Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[O:3]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH:15]=O.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH:8]=[CH:15][C:14]2[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:12]([O:11][CH3:10])[CH:13]=2)[O:3]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C=CC2=CC(=O)C(C)(C)O2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.9 %

Procedure:
To a mixture of 2,2,5-trimethyl-3(2H)-furanone (2.5 g, 19.8 mM) and 3,4,5-trimethoxybenzaldehyde (4.7 g, 23.8 mM) in ethanol was added 1N aqueous sodium hydroxide (4 mL, 4 mM). After the reaction mixture was stirred for 48 hours at room temperature, the solution was concentrated to 50 mL and diluted with water (300 mL). The aqueous layer was extracted with diethyl ether (4×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a dark yellow crystalline solid. The crude product was purified by chromatography (silica gel, petroleum ether-ethyl acetate) to give light yellow crystals (5.0 g, 83% yield), m.p. 149°-150° C.
Reaction SMILES: C(OCC1C=CC=CC=1)C1C=CC=CC=1.O1C=CC=C1.C([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:39]=[CH:38][O:37][CH:36]=1)C1C=CC=CC=1.[H][H]>[C].[Pd]>[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:39]=[CH:38][O:37][CH:36]=1
Reactant: c1ccc(COc2ccccc2-c2ccoc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: c1ccoc1
Product: Oc1ccccc1-c1ccoc1

Procedure:
The benzylether prepared by the procedure outlined in sub paragraph A above was converted to the hydrophenyl furane and follows: 10.2 grams 3-(2-benzyloxyphenyl)-furane was placed in 50 ml. of a 1:1 solution of methanol/acetic ester, and was hydrogenated with hydrogen in the presence of 1.5 gram 10% palladium carbon, at room temperature and slight pressure. After absorption of one equivalent of hydrogen, the catalyst was filtered off and the solvent carefully drawn off at 20° C. An intensely colored, unstable substance remained, which was identified by its NMR spectrum as the desired phenol.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:28]=[CH:27][C:19]3[O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:18]=3[CH:17]=2)=[O:15])[CH:8]=1)C.CO.C1COCC1.Cl>CC(OC)(C)C>[CH:17]1[C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=2[CH:27]=[CH:28][C:16]=1[C:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:29])=[O:3])[CH:12]=[CH:11][CH:10]=1)=[O:15]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc3oc4ccccc4c3c2)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C(O)C=Cc1cccc(NC(=O)c2ccc3oc4ccccc4c3c2)c1
Temperature: 40 °C

Procedure:
The ester (19) (46 mg, 0.12 mmol) was hydrolysed using Method C, except that MeOH (1 mL) and THF (1 mL) were used, and the reaction mixture was heated to 40° C. for 1 hour. After the reaction, TBME was added and the mixture acidified using 6N HCl. The aqueous was extracted with more TBME (×3), EtOAc (×3), dried (MgSO4) and the solvent concentrated in vacuo. The crude solid was triturated with DCM, filtered, washed with heptane and dried to give the title compound. Yield: 34 mg, 81%; LC-MS tr 2.08 min; HPLC Purity: 100%; MS (ES+) m/z 358 (M+H); 1H NMR (400 MHz; DMSO): δ 6.60 (d, 1H), 7.55-7.75 (m, 5H), 7.9 (d, 1H), 7.95-8.05 (m, 2H), 8.25 (s, 1H), 8.30 (d, 1H), 8.40 (d, 1H), 8.95 (s, 1H), 10.65 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.S(=O)(=O)(O)O.C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[C:21]2[CH:22]=[CH:23][C:18](=[O:17])[NH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Oc1ccccn1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1ccc(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c[nH]1
Temperature: 200 °C

