Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:5].Cl[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>C(Cl)Cl>[Cl:12][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][NH:2][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: NCC(=O)c1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A mixture of 2-amino-1-(3-chlorophenyl)ethanone hydrochloride from Step 79a (2.83 g, 13.7 mmol, 1 eq), ethyl chlorooxoacetate (1.87 g, 13.7 mmol, 1 eq), and CH2Cl2 (40 mL) is cooled in an ice-H2O bath. The mixture is treated with a solution of TEA (4.0 mL, 29 mmol, 2.1 eq) in CH2Cl2 (20 mL), and the reaction is warmed to room temperature overnight. Water is added and the organic layer is separated, dried over MgSO4, filtered., and evaporated. The resulting solid is triturated with hexane/2-propanol and dried in vacuo to provide the title compound (2.70 g, 72%). MS (ESI) for C12H12ClNO4 m/z 270 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C1(C)C=CC=CC=1>[OH:12][C:3]1[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[CH:26]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(Cl)c1cccc(-c2ccccn2)c1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2cccc(-c3ccccn3)c2)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-2-yl)benzoic acid (1.69 g, 8.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum to give 3-(pyridin-2-yl)benzoyl chloride. 1.66 g of crude product was obtained. To a solution of methyl 3-amino-2-hydroxybenzoate (0.84 g, 5 mmol) and pyridine (790 mg, 10 mmol) in toluene (50 mL) were added crude 3-(pyridin-2-yl)benzoyl chloride (1.6 g, 7.37 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain yellow solid of methyl 2-hydroxy-3-(3-(pyridin-2-yl)benzamido)benzoate (1.48 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([O:11][C:12]1[C:17]([C:18]2[NH:19][C:20](=[O:34])[C:21]3[C:22](=[C:24]([CH2:32][CH3:33])[N:25]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[N:26]=3)[N:23]=2)=[CH:16][C:15](I)=[CH:14][N:13]=1)[CH2:8][CH2:9][CH3:10]>C(N(CC)CC)C.C(#N)C.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>[CH2:7]([O:11][C:12]1[C:17]([C:18]2[NH:19][C:20](=[O:34])[C:21]3[C:22](=[C:24]([CH2:32][CH3:33])[N:25]([CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[N:26]=3)[N:23]=2)=[CH:16][C:15]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:14][N:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCN(C)C)nc2c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(CCN(C)C)nc2c(=O)[nH]1
Temperature: 60 °C
Yield: 93.2 %

Procedure:
Pd(PPh3)2Cl2 (11.2 mg, 0.016 mmol), trimethylsilylacetylene (179 μl, 1.29 mmol) and cuprous iodide (3 mg, 0.016 mmol) were added to a stirred slurry of 5-(2-butoxy-5-iodo-3-pyridinyl)-2-[2-(dimethylamino)ethyl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Example 44 in Annex 1, PCT Application, IB 00/01430) (330 mg, 0.647 mmol) in triethylamine (8 ml) and acetonitrile (2 ml) at room temperature under a nitrogen atmosphere. The mixture was heated at 60° C. for 3 h, cooled and extracted from brine with dichloromethane (2×100 ml). The organics were dried (MgSO4), filtered and concentrated to give a yellow solid. Purification by flash column chromatography (elution with DCM/MeOH, 95:5) gave the title compound as a pale brown oil (290 mg, 93%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@@H:21]([NH:45]C(=O)OC(C)(C)C)[CH2:22][C:23]([N:25]3[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]4[N:35]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:34]5[CH:41]=[CH:42][CH:43]=[CH:44][C:33]=5[N:32]=4)[CH2:26]3)=[O:24])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7].ClCCl.[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59]>CO.CC#N.O>[NH2:45][C@@H:21]([CH2:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]2[N:35]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:34]3[CH:41]=[CH:42][CH:43]=[CH:44][C:33]=3[N:32]=2)[CH2:26]1)=[O:24])[CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])=[CH:9][CH:10]=2)=[CH:19][CH:18]=1.[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(-c4ccc(C(=O)NCCOC)cc4)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(-c4ccc(C(=O)NCCOC)cc4)cc3)C2)nc2ccccc21

