Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:10])[CH:9]=1)(=[O:3])[CH3:2].C[Si](C)(C)[C:13]([F:16])([F:15])[F:14].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O.ClCCl>[Br:10][C:8]1[CH:9]=[C:4]([C:1]([OH:3])([CH3:2])[C:13]([F:16])([F:15])[F:14])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1cncc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-acetyl-5-bromopyridine (0.20 g, 1.0 mmol) in tetrahydrofuran (3.3 mL) were added a solution of trimethyl(trifluoromethyl)silane in tetrahydrofuran (0.5 M, 4.0 mL, 2.0 mmol) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 0.1 mL, 0.1 mmol). The resulting reaction mixture was stirred at room temperature for 1 h, then diluted with water and dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (0 to 6% dichloromethane in acetone) provided the title compound: LCMS m/z 271.75 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1 H), 8.68 (s, 1 H), 8.11 (s, 1 H), 3.12 (br s, 1 H), 1.82 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[NH:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)([O-])=O.NC1SC=C(C2C=CC(N)=CC=2)N=1>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[NH:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)N1
Agent: [Fe]
Agent: Nc1ccc(-c2csc(N)n2)cc1
Solvent: CC(=O)O
Product: Nc1ccc(C=C2NC(=O)NC2=O)cc1

Procedure:
To 3 g (12.9 mmol) of crude 4-nitro-benzylidene-hydantoin, melting point 300° C. (prepared as described in Example 6 under (a)) in 50 ml 80% acetic acid are added 3 g of iron powder at 100°. After 30 minutes the mixture is filtered over kieselguhr and the filtrate is evaporated down in vacuo. The evaporation residue is divided between EtOac and dilute aqueous ammonia solution; before the separation of the phases the mixture is filtered once more through kieselguhr. The organic phase is washed with water, dried, filtered and evaporated down in vacuo. The yellow foam obtained (0.80 g; 30.6% of theory) predominantly contains 4-amino-benzylidene-hydantoin (A) (Rf =0.55), but no 4-amino-benzyl-hydantoin (B) (Rf =0.48), according to DC (silica gel; toluene/EtOac/EtOH (4:2:1)).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>CN(C=O)C>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[N:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil, 1.89 g, 47 mmol) in 20 mL of DMF was added tert-butyl ethyl propanedioate (6.5 g, 34.7 mmol) at room temperature. The mixture was stirred for 30 min. A solution of 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol) in 10 mL of DMF was added. The mixture was stirred at r.t. overnight. The solvent was removed under reduce pressure. Water was added and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatography with silica gel to give tert-butyl ethyl (5-nitropyridin-2-yl)propanedioate: 1H-NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.51 (d, J=8.8 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 5.00 (s, 1H), 4.28 (q, J=7.2 Hz, 2H), 1.49 (s, 9H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[CH2:8][OH:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OC/C=C/c1ccc(Br)cc1
Temperature: -78 °C

Procedure:
To a solution of ethyl trans-4-bromocinnamate (8 mL, 42.6 mmol) in anhydrous dichloromethane (150 mL) under N2 was added diisobutylaluminum hydride in dichloromethane (128 mL, 1 M, 128 mmol) at −78° C. dropwise. After the addition, the mixture was allowed to warm from −78° C. to −30° C. over two hours. The mixture was then cooled back to −78° C. and aqueous 1 N HCl was added till acidic (pH=2). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 1.44 (t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6 Hz, 1H), 6.57 (dt, J=15 Hz, J=3 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 214 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4CCNCC4)c3F)s2)c1
Yield: 45.5 %

