Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][C:18]([OH:20])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:21]([C@H:24]1[C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][C:26](=[S:41])[NH:25]1)([CH3:23])[CH3:22].P([O-])(O)(O)=O.[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][C:18]([N:25]1[C@@H:24]([CH:21]([CH3:23])[CH3:22])[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:27][C:26]1=[S:41])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOCCCCCC/C=C/CC(=O)O
Reactant: CC(C)[C@@H]1NC(=S)OC1(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCOCCCCCC/C=C/CC(=O)N1C(=S)OC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere, (E)-10-heptyloxy-dec-3-enoic acid obtained in Step C-3 (209.7 mg, 0.698 mmol) and a commercially available reagent of (S)-4-isopropyl-5,5-diphenyl-oxazolidine-2-thione (207.5 mg, 0.698 mmol) were dissolved in dichloromethane (3.13 mL), and the mixture was cooled to 0° C. While maintaining the temperature at 0° C., N,N-dimethyl-4-aminopyridine (8.5 mg, 0.0698 mmol) and WSCl (173.9 mg, 0.907 mmol) were added in order. The mixture was stirred at 0° C. for 2.0 minutes and at room temperature for 16 hours. To the reaction solution was added an aqueous solution (4.2 mL) of 10% sodium dihydrogen phosphate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine in order, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The resulting residue was then purified with SP1 (SiO2 cartridge, 10% ethyl acetate/n-hexane, Rf=0.6) to obtain (E)-10-heptyloxy-1-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidin-3-yl)-dec-3-en-1-one (No. 6804254; 336.2 mg, 3 steps, 75% yield).
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:14]>ClCCl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13](=[O:14])[NH2:3])=[CH:17][CH:18]=1
Reactant: CCN(CC)c1ccccc1
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccc(OC(N)=O)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 256.4 %

Procedure:
Diethylaniline (0.33 μL, 2.1 μmol, 1.1 equiv) and 4-methoxyphenyl chloroformate (0.85 μL, 5.7 μmol, 3.0 equiv) were added separately, each in one portion, to a stirred solution of the amine (1.0 mg, 1.9 μmol, 1 equiv) in dichloromethane (0.15 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred at 0° C. for 40 min, then was quenched by the addition of a 1:1 mixture of water and saturated aqueous sodium hydrogen carbonate solution (3 mL). The mixture was extracted with ethyl acetate (2×10 mL) and the combined organic layer was washed with a 1:1 mixture of brine solution and saturated aqueous sodium hydrogen carbonate solution (5 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to leave a colorless oil. Purification by flash column chromatography (50% 70→% ethyl acetate-hexanes) gave the carbamic acid 4-methoxyphenyl ester derivative (0.9 mg, 70%) as a white solid.
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:22][C:6]2=[CH:7][C:8]3[C:9]([CH3:21])([CH3:20])[C:10](=[O:19])[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=3[CH:13]=[C:5]2[N:4]=1.[BH4-].[Na+].[CH3:25]O>O>[CH3:20][C:9]1([CH3:21])[C:8]2[CH:7]=[C:6]3[NH:22][C:3]([NH:2][CH3:25])=[N:4][C:5]3=[CH:13][C:12]=2[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]1=[O:19]
Reactant: CO
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC)nc3cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Freshly cut sodium (300 mg) is dissolved in dry MeOH (12 ml) and D5 (700 mg) is added and the mixture stirred for 5 min. Then p-formaldehyde (102 mg; 3.4 mmol) is added and the mixture stirred for 20 h at RT. After the addition of NaBH4 (93 mg; 2.46 mmol) the solution is heated under reflux for 2 h, cooled to RT and diluted with water. The aqueous layer is extracted with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4 and concentrated in vacuo. The compound (700 mg) is obtained by flash chromatography on silica gel eluted with CH2Cl2/MeOH (95:5).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][CH2:41][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCCN1CCOCC1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CCOCC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
In a 2-(5 mL Biotage microwave vial were mixed N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, 113 μmol), 4-(3-chloropropyl)morpholine (55.5 mg, 339 μmol, Eq: 3.0) and Cs2CO3 (147 mg, 452 μmol) in DMF (2 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min. Then, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-morpholinopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (62 mg, 94.2 μmol, 83.4%) as an off-white solid. MS (M+Na)+=680; 1H NMR (CDCl3) δ: 9.23 (s, 1H), 8.36 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.05 (s, 1H), 7.59 (d, J=9.1 Hz, 1H), 7.35 (dd, J=8.9, 2.1 Hz, 1H), 6.55 (t, J=74.4 Hz, 1H), 5.75 (s, 2H), 4.61 (t, J=6.4 Hz, 2H), 3.75 (br. s., 4H), 3.55-3.66 (m, 2H), 2.45 (br. s., 6H), 2.25 (br. s., 2H), 1.65 (s, 9H), 0.90-1.06 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[C:6]([O:11]CC)(=O)[CH:7]([CH3:9])[OH:8]>C(O)C>[C:6]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:11])[CH:7]([CH3:9])[OH:8]
