Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH2:21][CH2:22][CH3:23]>C(OCC)(=O)C.O>[NH2:1][C:2]1[C:7]([O:8][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCCCBr
Reactant: Nc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1cccnc1N
Temperature: 50 °C
Yield: 41.4 %

Procedure:
A reaction flask was loaded with 2-amino-3-hydroxypyridine (8 g), dimethylformamide (DMF) (50 ml), and anhydrous potassium carbonate (12 g), and the temperature was raised up to 50° C. with stirring, followed by dropwise addition of n-butylbromide (11.9 g) to the flask in 4 hours with stirring. Then, the mixture was stirred at 60° C. for 2 hours. The heating was stopped, and water (200 ml) was added to the mixture. Ethyl acetate was added to the mixture and the mixture was stirred, followed by collecting the ethyl acetate layer with a separating funnel. The layer was condensed by an evaporator to precipitate crystals, and then the crystals were broken up with hexane. The crystals were filtrated for collection and dried to give crystals of 2-amino-3-butoxypyridine (5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Cl-].[Cl-].[Al+3].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[O:31][CH3:32])[CH:21]=[CH:22][CH:23]=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:25]([O:31][CH3:32])=[CH:26][CH:27]=[C:28]([C:8]([C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:9])[C:29]=2[F:30])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cccc(F)c1-c1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 4-nitro-benzoyl chloride (1900 mg, 10.2 mmol) in nitrobenzene (6 mL) was added aluminum trichloride (1360 mg, 10.2 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 1 h, cooled to 0° C., and 3′-chloro-6-fluoro-2-methoxy-biphenyl (2.01 g, 8.5 mmol) in nitrobenzene (1 mL) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred 24 h. The reaction mixture was cooled to −10° C. and quenched with ice-water (50 mL), extracted with ethyl acetate (2×25 mL), washed with water (2×10 mL), saturated aqueuos sodium bicarbonate (10 mL), brine (30 mL), and dried over Na2SO4. After filtration and removal of solvent, the crude was purified by crystallization from ether-hexane to give I-133 (3.00 g, 91% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[CH:14]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(CBr)cc2c1

