Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[Br:22][CH2:23][CH2:24]O>C(Cl)Cl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][CH2:24][CH2:23][Br:22])(=[O:11])=[O:10]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(OCCBr)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
Anhydrous pyridine (8.5 mL, 105 mmol) and dry DCM (100 mL) were added to a 3-necked round-bottomed flask under a nitrogen atmosphere. The reaction flask was then cooled to about −20° C. with a dry ice/ethylene glycol bath. Trifluoromethanesulfonic anhydride (17 mL, 100 mmol) was added, whereupon a white/pink precipitate formed immediately. 2-Bromoethanol (7.1 mL, 100 mmol) was added after 5 minutes. The precipitate disappeared and then after a few minutes a new white precipitate formed. The reaction mixture was stirred for 20 minutes during which time it gradually warmed to r.t. The reaction mixture was then filtered through a phase separator and the residue was washed with 1:1 DCM/hexane (2×10 mL). The filtrate was run through a 4 cm silica plug with 1:1 DCM/hexane solution (300 mL). The solvent was removed in vacuo to give the title compound as a brown oil (21.2 g, 87%). δH (CDCl3) 4.76 (2H, t, J 6.4 Hz), 3.62 (2H, t, J 6.4 Hz).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][CH:20]=[O:21])[CH:6]=1)[OH:4].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O.C(OC(C)C)(=O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:3]([O:4][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:2][Br:1])=[CH:6][C:7]=1[NH:19][CH:20]=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Reaction time: 72 h
Yield: 67.9 %

Procedure:
(R)-2-Bromo-1-(3-formamido-4-benzyloxyphenyl)ethanol (9.9 g, 28 mmol) was dissolved in dimethylformamide (36 mL). Imidazole (2.3 g, 34 mmol) and tert-butyldimethylsilyl chloride (4.7 g, 31 mmol) were added. The solution was stirred under nitrogen atmosphere for 72 h. Additional imidazole (0.39 g, 5.7 mmol) and tert-butyldimethylsilyl chloride (0.64 g, 4.3 mmol) were added and the reaction was stirred for an additional 20 h. The reaction mixture was then diluted with a mixture of isopropyl acetate (53 mL) and hexanes (27 mL) and transferred to a separatory funnel. The organic layer was washed twice with a mixture of water (27 mL) and saturated aqueous sodium chloride (27 mL) followed by a final wash with saturated aqueous sodium chloride (27 mL). The organic layer was dried over sodium sulfate. Silica gel (23.6 g) and hexanes (27 mL) were added and the suspension was stirred for 10 min. The solids were removed by filtration and the filtrate concentrated under vacuum. The residue was crystallized from hexanes (45 mL) to afford 8.85 g (19 mmol, 68%) of the title compound as a solid. MS m/z: [M+H+] calcd for C22H30NO3SiBr 464.1. found 464.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:44]([O:46][C:47]([C:49]1[N:50]=[C:51]([CH:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[S:52][CH:53]=1)=[O:48])[CH3:45]>CN(C=O)C>[CH2:44]([O:46][C:47]([C:49]1[N:50]=[C:51]([CH:54]2[CH2:59][CH2:58][N:57]([C:10](=[O:12])[CH2:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:56][CH2:55]2)[S:52][CH:53]=1)=[O:48])[CH3:45]
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Reactant: CCOC(=O)c1csc(C2CCNCC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a solution of 2,5-dimethylphenylacetic acid (5.45 g, 27.4 mmol) in DMF (80 mL) is added diisopropylethylamine (85.4 mL, 411.32 mmol), followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (12.8 g, 32.9 mmol) at 0° C. After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester (6.59 g, 27.4 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (500 mL), washed with aqueous saturated sodium bicarbonate solution (500 mL) and the aqueous phase is re-extracted with ethylacetate (100 mL). The combined organic layers are washed with 0.5M HCl solution (400 mL) and brine (400 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 2-{1-[2-(2,5-dimethyl-phenyl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (10.46 g, 98%), which can be used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ=1.41 (t, 3H), 1.52-1.82 (m, 2H), 2.10-2.22 (m, 2H), 2.25 (s, 3H), 2.30 (s, 3H), 2.73-2.86 (m, 1H), 3.08-3.22 (m, 1H), 3.29-3.40 (m, 1H), 3.68 (s, 2H), 3.8-3.95 (m, 1H), 4.38-4.42 (q, 2H), 4.73-4.88 (m, 1H), 6.96 (s, 1H), 6.98-7.01 (d, 1H), 7.08 (d, 1H), 8.10 (s, 1H). MS: m/z=387 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]2.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[C:23]([Cl:25])[CH:24]=1>N1C=CC=CC=1.ClCCl>[Cl:25][C:23]1[CH:22]=[C:21]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]3)(=[O:27])=[O:28])[CH:20]=[C:19]([Cl:18])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6 g tert-butyl 5-amino-2,3-dihydro-indole-1-carboxylate are dissolved in 50 ml of pyridine and 50 ml dichloromethane. To this is added dropwise a solution of 6.5 g 3,5-dichlorophenylsulphonyl chloride in 50 ml dichloromethane and the mixture is stirred for 1 hour at ambient temperature. Then it is diluted with dichloromethane and washed with 1 N hydrochloric acid and with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30 to 30:70).
Reaction SMILES: C(OC([O:6][CH2:7][CH2:8][C:9]#[C:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])C)C.Cl>CC(C)=O.O.C(OCC)(=O)C>[OH:6][CH2:7][CH2:8][C:9]#[C:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CCOC(C)OCCC#CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(C#CCCO)OCc1ccccc1
Reaction time: 6 h
Yield: 99.9 %