Reactant: CCOC(=O)C(C)O
Reactant: CC(O)CN
Solvent: CCO
Product: CC(O)CNC(=O)C(C)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
22.6 g 1-amino-2-propanol was added to 56.5 g ethyl lactate at room temperature. The mixture was heated to reflux and stirred for 4 hours. The reaction mixture was cooled and left to stand overnight at room temperature. The following day the ethanol formed and the excess of ethyl lactate were removed from the reaction mixture by distillation, using a 20 cm vigreux column 43 g of N-lactoyl 1-amino-2-propanol (pale brown viscous liquid) was collected as residue and cooled to room temperature. The purity of the obtained product was confirmed by NMR analysis.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21][C:20]([S:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]3[C:31]([NH:33][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)=[O:32])(=[O:24])=[O:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[S:21][C:20]([S:22]([N:25]3[CH2:30][CH2:29][N:28]([C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:9])[CH2:27][C@@H:26]3[C:31]([NH:33][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)=[O:32])(=[O:23])=[O:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NOC1CCCCO1)[C@H]1CN(C(=O)Nc2ccccc2)CCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.1 %

Procedure:
A solution of phenyl isocyanate (38 mg) in CHCl3 (1 ml) was added to a solution of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150 mg) in CHCl3 (3 ml). After stirring for 30 minutes at ambient temperature, the reaction mixture was concentrated in vacuo to give 203 mg of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-[(N-phenyl)aminocarbonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as an amorphous powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.O.[Sn](Cl)Cl>CO>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:11])=[N:4][CH:5]=1
Reactant: O=[N+]([O-])c1cnc(F)c(Br)c1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1cnc(F)c(Br)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 3-bromo-2-fluoro-5-nitropyridine from step 131a above (5.0 g, 23 mmol) in MeOH (100 mL) was added tin(II) chloride dihydrate. The mixture was heated at reflux for 3 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with saturated aqueous NaHCO3 and EtOAc resulting in formation of an emulsion which was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Purification by chromatography (silica gel; hexane/EtOAc, 70:30) afforded 3.61 g (83%) of the title compound as a yellow solid: mp 91-92° C.; 1H NMR (CDCl3, 300 MHz) δ 7.15 (dd, J=2.5, 7.5 Hz, 1H), (dd, J=2.0, 2.5 Hz, 1H); MS (CI/NH3) m/z 191, 193 (M+H)+ 208, 210 (M+NH4)+.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:42])[C@@H:24]([NH:25][C:26](=[O:41])[CH2:27][C:28]4[N:29]=[C:30]([NH:33]C(OC(C)(C)C)=O)[S:31][CH:32]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:43][CH:44](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:45][C:46]2[N:47]=[N:48][NH:49][CH:50]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:33][C:30]1[S:31][CH:32]=[C:28]([CH2:27][C:26]([NH:25][C@@H:24]2[C:23](=[O:42])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:43][CH2:44][S:45][C:46]4[N:47]=[N:48][NH:49][CH:50]=4)[CH2:19][S:20][C@H:21]23)=[O:41])[N:29]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4c[nH]nn4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: Nc1nc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCSc4c[nH]nn4)CS[C@H]23)cs1
Reaction time: 0.83 h
Yield: 59.1 %

Procedure:
To a solution of 7β-[2-(2-t-butoxycarbonylaminothiazol-4-yl)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (779 mg: 0.784 mMol.) in a mixture of anisole (3 ml) and nitromethane (12 ml) at -40° C. is added a solution of aluminum chloride (0.83 g: 6.24 mMol.) in anisole (3 ml), and the mixture is stirred at -30° to -40° C. for 50 minutes. The reaction mixture is mixed with 1N-hydrochloric acid (6.3 ml), diluted with water, washed with ethyl acetate, and concentrated under reduced pressure to remove the remaining organic solvents. The residual solution is subjected to the chromatography over styrene-divinylbenzene copolymer (methanol: water=4:1) and resulting powder is washed with ethyl acetate to give 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid (225 mg) as white powder. Yield: 59%.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4](C(O)=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:30])=CC=1.C([N:42]([CH2:45]C)CC)C>CC(O)(C)C>[F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]2[NH:42][C:45](=[O:30])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:3]=12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Reactant: CCN(CC)CC
