Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[O:20][C:14]4=[C:15]([NH2:19])[N:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C(=O)N([I:28])C(=O)C1>CN(C=O)C>[I:28][C:18]1[CH:17]=[N:16][C:15]([NH2:19])=[C:14]2[O:20][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)=[CH:12][C:13]=12
Reactant: Nc1nccc2cc(-c3cccc4cnccc34)oc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2cc(-c3cccc4cnccc34)oc12
Reaction time: 0.08 h
Yield: 84.1 %

Procedure:
A suspension of 2-(isoquinolin-5-yl)furo[2,3-c]pyridin-7-amine (5.6 g, 21.5 mmol) in DMF (250 mL) was treated with NIS (8.73 g, 38.6 mmol) added portionwise with stirring over a period of 5 min. The mixture was stirred at RT overnight. The reaction was quenched with aqueous Na2S2O3, diluted with EtOAc (1 L) and the phases separated. The organic layer was concentrated in vacuo. Water was added to the residue resulting in the formation of a solid after stirring overnight. The material was collected by filtration and the filter cake was washed with water and hexane. The material was dried over P2O5 at 50° C. in a high vacuum oven to provide 7.0 g (84%) of the title compound as a brown solid. 1H NMR (300 MHz, CDCl3+CD3OD): δ 6.92 (s, 1H), 7.70 (t, J=8.1 Hz, 1H), 7.98 (s, 1H), 8.11 (t, J=7.5 Hz, 2H), 8.20 (d, J=6.0 Hz, 1H), 8.53 (d, J=6.0 Hz, 1H), 9.24 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,4,6-trichloroaniline to yield 2-[(2,4,6-trichlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:15]=[C:5]2[C:6](Br)=[CH:7][CH:8]=[C:9]([C:10]([OH:13])([CH3:12])[CH3:11])[N:4]2[N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.O>[NH2:1][C:2]1[N:15]=[C:5]2[C:6]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)=[CH:7][CH:8]=[C:9]([C:10]([OH:13])([CH3:12])[CH3:11])[N:4]2[N:3]=1
Reactant: CC(C)(O)c1ccc(Br)c2nc(N)nn12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(-c2ccc(Cl)cc2)c2nc(N)nn12
Temperature: 25 °C

Procedure:
To a solution of 2-(2-amino-8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-propan-2-ol (contaminated with ketone) (120 mg, 0.443 mmol) and 4-chlorophenyl boronic acid (155 mg, 0.987 mmol) in dioxane (6 mL) was added aqueous solution of Na2CO3 (2 M, 0.72 mL) and degassed with argon for 5 minute. To this was added PdCl2 (dppf)2.CH2Cl2 (30.34 mg, 0.04 mmol) and stirred at 90° C. for 90 minutes. The reaction mixture was cooled to room temperature and water (20 mL) was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off white solid (65 mg, 48%) which was contaminated with 1-[2-amino-8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-ethanone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Br:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27](I)=[CH:26][C:25]=1[F:32].C(=O)([O-])[O-].[Cs+].[Cs+]>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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27]2[CH:26]=[C:25]([F:32])[C:24]([Br:23])=[CH:29][C:28]=2[CH3:30])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(Br)c(F)cc1I
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(F)c(Br)cc1C
Temperature: 110 °C
Yield: 86.5 %

Procedure:
A pressure tube was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (2.31 g, 7.37 mmol), 1-bromo-2-fluoro-4-iodo-5-methylbenzene (2.79 g, 8.84 mmol, Oakwood Chemicals), XantPhos (0.213 g, 0.369 mmol), Pd2(dba)3 (0.169 g, 0.184 mmol), and cesium carbonate (6.00 g, 18.43 mmol). The whole was purged with argon. Then toluene (14.74 ml) was added. The tube was sealed and heated in the heating block at 110° C. for 17 h. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through celite with an aid of EtOAc. The filtrate was concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 0% to 30% EtOAc in heptane, to provide (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methylphenyl)amino)phenyl)acrylate (3.19 g, 86% yield) as yellow solid. m/z (ESI) [M+H]+=500.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.09 Hz, 3 H) 2.04 (s, 3 H) 4.04 (q, J=7.11 Hz, 2 H) 4.16 (s, 2 H) 6.27 (d, J=11.05 Hz, 1 H) 6.47 (d, J=15.94 Hz, 1 H) 6.78 (d, J=8.41 Hz, 1 H) 7.09-7.26 (m, 6 H) 7.34 (dd, J=8.02, 0.68 Hz, 1 H) 7.53-7.66 (m, 3 H).
Reaction SMILES: O[CH2:2][NH:3][CH:4]=[O:5].[CH2:6]([O:8][P:9]([O:13]CC)[O:10][CH2:11][CH3:12])[CH3:7]>C(O)C>[CH2:6]([O:8][P:9]([CH2:2][NH:3][CH:4]=[O:5])(=[O:13])[O:10][CH2:11][CH3:12])[CH3:7]
Reactant: CCOP(OCC)OCC
Reactant: O=CNCO
Solvent: CCO
Product: CCOP(=O)(CNC=O)OCC