Procedure:
N-Bromosuccinimide (1.1 g, 6.2 mmole) was added portionwise to a solution of 2-methyl-5-nitrobenzofuran (1.0 g, 5.6 mmole) and benzoyl peroxide (50 mg) in carbon tetrachloride (50 ml) and the reaction mixture was heated at reflux temperature for 6 hours in the presence of bright light. The reaction mixture was then cooled, filtered and the filtrate evaporated to dryness. The residue was recrystallised from petroleum ether to give the title compound, yield 0.75 g, m.p. 96°-98°.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@H:5]([N:27]1[C:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:34]2[C:29]([N:30]([CH3:45])[C:31](=[O:44])[N:32]([CH3:43])[C:33]2=[O:42])=[CH:28]1)[CH2:6][S:7]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:3].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH2:4][C@H:5]([N:27]1[C:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:34]2[C:29]([N:30]([CH3:45])[C:31](=[O:44])[N:32]([CH3:43])[C:33]2=[O:42])=[CH:28]1)[CH2:6][SH:7]
Reactant: CN(C)C[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)n1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C[C@@H](CS)n1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-((S)-1-Dimethylaminomethyl-2-tritylsulfanyl-ethyl)-1,3-dimethyl-5-phenyl-1,6-dihydro-pyrrolo[3,4-d]pyrimidine-2,4-dione (step 4) (1.3 g, 2.115 mmol) was dissolved in DCM (50 mL) and TFA (5 mL, 64.9 mmol) and triethylsilane (0.675 mL, 4.23 mmol) were added. The mixture was stirred at RT for 1 hour 20 mins. The reaction mixture was rigorously evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc/hexane, 10% MeOH/EtOAc and 10% (7N NH3 in MeOH)/EtOAc gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:25])[C:11]3[CH:15]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])[O:14][B:13]([OH:23])[C:12]=3[CH:24]=2)=[N:4][N:3]=1.O.[OH-].[Li+]>O.C1COCC1>[NH2:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:25])[C:11]3[CH:15]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])[O:14][B:13]([OH:23])[C:12]=3[CH:24]=2)=[N:4][N:3]=1
Reactant: CCOC(=O)C(C)C1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2nnc(N)s2)cc2c1C(C(C)C(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask was placed a solution of ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoate (500 mg, 1.32 mmol, 1.00 equiv, 96%) in H2O/THF (10/10 mL), then added lithium hydroxide hydrate (230 mg, 5.48 mmol, 4.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residual solution was adjusted to pH 3 with HCl (1 mol/L) and stirred for 30 min at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep Phenyl, 5 μm, 19×150 mm; Mobile phase, water (with 0.05% TFA) and CH3CN; Gradient, 17% CH3CN up to 30% in 8 min, up to 100% in 1.5 min; Detector, UV 220 & 254 nm. This resulted in 30.2 mg (6%) of 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoic acid as a white solid. H-NMR (300 MHz, DMSO-d6, ppm): δ1.284 (3H, d, J=7.2 Hz), 2.332 (3H, s), 3.120 (2H, m), 5.301 (1H, d, J=2.7 Hz), 7.082-7.141 (3H, m), 7.295 (1H, d, J=2.1 Hz), 9.180 (1H, s). MS (ESI) m/z: 336 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH:32]([NH2:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:32]([NH:45][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:31])([F:30])[F:29])[C:9]=3[CH:17]=2)[CH:19]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NC(c1ccccc1)c1ccccc1
Product: O=C(NC(c1ccccc1)c1ccccc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with benzhydrylamine as in General Procedure 10 to give the title compound. LCMS: m/z=612.98 (M+H+); retention time=1.06 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:15])[NH:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[CH3:16].C(ON[C:23]([C:25]1[CH:34]=C2[C:28](C(C)=CC(C)(C)N2)=[CH:27][CH:26]=1)=O)(C)(C)C>>[C:11]([O:10][NH:9][C:8]([C:4]1[C:3]([CH3:16])=[C:2]2[C:7]([C:27]([CH3:28])=[CH:26][C:25]([CH3:34])([CH3:23])[NH:1]2)=[CH:6][CH:5]=1)=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC1=CC(C)(C)Nc2cc(C(=O)NOC(C)(C)C)ccc21
Reactant: Cc1c(N)cccc1C(=O)NOC(C)(C)C
Product: CC1=CC(C)(C)Nc2c1ccc(C(=O)NOC(C)(C)C)c2C
Yield: 84 %

Procedure:
This compound was prepared from 2-amino-6-tert-butyloxycarbamoyltoluene (4.00 g, 18.0 mmol) in a manner similar to that described for 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,4-trimethylquinoline (EXAMPLE 13), affording 4.56 g (84%) of the desired dihydroquinoline as a white solid. Data for 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,4,8-tetramethylquinoline: 1H NMR (400 MHz, CDCl3) 6.94 and 6.88 (br ABq, 2H, JAB·8.3 Hz, 6,5-H), 6.16 (br s, 1H, HNBoc), 5.27 (s, 1H, 3-H), 3.61 [br s, 1H, (CH3)2CNH], 2.04 (s, 3H, 8-CH3), 1.97 (s, 3H, 4-CH3), 1.50 [s, 9H, (CH3)3CO)], 1.28 [s, 6H, 2-(CH3)2].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:20]I>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH3:20])=[O:8])=[CH:18][CH:19]=1
Reactant: CI
Reactant: COc1ccc(C(=O)Nc2cccc(OC)c2)cc1
Product: COc1ccc(C(=O)N(C)c2cccc(OC)c2)cc1

