Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15](=[O:17])[CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([N:32]3[C:44]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:38]4[C:33]3=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:29]=[CH:30][CH:31]=2)O1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH:34]1[C:33]2[N:32]([C:28]3[CH:27]=[C:26]([C:2]4[CH:3]=[CH:4][C:5]5[N:6]([C:15](=[O:17])[CH3:16])[C:7]6[C:12]([C:13]=5[CH:14]=4)=[CH:11][CH:10]=[CH:9][CH:8]=6)[CH:31]=[CH:30][CH:29]=3)[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Reactant: CC1(C)OB(c2cccc(-n3c4ccccc4c4ccccc43)c2)OC1(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)n1c2ccccc2c2cc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)ccc21
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of 1-(3-bromo-9H-carbazol-9-yl)ethanone (2.000 g, 6.94 mmol), 9-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9H-carbazole (2.56 g, 6.94 mmol), Pd2(dba)3 (0.064 g, 0.069 mmol), SPhos (0.057 g, 0.139 mmol) and potassium phosphate tribasic hydrate (4.80 g, 20.82 mmol) in toluene (100 mL) and water (10 mL) was stirred at 70° C. under nitrogen overnight. After cooling to room temperature, the organic phase was isolated. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane:DCM (1:4, v/v) as eluent to yield 1-(3-(3-(9H-carbazol-9-yl)phenyl)-9H-carbazol-9-yl)ethanone (2.9 g, 94%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[C:14]#[N:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:14]#[N:15]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: O=Cc1ccc(O)cc1
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)c(Cl)c1
Yield: 1.91 %

Procedure:
The above compound is prepared by nucleophilic displacement reaction of 4-hydroxy benzaldehyde and 3-chloro-4-fluorobenzonitrile under basic conditions as described in Example 243, step 1.91% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: COc1ccc(B(O)O)cc1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(OC)cc3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-methoxy-phenylboronic acid (49 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([N:6]([CH3:8])[CH3:7])=O.CO.Cl>C1COCC1>[CH3:8][N:6]([CH3:7])[CH2:4][CH2:3][C@@H:2]([NH2:1])[CH2:9][S:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)C(=O)C[C@@H](N)CSc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC[C@@H](N)CSc1ccccc1
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 1C (8.68 g) in THF (200 mL) was treated with BH3-dimethylsulfide (18.2 mL) at room temperature, stirred overnight, treated slowly with methanol (20 mL), followed by 2N HCl (50 mL), stirred overnight, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 5% 7N NH3/CH3OH in dichloromethane to give the desired product.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>ClCCl>[CH:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH2:11][CH2:10]1)=[O:8]
Reactant: C=C(C)C(=O)Cl
Reactant: O=CN1CCN(CCO)CC1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCN1CCN(C=O)CC1
Reaction time: 2 h

Procedure:
105.5 g (1.01 mol) of methacryloyl chloride were added dropwise between -30° and -35° C. to a stirred solution of 160 g (1.01 mol) of N-formyl-N-'-2-hydroxyethylpiperazine, 111 g (1.10 mol) of triethylamine and 100 mg of 2,6-di-tert.-butyl-4-methylphenol in 300 ml of dichloromethane and the mixture was stirred for two hours at the same temperature. The precipitate which deposited was filtered off and the filtrate was washed with sodium chloride solution, dried and concentrated to give 166.8 g (73% of theory) of a clear oil of N-formyl-N'-(methacryloyloxyethyl)piperazine. It was possible to elute this with methanol in high purity from a silica gel column after separating small amounts of by-products with ether/n-hexane (6:4).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:11])/[CH:7]=[CH:8]\[CH2:9][OH:10].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:10][CH2:9]/[CH:8]=[CH:7]\[CH2:6][O:11][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: OC/C=C\CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC/C=C\COS(C)(=O)=O
Reaction time: 3 h

