Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1Cl)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccccc1Cl)CCCC3
Yield: 73.1 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.300 g; 0.78 mmol), LHMDS 1N in THF (0.86 mL; 0.86 mmol), 1-iodopropane (0.114 mL; 1.17 mmol) in DMF (3.1 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.244 g (74%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[F:30][C@H:11]1[C@H:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1
Reactant: COc1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1F
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)cc1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A stirred solution of trans-tert-butyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate (100 mg, 0.31 mmol) in DCM (15 mL) at −78° C. was treated dropwise with DAST (0.08 mL, 0.6 mmol). The resulting mixture was stirred at −78° C. for 90 min. It was then quenched with ice water, warmed to rt, and extracted with DCM (50 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain 70 mg of (±)-rel-(3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate. LCMS (Method P) RT 1.11, 1.13 min, m/z 313 (M+H++CH3CN−t-butyl). Three batches of product (˜210 mg total) were combined and subjected to HPLC purification (Method A) to give 140 mg (±)-rel-(3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9H) 1.55-1.67 (m, 1H) 1.74-1.82 (m, 1H) 2.72-2.90 (m, 3H) 3.82 (s, 3H) 3.89-4.03 (m, 1H) 4.24-4.34 (m, 1H) 4.50-4.71 (m, 1H) 7.09 (d, J=1.51 Hz, 2H) 7.18-7.28 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B(O)O)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[N:24]([CH3:23])[CH:25]=[CH:26]4)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Product: CC(On1ccc2ncc(-c3ccc4c(ccn4C)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and (1-methyl-1H-indol-5-yl)boronic acid according to the procedure described in example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Mg].[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[CH:13]1>C(OCC)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:15]2([OH:18])[CH2:16][CH2:17][C:12]([CH3:19])([CH3:11])[CH:13]=[CH:14]2)=[CH:4][CH:3]=1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Mg]
Solvent: CCOCC
Product: CC1(C)C=CC(O)(Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A solution of 4-chlorobenzyl chloride (266 g, 1.65 mol) in diethyl ether (200 ml) was added slowly to a stirred mixture of magnesium (42 g, 1.7 mol) in diethyl ether (700 ml) to maintain the mixture at reflux. The mixture was warmed for a further 20 minutes after addition was complete. A solution of 4,4-dimethylcyclohex-2-en-1-one (226 g, 1.82 mol) in diethyl ether (60 ml) was then added dropwise over a period of 30 minutes so as to maintain the mixture at reflux and the mixture stirred overnight. The mixture was then quenched with water (250 ml) and hydrochloric acid (5M, 500 ml), extracted with diethyl ether (3×400 ml), backwashed once with sodium bicarbonate solution (5% w/v) and once with water and then dried with anhydrous magnesium sulphate. The solvent was then flashed off to give 369 g 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-2-en-1-ol as an oil.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1O.C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:16]1[C:14](=[O:15])[N:13]=[C:11]2[N:10]([C@@H:1]3[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@@H:2]3[O:12]2)[CH:17]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Temperature: 140 °C

Procedure:
500 mg (2.05 mmol) of uridine 1, 570 mg of (2.65 mmol, 1.3 gram-equivalent (eq)) of diphenyl carbonate, and 10 mg (0.12 mmol, 0.059 eq) of sodium bicarbonate are dissolved in 1 mL of dimethyl formamide and heated to 140° C. After the starting materials are completely consumed, the solution is cooled down to room temperature to form white precipitates. The white precipitates are washed by ice formic acid. Residual part of the solution is removed at reduced pressure. After collection, a white powder product (2,2′-cyclouridine) 2 is obtained. Its weight and yield are 370 mg and 80%, respectively.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16][OH:17])([O-])=O>C1COCC1>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16][OH:17]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ccc1NCCO

Procedure:
2-{[2-nitro-4-(trifluoromethyl)phenyl]amino}ethanol (3.05 g, 12 mmol) was dissolved in THF (10 ml) and hydrogenated at 70 psi. After the removal of catalyst the product was obtained by evaporating the solvent and used for the next step (2.70 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[CH2:5]2.[H-].[Na+].O.[O:20]1CC[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([CH3:14])([O:16][C:21](=[O:20])[CH3:22])[CH3:15])[CH2:5]2
Reactant: C1CCOC1
Reactant: CC(C)(O)CN1Cc2cc(Br)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)OC(C)(C)CN1Cc2cc(Br)ccc2C1=O
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, 50 mg of 5-bromo-2-(2-hydroxy-2-methyl-propyl)-1-oxo-isoindoline obtained in Example 177-1) was dissolved in tetrahydrofuran. 21 mg of acetatic anhydride and 20 mg of sodium hydride were added and the mixture was heated under reflux for 4 hours. The reaction solution was cooled down to room temperature, water was added and the products were extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=1/2) to obtain 44 mg of the above compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[NH:27][C:28]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)=[O:29]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:34]([C:33]3[CH:32]=[CH:31][C:30]([C:28]([NH:27][C:19]4[NH:18][C:26]5[C:21]([CH:20]=4)=[CH:22][CH:23]=[CH:24][CH:25]=5)=[O:29])=[CH:37][CH:36]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(C(=O)Nc2cc3ccccc3[nH]2)cc1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4cc5ccccc5[nH]4)cc3)[nH]c2c1

Procedure:
Compound 663 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(2-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C25H22N4O3: 427.17; found: 426.99.