Procedure:
tert-butyl (R)-1-(4′-(2-methoxyethylcarbamoyl)biphenyl-4-yl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (86B) (0.053 mmoles, 0.038 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir under nitrogen for 4 hrs. The solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in Methanol (3 mL), filtered, and then purified by preparative LC/MS (0.5-50% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford 4′-((R)-2-amino-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)-N-(2-methoxyethyl)biphenyl-4-carboxamide (177) as its trifluoroacetic acid salt and as a white flocculent solid (0.033 mmoles, 0.024 g, 62% yield). ESI-MS: m/z 612.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.62 (m, 1H) 1.74-2.21 (m, 5H) 2.58-2.86 (m, 3H) 2.90-3.16 (m, 4H) 3.16-3.25 (m, 3H) 3.28 (s, 3H) 3.30-3.51 (m, 7H) 3.64-4.19 (m, 2H) 4.27-4.70 (m, 4H) 7.36-7.50 (m, 4H) 7.68-7.82 (m, 6H) 7.95 (dd, J=8.46, 2.40 Hz, 2H) 8.54-8.63 (m, 1H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:15](=[O:17])[N:14]4[C:18]([CH3:21])=[N:19][N:20]=[C:13]4[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:11]=3[N:10]=[C:9]2[C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=CC=1.FC(F)(F)C(O)=O>>[CH3:21][C:18]1[N:14]2[C:15](=[O:17])[C:16]3[NH:8][C:9]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[N:10][C:11]=3[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]2=[N:20][N:19]=1
Reactant: CCCCCn1c2nc(-c3nccs3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Solvent: O=C(O)C(F)(F)F
Product: CCCCCn1c2nc(-c3nccs3)[nH]c2c(=O)n2c(C)nnc12
Temperature: 55 °C
Reaction time: 8 h

Procedure:
The mixture of 6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(1,3-thiazol-2-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.22 mmol) in trifluoroacetic acid (5 mL, 65 mmol) was stirred at 55° C. overnight. The reaction solution was concentrated and purified using preparative LCMS to yield the desired product. LCMS calculated for C15H18N7OS: 344.1. found: 344.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.CO.Cl.[CH3:14]N(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:14][O:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:10]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cccc(C(=O)O)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(C)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Suspend 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol) in methylene chloride (200 mL). Cool to 0° C. Add methanol (10 mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (18.2 g, 94.8 mmol). Stir the mixture at room temperature for 6 hours, wash with water and brine, and dry over sodium sulfate. Filter the mixture and concentrate in vacuo. Chromatograph the residue on SiO2 (50% ethyl acetate/hexanes) to obtain the desired subtitled intermediate, 9.66 g (92%), as a colorless liquid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH2:7].CN(C=O)C.[Br:13][C:14]1[C:15](=[O:36])[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:17]([C:24](OC)=[O:25])[N:18]([CH2:20][CH:21](O)O)[CH:19]=1.[Br-]>C(#N)C.C(O)(=O)C>[Br:13][C:14]1[C:15](=[O:36])[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:17]2[C:24](=[O:25])[N:7]3[CH2:6][C@H:2]4[CH2:3][CH2:4][CH2:5][N:1]4[C@@H:21]3[CH2:20][N:18]2[CH:19]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(O)O
Reactant: NC[C@H]1CCCN1
Agent: [Br-]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C1c2c(OCc3ccccc3)c(=O)c(Br)cn2C[C@@H]2N1C[C@H]1CCCN12
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
A reactor was charged with [(2R)-2-pyrrolidinylmethyl]amine (0.75 kg) and 4.6 L of DMF was added followed by 0.45 kg of glacial acetic acid. Acetonitrile (41.4 L) was then added and the mixture was agitated for 15 minutes. To the reaction mixture was added methyl 5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate (2.30 kg). After stirring for 20 minutes at ambient temperature, the mixture was heated at 75-85° C. until the bromide starting material was consumed by HPLC analysis (about 6 hrs). Upon completion, the mixture was cooled until the reflux subsided and then charged with 6.9 L of methanol and the mixture was heated at reflux for about 45 minutes then cooled to 15° C. and filtered and dried to provide (4aS,13aR)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-9,11-dione (1.93 kg, 78%) as a white solid). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.65 (m, 1H), 7.54 (m, 2H), 7.33 (m, 3H), 5.15 (d, 1H), 4.99 (d, 1H), 4.60 (m, 1H), 4.36 (m, 1H), 4.03 (m, 1H), 3.90 (m, 1H), 3.65 (m, 1H), 3.06-2.84 (m, 3H), 1.92-1.60 (m, 4H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2cccc(Cl)c2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 3-Chloroaniline instead of 3-chloroaniline to yield the final compound as a white solid, MS (ISP): m/e=342.0, 344.1 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][C:16]([C:25](OCC)=[O:26])([C:20](OCC)=[O:21])[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][C:16]([CH2:20][OH:21])([CH2:25][OH:26])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C1(C(=O)OCC)OCCN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1(CO)CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a stirring suspension of lithium aluminum hydride (8.49 g) in THF (500 ml) was added diethyl 4-benzyl-3-oxomorpholine-2,2-dicarboxylate (25 g) under ice-cooled bath, and the mixture was stirred for 1 hour at room temperature. Then the whole was warmed up to 65° C. (inner temperature), and the mixture was stirred for 2 hours. The whole was cooled with ice-cooled bath, and water (8.5 ml) was added dropwise to the mixture. The whole was stirred for 15 minutes. 4 N NaOH (8.5 ml) was added to the mixture, and the whole was stirred for 15 minutes. Then water (25.5 ml) was added again to the mixture and the whole was stirred for 1 hour at room temperature. The white precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diisopropyl ether, and tritulated to yield white solid, which was collected by filteration to give (4-benzylmorpholine-2,2-diyl)dimethanol (10.3 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].CO.O.O.[OH-].[Li+]>C1COCC1>[C:21]([O:20][C:18]([N:11]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[CH:8][N:9]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1nccnc1N(C(=O)OC(C)(C)C)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(c1cccnc1)c1nccnc1C(=O)O
Temperature: 25 °C