Procedure:
In an ice bath, 26 ml of methanesulfonyl chloride was added dropwise in to a mixture of 10 g of cis-2-buten-1,4-diol, 63 ml of triethylamine and 1000 ml of ethyl acetate, followed by stirring at the same temperature for 3 hours. Then, the insoluble matters were removed by filtration. The filtrate was further filtered through silica gel and washed with ethyl acetate. Then, the filtrate was evaporated, to give 21.4 g of cis-1,4-bis(methanesulfonyloxy)-2-butene.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>CC(O)=O.O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N:11]=[N+:16]=[N-:17])=[CH:6][CH:5]=2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2cc(N=[N+]=[N-])ccc2[nH]1
Yield: 65.7 %

Procedure:
In an oven dried, 250 mL round bottom flask flushed with argon, compound 33 (400 mg, 2.74 mmol, 146.19 MW) was dissolved in 90% AcOH (20 mL). After complete solvation, the reaction was placed at 0° C. and protected from light with foil. NaNO2 (1.1×, 3.01 mmol, 208 mg, 69.00 MW) dissolved in cold H2O (2 mL) was added dropwise and stirred for ten minutes. NaN3 (1.1×, 3.01 mmol, 196 mg, 65.01 MW) dissolved in cold H2O (2 mL) was added dropwise. After one hour the reaction was poured into water (40 mL), which was extracted 3 times with CH2Cl2 (40 mL each). The extracts were washed with sodium bicarbonate and brine (100 mL each), dried with sodium sulfate, filtered and concentrated. Purification by silica flash chromatography (100% CH2Cl2) yielded the azide as a light brown solid (310 mg, 66%). 1H NMR (600 MHz, d6-DMSO): δ 11.025 (s, 1H, N—H), 7.295-7.281 (d, J=8.4, 1H, indole-7H), 7.131-7.127 (d, J=2.4, 1H, indole-4H), 6.737-6.719 (dd, J1=8.4, J2=2.4, 1H, indole-6H), 6.108-6.106 (d, J=1.2, 1H, indole-3H), 2.369 (s, 1H, methyl). 13C NMR (150 MHz, d6-DMSO): δ 137.5, 133.9, 130.0, 129.5, 111.7, 111.6, 108.5, 99.0, 13.4. Melting point: 57-60° C. TLC (in 1:1 ethyl acetate:hexanes) Rf=0.56. IR (film): 3409 cm−1, 2111 (aryl-azide). Elemental analysis calculated for C9H8N4: C, 62.78; H, 4.68; N, 32.54. found: C, 62.95; H, 4.68; N, 32.53.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8](OCC)(=[O:12])[C:9]([CH3:11])=O>C(O)CCC>[CH3:11][C:9]1[C:8](=[O:12])[O:4][CH2:3][C:2]([CH3:7])([CH2:5][OH:6])[N:1]=1
Reactant: CC(N)(CO)CO
Reactant: CCOC(=O)C(C)=O
Solvent: CCCCO
Product: CC1=NC(C)(CO)COC1=O

Procedure:
The results presented herein above and as shown in the schematic FIGS. 1 and 2 indicate that direct condensation of 2-amino-2-methyl-1,3-propanediol (1) with ethyl pyruvate in 1-butanol at reflux, followed by vacuum distillation, gives the 2,4-dimethyl-4-hydroxymethyl-1,3-oxazolidine-2-carboxylic acid ester of 5,6-dihydro-3,5-dimethyl-5-hydroxymethyl-1,4-oxazin-2-one (2). Evidence for the structure of the latter compound (2) is derived from elemental analysis, 1H NMR, IR and UV spectra, as well as chemical behavior. As described more specifically supra, the 1H NMR spectrum of 2 in deuteriochloroform showed four methyl singlets between 1.2 and 2.3 ppm, along with two very complex patterns between 3.3 and 4.7 ppm for the four --CH2 --O groups. The sharpness of the four methyl singlets suggests that 2 is mostly one of four possible diasteroisomers. The IR spectrum showed the bands characteristic of OH and/or NH stretching at 3000-3500, a very strong band at 1735 (C= O) and a band at 1635 cm-1 (C=N). The UV spectrum of 2 in 2-propanol solvent showed a maximum at 323 nm, characteristic of the oxazinone ring.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:10][C:11]1[C:12]([CH:17]=O)=[N:13][CH:14]=[CH:15][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:10][C:11]1[C:12]([CH2:17][NH:9][CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccnc1CN
Reactant: O=Cc1ncccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCc1ncccc1Cl