Solvent: CC(C)(C)O
Product: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(I)cc1F
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid (70 mg, 0.17 mmol) in t-BuOH (3 mL) was added DPPA (82 mg, 0.29 mmol) followed by triethylamine (36 mg, 0.36 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (white solid, 62 mg, 89.2% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.67 (s, 1H), 7.96 (d, 1H), 7.76 (d, 1H), 7.50 (m, 1H), 7.39 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(NC(=O)C2C=CC=NC=2NC2CC(C)(C)NC(C)(C)C2)C=CC=1.[CH2:51](Cl)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.BrCCO>>[CH2:51]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:23])[CH2:18]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: ClCc1ccccc1
Reactant: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@H]1CCCNC1
Agent: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1
Agent: OCCBr
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@H]1CCCN(Cc2ccccc2)C1
Yield: 68.2 %

Procedure:
The title compound was prepared in the same manner as in Example 21, with the exception that (S)—N-(3-chlorophenyl)-2-(3-piperidylamino)nicotinamide of Example 20-B, instead of N-(3-chlorophenyl)-2-(2,2,6,6-tetramethylpiperidin-4-ylamino)nicotinamide, and benzylchloride, instead of 2-bromoethanol, were used in the same molar amounts (Yield: 68.2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:17])([CH3:16])[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12].C(NC(C)C)(C)C.[Li].[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:17])([CH3:16])[CH2:9][CH:10]([C:11]([F:13])([F:14])[F:12])[O:15][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CC(O)C(F)(F)F)c1ccccc1Br
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a round bottom flask was added 4-(2-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-ol (1.76 g, 5.66 mmol) in 30 mL of dry THF at 0° C. under nitrogen, followed by the dropwise addition of a solution of 2 M lithium diisopropylamine in THF (5.7 mL, 11.4 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, followed by the addition of tert-butyldimethylsilyl chloride (4.26 g, 28.3 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then concentrated, diluted with 500 mL of ethyl acetate, and washed with 100 mL of saturated sodium bicarbonate solution. The organic phase was separated, washed with 100 mL of water, 100 mL of brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography. The column was eluted with hexane to afford 875 mg (36%) of [3-(2-bromophenyl)-3-methyl-1-trifluoromethylbutoxy]-tert-butyldimethylsilane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[C:16]([OH:18])[C:15]([CH3:19])=[CH:14][C:12]=1[NH2:13]>>[CH3:10][C:11]1[CH:17]=[C:16]([OH:18])[C:15]([CH3:19])=[CH:14][C:12]=1[NH:13][C:2]1[N:7]=[C:6]([NH:13][C:12]2[CH:14]=[C:15]([CH3:19])[C:16]([OH:18])=[CH:17][C:11]=2[CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: Fc1cnc(Cl)nc1Cl
Product: Cc1cc(Nc2ncc(F)c(Nc3cc(C)c(O)cc3C)n2)c(C)cc1O

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2,5-dimethyl-4-hydroxyaniline were reacted to yield N2,N4-bis(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.63 (d, 1H, J=4.2 Hz), 7.05 (s, 1H), 6.97 (s, 1H), 6.64 (1H), 6.54 (s, 1H), 2.12 (s, 6H), 2.06 (s, 3H), 2.03 (s, 3H), 2.03 (s, 3H); 19F NMR (CD3OD): −48488; LCMS: ret. time: 18.28; purity; 94%; MS (m/e): 369 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:39].[CH2:50]([N:52]([CH2:55]C)[CH2:53][CH3:54])[CH3:51].N1CCCC1>O1CCCC1>[N:52]1([C:55]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[CH:12]=[C:11]([C:13]4[CH:36]=[CH:35][C:16]5[N:17]([C:20]6[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:23]=[CH:24][CH:25]=6)[CH:18]=[N:19][C:15]=5[CH:14]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)=[O:39])[CH2:53][CH2:54][CH2:51][CH2:50]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Agent: Cl
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCN(C(=O)N6CCCC6)CC5)c4)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt (20.0 mg, 0.0385 mmol) in tetrahydrofuran (1 mL) was added p-nitrophenyl chloroformate (12 mg, 0.058 mmol), triethylamine (16 μL, 0.12 mmol). The solution was stirred at r.t. for 1 h, then pyrrolidine (6.4 μL, 0.077 mmol) was added. The reaction solution was stirred at r.t. overnight, and then heated at 100° C. 2 h. LC/MS analysis showed reaction was finished. The reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=581.3
