Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[C:9]([CH3:16])[C:8]=1[Br:17])(=[O:5])[CH3:4].[CH2:18](Br)[CH:19]=[CH2:20]>O1CCCC1>[CH2:20]([N:6]([C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[C:9]([CH3:16])[C:8]=1[Br:17])[C:3](=[O:5])[CH3:4])[CH:19]=[CH2:18]
Reactant: COc1c(C)cc(NC(C)=O)c(Br)c1C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C(C)=O)c1cc(C)c(OC)c(C)c1Br
Temperature: 0 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
Sodium hydride (1.1 g, 27 mmol, 60% dispersion in oil) contained in a round-bottom flask fitted with a reflux condenser was washed using dry hexanes, tetrahydrofuran (50 mL) was added, and the suspension was stirred at 0° C. under a nitrogen atmosphere. A solution of 4-acetamido-3-bromo-2,6-dimethylanisole (7.3 g, 27 mmol) dissolved in tetrahydrofuran (50 mL) was added dropwise using a canulla over about 0.5 h. Allyl bromide (4.85 mL, 84.8 mmoI) was added to the cold solution in one portion, and the mixture was warmed to 60° C. and held there for 17 h. The reaction mixture was quenched with saturated aq. ammonium chloride and extracted with diethyl ether. The combined extracts were washed with brine and dried (MgSO4). Removal of solvents and purification of the resulting viscous liquid by flash column chromatography using 1:3 ethyl acetate:hexanes as eluent gave N-allyl-4-acetamido-3-bromo-2,6-dimethylanisole (8, 8.7 g, 85% yield) as a viscous liquid. Spectral data: 13C NMR: δ 15.2, 16.3, 21.5, 50.1, 59.3, 117.1, 123.3, 129.2, 130.2, 132.37, 132.4, 136.5, 156.2, 169.1; HRMS: calcd. for C14H19BrNO2 (M+H+) 312.0599, fnd. 312.0586.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.Cl.[C:15]1([CH:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:29]1([CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[CH:6]3)[CH2:25][CH2:24]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCCCn1cnc2ccccc21
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: c1ccc(C(OC2CCN(CCCn3cnc4ccccc43)CC2)c2ccccc2)cc1

Procedure:
A mixture of 6 parts 1-(3-chloropropyl)-1H-benzimidazole, 7.6 parts of 4-(diphenylmethoxy)piperidine hydrochloride, 10.6 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethoxy)-1-piperidinyl]propyl}-1H-benzimidazole; mp. 110.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[S:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28]OC(OC)N(C)C.Cl.[CH2:37]([O:39][NH2:40])[CH3:38].[OH-].[Na+]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[S:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20]/[CH:28]=[N:40]/[O:39][CH2:37][CH3:38])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCON
Reactant: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCO/N=C/NC(=O)c1ccc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-2-methyl-benzamide (200 mg) and N,N-Dimethylformamide dimethylacetal (4 mL) was refluxed under Argon for one hour then the solution was concentrated in vacuo. The residue was dissolved in 1,4-dioxane (2 mL) and a solution of O-ethylhydroxylamine hydrochloride (2.8 eq.) and sodium hydroxide (6 eq.) in water (1.6 mL) and acetic acid (1.6 mL) was added. The solution was stirred at rt for 10 minutes. It was then quenched by addition of water and extracted with methyl tert-butyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated. Flash Chromatography eluting with Cyclohexane:EtOAc afforded 237 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1.CC(=CC)C.Cl([O-])=[O:21].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:21])=[O:14])=[CH:5][CH:4]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc(C=O)c2ccccc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
4-Methoxy-1-naphthaldehyde (10 g, 53.72 mmol) was dissolved in t-butanol (75 ml) and 2-methyl-2-butene (35 ml) was added at room temperature. A solution of sodium chlorite (7.99 g, 70.63 mmol) and sodium dihydrogen orthophosphate (9.15 g, 76.27 mmol) in water (50 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was washed with a solution of 2MHCl (100 ml) and the solid was filtered and washed with dichloromethane (100 ml) and water (100 ml) and dried in vacuo. The solid was recrystallised from methanol to give 5.95 g (55%) of 4-methoxy-1-naphthoic acid as cream crystals.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:13]=[O:14]>>[O-:13][OH:14].[CH:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=O
Agent: c1ccc(C2CCCCC2)cc1
Product: [O-]O