Procedure:
Using General Procedure B: Reaction of C-(3-methyl-pyridin-2-yl)-methylamine and 3-chloro-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave (3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine as a yellow oil. Using General Procedure A: Reaction of (3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine, 2-bromomethyl-5-cyano-benzoic acid methyl ester, and DIPEA in CH3CN gave 2-{[(3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3) δ 2.12 (s, 3H), 3.85 (s, 3H), 3.90 (s, 2H), 3.97 (s, 2H), 4.22 (s, 2H), 7.03 (dd, 1H, J=7.8, 4.8 Hz), 7.13 (dd, 1H, J=7.8, 4.8 Hz), 7.32 (d, 1H, J=6.9 Hz), 7.52-7.63 (m, 2H), 7.71 (d, 1H, J=8.1 Hz), 7.94 (d, 1H, J=1.5 Hz), 8.30 (d, 1H, J=4.5 Hz), 8.42 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:33]2[CH2:32][CH2:31][N:30]([C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[CH2:35][CH2:34]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
3.76 ml (35.082 mmol) of 4-fluoronitrobenzene are dissolved in 40 mL DMA and combined with 9.25 mL (52.62 mmol) of N-ethyldiisopropylamine and 7.6 ml (38.59 mmol) of 1-(benzyloxycarbonyl)-piperazine. The reaction mixture is stirred for 18 h at 80° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier material used is silica gel and the eluant used is a mixture consisting of cyclohexane:ethyl acetate (50:50).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([F:16])([F:15])[F:14].C(=O)=O>CN(C)C=O.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:6][CH:5]=1
Reactant: FC(F)(F)CCl
Reactant: Sc1ccc(Cl)cc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)CSc1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
A two-necked flask having a dry ice condenser fitted on top was charged with 50 ml of dry dimethylformamide and 2 g of a 60% strength by weight suspension of sodium hydride in paraffin, and subsequently 7.3 g of 4-chlorothiophenol in 10 ml of dimethylformamide were added dropwise. Chlorotrifluoroethane was then passed in at a reaction temperature of about 60° C., until the gas began to condense in the dry ice condenser. The mixture was stirred for a further 5 hours and the course of the reaction was monitored by thin-layer chromatography (silica gel; ethyl acetate/petroleum ether 1/5). The reaction mixture was worked up by pouring into water and extracting with dichloromethane. The combined organic extracts were dried and the solvent was distilled off at reduced pressure. The oily residue was subsequently distilled (43°-45° C./0.1 mbar), giving 8.8 g of 4-chloro(2',2',2'-trifluoroethylthio)benzene
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.C(N(CC)C(C)C)(C)C.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][N:5]2[C:30]([C:26]1[O:25][CH:29]=[CH:28][CH:27]=1)=[O:31]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)c2ccco2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A 100 mL round bottomed flask fitted with a nitrogen inlet was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.500 g, 1.858 mmol), 1,2-dichloroethane (20 mL), N,N-diisopropylethylamine (1.0 mL, 5.73 mmol), and furan-2-carbonyl chloride (0.366 mL, 3.72 mmol). The reaction mixture was heated to 50° C. for 2 h with magnetic stirring. After for 2 h, the reaction was washed with 1 N aqueous sodium hydroxide solution (15 mL). The organic layer was removed and set aside. The aqueous layer was washed with 1,2-dichloroethane (20 mL) and the organic layers were combined and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 2:1 hexanes-ethyl acetate) to afford (S)-1-(6-bromo-4-(furan-2-carbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.58 g, 86% yield) as a viscous yellow oil. MS (ESI, pos. ion) m/z 417 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:17]([CH3:19])[CH3:18])[C:5]2[CH2:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[OH2:20].OO.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([N:17]([CH3:19])[CH3:18])[C:5]2[CH2:10][C@H:9]([OH:20])[C@@H:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: CN(C)c1nc(Cl)nc2c1CC=C2c1ccccc1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1nc(Cl)nc2c1C[C@H](O)[C@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-chloro-N,N-dimethyl-7-phenyl-5H-cyclopenta[d]pyrimidin-4-amine (113 mg) in THF (2 mL) at rt was added borane dimethyl sulfide complex in THF (2.0 M solution, 0.41 mL), and the reaction mixture was stirred at rt for 5 h. Water (0.50 mL) was added carefully, followed by 30% H2O2 (0.50 mL) and 1 N NaOH (1 mL). 5 mL EtOAc was added, and the r×n mixture was stirred at rt for 12 h. The crude product was purified by prep. TLC eluting with 50% EtOAc/Hexanes to give the title compound as a yellowish solid (44 mg). LC-MS (M−H2O+H)+=290.05.
Reaction SMILES: Cl.[NH:2]=[C:3]1[C:11]([CH3:13])([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[CH3:14].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>N1C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:2]=[C:3]2[C:11]([CH3:12])([CH3:13])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]2[CH3:14])=[O:21])=[CH:18][CH:17]=1
Reactant: CN1C(=N)C(C)(C)c2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CN1C(=NC(=O)c2ccc(Cl)cc2)C(C)(C)c2ccccc21