Procedure:
Combine 50.6 g. (0.2 mole) of 4,4'-dichlorobenzhydrol with 57.1 g. (0.6 mole) of 2-hydroxy pyridine, with stirring heat to 200° C. and add dropwise 1.0 ml. of concentrated sulfuric acid. Increase the reaction temperature to 240°-250° C. and maintain at that temperature range while collecting water emanating from the reaction. Cool the reaction mixture, add a mixture of ethyl acetate and water with stirring and separate the liquid phases. Dry the organic phase, reduce the volume of ethyl acetate, cool to precipitate the crude product, yield 43 g. Crystallization from ethanol affords the product of this step, m.p. 211°-215° C.
Reaction SMILES: [NH:1]([C:9](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:10])[C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[CH:28][CH:27]=1.[F:38][C:39]([F:51])([F:50])[S:40]([C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1)(=[O:42])=[O:41]>>[F:38][C:39]([F:51])([F:50])[C:6]([OH:8])=[O:7].[OH:4][CH:3]([C@H:2]1[N:1]([CH2:36][C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]=[CH:27][CH:28]=2)[C:9](=[O:10])[N:47]([C:46]2[CH:48]=[CH:49][C:43]([S:40]([C:39]([F:50])([F:38])[F:51])(=[O:41])=[O:42])=[CH:44][CH:45]=2)[C:6]1=[O:7])[CH3:5]
Reactant: O=Cc1ccnc2ccccc12
Reactant: C[C@H](O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: CC(O)[C@@H]1C(=O)N(c2ccc(S(=O)(=O)C(F)(F)F)cc2)C(=O)N1Cc1ccnc2ccccc12
Product: O=C(O)C(F)(F)F

Procedure:
The compound is prepared from 0.05 mmol of resin, 0.15 mmol of N-Fmoc-D-Thr(OH), 0.25 mmol of 4-quinolinecarboxaldehyde and 0.125 mmol of 4-(trifluoromethanesulfonyl)aniline, in the same way as in Example 1. After purification by preparative LC-MS, 3.4 mg of expected product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN([CH:23]([CH3:25])[CH3:24])C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][C:51]1C=CC=[CH:53][C:52]=1[SH:57]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([S:57][C:52]2[CH:53]=[CH:25][C:23]([CH3:24])=[CH:50][CH:51]=2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccccc1S
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(SC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (5 g, 21.8 mmol, 1 eq.) and DIEA (7.6 mL, 44 mmol, 2 eq.) in DMF was added HATU (9.12 g, 24 mmol, 1.1 eq.) and stirred at room temperature for 30 min. Methylbenzenethiol (3 g, 24 mmol, 1.1 eq.) in 45 mL of DMF was added and the resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography (0-20% ethyl acetate/heptane) to give the title compound as a white solid (6.6 g, 90% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.28 (m, 4H), 4.13 (m, 2H), 2.81 (m, 3H), 2.39 (s, 3H), 1.97 (m, 2H), 1.73 (m, 2H), 1.48 (s, 9H), MS (ESI) m/z 336.6 (M+H)+. Exact mass calculated for C18H26N1O3S, 336.2. MS (ESI) m/z 279.9 (M+H without t-butyl). Retention time: 1.27 min (5-95% CH3CN/H2O over 2 min with 0.1% formic acid, Inertsil 3×3 mm C-8-3 column with flow rate of 2 mL/min).
Reaction SMILES: Br.C([O:4][P:5]([C:10]1[CH:15]=[CH:14][C:13]([P:16]([O:21]CC)(=[O:20])[O:17]CC)=[CH:12][CH:11]=1)(=[O:9])[O:6]CC)C.C(OCC)C.C(=O)=O>C(O)(=O)C.C(O)C>[C:13]1([P:16]([OH:21])(=[O:17])[OH:20])[CH:12]=[CH:11][C:10]([P:5]([OH:6])(=[O:4])[OH:9])=[CH:15][CH:14]=1
Reactant: CCOP(=O)(OCC)c1ccc(P(=O)(OCC)OCC)cc1
Agent: Br
Agent: O=C=O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCO
Product: O=P(O)(O)c1ccc(P(=O)(O)O)cc1
Temperature: 80 °C
Yield: 88.1 %

Procedure:
93 ml of HBr at 33% by weight in acetic acid are added to 6.68 g of 1.4-benzene-diphosphonic acid tetra-ethyl ester and the mixture is heated to 80° C. for 4 hours. After cooling to ambient temperature 200 ml of diethyl-ether are added and the mixture, after brief agitation, is cooled to -78° C. in a bath of ethanol and dry ice. The oily precipitate obtained is recovered by decantation and subjected twice more to the dispersion process with ether and low-temperature precipitation. The oily residue obtained is vacuum dried (1 mm Hg) at 50° C. for 8 hours, obtaining 4.0 g of 1,4-benzene-diphosphonic acid in the form of a white solid. Yield in moles 89%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH2:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12.C(N(CC)CC)C>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12)=[O:8]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Cl)Cc1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 2 h