Reaction SMILES: [C:1]([C:4]([S:7]([CH2:10][CH:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([OH:14])=O)(=[O:9])=[O:8])([CH3:6])[CH3:5])(=[O:3])[NH2:2].[NH2:22][C@@H:23]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:24]([NH:26][C@@H:27]([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:28]([OH:34])[C@H:29]([CH:31]1[CH2:33][CH2:32]1)[OH:30])=[O:25].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:1]([C:4]([S:7]([CH2:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([NH:22][C@@H:23]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:24]([NH:26][C@@H:27]([CH2:35][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)[C@@H:28]([OH:34])[C@H:29]([CH:31]1[CH2:32][CH2:33]1)[OH:30])=[O:25])=[O:14])(=[O:8])=[O:9])([CH3:5])[CH3:6])(=[O:3])[NH2:2]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C(N)=O)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)S(=O)(=O)C[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 239 mg (0.76 mmol) of rac-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamic acid, 250 mg (0.69 mmol) of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, 77 mg (0.76mmol) of triethylamine, 118 mg (0.76 mmol) of HOBT and 289 mg (0.76 mmol) of HBTU in 10 ml of dimethylformamide was stirred at room temperature overnight. Subsequently, the reaction solution was evaporated to dryness in a high vacuum, the residue was taken up in 75 ml of ethyl acetate and washed twice with 20 ml of saturated sodium hydrogen carbonate solution each time. The ethyl acetate solutions were dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification and separation of the two epimeric products, the residue (450 mg) was chromatographed on 30 g of silica gel using a 97:3:0.1 o mixture of methylene chloride, methanol and ammonia as the eluent. After lyophilization from dioxan and water there were obtained the less polar epimer (S)-α-[(R)-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imidazole-4-propionamide as a colourless amorphous powder, MS: 660 (M+H)+, and the more polar epimer (S)-α-[(S)-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamamido]-N-[(1S ,2R,3S)-1-(cyclohexylmethyl )-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, likewise as a colourless amorphous powder, MS: 660 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1)[C:6](=[O:13])[CH2:7][CH2:8][C:9]([O:11]C)=[O:10])[CH2:2][CH2:3][CH3:4].C([Sn]([N:42]=[N+:43]=[N-:44])(CCCC)CCCC)CCC.[OH-].[K+]>CC1C=CC=CC=1C>[CH2:1]([N:5]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[NH:44][N:43]=[N:42][N:28]=2)=[CH:19][CH:20]=1)[C:6](=[O:13])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC(=O)OC
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)CCC(=O)O
Reaction time: 2 h

Procedure:
A solution of 8.8 g (22.7 mmol) of 3-methoxycarbonylpropanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide and 9.8 g (29.5 mmol) of tributyltin azide in 100 ml of o-xylene is heated under reflux for 20 hours. The reaction mixture is then cooled to 20° and 100 ml of 1N potassium hydroxide solution are added thereto. The reaction mixture is stirred thoroughly for 2 hours, and the aqueous phase is separated and acidified with 2N hydrochloric acid. The resin which separates is extracted with ethyl acetate. The crude product, obtained by concentration of the ethyl acetate phase by evaporation, is flash-chromatographed on 500 g of silica gel [toluene/isopropanol/glacial acetic acid (170:30:2)] to yield 3-carboxypropanoic acid N-butyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amide in the form of a light-brown foam that has an Rf value of 0.20 [toluene/isopropanol/glacial acetic acid (170:30:2)]. ##STR8##
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([C:6]#[N:7])=[C:4]([CH3:12])[N:3]=1.CC(C[AlH]CC(C)C)C.O.NC1N=C(C)C(CN[C:33]([C:35]2[CH:36]=[N:37][N:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44](OC)=[CH:43][CH:42]=3)[CH:39]=2)=[O:34])=C(C)C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CN(C1C=CN=CC=1)C.CO>[NH2:1][C:2]1[N:3]=[C:4]([CH3:12])[C:5]([CH2:6][NH:7][C:33]([C:35]2[CH:36]=[N:37][N:38]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:39]=2)=[O:34])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(N)nc(C)c1C#N
