1′-carbonyldiimidazole (5 g, 31 mmol) and 2-hydroxy-2-methylpropanenitrile (2.6 g, 31 mmol) in DCM was stirred at rt overnight. Water was added and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel, eluting with ethyl acetate, to give 2.7 g (50%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH3:27])=[C:20]2[C:15]=1[C:16](=[O:38])[C:17]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[C:18]([CH:28]=O)[NH:19]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:13][C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH3:27])=[C:20]2[C:15]=1[C:16](=[O:38])[C:17]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)=[C:18]([CH2:28][N:10]1[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]1)[NH:19]2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c(C=O)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c(CN3CCN(c4ccccn4)CC3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
1-(2-Pyridyl)piperazine (551 mg, 3.38 mmol) was added to a 1,2-dichloromethane solution (20 ml) of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carbaldehyde (800 mg, 2.25 mmol) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (670 mg, 3.16 mmol) was added to the resulting mixture and stirred at room temperature for 4 hours. Dichloromethane was added to the resulting reaction mixture, washed with water, and then the mixture was dried over sodium sulfate. Thereafter, the solvent was removed under reduced pressure. The residue was then purified using NH silica gel column chromatography (dichloromethane:ethyl acetate=1:1). The solvent was removed under reduced pressure and the residue was recrystallized from ethyl acetate-n-hexane, giving a white powder of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-quinolin-4-one (400 mg, yield: 35%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH:18]2[NH:22][C:21](=[O:23])[NH:20][C:19]2=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].N1CCOCC1.C=O.O1CCN(CN2[C:44](=O)[CH:43]([CH2:46][CH2:47][C:48]3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)[CH:49]=3)NC2=O)CC1.BrCCCCCC>>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][CH:18]2[N:22]([CH2:44][CH2:43][CH2:46][CH2:47][CH2:48][CH3:49])[C:21](=[O:23])[NH:20][C:19]2=[O:24])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(CCC2NC(=O)N(CN3CCOCC3)C2=O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(CCC2NC(=O)NC2=O)cc(C(C)(C)C)c1O
Agent: C=O
Solvent: CCCCCCBr
Solvent: C1COCCN1
Product: CCCCCCN1C(=O)NC(=O)C1CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
5-(3',5' -di-tert-butyl-4'-hydroxyphenylethyl)hydantoin is treated with morpholine and formaldehyde according to the procedure of O. O Orazi and R. A. Corral, Tetrahedron, 15, 93 (1961) to prepare the corresponding 3-N-morpholinomethyl-5-(3',5' -di-tert-butyl-4'-hydroxyphenylethyl)hydantoin. This material is then alkylated in the 1-position with 1-bromohexane as described in Example 25. The morpholinomethyl group is removed by subsequent hydrolysis according to the procedure of O. O. Orazi and R. A. Corral, Experientia, 21, 508 (1965) to give 5-(3',5' -di-tert-butyl-4'-hydroxyphenylethyl)-1-n-hexylhydantoin.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:23][P:24]([O:30]C(C)C)([O:26]C(C)C)=[O:25])=[CH:8][CH:9]([NH:20]C=O)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2].C[Si](C)(C)Br.C(O)C1C=CC=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:23][P:24]([OH:26])([OH:30])=[O:25])=[CH:8][CH:9]([NH2:20])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(=CC(NC=O)C(=O)OCc1ccccc1)CP(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: OCc1ccccc1
Solvent: ClCCl
Product: CC(=O)OCCC(=CC(N)C(=O)OCc1ccccc1)CP(=O)(O)O
Reaction time: 24 h

Procedure:
1.75 g (3.6 mmol) of benzyl 6-acetoxy-2-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate are dissolved in 15 ml of CH2Cl2. Then 1.88 ml (14.5 mmol) of trimethylbromosilane are added to this solution at room temperature. The reaction mixture is allowed to stand for 24 hours at room temperature. After addition of 15 ml of benzyl alcohol the reaction mixture is allowed to stand for 48 hours at room temperature and then concentrated by evaporation at 70° C. under a high vacuum. The residue is dissolved in 15 ml of ethanol and then a mixture of 15 ml of propylene oxide and 15 ml of ethanol is added dropwise to this solution. The suspension so obtained is stirred for 30 minutes in an ice bath and then filtered with suction. The crystals so obtained are recrystallised hot from ethanol/water and dried, giving white crystals of benzyl 6-acetoxy-2-amino-4-phosphonomethyl-hex-3-enoate. Melting point: 204°-205° C. (decomp.).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:32][C:33]([OH:35])=O.[C:43]([NH:46][NH2:47])(=[O:45])[CH3:44]>C(Cl)Cl.O>[C:39]([O:38][C:36](=[O:37])[NH:30][CH2:31][CH2:32][C:33]([NH:47][NH:46][C:43](=[O:45])[CH3:44])=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(=O)NN
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NNC(=O)CCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
EDCI.HCl (3.05 g, 15.95 mmol), HOBt (1.66 g, 12.27 mmol) and triethylamine (2.22 ml, 15.95 mmol) are added to a stirred solution of BOC-β-Ala-OH (2.32 g, 12.27 mmol) in DCM (60 ml). After stirring for 30 min at 0° C. acetic acid hydrazide (1.0 g, 13.5 mmol) is added in one portion. The reaction mixture is stirred at 0° C. for 1 hour. The reaction is diluted with water and extracted several times with DCM. The organic extract is dried (MgSO4) and the solvent is removed to give an oil. Purification by chromatography on silica, eluting with EtOAc increasing to EtOAc:EtOH 10:1, affords the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[CH2:17]([NH:21][C:22]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>C(O)CCC>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:27]2[CH2:28][CH2:29][CH:24]([C:22](=[O:23])[NH:21][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:25][CH2:26]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CCCCNC(=O)C1CCNCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCCCNC(=O)C1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Product: Cl
Yield: 26.9 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (1.2 g), 4-(N-n-butylcarbamoyl)piperidine (1.01 g) and triethylamine (2.52 g) in n-butanol (105 ml) were heated under reflux for 24 hours. The mixture was then cooled, the solvent evaporated in vacuo, and the resultant solid shaken with chloroform and water. The solid product was collected by filtration, and recrystallised twice from ethanol to give 4-amino-6,7-dimethoxy-2-[4-(N-n-butylcarbamoyl)piperidino]quinazoline hydrochloride (0.57 g), m.p. 263°-264°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([CH:18]=[CH2:19])[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.[OH-].[Na+:21].[ClH:22]>CO>[Cl-:22].[Na+:21].[Na+:21].[Na+:21].[Cl-:22].[Cl-:22].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([CH:18]=[CH2:19])[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: C=Cc1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=Cc1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Product: [Cl-]
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-(5-methyl-2-pyridinyl)-5-vinylbenzoate (1.51 g, 5.97 mmol) in methanol (20 mL) was added sodium hydroxide (1 N, 17.9 mL, 17.9 mmol). The reaction mixture was stirred at 50° C. for 18 h. The mixture was cooled to ambient temperature, and hydrogen chloride (6N, 2.98 mL, 17.9, mmol) was added. The mixture was stirred for 30 min and was concentrated to dryness to give the tri-sodium chloride adduct of the title compound (2.5 g). MS 240.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(=O)[O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][N:22]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:27]1=[O:33])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CCCC1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of 1.0 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide, 0.35 g of glutaric anhydride and 0.85 ml of triethylamine in 30 ml of dry toluene was heated at reflux under a nitrogen atmosphere for 7 hours. The mixture was cooled to room temperature and washed with 2M aqueous hydrochloric acid, 5% aqueous sodium hydrogen carbonate and brine. The organic phase was dried over anhydrous magnesium sulphate and the solvent was then evaporated. The residue was triturated with diethyl ether to give 0.623 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-(2,6-dioxopiperidino)valeramide in the form of a white solid.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1.Br[CH2:19][Cl:20]>>[Cl:20][CH2:19][S:8][C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1