Procedure:
The mole ratio of N-(hydroxymethyl)formamide to triethylphosphite in step (2) of the process of the invention is 1:1. The reaction is conducted in the presence of heat and at a temperature sufficient to cause the reaction to go to completion. The reactants are heated until ethyl alcohol starts to evolve and this occurs at reflux temperature. When triethylphosphite is used, this temperature is approximately 120°-125° C. At this point, the alcohol is distilled off, leaving the product diethyl-N-(formyl)aminomethylphosphonate as the residue.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C(OC1C=CC(O)=CC=1)C1C=CC=CC=1>N1C(C)=CC(C)=CC=1C.C(OCC)(=O)C>[S:5]1[CH:6]=[CH:2][C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]1=2
Reactant: Brc1csc2ccccc12
Agent: Oc1ccc(OCc2ccccc2)cc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: c1ccc2sccc2c1
Yield: 28 %

Procedure:
To a solution of 3-bromo-benzo[b]thiophene (69.62 g, 0.325 mol) in 55 mL of anhydrous collidine under N2 was added 4-benzyloxyphenol (97.6 g, 0.488 mol) and cuprous oxide (23.3 g, 0.163 mol). The mixture was heated to reflux for 24 hours. Upon cooling, the reaction mixture was diluted with ethyl acetate (200 mL) and the crude mixture filtered through a pad of Celite® (Aldrich, Milwaukee, Wis.) to remove inorganic salts. The filtrate was washed with 1N hydrochloric acid (3×150 mL). The organic was dried (sodium sulfate) and concentrated in vacuo to a liquid. Thianaphthene was removed by distillation (10 mm Hg, 115-120° C.). The remainder of the material was chromatographed (silicon dioxide, hexanes: ethyl acetate 85:15) to provide 12.2 g of benzo[b]thiophene and 12.95 g (35% based on recovered starting material) of [3-(4-benzyloxy)phenoxy]benzo-[b]thiophene as an off-white solid. mp 84-86° C. 1H NMR (CDCl3) d 7.91-7.83 (m, 2H), 7.47-7.34 (m, 7H), 7.04 (q, JAB =9.0 Hz, 4H), 6.47 (s, 1H), 5.07 (s, 2H). Anal. Calcd. for C21H16O2S: C, 75.88; H, 4.85. Found: C, 75.75; H, 5.00.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].COB(OC)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([S:31]([NH:34][C:35]3[C:40]([O:41][CH3:42])=[N:39][C:38]([CH3:43])=[CH:37][N:36]=3)(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1.C(O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:42][O:41][C:40]1[C:35]([NH:34][S:31]([C:30]2[C:25]([C:22]3[CH:23]=[CH:24][C:19]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[CH:20][CH:21]=3)=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:33])=[O:32])=[N:36][CH:37]=[C:38]([CH3:43])[N:39]=1
Reactant: COB(OC)c1cccnc1
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(-c2cccnc2)cc1
Temperature: 85 °C
Yield: 36.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (25 mg) was added to a deoxygenated solution of sodium carbonate (223 mg), dimethoxy-(3-pyridyl)borane (116 mg) and 2-(4-iodophenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (828 mg) in a mixture of water (1.8 ml), ethanol (3 ml) and toluene (6 ml). The mixture was stirred and heated under argon at 85° C. for 17 hours and then allowed to cool to ambient temperature. Water was added and the reaction mixture was washed three times with ethyl acetate. The aqueous layer was acidified to pH 7 with 2M hydrochloric acid and extracted six times with ethyl acetate. These extracts were combined, washed with saturated sodium chloride solution then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-8% methanol/dichloromethane to give N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[3-pyridyl]phenyl)pyridine-3-sulphonamide (123 mg) as a solid; 1H NMR (CDCl3): 2.3 (s, 3H), 3.7 (s, 3H), 7.3-7.7 (m, 7H), 7.92 (m, 1H), 8.55-8.75 (m, 2H), 8.8 (dd, 1H), 8.9 (d, 1H); mass spectrum (+ve ESP): 434 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:14])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25](I)[CH3:26]>CN(C=O)C.O>[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[N:17]([CH2:25][CH3:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:14])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCI
Reactant: CN(Cc1cc2ccccc2[nH]1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(CN(C)C(=O)OCc2ccccc2)cc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
NaH (60% dispersion in mineral oil, 0.25 g, 7.1 mmole) was added portionwise, allowing for gas evolution, to a solution of 2-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole (1.40 g, 4.75 mmole) in DMF (35 mL) at 0° C. When the NaH addition was complete, ethyl iodide (0.42 mL, 5.2 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated to afford the title compound (1.30 g, 87%) as an orange solid: MS (ES) m/e 323 (M+H)+.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[Cl:15][C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH2:39][CH2:40]Cl)[CH2:35][CH2:34]3)[C:18]=2[CH:17]=1.[OH:42][C:43]1[CH:57]=[CH:56][C:46]([O:47][CH2:48][C@@H:49]([OH:55])[CH2:50][NH:51][CH:52]([CH3:54])[CH3:53])=[CH:45][CH:44]=1.[OH-].[Na+]>CS(C)=O>[CH3:54][CH:52]([NH:51][CH2:50][C@H:49]([OH:55])[CH2:48][O:47][C:46]1[CH:45]=[CH:44][C:43]([O:42][CH2:40][CH2:39][N:36]2[CH2:35][CH2:34][N:33]([CH2:32][CH2:31][CH2:30][N:19]3[C:18]4[CH:17]=[C:16]([Cl:15])[CH:29]=[CH:28][C:27]=4[S:26][C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:38][CH2:37]2)=[CH:57][CH:56]=1)[CH3:53]
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CC(C)NC[C@H](O)COc1ccc(O)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)NC[C@H](O)COc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a mixture of the dihydrochloride salt of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (12.4 g) and (S)-1-(4-hydroxyphenoxy)-3-(1-methylethyl)amino-2-propanol (6.2 g) in 100 ml dimethylsulfoxide was added 15.25 ml of 5N sodium hydroxide solution and the mixture was stirred under argon for 2 hours at 50°. The reaction was worked up as in method A to give 14.7 g of the crude (S)-1-(1-methylethylamino)-3-[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]piperazin-1-yl]ethoxy]phenoxy]-2-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][OH:13])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:31]3[CH:30]=[N:29][CH:28]=[N:27][C:26]=3[N:25]([CH:32]([CH3:34])[CH3:33])[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:12][OH:13])[C:9]([NH:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]([C:23]3[C:31]4[CH:30]=[N:29][CH:28]=[N:27][C:26]=4[N:25]([CH:32]([CH3:34])[CH3:33])[CH:24]=3)=[O:22])[CH:16]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C(CO)c1ccc(Cl)cc1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)C(CO)c3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 3 %