Procedure:
FIG. 1 is a flow diagram of a process for producing phenol and/or cyclohexanone according to a first example of the present application, in which a feedstock comprising cyclohexylbenzene is provided by line 102 to an oxidation reactor 106. A stream comprising oxygen, conveniently air, is also provided to the oxidation reactor 106 by way of line 104. Conditions within oxidation reactor 106 are such that cyclohexylbenzene in the feedstock is oxidized to form cyclohexylbenzene hydroperoxide. An oxidation catalyst, such as the heteroatom containing-compound N-hydroxyphthalimde (NHPI), may be also introduced to oxidation reactor 106, by means not shown in FIG. 1, to facilitate the oxidation reaction.
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C(OCC)(=O)C>[Pd].C(O)(C)C.O>[C:9]1([C:12]2([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][CH2:15]2)[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: O=C(O)C1(c2ccccc2)CCC1
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 73.7 %

Procedure:
A stirred suspension of palladium on carbon (3.6 g, 5%) in isopropanol (200 mL) was treated in one portion with a solution of ammonium formate (9 g) in water (12.5 mL) followed by a solution of 1-(4-chloro-phenyl)-cyclobutanecarboxylic acid (15 g) in isopropanol (150 mL) also in one portion. The resultant suspension was stirred at 65° C. for 30 minutes and then treated with a further aliquot of a solution of ammonium formate (9 g) in water (12.5 mL). After stirring at 65° C. for a further 4.5 hours the reaction mixture was filtered through Hyflo and the filter pad was washed three times with isopropanol (75 mL). The combined filtrate and washings were evaporated. The solid obtained after standing at room temperature for 3 days was treated with ethyl acetate (350 mL) and water (150 mL) and the organic phase was separated, then dried over magnesium sulfate and then evaporated to give the title compound (9.25 g) as a white solid. LC-MS: RT=3.08 minutes, MS(ES+): very weak 177(M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[CH2:13][N:12]2[N:8]([C:9](=[O:22])[CH:10]([NH:14]C(OC(C)(C)C)=O)[CH2:11]2)[C:7]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])=[O:5])C.[ClH:29].[C:30](O)(=O)[CH3:31]>>[ClH:29].[CH2:30]([C:4]([C:6]1[CH2:13][N:12]2[N:8]([C:9](=[O:22])[CH:10]([NH2:14])[CH2:11]2)[C:7]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])=[O:5])[CH3:31]
Reactant: CC(=O)O
Reactant: C=CCOC(=O)C1=C(C(=O)OCC)CN2CC(NC(=O)OC(C)(C)C)C(=O)N12
Agent: Cl
Product: C=CCOC(=O)C1=C(C(=O)CC)CN2CC(N)C(=O)N12
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, allyl 3-(ethyloxycarbonyl)-7-(R,S)-(t-butoxycarbonylamino)-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate (120 mg, 0.304 mmol) was combined with 3N hydrochloric acid in glacial acetic acid (5 ml) and the solution was stirred for 5 minutes then concentrated in vacuo. The resultant oil was dried in vacuo for 1.6 hours to yield allyl 3-(ethylcarbonyl)-7-(R,S)-amino-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=O)=[CH:5][CH:4]=1)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[S:42])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(NS(=O)(=O)c4ccccc4)ccc32)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CCC(=S)N2CCCc3cc(NS(=O)(=O)c4ccccc4)ccc32)cc1

Procedure:
4.9 g of 1-[3-(4-cyano-phenyl)propionyl]-6-phenylsulphonamido-1,2,3,4-tetrahydro-quinoline are dissolved in 110 ml of toluene and boiled with 2.5 g Lawesson reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide] for 1 hour at 110-120° C. Then the mixture is evaporated to dryness and the residue is chromatographed over a silica gel column with methylene chloride/ethyl acetate=19:1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[C:5]([CH3:17])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:30][O:31][C:32]1[CH:38]=[C:37]([C:39]2[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH:44]=2)[C:36]([N+:46]([O-:48])=[O:47])=[CH:35][C:33]=1[NH2:34]>CC(O)CCC>[CH3:30][O:31][C:32]1[CH:38]=[C:37]([C:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH:40]=2)[C:36]([N+:46]([O-:48])=[O:47])=[CH:35][C:33]=1[NH:34][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[C:5]([CH3:17])=[CH:4][N:3]=1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1N
Reactant: Cc1cnc(Cl)nc1-c1cnn2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCC(C)O
Product: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cnn3ccccc23)n1
Yield: 63.2 %