Reactant: COc1ccc(Cn2cc(C(=O)NCc3c(C)cc(N)nc3C)cn2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: COc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
A mixture of 6-amino-4-methoxy-2-methylnicotinonitrile (100 mg, 0.613 mmol) in THF (4 ml) was cooled to −78° C., and treated with DIBAL-H (1M in THF, 3.68 ml, 3.68 mmol). The mixture was slowly warmed to rt. Stirring was continued for 24 h at rt, before the reaction mixture was carefully transferred to an ice-cold mixture of MeOH (50 ml) and water (0.2 ml, 11.0 mmol). The resulting suspension was adsorbed on celite (ca. 30 cm3) and dried in vacuo. Elution with DCM-MeOH (9:1, 200 ml) and removal of all volatiles afforded a yellow oil. Dry THF (5 ml), 1-benzyl-1H-pyrazole-4-carboxylic acid (79.0 mg, 0.389 mmol, prepared in analogy to example 13), DIPEA (0.209 ml, 1.20 mmol), DMAP (1.8 mg, 0.015 mmol) and HATU (148 mg, 0.389 mmol) were added, and the reaction mixture was stirred at it for 14 h, before it was concentrated to dryness. The crude product was purified by column chromatography (CombiFlash Rf, 13 g RediSep Rf C18, MeCN:water 5:95+0.1% TFA to MeCN), followed by preparative HPLC (Waters Sunfire Prep C18 OBD 5 um, 100×30 mm, A: H2O+0.1% TFA, B: MeCN+0.1% TFA, 5-35% B in 15 min, 30 ml/min, rt) to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): 2.47 (s, 3H), 3.91 (s, 3 H), 4.22 (d, 2H), 5.33 (s, 2H), 6.26 (s, 1H), 7.22-7.27 (m, 2H), 7.28-7.38 (m, 3H), 7.53 (br, s, 2H), 7.86 (s, 1H), 8.09 (t, 1H), 8.23 (s, 1H), 12.95 (s, 1H); LCMS RtK=0.82 min, [M+H]+=352.4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:12][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Reactant: O=[N+]([O-])O
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1C
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
1,4-Dihydro-6,7-dimethylquinoxalin-2,3-dione (J. Liebigs Ann. Chem., 1982, 754-761, 10.0 g, 52.6 mmol) was added in portions over 10 minutes to concentrated nitric acid (density, 1.42 gcm-3, 100 ml) at 0° C. After 5 minutes, the cooling bath was removed and the mixture was stirred at 20° C. for 7 hours, using cooling when necessary to maintain this temperature. The solution was poured into iced water, and the resulting solid filtered off and dried under reduced pressure at 75° C. to give 1,4-dihydro-6,7-dimethyl-5-nitroquinoxalin-2,3-dione (7.44 g, 60%) as a pale yellow solid, mp 280°-290° C. (dec.) (from dimethylformamide/water).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:12]1[N+:17]([O-:18])=[C:16]2[CH2:19][CH2:20][CH2:21][C:15]2=[C:14]([Cl:22])[CH:13]=1>O1CCOCC1.C(Cl)Cl>[Cl:22][C:14]1[CH:13]=[C:12]([O:4][CH:1]([CH3:3])[CH3:2])[N+:17]([O-:18])=[C:16]2[CH2:19][CH2:20][CH2:21][C:15]=12
Reactant: [O-][n+]1c(Cl)cc(Cl)c2c1CCC2
Reactant: CC(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)Oc1cc(Cl)c2c([n+]1[O-])CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of iso-propanol (0.047 g, 0.79 mmol) in dioxane (3 mL) at rt was added potassium tert-butoxide (0.053 g, 0.47 mmol). The mixture was stirred at rt for 30 min. Then, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.100 g, 0.39 mmol) in dioxane (1 mL) was added and the mixture was heated under microwave irradiation to 100° C. for 30 min. After this time, the mixture was diluted with methylene chloride and washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.079 g, 88%) as a white solid. MW=227.69. 1H NMR (CDCl3, 300 MHz) δ 6.73 (s, 1H), 4.90-4.85 (m, 1H), 3.23 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H), 1.44 (d, J=6.0 Hz, 6H); APCI MS m/z 228 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:10](=[O:19])[C@@H:9]2[CH2:20][CH2:21][C@@H:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[OH:23])[CH:5]=[CH:6][CH:7]=1.[OH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]2[C@H:8]([C:4]3[CH:3]=[C:2]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([OH:31])[CH:37]=4)[CH:7]=[CH:6][CH:5]=3)[C@@H:9]([CH2:20][CH2:21][C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[OH:23])[C:10]2=[O:19])=[CH:13][CH:14]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2cccc(Br)c2)N1c1ccc(F)cc1