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][O:10][CH3:11].C([Li])CCC.CON(C)[C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30]>C1COCC1.CCCCCC>[CH3:11][O:10][CH:9]=[CH:8][C:3]1[CH:4]=[CH:5][C:6]([C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])=[CH:7][CH:2]=1
Reactant: C=CCCCCCCCCC(=O)N(C)OC
Reactant: COC=Cc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCCCCCCCCC(=O)c1ccc(C=COC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-bromo-(2-methoxyethenyl)benzene (2.13 g) in THF (20 ml) at -78° is added dropwise a 2.5M solution of n-butyllithium in hexane (4.2 ml). The temperature is not allowed to rise above -55°. After 90 min, a solution of N-methoxy-N-methyl-10-undecenamide (2.3 g) in THF (5 ml) is added dropwise, and the mixture stirred an additional 60 min at -78°. The mixture is not allowed to warm, but is immediately quenched by the addition of 10% aqueous citric acid. The mixture is extracted with dichloromethane, and the extracts are dried, filtered, and concentrated. The crude product is chromatographed with 1:1 dichloromethanehexane, to provide 1-(4-(2-methoxyethenyl)phenyl)-10-undecen-1-one as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[NH:4][C:3]1=[O:13].[C:14](=O)([O-])[O-].[K+].[K+].CI>COCCOC.O>[CH3:14][N:4]1[C:5]([C:9]([F:10])([F:12])[F:11])=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]1=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)cc(C(F)(F)F)[nH]c1=O
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(C)c1=O
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a suspension of 3-methyl-6-(trifluoromethyl)uracil (20.6 mmol, 4.0 g) and powdered potassium carbonate (41.2 mmol, 5.7 g) in DME (30 mL) was added methyl iodide (82.4 mmol, 5.13 mL). Then, the reaction mixture was refluxed for 4 h at which time the TLC analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). Then, the DME was removed under reduced pressure to afford a white suspension. The solids were collected by filtration and washed with water. After air drying, 3.55 g (83% yield) of 1,3-dimethyl-6-(trifluoromethyl)uracil was obtained as a white solid: mp 85-87° C. EI-HRMS m/e calcd for C7H7F3N2O2 (M+) 208.0459, found 208.0460.
Reaction SMILES: C([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)C.[N+:16]([O-:19])(O)=[O:17].Cl[C:21]1C=CC=C[C:22]=1Cl>>[N+:16]([CH2:21][CH2:22][C:5]1[C:4]2[NH:3][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:19])=[O:17]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: Clc1ccccc1Cl
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])CCc1cccc2c1[nH]c1ccccc12

Procedure:
Into a flask were charged 100 g of 9-ethylcarbazole and 245 g of o-dichlorobenzene, and then nitration was carried out using nitric acid. The reaction solution was neutralized, and the oil layer separated was washed with water to provide 370 g of an o-dichlorobenzene solution of nitroethylcarbazole. The yield of 3-nitro-9-ethylcarbazoic was 90%. The resulting solution contained 110 g of 3-nitro-9-ethylcarbazole, 8 g of 1-nitro-9-ethylcarbazole. The content of the nitrate was 250 ppm.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=O)(C)(C)C.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:20]=[C:21]([S:25]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.[CH2:39](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)[C:40]1[CH:45]=CC=C[CH:41]=1>>[CH2:6]([NH:8][C@H:9]([C:14]([NH:36][C@@H:33]1[C@@H:31]2[C@@H:30]([CH2:29][N:28]([S:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:37])[F:38])[CH:20]=3)(=[O:26])=[O:27])[CH2:32]2)[CH2:35][CH2:34]1)=[O:16])[CH2:10][CH2:11][CH3:13])[C:40]([CH3:45])([CH3:41])[CH3:39]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCC[C@H](NCC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-2-(Neopentylamino)pentanoic acid from Step A of Example 246 for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step D of Example 252 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.38-8.39 (bs, 1H), 8.19-8.21 (m, 1H), 8.13-8.16 (m, 1H), 7.90-7.93 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 4.21-4.28 (m, 1H), 3.87 (dd, J=9.9, 2.8 Hz, 1H), 3.15-3.21 (m, 3H), 2.97 (dd, J=9.6, 7.3 Hz, 1H), 2.45-2.59 (m, 2H), 2.40 (d, J=11.2 Hz, 1H), 2.31 (d, J=11.2 Hz, 1H), 1.93-2.00 (m, 1H), 1.76-1.89 (m, 2H), 1.61-1.93 (m, 1H), 1.61-1.70 (m, 1H), 1.41-1.58 (m, 3H), 1.31 (ddt, J=9.4, 13.0, 6.5 Hz, 1H), 0.92 (s, 9H), 0.86 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 504 (M+H)+.