Procedure:
The procedure of Preparation Example 14 was repeated, except that 4-methoxy-N-(3-methoxyphenyl)benzamide was used in place of 4-methoxy-N-(4-methoxyphenyl)benzamide, and 1.2 ml of methyl iodide was used in place of ethyl iodide. Thus, there was obtained 625 mg of 4-methoxy-N-(3-methoxyphenyl)-N-methylbenzamide.
Reaction SMILES: [CH2:1]([N:4]([CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH2:17][CH2:16][CH2:15]2)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[O:34]>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:33]([N:18]2[C:19]3[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:22])=[CH:21][CH:20]=3)[CH2:15][CH2:16][CH2:17]2)=[O:34])=[CH:37][CH:38]=1
Reactant: C=CCN(C)CCCCCCOc1ccc2c(c1)CCCN2
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)CCCN2C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To 60.4 mg (0.2 mmol) Allyl-methyl-[6-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-hexyl]-amine in 2 ml CH2Cl2 1 drop of Huenig's base and 57 mg (0.3 mmol) 4-chlorophenyl chloroformate in 1 ml CH2Cl2 were added. The solution was stirred at RT for 30 min, was concentrated and the residue was dissolved in ether and a saturated aqueous solution of NaHCO3. The inorganic phase was extracted with ether and the combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 19:1 yielded 46 mg (50%) 6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester as colorless oil, MS: 457 (MH+, 1Cl).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:24])[C:7](=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)[C:27](O)=[O:28]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]2[O:24][C:27](=[O:28])[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(C=C2C=C(C(C)(C)C)C=C(C(C)(C)C)C2=O)cc1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1C
Temperature: 80 °C
Yield: 66 %

Procedure:
A solution of 645 mg (2.0 mmol) of a mixture of 2,4-di-tert-butyl-6-(3,4-dimethyl-benzylidene)-cyclohexa-2,4-dienone (compound (301). Table 3) and the corresponding dimer (compound (401), Table 4), prepared according to Example 1b, in 7 ml of toluene is degassed using argon and then 58 mg (0.05 mmol) of tetrakis(triphenylphosphine)-palladium(0) and 23 mg (0.20 mmol) of trifluoroacetic acid are added. The autoclave is flushed with carbon monoxide and sealed, and a carbon monoxide pressure of 5 bar is then applied. The reaction mixture is maintained at 80° C. for 20 hours. After cooling to room temperature, the reaction mixture is poured into water and extracted three times using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 464 mg (66%) of 5,7-di-tert-butyl-3-(3,4-dimethyl-phenyl)-3H-benzofuran-2-one (compound (101), Table 1), m.p. 130-132° C. Analysis, calculated: C 82.24; H 8.63%. Analysis, found: C 82.20; H 8.68%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C:10]23[C:16]([CH3:18])([CH3:17])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[N:24]1.C([O-])(=O)C.[NH4+]>CCO>[Cl:21][C:5]1[C:6]([NH:9][C:10]23[C:16]([CH3:17])([CH3:18])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)=[C:7]2[N:8]=[C:28]([C:26]3[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Cn1cc(C=O)cn1
Reactant: CC12CCC(Nc3c(Cl)cnc(N)c3N)(CC1=O)C2(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cn1cc(-c2nc3c(NC45CCC(C)(C(=O)C4)C5(C)C)c(Cl)cnc3[nH]2)cn1
Temperature: 70 °C

Procedure:
4-(2,3-diamino-5-chloropyridin-4-ylamino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (10) (380 mg, 1.23 mmol), 1-methyl-1H-pyrazole-4-carbaldehyde (135 mg, 1.23 mmol) were taken in EtOH (15 ml) to which ammonium acetate (112 mg) was added and the reaction mixture was heated at 70° C. for 48 h. Crude LCMS showed the desired product along with trace of starting material. The reaction mixture was allowed to come to rt and the precipitated was filtered and washed well with ethanol to afford the desired product (478 mg, 25%) as an off white solid. NMR: δ (1H, 400M Hz, DMSO-d6): 0.90 (3H, s), 0.91 (3H, s), 1.09 (3H, s), 1.40-1.80 (3H, m), 2.30-2.60 (1H, m), 3.00-3.10 (1H, m), 3.51-3.70 (1H, m), 3.93 (3H, s), 5.36 (1H, s), 8.00 (1H, s), 8.04 (1H, s), 8.31 (1H, s), 13.09 (1H, s). LCMS (254 nm): [M+H]+ 399.00 (96.43%). HPLC: 254 nm (94.06%)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[OH:10])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]>CS(C)=O>[F:27][C:21]1[CH:20]=[C:19]([O:10][C:4]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=2[CH2:1][CH3:2])[C:18]([Cl:17])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]
Reactant: CCc1cc(F)ccc1O
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCc1cc(F)ccc1Oc1cc(F)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.2 %