Procedure:
A solution of the product from Example 31B (122.1 g, 0.442 mole) in acetone (400 mL) was treated at ambient temperature with an aqueous hydrochloric acid solution (0.5 N, 200 mL). The reaction mixture was stirred for 6 hours and then diluted with water and ethyl acetate. The layers were separated, and the organic layer was dried over magnesium sulfate, filtered and concentrated to provide the title compound as a colorless oil (90.17 g, 100%). 1H NMR (300 MHz, CDCl3) δ 2.61 (t, 2H), 3.79 (t, 2H), 5.19 (s, 2H), 7.32-7.40 (m, 5H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([CH3:17])[C:5]([NH:7][C:8]1[S:12][N:11]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)=[O:6].[OH-].[K+].O>C(O)C.C(O)C.O>[CH3:14][C:13]([C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH:4]([CH3:17])[C:5]2=[O:6])[S:12][N:11]=1)([CH3:16])[CH3:15]
Reactant: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)ns1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1CCN(c2cc(C(C)(C)C)ns2)C1=O
Temperature: 25 °C
Yield: 46.1 %

Procedure:
To a stirred solution of 0.5 g of 4-chloro-N-[3-(1,1-dimethylethyl)-5-isothiazolyl]-2-methylbutanamide dissolved in 30 ml ethanol was slowly added 0.112 g of potassium hydroxide dissolved in ethanol/water. The mixture was stirred at room temperature for about one-half hour and poured into water. The solution was extracted with diethyl ether, and the organic phase was washed with water, filtered, dried, filtered again, and finally evaporated to dryness under reduced pressure. The product crystallized from Skellysolve B to provide about 0.2 g of 1-[3-(1,1-dimethylethyl)-5-isothiazolyl]-3-methyl-2-pyrrolidinone. Yield 46%. mp 111°-113° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([NH:6][C:21](=[O:22])[O:23][CH2:24][CH3:25])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: CCOC(=O)Cl
Reactant: COc1cc(N)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.5 %

Procedure:
To a solution of 3,4,5-trimethoxyaniline (6 g) in tetrahydrofuran (125 ml) at room temperature was added potassium carbonate (5.42 g) followed by ethyl chloroformate (3.55 g). The mixture was stirred at room temperature for 48 hours, then solvent removed under reduced pressure. The residue was stirred with diethyl ether and filtered. The solid material remaining on the filter was extracted with acetone, the organic extracts combined, and solvent removed from the combined extracts under reduced pressure, to give a residue of ethyl 3,4,5-trimethoxyphenylcarbamate (6.05 g)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:19][CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CCO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:19][CH3:20])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1
Reactant: COC(C(=O)O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(C(=O)O)c1ccc(O)cc1

Procedure:
(RS)-(4-Benzyloxy-phenyl)-methoxy-acetic acid (example 3.1) was hydrogenated at rt and normal pressure using 10% Pd/C as a catalyst and EtOH as a solvent to give (RS)-(4-hydroxy-phenyl)-methoxy-acetic acid as a light grey solid. MS 181.4 ([M−H]−)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1S(=O)(=O)c1ccccc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and benzene sulfonyl chloride were used for a similar reaction and treatment as Example 169, and the title compound was obtained as a colorless crystalline powder.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[Cl:19])[C:12]([O:14][CH3:15])=[O:13].[ClH:22].C([O-])(O)=O.[Na+].N>CC#N.[Cu](Cl)Cl>[Cl:22][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[Cl:19])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(N)c(Cl)c(OC)c1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: N
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(Cl)c(OC)c1
Temperature: 65 °C
Yield: 79 %