Reactant: OB(O)c1cccc(O)c1
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2cccc(-c3cccc(O)c3)c2)N1c1ccc(F)cc1
Yield: 44.6 %

Procedure:
(3R,4S)-4-(3-Bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (43 mg, 0.091 mmol) was coupled with 3-hydroxyphenyl boronic acid (18 mg, 0.13 mmol) under standard Suzuki conditions illustrated by Example 42. Purified by chromatography (silica gel, 10% to 90% ethyl acetate-hexane) to afford (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-3-yl)azetidin-2-one (19.7 mg, 45% yield); Rf 0.30 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.57-7.40 (m, 3H), 7.34-7.22 (m, 6H), 7.10 (ddd, 7.7, 1.6, 0.9 Hz 1H), 7.04-6.90 (m, 5H), 6.84 (ddd, J=8.2, 2.6, 0.9 Hz, 1H), 5.10 (br s, 1H), 4.72 (t, J=5.9 Hz, 1H), 4.67 (d, J=2.4 Hz, 1H), 3.16 (ddd, J=5.0, 2.6, 2.4 Hz, 1H), 2.26 (br s, 1H), 2.08-1.88 (m, 4H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH:28](B1OC(C)(C)C(C)(C)O1)=[CH2:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH:12][C:13]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]3[C:16]([CH:17]4[CH2:27][CH:18]4[CH2:19][O:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[C:2]([CH:28]=[CH2:29])[CH:7]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Yield: 169.7 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 41, 0.1 g), vinyl boronic acid pinacol ester (0.073 g), bis(triphenylphospine)palladium (II) chloride (0.034 g) and cesium carbonate (0.215 g) in dioxane (5 mL) and water (1 ml) was degassed and purged with argon then irradiated in a microwave at 130° C. for 20 minutes. After cooling, the mixture was partitioned between 1M hydrochloric acid and ethyl acetate. The organic layer was dried (MgSO4) and filtered and the filtrate evaporated to dryness to give methyl (1aRS,7bSR)-5-(4-fluoro-2-vinylbenzenesulfonyl-amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.15 g) as a yellow glass.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH:14]1[CH2:17][CH2:16][CH2:15]1.CN([CH:21]=[O:22])C.O>C1COCC1>[CH:14]1([S:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:21]=[O:22])[CH2:17][CH2:16][CH2:15]1
Reactant: CN(C)C=O
Reactant: Brc1ccccc1SC1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccccc1SC1CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a solution of n-butyllithium (7.35 mL of a 1.6 M solution in hexanes, 11.7 mmol) in dry THF (15 mL) at −78° C. was added dropwise over 10 minutes a solution of (2-bromophenyl)(cyclobutyl)sulfane (1.19 g, 4.89 mmol) in dry THF (15 mL) and the resulting solution stirred at −78° C. for 30 minutes. Anhydrous DMF (1.14 mL, 14.7 mmol) was then added, and the solution stirred at −78° C. for 5 minutes, before allowing to warm to room temperature and stirring for a further 1 hour. Water was then added, and the volatiles removed in vacuo, before extracting the mixture with ethyl acetate (×3). The combined organics were washed with brine, then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified using flash column chromatography on silica gel (eluting with a gradient of 0 to 5% ethyl acetate) to afford 2-(cyclobutylthio)benzaldehyde (450 mg, 2.34 mmol, 48%).
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[O:19])[CH2:3]1.CCN(S(F)(F)[F:38])CC>C(Cl)Cl>[F:38][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[O:19])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(OCc1cccc(C(F)(F)F)c1)[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(OCc1cccc(C(F)(F)F)c1)[C@H]1C[C@H](F)CN1Cc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of (2R,4R)-3-(trifluoromethyl)benzyl 4-hydroxy-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D8) (200 mg, 0.45 mmol) in DCM (20 ml) cooled at −20° C. was treated with DAST (0.148 ml, 1.11 mmol) and the mixture was first stirred 1 h at −20° C. then 18 hrs at RT. The reaction was quenched with NaHCO3 sat. sol. and the aqueous phase extracted with DCM (3×5 ml), dried over MgSO4 and evaporated. The residue was purified by Biotage SNAP-Si column (25 g) eluting with petroleum ether/EtOAc from 90/10 to 80/20. Collected fractions, after solvent evaporation afforded the title compound (D9) (110 mg)