Procedure:
To a solution of 2-ethyl-4-fluorophenol (364 mg, 2.60 mmol) in DMSO (10 mL) was added cesium carbonate (1690 mg, 5.19 mmol) and the mixture stirred at room temperature for 5 minutes. 5-chloro-2,4-difluorobenzoic acid (500 mg, 2.6 mmol) was added and the reaction heated to 110° C. for 18 hours. The reaction was cooled and quenched by the addition of 1N HCl (30 mL) and extracted into ethyl acetate (3×30 mL). The organic layers were combined, washed with brine (30 mL) and concentrated in vacuo before purifying using silica gel column chromatography eluting with ethylacetate:heptane 12:88 to 100:0 to furnish the title compound as a white solid (465 mg, 57%).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:36])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[O:21])[CH2:11]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:36])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[O:21])[CH2:11]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2C)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(CO)C3)ccc2C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To a solution of methyl 3-[[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-1-yl]-2-methyl-benzoyl]amino]-2,4-dimethyl-benzoate (0.35 g, 0.686 mmol) in THF (50 ml) is added Bu4NF 1.0 M in THF (0.537 g, 2.05 mmol) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 2 hours, the reaction mixture is diluted with ice-water and extracted twice with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) over a gradient using 50% ethyl acetate in hexane to afford the title compound as a brown solid (150 mg, 51%).
Reaction SMILES: [OH-:1].[K+].O[C:4]12[CH:18]=[CH:17][CH:16]=[CH:15][CH:5]1[CH2:6][CH:7]2[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.BrCCCBr.CCOCC>[NH2:9][CH2:8][CH2:7][CH2:6][O:1][C:17]1[CH:18]=[C:4]2[CH:7]([CH2:8][N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:6][C:5]2=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: OC12C=CC=CC1CC2CN1CCCCC1
Agent: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOCC
Product: NCCCOc1ccc2c(c1)C(CN1CCCCC1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Potassium hydroxide (1.5 g, 10%) is added over a period of 1 hour 15 min to a stirred suspension of 3-hydroxy-1-(1-piperidinylmethyl)benzocyclobutene (1.0 g), and tetrabutylammonium chloride (0.13 g) in 1,3-dibromopropane (4.6 ml) and the resulting mixture stirred at RT under nitrogen for two days. The reaction mixture is partitioned between ice-water and ether and the aqueous layer separated and extracted with ether. The combined organic extract is washed with water, ice cold 5% aqueous HCl thereby forming a precipitate which is filtered and washed with ether. The acidic layer is alkalized forming an oily precipitate which is taken up in ether. The combined ether fractions are washed with water, dried over Na2SO4, filtered and concentrated in vacuo yielding the desired product as an oil which is used in the next step without further purification.
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:29])[C@@H:13]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:15]SC)[C@H:7]([CH2:30][S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[CH2:6]1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH:1]([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:12]2=[O:29])[C@H:7]([CH2:30][S:31]([CH:34]([CH3:35])[CH3:36])(=[O:32])=[O:33])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CCC(OC(C)C)C[C@H]1CS(=O)(=O)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of benzyl (S)-1-((1S,2R)-4-isopropoxy-2-(isopropylsulfonyl methyl)cyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (2.8 g, 5.16 mMol) was stirred at rt. After 24 h the solution was evaporated. The residue was redissolved in CH2Cl2 and evaporated. This process was repeated four more times. The residue was dried in vacuo to get a yellow foamy solid. This solid was dissolved in DMSO and treated with Cs2CO3 (3.36 g, 10.32 mMol). The reaction was set to stir at rt. After 4 h, the reaction was quenched with saturated aq. NH4Cl. Extracted the reaction mixture with EtOAc three times. The combined organic layer was washed with brine twice. It was dried (MgSO4), filtered, concentrated and chromatographed to get benzyl (S)-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate A (faster isomer, 0.41 g, oil) and benzyl (S)-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate B (slower isomer, 0.62 g, white solid).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:19][C:20]1[N:29]=[C:28]([N:30]2[CH2:36][C:35]3[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:34]=3[O:33][CH2:32][CH2:31]2)[C:27]2[CH2:26][C:25]([CH3:45])([CH3:44])[CH2:24][CH2:23][C:22]=2[N:21]=1>>[NH2:1][C:2]1[C:7]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][C:5]([C:38]2[CH:39]=[CH:40][C:34]3[O:33][CH2:32][CH2:31][N:30]([C:28]4[C:27]5[CH2:26][C:25]([CH3:44])([CH3:45])[CH2:24][CH2:23][C:22]=5[N:21]=[C:20]([CH3:19])[N:29]=4)[CH2:36][C:35]=3[CH:37]=2)=[CH:4][N:3]=1
Reactant: CN1CC[C@H](NS(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: Cc1nc2c(c(N3CCOc4ccc(B(O)O)cc4C3)n1)CC(C)(C)CC2
Product: Cc1nc2c(c(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)N[C@@H]6CCN(C)C6)c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Synthesized according to the method of example 5 using (S)-2-amino-5-bromo-N-(1-methylpyrrolidin-3-yl)pyridine-3-sulfonamide (reagent preparation 25) and [4-(2,6,6-trimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.52 (d, 1H), 8.07 (d, 1H), 7.61 (d, 1H), 7.45 (dd, 1H), 7.02 (d, 1H), 6.68 (br s, 2H), 4.57 (s, 2H), 4.25 (br t, 2H), 3.82 (br m, 2H), 3.63 (br m, 1H), 2.65 (t, 2H), 2.43 (m, 4H), 2.33 (s, 3H), 2.22 (br m, 2H), 2.13 (s, 3H), 1.84 (s, 5H), 1.57 (t, 2H), 1.45 (m, 1H), 0.83 (s, 6H); MS (EI) for C30H39N7O3S: 578 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6]C(=O)OCC2C=CC=CC=2)[C@@H:4]([CH2:17][N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=[O:24])[NH:3]1>CCO.CO.[Pd]>[NH2:6][C@@H:5]1[C:2](=[O:1])[NH:3][C@@H:4]1[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24]
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1ccccc1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: N[C@@H]1C(=O)N[C@@H]1CN1CCCCC1=O
Reaction time: 3 h