Procedure:
By reacting 15 g. of the hydrochloride of 2-imino-1,3,3-trimethylindoline (m.p. 271°-273° C) in 100 ml. of pyridine with 16.30 g. of p-chlorobenzoylchloride at the room temperature for 5 hours, 15.2 g. of the title compound are obtained. B.p. 192° C/0.1 mmHg.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:20])[NH:3]1.Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1>CC(N(C)C)=O.[Cu-]=O>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([C:5]2([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:20])[N:3]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:31])([F:33])[F:32])[CH:23]=3)[C:2](=[O:1])[NH:6]2)=[CH:13][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: C=CCOCC1(c2ccc(C#N)cc2)NC(=O)NC1=O
Agent: O=[Cu-]
Solvent: CC(=O)N(C)C
Product: C=CCOCC1(c2ccc(C#N)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 130 °C

Procedure:
To a solution of 675 mg of 4-[2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-4-yl]benzonitrile and 622 mg of 4-bromo-2-trifluoromethylbenzonitrile in DMAC (2.5 mL) 214 mg of copper (I) oxide is added. The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in DCM, washed with a 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane: 0/100 to 50/50) to give the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH2:23]([N:25]([CH2:44][CH3:45])[C:26](=[O:43])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)[CH3:24].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:29]3[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=3[CH3:33])[C:26]([N:25]([CH2:44][CH3:45])[CH2:23][CH3:24])=[O:43])[C:3]=2[CH2:13][NH:12][C:11]1=[O:14]
Reactant: CCN(CC)C(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)C(=O)c1ccc(C)c(-c2nc(SC)nc3c2CNC(=O)N3c2c(F)cccc2F)c1