Procedure:
A suspension of copper (II) chloride (0.97 g, 7.2 mmol) and tert-butyl nitrite (1.07 mL, 9.04 mmol) in anhydrous MeCN (5 mL) was warmed to 65° C. A solution of methyl 3-amino-4-chloro-5-methoxybenzoate (4) (1.3 g, 6.0 mmol) in anhydrous MeCN (3 mL) was added dropwise. Once the addition was complete the mixture was allowed to cool to RT and poured on to 1M HCl (15 mL). The acidic mixture was neutralized with satd. NaHCO3 solution and aq. ammonia (35%, 5 mL) was added. The product was extracted with DCM (25 mL) and then washed with aq. ammonia (17.5%, 20 mL) and brine (2×20 mL). The solvent was removed in vacuo and the residue was triturated with 10% EtOAc in isohexane to afford methyl 3,4-dichloro-5-methoxybenzoate (5) (1.17 g, 79% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ: 7.72 (1H, d), 7.57 (1H, d), 3.98 (3H, s), 3.89 (3H, s).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([N-]C(C)C)(C)C.[Li+].[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([CH3:35])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:10][O:9][C:1](=[O:8])[CH:2]([CH:31]([C:30]1[CH:33]=[CH:34][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:28][C:29]=1[CH3:35])[OH:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCCCCCC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(C(=O)OC)C(O)c1ccc(OCc2ccccc2)cc1C

Procedure:
In analogy to the procedure described in example 125 a], methyl heptanoate was deprotonated with lithium diisopropylamide and reacted with 4-benzyloxy-2-methyl-benzaldehyde in tetrahydrofuran to obtain 2-[(4-benzyloxy-2-methyl-phenyl)-hydroxy-methyl]-heptanoic acid methyl ester as a mixture of two diastereomeric racemates as light yellow oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[Na].[CH3:13][CH:14]1[CH2:19][C:18](=O)[CH2:17][C:16](=[O:21])[CH:15]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C.O>[OH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C:17]2[C:16](=[O:21])[CH:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:14]([CH3:13])[CH2:19][C:18]=2[O:1][N:2]=1
Reactant: ON=C(Cl)c1ccccc1O
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1C
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1C(=O)c2c(-c3ccccc3O)noc2CC1C
Temperature: 25 °C

Procedure:
N,2-Dihydroxybenzenecarboximidoyl chloride in 100 mL of ethanol was added to sodium salt of ethyl 2-methyl4,6-dioxocyclohexanecarboxylate in a solvent mixture of 125 mL of water and 75 mL of ethanol at a temperature of 55° C. over an hour. The reaction mixture was maintained at this temperature for 4 hours and then cooled down to room temperature. After diluting with water (100 mL), the mixture was extracted with ethyl acetate (2×100 mL). The resulting extract was washed with saturated sodium chloride aqueous solution (150 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was treated with diethyl ether to give the product (2.48 g) as white powders. The residue was further purified by silica gel preparative thin layer chromatography to give additional 2.15 g of the product as white powders (total amount yielded at the 2 steps: 4.63 g, yield: 60%). The physicochemical properties of the compound obtained are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][NH:19][C:18]3=[O:23])[O:14][CH2:13][CH2:12][N:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:33]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][N:19]([CH3:33])[C:18]3=[O:23])[O:14][CH2:13][CH2:12][N:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN2CCCNC2=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCN(C[C@H]2OCCN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(Cl)c(Cl)c2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-[(2-oxotetrahydropyrimidin-1(2H)-yl)methyl]-1,4-oxazepane-4-carboxylate (300 mg) in DMF (3 mL) was added sodium hydride (60% in oil, 31 mg), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added dropwise methyl iodide (190 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (180 mg).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[OH:11])[CH2:8]2.[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:14]1[C:13]([Cl:12])=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[C:16]([F:26])[CH:15]=1)[CH2:8]2
Reactant: OC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OC2C3CC4CC(C3)CC2C4)cc1F
Temperature: 70 °C
Yield: 21.1 %