Procedure:
Prepared according to example 7, step 3. A solution of benzyl ((3S,4R)-2-oxo-4-((2-oxopyridin-1(2H)-yl)methyl)azetidin-3-yl)carbamate (157 mg, 0.480 mmol) in EtOH:MeOH (5:1, 4.8 mL) was evaculated and backfilled with argon (2×) followed by addition of Pd on C (10%, 33 mg). The system was evacuated and backfilled with H2 (3×). After 3 h of stirring the mixture was filtered over celite, washing with MeOH and concentrated in vacuo. The crude residue was used as such in following step.
Reaction SMILES: [C-:1]#[N:2].[K+].[OH:4][CH2:5][C:6]([CH2:11][OH:12])([CH2:9][OH:10])[CH2:7]Br>C(#N)C>[OH:4][CH2:5][C:6]([CH2:11][OH:12])([CH2:9][OH:10])[CH2:7][C:1]#[N:2]
Reactant: [C-]#N
Reactant: OCC(CO)(CO)CBr
Agent: [K+]
Solvent: CC#N
Product: N#CCC(CO)(CO)CO
Yield: 78 %

Procedure:
0.07 mol of KCN is added to 0.055 mol of 2,2-bis(hydroxymethyl)-3-hydroxypropyl bromide and the mixture is dissolved in 50 ml of acetonitrile and refluxed for 5 h, with stirring. After the solution has cooled, the solid is filtered off with suction and the mother liquor is concentrated. The residue is dissolved in chloroform, the residual KBr is separated off and the solvent is distilled off after drying. The desired nitrile is separated from the residue as a pale yellowish oil by column chromatography. Yield: 78%.