Procedure:
2-(4-Chloro-phenyl)-3-hydroxy-propionic acid (570 mg, 2.84 mmol) (Preparation 244) was added to a solution of (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (200 mg, 0.71 mmol) (Preparation 95) in THF (5 mL). Di-isopropyl ethylamine (0.64 mL, 3.56 mmol), EDCI.HCl (273 mg, 1.42 mmol) and HOBT (193 mg, 1.42 mmol) were added and the mixture was stirred at 25° C. for 48 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by preparative TLC (dichloromethane:methanol 93:7) to afford the title compound as a yellow solid in 3% yield, 10 mg.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:32][C:33]([O:35][CH2:36]I)=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:36][O:35][C:33]([O:32][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)(C)COC(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)OCC(C)(C)C)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 92.6 %

Procedure:
In the same manner as in Example 81, 193 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 129 mg of neopentyloxycarbonyloxymethyl iodide.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[C@H:14]2[CH3:35])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:38]Br>C(Cl)(Cl)Cl>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30](=[O:34])[CH:31]([Br:38])[CH2:32][CH3:33])[C@H:14]2[CH3:35])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CCCC(=O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCC(Br)C(=O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-butyryl-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (300 mg, 0.554 mmol) in CHCl3 (3 mL) at 0° C. under N2, was added dropwise a solution of bromine (0.030 mL, 0.582 mmol) in CHCl3 (2 mL). The reaction was stirred at 0° C. for 1 h. The reaction mixture was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-bromobutanoyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS calc.=622.0; found=621.7 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.91 (s, 1H); 7.85 (d, J=5.1 Hz, 1H); 7.83-7.77 (m, 2.5H); 7.74-7.69 (m, 1.5H); 5.79 (d, J=7.8 Hz, 0.5H); 5.74 (d, J=7.9 Hz, 0.5H); 5.06-4.92 (m, 2H); 4.57 (d, J=16.4 Hz, 0.5H); 4.47 (d, J=16.0 Hz, 0.5H); 4.24-4.16 (m, 1H); 2.35-2.25 (m, 1H); 2.19-2.09 (m, 1H); 1.18-1.16 (m, 3H); 0.80 (d, J=6.6 Hz, 1.5H); 0.78 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: [CH:1]1[C:15](=[O:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.C1C=CN=CC=1.[FH:23].C([O-])([O-])=O.[Ca+2]>O1CCOCC1>[F:23][C@@H:5]1[C@H:6]([OH:11])[C@@H:7]([CH2:9][OH:10])[O:8][C@H:4]1[N:3]1[CH:2]=[CH:1][C:15](=[O:16])[NH:14][C:13]1=[O:12]
Reactant: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Reactant: F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Temperature: 0 °C
Yield: 79 %