Procedure:
To a solution of 2-adamantanol (3.09 g, 20.26 mmol) in anhydrous dimethylsulfoxide (40 mL) was added tert-butyl 5-chloro-2,4-difluorobenzoate (6.56 g, 26.38 mmol) and cesium carbonate (13.20 g, 40.51 mmol), and the reaction mixture was heated at 70° C. for 16 hours. The solution was then cooled to ambient temperature and charged with an additional portion of 2-adamantanol (0.51 g, 3.34 mmol) and the reaction mixture was heated at 70° C. for an additional 24 hours. This process was repeated twice by addition of 2-adamantanol (0.49 g, 3.21 mmol) and (0.51 g, 3.31 mmol) respectively over an additional 48 hours. The mixture was cooled to ambient temperature and diluted with water (300 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from hexanes and then triturated with methanol to give the title compound (1.63 g, 16%): 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.8 Hz, 1H), 6.62 (d, J=12.5 Hz, 1H), 4.49 (br s, 1H), 2.20-2.10 (m, 4H), 1.99-1.68 (m, 10H), 1.57 (s, 9H).
Reaction SMILES: [OH:1][C@:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH:7]([CH3:9])[CH3:8])[CH2:3][C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.C1C[O:34][CH2:33][CH2:32]1>>[OH:6][C:4]1[CH2:3][C@@:2]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)([CH:7]([CH3:9])[CH3:8])[O:1][C:33](=[O:34])[CH:32]=1
Reactant: C1CCOC1
Reactant: CC(C)[C@](O)(CCc1ccc(O)cc1)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)[C@]1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared using (S)-3-hydroxy-3-[2-(4-hydroxy-phenyl)-ethyl]4-methyl-pentanoic acid (0.45 g, 1.78 mmol) from Example UUUU, THF (10 mL), and CDI (0.58 g, 3.58 mmol). The reaction was stirred 15 overnight at room temperature then added to bis[3-ethoxy-3-oxopropanoato(1-)-O,O']-magnesate (1.5 g, 5.2 mmol) from Example VVVV and the reaction stirred for 3 days at room temperature. The reaction was concentrated and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was washed with aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. 20 The crude product was cyclized as described in General Method 7 using 10 mL of THF and 150 mL of 0.1N NaOH. Purification by silica gel chromatography, eluting with CH2Cl2 :MeOH (98:2) gave the title compound. 1H-NMR (DMSO-d6) δ 0.83 (d, 3 H), 0.86 (d, 3 H), 1.78 (m, 2 H), 2.06 (m, 1 H), 2.25 (d of ABX q, 1 H), 2.39 (m, 2 H), 2.53 (d of ABX q, 1 H), 4.89 (s, 1 H), 6.6 (d, 2 H), 6.89 (d, 2 H), 9.1 (br s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)=[O:9])[CH:7]=1.C(OC(N1CC2C(CNC2)C1)=O)(C)(C)C.Cl[C:39]1[CH:44]=[C:43]([CH3:45])[N:42]=[C:41]([CH3:46])[N:40]=1.ClC1N=C(C)C=C(C)N=1>CC(O)=O>[CH3:46][C:41]1[N:40]=[C:39]([N:14]2[CH2:13][CH:12]3[CH:16]([CH2:17][N:10]([C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:18]4[N:22]=[CH:21][CH:20]=[N:19]4)=[O:9])[CH2:11]3)[CH2:15]2)[CH:44]=[C:43]([CH3:45])[N:42]=1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC2CNCC2C1
Reactant: Cc1cc(Cl)nc(C)n1
Agent: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: Cc1cc(C)nc(Cl)n1
Solvent: CC(=O)O
Product: Cc1cc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)nc(C)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 23, substituting (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (Intermediate 21) for hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester and 4-chloro-2,6-dimethylpyrimidine for 2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd for C21H22FN7O, 407.19; m/z found, 408.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:23])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([O:43][CH3:44])[CH:34]=1)=[O:32]>O>[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:16]=[CH:17][C:12]=3[N:11]([S:39]([C:36]3[CH:37]=[CH:38][C:33]([C:31]([O:30][CH3:29])=[O:32])=[CH:34][C:35]=3[O:43][CH3:44])(=[O:41])=[O:40])[C:10]2=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COCCOc1ccc2[nH]c(=O)n(C3CCCCC3)c2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
0.095 g of sodium hydride as a 60% dispersion in oil is added in portions to a mixture of 0.7 g of 3-cyclohexyl-1,3-dihydro-5-(2-methoxyethoxy)-2H-benzimidazol-2-one and 50 ml of DMF and the mixture is stirred for 30 minutes at RT. 0.6 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride is then added and the mixture is stirred for two hours at RT. The reaction mixture is poured into a mixture of water and ice, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 0.8 g of the expected product, which is used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH:4]=O.Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21].C([O-])(=O)C.[Na+]>CO>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][N:21]=[CH:4][C:3]1[C:2]([Br:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=1[Br:11]
Reactant: Cc1cc(Br)c(C=O)c(Br)c1
Reactant: NNc1ccccc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)c(C=NNc2ccccc2F)c(Br)c1

Procedure:
2,6-Dibromo-4-methylbenzaldehyde (600 g, 2.16 mmol), (2-fluorophenyl)hydrazine hydrochloride (351 mg, 2.16 mmol) and sodium acetate (180 mg, 2.19 mmol) were heated in methanol (15 mL) under reflux for 2 hours. The methanol was evaporated and the residue partitioned between dichloromethane (30 mL) and aqueous brine (30 mL). The organic phase was separated, combined with additional dichloromethane extracts (2×15 mL), washed with aqueous sodium bicarbonate (2×15 mL), passed through a hydrophobic frit and evaporated to the title compound (767 mg).