Procedure:
3-(tert-Butoxycarbonyl-pyridin-3-yl-amino)-pyrazine-2-carboxylic acid methyl ester (364 mg, 1.1 mmol) was dissolved in 10 ml THF. 5 ml methanol, 5 ml water and lithium hydroxide hydrate (139 mg, 3.30 mmol) were added and stirred over night at room temperature. The organic solvent was evaporated and the residue was neutralized with 2N HCl-solution. The mixture was evaporated to dryness and used without further purification for the next step [(405 mg, >100%), MS: m/e=315.2 (M+H−)].
Reaction SMILES: [Br:1]Br.[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[OH-].[Na+]>C(O)(=O)C>[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:1])=[CH:7][CH:6]=1
Reactant: CNc1ccccc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 102.2 %

Procedure:
A solution of 179 g of bromine in 120 ml of acetic acid was added at less than 40° C. over 45 minutes under an inert atmosphere to a mixture of 120 g of N-methyl-aniline and 600 ml of acetic acid and the mixture was stirred for 75 minutes and then was cooled to room temperature and poured into a mixture of ice and water. The pH of the mixture was adjusted to 10 by addition of sodium hydroxide and the mixture was extracted with methylene chloride. The organic phase was washed with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure to obtain 213 g of N-methyl-4-bromo-aniline.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4].N1C=CN=C1.[C:47]([Si:51]([CH3:54])([CH3:53])Cl)([CH3:50])([CH3:49])[CH3:48]>CN(C)C=O.O.C(OCC)(=O)C>[Si:51]([O:1][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:30])=[CH2:4])([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:54])[CH3:53]
Reactant: C=C(CO)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(CO[Si](C)(C)C(C)(C)C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1

Procedure:
A solution of (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (20 g) and imidazole (5.6 g) in dry dimethylformamide (45 ml) was treated with t-butyl dimethyl chlorosilane (6.77 g) at room temperature for 2 hours. The reaction mixture was diluted with cold water (200 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml). The combined extracts were washed successively with 5% hydrochloric acid solution (80 ml×2) and brine (80 ml), and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate in vacuo, the concentrate was crystallized from isopropanol to give crystals of (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 90°-92° C.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:23][N:24](C=O)C.[C-]#N.[K+]>O>[C:23]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)#[N:24]
Reactant: CN(C)C=O
Reactant: COc1cccc(CCCOS(=O)(=O)c2ccc(C)cc2)c1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: COc1cccc(CCCC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 1-tosyloxy-3-(3-methoxyphenyl)propane (125 g, 0.39 mole) and DMF (400 mL) was stirred at 0° as a solution of KCN (30 g, 0.46 mole) and water (70 mL) was added dropwise. The reaction mixture was stirred at 65°-70° for 1 hour, was cooled to room temperature and poured onto ice water. The solution was extracted with ether. The extracts were washed with water, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated to yield 62 g yellow oil, (91%), M+ 175.
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]2[NH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[N:14]=2)=[O:7])[CH:5]=[CH:4]N=C1.C[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37]CN>C(OCC)(=O)C>[CH3:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:4][CH2:5][NH:1][C:6]([NH:8][C:9]1[NH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[N:14]=1)=[O:7]
Reactant: Cc1cc(=O)nc(NC(=O)n2ccnc2)[nH]1
Reactant: COCCOCCOCCOCCOCCOCCOCCN
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCOCCOCCOCCNC(=O)Nc1nc(=O)cc(C)[nH]1
Yield: 60.1 %