Procedure:
5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.720 g, 2.1 mmol), N,N-diethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide from above (1.09 g, 3.15 mmol), and K2CO3 (0.868 g, 6.3 mmol), were taken up in dioxane (42 mL) and water (8.5 mL). The mixture was degassed with argon for 30 min and tetrakis-(triphenylphosphine)palladium(0) (0.183 g, 0.15 mmol) was added. The mixture was then heated under argon at 950 C for 18 h. The solvents were pumped off and after aqueous workup, the crude material was flashed on silica gel (150 g) eluted with a EtOAc/CH2Cl2 gradient to give the title compound as a white amorphous solid. mp 127-129° C. LC-MS m/z 498 (M+H)+, 2.11 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:33])([F:32])[CH2:29][CH2:30]O>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:30][CH2:29][C:28]([F:33])([F:32])[F:27])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCC(F)(F)F
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCCC(F)(F)F)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3,3,3-trifluoropropanol in analogy to Example 9c): MS (ISP): 492.2 and 494.2 (M+H)+, 392.0 and 394.0 ((M-Boc)+H)+ (100%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:11])/[C:4](=[N:8]/[O:9][CH3:10])/[C:5]([OH:7])=O.[NH2:12][CH:13]1[C:38](=[O:39])[N:15]2[C:16]([C:27]([O:29][CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[S:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:11])/[C:4](=[N:8]/[O:9][CH3:10])/[C:5]([NH:12][C@@H:13]1[C:38](=[O:39])[N:15]2[C:16]([C:27]([O:29][CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[S:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12)=[O:7]
Reactant: CO/N=C(\C(=O)O)C(=O)CCl
Reactant: C[Si](C)(C)CCOCOC(=O)C1=C(CSc2cnns2)CS[C@@H]2C(N)C(=O)N12
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CO/N=C(/C(=O)CCl)C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOCC[Si](C)(C)C)=C(CSc3cnns3)CS[C@H]12
Yield: 20.7 %

Procedure:
A solution of 4-chloro-2-(Z)-methoxyimino-3-oxobutanoic acid (2.17 g, 4.77 mmol.), 2-(trimethylsilyl)ethoxymethyl 7-amino-3-[(1,2,3-thiadiazol-5-yl)thiomethyl]ceph-3-em-4-carboxylate (0.85 g, 4.77 mmol.), and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (1.18 g, 4.77 mmol.) in 40 ml of methylene chloride was stirred at room temperature for 3 hours then worked up as described in Example 6 to afford 0.615 g of the ester. NMR (CDCl3) δ 0.03 [S, 9H, --Si(CH3)3 ], 0.97 (t, 2H, J=7.5 Hz, --CH2Si--), 3.62 (pair of d, 2H, J=18 Hz, endocyclic --CH2S--), 3.75 (m, 2H, --OCH2 --), 4.17 (pair of d, 2H, J=13.3 Hz, exocyclic --CH2S), 4.18 (S, 3H, --OCH3), 4.63 (S, 2H, --ClCH2 --), 5.07 (d, 1H, J=4.9, 6H of 7ACA), 5.38 (pair of d, 2H, J=6.0 Hz, --OCH2O), 5.87 (dd, 1H, J=4.9 and 8.5 Hz, 7H of 7ACA), 7.22 (d, 1H, J=8.5 Hz, --NH--), 8.52 (S, 1H, thiadiazole H).
Reaction SMILES: [OH:1][CH:2]([CH:14]=[CH2:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].C(OC=C)(=O)C>C(OC(C)C)(C)C>[OH:1][C@@H:2]([CH:14]=[CH2:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: C=CC(O)CCCCCCCC(=O)OC
Solvent: CC(C)OC(C)C
Solvent: C=COC(C)=O
Product: C=C[C@H](O)CCCCCCCC(=O)OC
Temperature: 30 °C
Reaction time: 62 h
Yield: 30.4 %

Procedure:
To a solution of methyl 9-hydroxy-10-undecenate (500 mg) in diisopropyl ether (12 ml) was added vinyl acetate (323 μl) and Lipase PS (AMANO SEIYAKU Co., Ltd.) (500 mg) and then shaken for 62 hours at 30° C. The reaction mixture was filtrated and the filtrate was poured into ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate anhydride, and then evaporated under reduced pressure. The resulting product was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give (R)-methyl 9-hydroxy-10-undecenate (152 mg, 30.4%).