Procedure:
A solution of 3-(2-chloro-5-methylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 5, 271 mg, 1.00 mmol), p-toluene sulphonic acid monohydrate (271 mg, 1.43 mmol) and 2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 250 mg, 0.95 mmol) were heated in 2-pentanol (12 mL) at reflux under N2 for 30 h. The mixture was then concentrated in vacuo and the residue was dissolved in CH3OH. Purification by ion exchange chromatography (SCX column), eluting with 7M methanolic ammonia, gave the title compound (283 mg, 63%) as an orange powder after trituration with CH3CN. 1H NMR: 2.28-2.36 (5H, m), 2.44 (3H, s), 2.60 (2H, t), 3.00 (2H, d), 4.00 (3H, d), 5.64 (1H, s), 6.97 (1H, s), 7.13 (1H, m), 7.40 (1H, m), 8.27 (1H, s), 8.39 (1H, s), 8.53 (1H, d), 8.61 (1H, s), 8.83 (1H, d), 8.87 (1H, s); m/z: ES− MH− 470.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30]([N:34]1[CH:38]([CH3:39])[CH2:37][CH2:36][C@@H:35]1[C:40]([NH:42][CH:43]([CH3:45])[CH3:44])=[O:41])=[N:29][N:28]=[CH:27]2.C(O)C.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C.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>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([N:34]3[CH:38]([CH3:39])[CH2:37][CH2:36][C@@H:35]3[C:40]([NH:42][CH:43]([CH3:45])[CH3:44])=[O:41])=[N:29][N:28]=[CH:27]4)[CH:7]=2)=[O:22])[CH2:2][CH2:3]1
Reactant: CC(C)NC(=O)[C@H]1CCC(C)N1c1nncc2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3C(C)CC[C@@H]3C(=O)NC(C)C)nncc2c1
Reaction time: 0.17 h

Procedure:
N-Cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (64 mg, 212 μmol), tetrakis(triphenylphosphine)palladium (18 mg, 16 μmol), and (R)-1-(6-bromophthalazin-1-yl)-N-isopropyl-5-methylpyrrolidine-2-carboxamide (40 mg, 106 μmol) were dissolved/suspended in ethanol (2120 μl, 106 μmol) before potassium carbonate −1 M in water (424 μl, 424 μmol) was added to the vial which was then placed in the microwave for 10 min at 160° C. The reaction mixture was diluted with 75 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 3 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give crude. After purification by chromatography, the title compound was obtained. MS (ES+): 472 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[C:23]([O-])(=O)C.[Na+].C=O>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:2]2[NH:1][C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)[CH2:19][CH2:18]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Product: Fc1ccccc1N1CCN(Cc2cc3cccnc3[nH]2)CC1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol),1-(2-fluorophenyl)piperazine (72.0 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.62 (m, 4H) 3.14 (m, 4H) 4.03 (s, 2H) 5.60 (s, 1H) 7.09 (m, 3H) 7.14 (m, 2H) 8.06 (dd, J=8.31, 1.53 Hz, 1H) 8.20 (dd, J=4.75, 1.70 Hz, 1H). (ESI) m/z 311 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C=O)C.[NH2:15][C@H:16]([CH:27]1[CH2:30][CH2:29][CH2:28]1)[C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18].[Cl:31][C:32]1[N:39]=[C:38](Cl)[C:37]([F:41])=[CH:36][C:33]=1[C:34]#[N:35]>O>[Cl:31][C:32]1[N:39]=[C:38]([NH:15][C@H:16]([CH:27]2[CH2:28][CH2:29][CH2:30]2)[C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH3:18])[C:37]([F:41])=[CH:36][C:33]=1[C:34]#[N:35]
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@H](N)C1CCC1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)[C@H](Nc1nc(Cl)c(C#N)cc1F)C1CCC1
Reaction time: 3 h

Procedure:
DIPEA (17 ml) was added to a DMF (30 ml) solution containing tert-butyl ((1R,2S)-1-amino-1-cyclobutylpropan-2-yl)carbamate and 2,6-dichloro-5-fluoronicotinonitrile (16.2 g) obtained in the 5th step at 70° C., followed by stirring for 3 hours. The reaction solution was adjusted to room temperature and water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and the organic layers were dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 1:1). A white solid of tert-butyl ((1R,2S)-1-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-1-cyclobutylpropan-2-yl)carbamate (16.5 g) was thus obtained.
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].CN(C1C=CC=CN=1)C.[CH2:25]([C:27]([C:46]1[CH:51]=[CH:50][C:49](/[CH:52]=[CH:53]/[C:54]([C:60]([F:63])([F:62])[F:61])([OH:59])[C:55]([F:58])([F:57])[F:56])=[C:48]([CH3:64])[CH:47]=1)([C:30]1[CH:35]=[CH:34][C:33]([B:36]2[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:28][CH3:29])[CH3:26]>CN(C)C=O.O>[C:11]([Si:8]([CH3:10])([CH3:9])[O:59][C:54]([C:60]([F:63])([F:62])[F:61])([C:55]([F:56])([F:57])[F:58])/[CH:53]=[CH:52]/[C:49]1[CH:50]=[CH:51][C:46]([C:27]([C:30]2[CH:35]=[CH:34][C:33]([B:36]3[O:40][C:39]([CH3:41])([CH3:42])[C:38]([CH3:44])([CH3:43])[O:37]3)=[C:32]([CH3:45])[CH:31]=2)([CH2:25][CH3:26])[CH2:28][CH3:29])=[CH:47][C:48]=1[CH3:64])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(/C=C/C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.7 %