Procedure:
A solution of tert-butyl 4-((3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinamido)methyl)piperidine-1-carboxylate (0.78 g, 1.40 mmol, described in Example 3) in dichloromethane (4 mL) and trifluoroacetic acid (4 mL) was stirred at 23° C. for 1 hour. The reaction was then concentrated to dryness and diluted with 10% water in acetonitrile+0.05% trifluoroacetic acid. This was purified on Preparative HPLC (acetonitrile/water/ammonium acetate) to give the title material (0.292 g, 45%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.12-1.23 (2H, m), 1.69 (2H, d, J=11.9 Hz), 2.31 (3H, s), 2.56-2.65 (2H, m), 3.08 (2H, d, J=12.4 Hz), 3.15 (2H, t, J=6.19 Hz), 6.86 (1H, d, J=5.31 Hz), 6.92 (1H, s), 7.06 (1H, t, J=5.31 Hz), 7.82 (1H, s), 8.17 (1H, d, J=5.30 Hz), 8.26 (1H, d, J=5.05 Hz), 8.74 (1H, t, J=6.06 Hz). LC/MS (M+H)+: 459. HPLC ret. time (Condition C): 3.333 min.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].I[CH2:30][CH2:31][CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][C:40](=O)[CH2:41][C:36]=2[NH:35][C:34]1=[O:43].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:30][CH2:31][CH2:32][N:33]3[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[NH:35][C:34]3=[O:43])[CH2:8][CH2:7]2)[CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=C1C=Cc2c([nH]c(=O)n2CCCI)C1
Reactant: COC(=O)c1cccc(CN2CC(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CC(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 62.4 %

Procedure:
A mixture of methyl 3-((1-oxo-4-phenyl-2,8-diazaspiro[4.5]decan-2-yl)methyl)benzoate (500 mg, 1.206 mmol, 1 equiv), 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one-one (364.4 mg, 1.206 mmol, 1 equiv), and potassium carbonate (500 mg, 3.62 mmol, 3 equiv) in N,N-dimethylformamide was stirred at 65° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.4, gradient—10% methanol in dichloromethane) to afford the title compound as a white solid (416 mg, 62%); 1H NMR (400 MHz, DMSO-d6): δ 0.99 (bs, 1H); 1.57-1.59 (m, 2H); 1.67-1.74 (m, 3H); 1.86 (bs, 1H); 2.22-2.39 (m, 4H); 2.73-2.76 (m, 2H); 3.25-3.27 (m, 1H); 3.59-3.62 (m, 1H); 3.76 (t, 2H, J=6.8 Hz); 3.86 (s, 3H); 4.55 (s, 2H); 6.94-6.95 (m, 3H); 7.09-7.11 (m, 3H); 7.20-7.24 (m, 3H); 7.51-7.58 (m, 2H); 7.88-7.90 (m, 2H); 10.77 (s, 1H); MS for C33H36N4O4 m/z 553.11 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1>[Pd].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=[O:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH:2]=1
Reactant: O=C1C(=Cc2cccnc2)N2CCC1CC2
Agent: [Pd]
Solvent: CO
Product: O=C1C2CCN(CC2)C1Cc1cccnc1
Reaction time: 4 h

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (1.0 g, 4.7 mmol) was combined with 50 ml methanol and 0.2 g palladium on charcoal (5% w/w) in a hydrogenation vessel. Hydrogenation (50 psig) was carried out for 4 hrs., after which time the slurry was carefully filtered through a pad of Celite filter aid. Evaporation of solvent gave 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-one as white semisolid, which dissolved in ethanol give a white crystalline solid upon cooling (0.82 g 88%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:24]#[N:25])([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[C:24]([C:11]1([NH:14][C:15](=[O:16])[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[N:19][CH:18]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)#[N:25]
Reactant: Cc1cncc(C(=O)NC2(C#N)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cncc(C(=O)NC2(C#N)CCNCC2)c1