Procedure:
To a solution of 100 milligrams (0.6 millimole) of 2-thiopheneacetyl chloride in 5 milliliters of absolute methylene chloride was added slowly a slurry of 137 milligrams (0.5 millimole) of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and 86 milligrams (0.9 millimole) of triethylamine in 10 milliliters of absolute methylene chloride. The addition was carried out at -15° C., with stirring. After the addition, stirring was continued for two hours at -15° C. and for one and one-half hours at room temperature. The reaction mixture was then cooled and filtered to separate the precipitated solid. The solid, 80 milligrams, was analyzed on bioautogram. Bioautogram showed that approximately 50 percent of the sample was 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and another 50 percent was the desired 7-(2-(2-thienyl)acetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[C:25]1([CH:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:25]1([CH:31]([NH:33][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[N:1]=2)=[O:13])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: CC(N)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)c1ccc2cnccc2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1-phenylethylamine (56.1 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a clear oil (78.7 mg, 99%).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1)[NH2:20].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[NH:10][C:3]2[C:2]([NH:20][C:19]3[CH:21]=[CH:22][C:23]([O:24][C:25]4[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=4)=[C:17]([CH3:16])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5ccco5)[nH]c34)cc2C)cn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (161 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (25 mL×2) and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Chloroform-diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (114 mg).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([F:15])([F:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)C.[OH-].[Na+]>C(O)C.C(Cl)Cl>[F:14][C:7]([F:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCC(F)(F)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: OCCC(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of Intermediate 76 (0.30 g, 1.40 mol) in ethanol (4 mL) was added a solution of 35% sodium hydroxide (1 mL). The mixture was stirred at room temperature for 2 hours. The crude reaction was diluted with methylene chloride (50 mL), washed with water (1×30 ML) and 1N hydrochloric acid (2×30 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (0.22 g, 89%) as orange oil, and was used in the next step without further purification.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)[Cl:8].[Si]([O:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33](=O)[CH2:34][CH2:35][O:36]2)=[CH:31][CH:30]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O>C(Cl)Cl>[Cl:8][C:33]1[C:32]2[C:37](=[CH:38][C:29]([OH:28])=[CH:30][CH:31]=2)[O:36][CH2:35][C:34]=1[CH:4]=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](Oc1ccc2c(c1)OCCC2=O)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=CC1=C(Cl)c2ccc(O)cc2OC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of DMF (2 mL) in DCM (7.5 mL) was added dropwise POCl3 (1.39 mL) at 0° C., followed by stirring at room temperature for 30 minutes. Subsequently, to the reaction liquid was added dropwise a solution of 7-{[tert-butyl(diphenyl)silyl]oxy}-2,3-dihydro-4H-chromen-4-one (2.00 g) in DCM (11 mL), followed by stirring at room temperature for 1 hour and at 50° C. for 3 hours. To the reaction liquid was added water, followed by extraction with EtOAc twice. The organic layer was combined, washed with water and brine, and dried over MgSO4, and the liquid was concentrated. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain 4-chloro-7-hydroxy-2H-chromene-3-carbaldehyde (720 mg).
Reaction SMILES: [Br:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>N1C=CC=CC=1.ClCCl.Cl>[Br:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: BrC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2CCC(Br)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Bromopiperidine (5.75 g, 23.5 mmol) was dissolved in pyridine (50 mL) and treated with tosyl chloride (5.8 g, 30.5 mmol). The reaction mixture was stirred for 12 h at r.t. and then diluted with dichloromethane (150 mL) and HCl (1 M aqueous solution, 50 mL). The organic layer was washed with brine (80 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (40% EtOAc/hexane) to give 4-bromo-1-tosylpiperidine as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.27-4.24 (m, 1H), 3.20-3.17 (m, 2H), 3.13-3.11 (m, 2H), 2.46 (s, 3H), 2.23-2.17 (m, 2H), 2.08-2.05 (m, 2H); MS (ESI) 318.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=1[S:31]([CH3:34])(=[O:33])=[O:32]>C(#N)C.C(N(CC)C(C)C)(C)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:30][CH:28]([C:25]4[CH:26]=[CH:27][C:22]([CH3:21])=[C:23]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=4)[CH3:29])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(C(C)N)cc1S(C)(=O)=O
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NC(C)c4ccc(C)c(S(C)(=O)=O)c4)c3C2)c(C#N)c1
Yield: 49.9 %

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (360 mg, 1.26 mmol) and 1-(4-methyl-3-(methylsulfonyl)phenyl)ethanamine (400 mg, 1.88 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (1 mL) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light yellow solid (290 mg).
Reaction SMILES: [C:1]([NH:20][C@@H:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]I.O>CCOCC>[CH3:23][C:22]([OH:24])([C@@H:21]([NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH3:26])[CH3:27]
Reactant: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reactant: C[Mg]I
Solvent: CCOCC
Solvent: O
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)O