Procedure:
The title compound is prepared via a modification of a literature procedure, J. Fox, et al., J. Org. Chem., Vol. 29, pp. 558-564 (1964). Thus, 2,2′-cyclouridine (5.65 g, 25 mmol) is treated with a solution of 70% hydrogen fluoride/pyridine (65 mL) in anhydrous dioxane (500 mL) at 120° C. in a sealed steel vessel for twenty hours. The reaction mixture is cooled to ice temperature, poured into ice (400 mL), and the pH is adjusted to 7 by addition of solid CaCO3. After the solvent is evaporated in vacuo (1 torr), the residue is dissolved in methanol, adsorbed onto silica gel, and purified by column chromatography using silica and ethyl acetatemethanol (v/v, 20:1) as eluent to give 2′-deoxy-2′-fluoro-uridine as a white solid (4.81 g, 79%). The 5′-DMT and 3′-cyanoethoxy-diisopropyl phosphoramidite derivatized nucleoside are obtained in accordance with the procedures of examples 65 and 66.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([Br:23])[CH:20]=[C:19]([Br:24])[C:18]=3[NH2:25])[CH2:12][CH2:11]2)=[O:8])[CH2:3][CH2:2]1.[C:26]([Cl:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(OC(C)C)(C)C>N1C=CC=CC=1>[ClH:34].[O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([Br:23])[CH:20]=[C:19]([Br:24])[C:18]=3[NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:12][CH2:11]2)=[O:8])[CH2:3][CH2:2]1
Reactant: Nc1c(Br)cc(Br)cc1CN1CCN(CC(=O)N2CCOCC2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Product: O=C(Nc1c(Br)cc(Br)cc1CN1CCN(CC(=O)N2CCOCC2)CC1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 0.423 part of N1 -(morpholinocarbonylmethyl)-N4 -(2-amino-3,5-dibromobenzyl)piperazine in 4 volume parts of pyridine is added 0.25 part of benzoylchloride, and the mixture is kept standing overnight at room temperature. The solvent is distilled off, and residue is chromatographed over alumina. Ethyl acetate eluates gives oily substance. The resultant oily substance is treated with ethanolic hydrochloric acid, and to the resultant is added isopropyl ether to give N1 -morpholinocarbonylmethyl-N4 -(2-monobenzoylamino-3,5-dibromobenzyl)piperazine hydrochloride melting at 162° to 164° C.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.Cl.[C:12]([NH:16][NH2:17])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(O)C>[C:12]([N:16]1[C:9]([NH2:10])=[C:6]([C:7]#[N:8])[C:4]([CH3:5])=[N:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NN
Reactant: CCOC(C)=C(C#N)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 148.1 %

Procedure:
To a slurry of 1-ethoxyethylidene malononitrile (68.0 g, 0.5 mol), tert-butylhydrazine hydrochloride (62.3 g, 0.5 mol) in ethanol (500 ml) was added triethylamine (70 ml, 0.5 mol). The reaction mixture was stirred at room temperature for 2 hours, cooled in an ice-bath and a solid was collected by filtration and was washed with ether. The mother liquor was concentrated and the solid residue was recrystallized from ethanol. The two solid fractions were combined and dried at 65° C. in high vacuum for 24 hours to afford 132 g of 1-tert-butyl-3-methyl-5-amino-1H-pyrazole-4-carbonitrile as a white solid which is contaminated with triethylamine hydrochloride (approximately 2/3 mol).
Reaction SMILES: [OH:1][CH:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]([O:15][CH3:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12]>[OH-].[Na+].CO>[OH:1][CH:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]([O:15][CH3:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCCCCCCCC(O)C(CCCCCCCC(=O)OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)C(CCCCCCCC(=O)O)OC

Procedure:
The methyl 10-hydroxy-9-methoxyoctadecanoate (3) (4.0 g; 0.012 mol) was dissolved in 1N methanol sodium hydroxide solution (100 mL) (Aldrich) and heated under reflux for 12 h. The methanol was removed from the reaction mixture and the crude product was dissolved in 100 mL water. The aqueous solution was neutralised with hydrochloric acid (Aldrich) and the product extracted with 3×50 mL dichloromethane (J. T. Baker). The dichloromethane solution was washed with 3×50 mL water and dried over anhydrous sodium sulfate (J. T. Baker). The dichloromethane solution was filtered and the solvent was removed to obtain the intermediate compound 4.