Procedure:
A solution of 4-cyano-4-[(5-methyl-pyridine-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.48 g, 1.39 mmol) in 4 M HCl in dioxane (7 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. Note: The product is contaminated with some primary amide (partial hydrolysis of the nitrile). MS (ISP): 245.4 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]=O.Cl.[C:16]([O:20][C:21](=[O:28])[C@H:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:23])([CH3:19])([CH3:18])[CH3:17].C([BH3-])#N.[Na+].C(O)(=O)C>CO.C(Cl)(Cl)Cl.C(OCC)(=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][NH:23][C@@H:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:28]
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](NCCN1C(=O)c2ccccc2C1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
A solution of the product of Example 3E (9.34 g, 49.4 mmol) in methanol (33 mL) was treated with L-tert-leucine tert-butyl ester hydrochloride (10 g, 44.9 mmol), sodium cyanoborohydride (5.6 g, 89.8 mmol), and acetic acid (1.5 ml, 26.2 mmol), stirred at 25° C. for 4 hours, and partitioned between chloroform and saturated NaHCO3. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with first with 66% chloroform in hexanes and then with 33% ethyl acetate in chloroform to give the title compound (10.5 g, 59% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccc(F)cc1Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc(F)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A stirred solution of 20.0 g (0.137 mole) of 2-chloro-4-fluorophenol in 150 mL of pyridine was cooled in an ice bath. To this solution was added portionwise 31.2 g (0.164 mole) of 4-methylphenylsulfonyl chloride. After complete addition, the mixture was stirred for 2 hours, then allowed to stand in a freezer for approximately 16 hours. The mixture was poured into ice water, filtered, and the filter cake washed with water. The solid was dried in a dessicator to yield 41.0 g of 2-chloro-4-fluorophenyl 4-methylphenylsulfonate, mp 92°-94° C.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].CC([Si](C)(C)O[C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)(C)C.[Bi](Br)(Br)Br.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:4][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)[CH2:2][CH3:3]
Reactant: CCC=O
Reactant: CCOC(=O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: Br[Bi](Br)Br
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: CCCO[C@H]1CC[C@H](C(=O)OCC)CC1
Reaction time: 1.5 h

Procedure:
Propionaldehyde (6.4 g) in acetonitrile (50 mL) was added over 30 minutes to a solution of cis/trans ethyl 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D1, 25.2 g), bismuth tribromide (4.4 g) and triethylsilane (17.5 mL) in acetonitrile (300 mL) and the mixture was stirred for a further 1.5 hours. The solvent was partially removed then the residue was treated with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried with anhydrous sodium sulphate and the solvent was removed to give the title compounds contaminated with silicone residues (39.1 g).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:13][C:14]1([CH3:17])[CH2:16][O:15]1>>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:13][C:14]([CH3:17])([OH:15])[CH3:16])[CH:6]=1
Reactant: Ic1c[nH]cn1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(O)Cn1cnc(I)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
A mixture of 4-iodo-1H-imidazole, Cs2CO3 in 2,2-dimethyl oxirane was stirred at 120° C. for 20 min under irradiation with microwave. The reaction mixture was concentrated, and purified to give 1-(4-iodo-1H-imidazol-1-yl)-2-methylpropan-2-ol (Yield=71%). LC-MS: m/z=266 [M+H+] 1H NMR (CDCl3, 400 MHz): δ7.36 (s, 1H), 7.06 (s, 1H), 3.84 (s, 2H), 1.22 (s, 6H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].CC1(C)C(C)(C)OB([C:20]2[CH2:29][CH2:28][C:23]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:22][CH:21]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[C:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH:21]=1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(C2=CCC3(CC2)OCCO3)n1

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (2.0 equiv.) and Pd(dppf)Cl2-DCM (0.2 equiv.) to give 5-fluoro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)picolinic acid. LC/MS=280.2 (M+H), Rt=0.66 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([O:16]C)=O)[CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][CH2:19][CH:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][CH:20]([OH:32])[CH2:19][NH:18][C:14](=[O:16])[C:10]1[CH:9]=[C:8]([NH:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:13]=[CH:12][N:11]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: COC(=O)c1cc(NC2CCOCC2)ccn1
Solvent: CO
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cc(NC2CCOCC2)ccn1
Yield: 34.7 %