Procedure:
To a suspension of 4.38 g of 2-(1-imidazolylcarbonylamino)-6-methyl-4[1H]-pyrimidinone 1A (0.02 mol) in 200 ml of ethyl acetate were added 7.4 g of 2,5,8,11,14,17,20 heptaoxadocosan-22-amine (0.0218 mol). The reaction mixture was refluxed for 12 hours. The mixture was then allowed to return to room temperature, and was evaporated under reduced pressure. The residue was taken up in acetone (50 ml) and then filtered to remove the imidazole. The filtrate was evaporated under reduced pressure and then taken up again in 50 ml of acetone and filtered. The filtrate was evaporated under reduced pressure. 5.9 g of the expected product were thus obtained in the form of a pasty oil, in a yield of 60%. 1H and 13C NMR spectra compliant.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)\[CH3:5].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Br:1][CH2:2][CH:3]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]1([CH3:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: C/C(=C\CBr)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1C(CBr)C1(C)c1cccc([N+](=O)[O-])c1
Yield: 9.4 %

Procedure:
To a solution of 1-[(E)-3-bromo-1-methyl-1-propenyl]-3-nitrobenzene (Preparation 4, 4 g, 15.6 mmol) in dichloromethane (5 ml) was added rhodium (II) acetate dirner (100 mg, 0.22 nmnol). To the mixture was added dropwise at room temperature over 4.5 h a solution of ethyl diazoacetate (3.1 ml, 2.84 g, 25 mmol) in dichloromethane (15 ml). The mixture was filtered, concentrated in vacuo, and the residue purified by silica column (100 g) chromatography, eluting with 2:1 hexane/dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo, then purified further by preparative HPLC (Condition 1). Combination and evaporation of appropriate fractions gave the title compound as a colourless oil (0.5 g, 11%).
Reaction SMILES: FC(F)(F)S([C:6]1[C:14]2[S:13][C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=O)=O.[Cl-].[Li+].[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:26]=1.C([Sn](C=C)(C=C)C=C)=C>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>[CH:25]([C:6]1[C:14]2[S:13][C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[CH2:26]
Reactant: CCNC(=O)Nc1nc2cccc(S(=O)(=O)C(F)(F)F)c2s1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=C[Sn](C=C)(C=C)C=C
Agent: [Cl-]
Product: C=Cc1cccc2nc(NC(=O)NCC)sc12
Temperature: 100 °C
Yield: 24.5 %

Procedure:
Similar to the synthesis of Example 203, a mixture of 1-(7-trifluoromethylsulfonyl-2-benzothiazolyl)-3-ethylurea (0.050 g, 80% pure, 0.11 mmol), lithium chloride (0.039 g, 0.92 mmol, 8.4 eq), triphenylphosphine (0.017 g, 0.066 mmol, 0.6 eq), Pd(PPh3)2Cl2 (0.009 g, 0.013 mmol, 0.12 eq), tetravinyltin (0.040 mL, 0.22 mmol, 2.0 eq), and a crystal of 2,6-di-tert-butyl-4-methylphenol was purged with nitrogen gas, and was heated at about 100° C. for about 1.5 hours. The mixture was taken up in MeOH, filtered, concentrated, and purified by HPLC and preparative TLC in ethyl acetate/heptane mixture to obtain 0.004 g (14%) of the desired compound. LC/MS 248 (M+1); LC retention time 2.96 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:10][S:9]2(=[O:24])=[O:23])[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH:17]1([NH:16][C:11]2[O:12][C:13]([CH3:15])([CH3:14])[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)[CH:3]=3)[S:9](=[O:24])(=[O:23])[N:10]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(Br)c1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(-c2cncnc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
Under inert gas, 80 mg of [5-(3-bromophenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]cyclohexylamine, 30 mg of pyrimidine-5-boronic acid and 251 mg of cesium carbonate were dissolved in a mixture of 1.2 ml of dioxane and 0.4 ml of water. After purging with argon for 10 minutes, 15 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium were added and the reaction mixture was stirred at 80° C. for 2 hours. After cooling to room temperature, the mixture was admixed with 50 ml of ethyl acetate and washed with 15 ml of water and 15 ml of saturated aqueous sodium chloride solution, and the organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and lyophilized. This gave the product (6.4 mg) with a molecular weight of 414.5 g/mol (C21H26N4O3S); MS (ESI): m/e=415 (M+H+).
Reaction SMILES: [CH:1]([O:4]P(O)OC(C)C)(C)[CH3:2].[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:11][N:12]([C:1](=[O:4])[CH3:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNc1ccccc1
Reactant: CC(C)OP(O)OC(C)C
Product: CC(=O)N(C)c1ccccc1
Yield: 53 %

Procedure:
Example 34 was repeated, except that 0.05 mole of phosphorous diisopropyl ester was used in place of phosphorous monoethyl ester and 0.05 mole of N-methylaniline was used in place of aniline, to obtain N-methylacetanilide, yield 53% based on N-methylaniline.