Procedure:
To a stirred solution of (3S)-3-(trityl-amino)-pentan-2-one (0.59 g, 1 eq, 1.72 mmol) in Et2O (100 mL) under an argon atmosphere at room temperature, was added methylmagnesium iodide (3 M in Et2O, 1.72 mL, 3 eq, 5.16 mmol) dropwise. The solution was placed in a preheated oil bath at 45° C. and refluxed at this temperature for 16 h. The mixture was recooled to 0° C., H2O (100 mL) added, the solution filtered through Celite, and the Celite washed with more Et2O (50 mL). The combined organic phase was separated, the aqueous phase was extracted with Et2O (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane: Et2O (100:0→90:10) to afford the title compound as a light yellow oil. Yield: 0.10 g (16%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.27 (t, J=7.10 Hz, —NHCH(CH2CH3)CH(CH3)OH), 0.99 & 1.25 (2×s, 6H, —NHCH(CH2CH3)C(CH3)2OH), 0.75-1.42 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 1.88 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 2.92 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.32 (s, 1H, —NHCH(CH2CH3)C(CH3)2OH), 7.18-7.46 (m, 15H, 3×Ph).
Reaction SMILES: [OH-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][N:10]1[C@@H:13]([CH3:14])[C@@H:12]([CH2:15][CH:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[C:11]1=[O:28].O.S([O-])(O)(=O)=[O:31].[Na+]>O1CCOCC1.CCOC(C)=O>[C:22]1([CH:19]2[CH2:20][CH2:21][CH:16]([CH2:15][C@H:12]([C@@H:13]([NH:10][O:9][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8][O:3]3)[CH3:14])[C:11]([OH:28])=[O:31])[CH2:17][CH2:18]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)([O-])O
Reactant: C[C@H]1[C@@H](CC2CCC(c3ccccc3)CC2)C(=O)N1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NOC1CCCCO1)[C@@H](CC1CCC(c2ccccc2)CC1)C(=O)O
Reaction time: 18 h
Yield: 92 %

Procedure:
A solution of 3 N sodium hydroxide (18.7 mL) is added dropwise to a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(4-phenylcyclohexylmethyl)-4-methylazetidin-2-one (3.6 g, 0.010 mol) in dioxane (50 mL) at 25° C. and the mixture is stirred for 18 h. Water (10 mL) is added to the reaction mixture and an additional 5 mL of 3 N sodium hydroxide is added dropwise and the mixture is stirred an additional 8 h. The reaction mixture is mixed with water (200 mL), 1 M sodium hydrogen sulfate (60 mL) and EtOAc (100 mL). The aqueous phase is extracted with EtOAc. The combined organic phase is washed with water and saturated sodium chloride solution, dried (sodium sulfate) and concentrated in vacuo to give 3.44 g (92%) of (2R,3S)-2-(4-phenylcyclohexylmethyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as a white solid. The product is used without further purification:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3ccc([N+](=O)[O-])cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
3-Methyl-6-nitro-1H-indazole (436 mg, 2.46 mmol) was dissolved in 25 ml of dichloromethane at room temperature. DMAP (5 mg) and pyridine (1.1 eq, 0.38 ml) were added followed by tosyl chloride (1.1 eq, 516 mg). The mixture was allowed to stir at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 Hexanes/Ethyl Acetate) to give 3-methyl-6-nitro-1-(toluene-4-sulfonyl)-1H-indazole (850 mg, quant) as a light brown crystalline solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([CH2:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([S:29][CH3:30])=[CH:24][CH:23]=2)([OH:18])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([F:17])[CH:9]=1)([CH3:7])[CH3:6].I([O-])(=O)(=O)=[O:34].[Na+]>CO.[Cl-].[Na+].O>[F:32][C:2]([F:1])([F:31])[C:3]([CH2:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([S:29]([CH3:30])=[O:34])=[CH:24][CH:23]=2)([OH:18])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([F:17])[CH:9]=1)([CH3:7])[CH3:6]
Reactant: CSc1ccc2[nH]c(CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cc2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc2[nH]c(CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cc2c1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(5-methylsulfanyl-1H-indol-2-ylmethyl)pentan-2-ol (25 mg, 0.053 mmol) in 10 mL of methanol was added sodium periodate (150 mg, 0.70 mmol). After 1 hour, the mixture was diluted with brine and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with three 7 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative TLC on silica gel eluting with ethyl acetate to afford 19.8 mg (77% yield) of the title compound.