Reactant: ClCBr
Reactant: Sc1cc2ccccc2s1
Solvent: CCN(CC)CC
Product: ClCSc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (20 mmol) was added to a mixture of 2-mercaptobenzo[b]thiophene [see J. Chem. Soc. (C), 2731(1970)] (20 mmol) and bromochloromethane (400 mmol). The mixture was stirred for 30 minutes at room temperature, washed with water and the dried (MgSO4) solution evaporated. Yield 4.08g (95%). 1H-NMR (CDCl3, δ): 4.88 (s, --CH2 --), 7.0-8.0 (m,5H,Ar). The product was used in Example 30 without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][Si](C(C)(C)C)(C)C)=[C:10]([F:22])[CH:9]=2)=[CH:4][CH:3]=1.C([Si:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37]C=2)[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)CCCC.Br[CH2:42][C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]>>[CH2:35]([Si@H:28]1[CH2:29][CH2:30][C@H:31]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:42][C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])=[C:10]([F:22])[CH:9]=3)=[CH:6][CH:7]=2)[CH2:32][CH2:33]1)[CH2:40][CH2:39][CH2:38][CH3:37]
Reactant: FC(F)(F)C(F)(F)CBr
Reactant: CCCCC[Si]1(c2ccccc2)CCC(=O)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1F
Product: CCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OCC(F)(F)C(F)(F)F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 17 was repeated using 4'-bromo-3-fluoro-4-(t-butyldimethylsiloxy)biphenyl, 4-pentyl-4-phenyl-4-silacyclohexanone, and 1-bromo-2,2,3,3,3-pentafluoro-n-propane, thereby obtaining the intended compound.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][N:6]([C:8]([NH:10][CH2:11][CH3:12])=[NH:9])[N:5]=[CH:4]1)[CH3:2].CCN(C(C)C)C(C)C.Cl[S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30])(=[O:25])=[O:24]>C(Cl)Cl>[CH2:11]([NH:10][C:8](=[N:9][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30])(=[O:25])=[O:24])[N:6]1[CH2:7][CH:3]([CH2:1][CH3:2])[CH:4]=[N:5]1)[CH3:12]
Reactant: CCNC(=N)N1CC(CC)C=N1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1cccc(C(=O)O)c1)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
Under N2 atmosphere, 1.0 g 4,N-diethyl-4,5-dihydro-pyrazole-1-carboxamidine was dissolved in 15 mL dry DCM, and 1.14 mL DiPEA and 1.31 g of 3-(chlorosulfonyl)benzoic acid were added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was purified by flash chromatography (first column with DCM/MeOH/acetic acid 84:15:1; second column with DCM/MeOH/NH4OH 84:15:1) to yield 0.08 g (4%) of an off-white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH-](CC)CC)C.[Li+].C(OCC)(=O)C.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 83 %

Procedure:
A solution of 2-(S)-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (compound (3), 4.6 g, 0.016 mol) in anhydrous tetrahydrofuran (50 mL, THF) was cooled to 0° C. 1.0 M Lithium triethylborohydride in THF (38 mL, 3.17 g, 0.029 mol) was added dropwise to the reaction mixture while maintaining reaction temperature below 0° C. The reaction mixture was refluxed for overnight (˜11 hour). HPLC showed absence of starting material. Reaction mixture was cooled to 0° C. and ethyl acetate (50 mL) was slowly added followed by addition of distilled water (50 mL) while maintaining temperature below 10° C. The organic layer was separated and washed with distilled water (2×50 mL), 1 M H3PO4(2×50 mL) and saturated NaHCO3 (2×50 mL), dried over MgSO4, filtered, and concentrated to leave an oily residual product (2.46 g, 53.5% yield). 1H NMR (CDCl3): δ 1.16 (d, 3H, CH3), 1.47 (s, 9H, 3×CH3), 1.50–1.82 (m, 2H, CH2), 1.84–2.03 (m, 2H, CH2), and 3.86 (m, 1H, CH).