Procedure:
Triethylamine (0.10 mL, 0.72 mmol), t-butyldimethylsilyl chloride (48.5 mg, 0.322 mmol) and dimethylaminopyridine (1 mg, 0.008 mmol) were added to a solution of (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 47.0 mg, 0.082 mmol) in N,N-dimethylformamide (0.10 mL), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=50/1) to give the title compound (47 mg, 84%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:30]2([CH3:31])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:32])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([C:23]([OH:25])=[O:24])[CH3:22])[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:41]OC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C(O)=O)C)C[C@@H](OC(OC)=O)C1)=O>>[Si:1]([O:8][C@@H:9]1[C@@:30]2([CH3:31])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:32])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([C:23]([O:25][CH3:41])=[O:24])[CH3:22])[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: CC(C(=O)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Product: COC(=O)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 84.6 %

Procedure:
The procedure of Example 7 was repeated except that 112 mg of 1α,3β-bis(t-butyldimethylsilyloxy)pregna-5,7-diene-20-carboxylic acid obtained in Example 23 was used in lieu of 85 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carboxylic acid to give 91 mg of methyl 1α,3β-bis(t-butyldimethylsilyloxy)pregna-5,7-diene-20-carboxylate.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=O)(C)(C)C.C1C=CC(/C(/C2C=CC([N+]([O-])=O)=CC=2)=N/O)=CC=1.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[F:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH2:57][NH2:58]>>[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40]([C:9]2([C:13]([NH:58][CH2:57][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=3[F:50])=[O:15])[NH:8][CH2:12][CH2:11][S:10]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Reactant: NCc1ccccc1F
Agent: O=[N+]([O-])c1ccc(/C(=N\O)c2ccccc2)cc1
Product: O=C(NCc1ccccc1F)C1(S(=O)(=O)c2ccc(-c3ccccc3)cc2)NCCS1

Procedure:
Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and (2-fluorophenyl)methanamine, the title compound was obtained in 88.6% purity by HPLC.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].C(OC([N:12]1[C@H:16]([CH:17]([OH:27])[C:18]2[N+:19]3[C:20](=[CH:23][N:24]([CH3:26])[CH:25]=3)[S:21][CH:22]=2)[CH2:15][C@H:14]([S:28][C:29]2[C@H:30]([CH3:46])[C@@H:31]3[C@@H:41]([C@H:42]([OH:44])[CH3:43])[C:40](=[O:45])[N:32]3[C:33]=2[C:34]([O:36]CC=C)=[O:35])[CH2:13]1)=O)C=C.CNC1C=CC=CC=1.O>ClCCl.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>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:44][C@@H:42]([C@H:41]1[C:40](=[O:45])[N:32]2[C:33]([C:34]([OH:36])=[O:35])=[C:29]([S:28][C@H:14]3[CH2:15][C@@H:16]([CH:17]([OH:27])[C:18]4[N+:19]5[C:20](=[CH:23][N:24]([CH3:26])[CH:25]=5)[S:21][CH:22]=4)[NH:12][CH2:13]3)[C@H:30]([CH3:46])[C@H:31]12)[CH3:43]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3csc4cn(C)c[n+]34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CNc1ccccc1
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(O)c4csc5cn(C)c[n+]45)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (18.1 mg) is added to a solution of 55 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(6-methylimidazo[5,1-b]thiazolium-3-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate perchlorate (stereoisomer B) and 0.051 ml of N-methylaniline in 0.7 ml of dry dichloromethane, and the mixture is stirred in an argon atmosphere at room temperature for 45 min. Distilled water (3 ml) is added thereto, the mixture is washed three times with 3 ml of ethyl acetate, and the aqueous layer is filtered, followed by concentration under reduced pressure and freeze drying to give 31 mg of a light orange flocculent material. The light orange flocculent material is purified by column chromatography on Cosmosil 5C18-MS (water:methanol=10:1) to give 3.9 mg of the title compound as a colorless flocculent material.