Procedure:
To a solution of compound methyl 4-((tetrahydro-2H-pyran-4-yl)amino)picolinate (50 mg, 0.21 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (44 mg, 0.21 mmol) in MeOH (2 mL) was stirred at 100° C. under microwave heating for 3 h. The reaction mixture was purified by prep-HPLC to give the title compound (29.9 mg, Yield 34.4%). 1H NMR (400 MHz, CD3OD): δ 7.95 (d, J=5.6 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.13-7.05 (m, 3H), 7.03-6.98 (m, 1H), 6.62 (dd, J=2.4, 5.6 Hz, 1H), 4.07 (quin, J=6.0 Hz, 1H), 4.01-3.93 (m, 2H), 3.72 (s, 2H), 3.66-3.60 (m, 1H), 3.60-3.57 (m, 1H), 3.57-3.52 (m, 2H), 3.49-3.42 (m, 1H), 2.95-2.89 (m, 2H), 2.87-2.81 (m, 2H), 2.65 (d, J=6.0 Hz, 2H), 1.97 (d, J=12.8 Hz, 2H), 1.59-1.47 (m, 2H). LCMS (m/z): 411.1 (M+1).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>>[CH:29]([O:28][C:26]([N:11]1[CH2:12][C@H:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])(=[O:17])=[O:16])[CH2:14][C@H:10]1[C:8](=[O:9])[NH:7][C:4]1([C:2]#[N:3])[CH2:6][CH2:5]1)=[O:27])([CH3:31])[CH3:30]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Product: CC(C)OC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was acylated with isopropyl chloroformate in analogy to experiment L21 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylcarbamoyl)-pyrrolidine-1-carboxylic acid isopropyl ester as a colorless oil. MS: 440.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CO>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: O=C(O)c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 50 °C
Yield: 76.2 %

Procedure:
The product from Example 60A (1.0 g, 3.03 mmol) and borane tetrahydrofuran complex (6.06 mL, 6.06 mmol) were combined in tetrahydrofuran (15.15 mL) and heated at 50° C. for 2 hours, cooled, treated with 10 mL of methanol, heated at 50° C. for 1 hour, cooled and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate in heptanes) afforded the title compound (0.73 g, 76%).
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:16]O.S([O-])(O)(=O)=O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Br:2][CH2:16][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]=1[Cl:5]
Reactant: BrP(Br)Br
Reactant: OCc1cccc(C(F)(F)F)c1Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(CBr)c1Cl
Reaction time: 1 h
Yield: 57 %

Procedure:
Phosphorus tribromide (11.75 ml, 125 mmol) was added to a solution of crude (2-chloro-3-(trifluoromethyl)phenyl)methanol (9.37 g, 44.5 mmol) in dioxane (200 ml). The reaction mixture was stirred for 1 hour. Another portion of phosphorus tribromide (11.75 ml, 125 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. It was diluted with ethyl acetate (200 ml). A 10% aqueous solution of sodium hydrogensulphate (200 ml) was added, while cooling with a water bath. The phases were separated. The organic phase was washed with a 10% aqueous solution of sodium hydrogensulphate (100 ml). The combined aqueous layers were extracted with ethyl acetate (100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (150 g), using ethyl acetate/heptane (1:3) as eluent, to give 6.94 g of 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[C:13]1[NH:17][N:18]=[CH:19][C:12]1=[CH:11][CH:10]=2)([O:3]CC)=[O:2].[OH-].[Na+]>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[C:13]1[NH:17][N:18]=[CH:19][C:12]1=[CH:11][CH:10]=2)([OH:3])=[O:2]
Reactant: CCOC(=O)c1cnc2ccc3cn[nH]c3c2c1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc2ccc3cn[nH]c3c2c1O
Yield: 92 %

Procedure:
A mixture of 8-carboethoxy-9-hydroxy-1H-pyrazolo[3,4-f]quinoline (12.31 g, 47.8 mmol) and 10% aqueous sodium hydroxide (96 ml) was refluxed for 8 hours, at which time the dark-colored solution was treated with decolorizing carbon and filtered through diatomaceous earth (Celite™). The filtrate was neutralized with 6M HCl and the resulting precipitate isolated by filtration. The light brown solid was air dried to give 8-carboxy-9-hydroxy-1H-pyrazolo[3,4-f]quinoline (10.08 g, 92%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C1N2CCN(CC2)C1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][O:16][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](CO)CC1
Agent: C1CN2CCN1CC2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-[4-(tert-butyldimethylsilanyloxy)cyclohexyl]methanol (555 mg, 2.24 mmol) in DCM (20 mL) at 0° C. was added DIPEA (0.59 mL, 3.37 mmol), DMAP (20 mol %, 54 mg), and p-toluene-sulfonyl chloride (570 mg, 2.68 mmol). The reaction mixture was stirred at room temperature for 2 h, DABCO (250 mg) was added. The reaction mixture was stirred overnight. The solution was diluted with DCM, washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Solvent was removed in vacuo to give the title intermediate. 1H NMR (300 mHz, CD3OD): 7.75-7.77 (d, 2H), 7.40-7.42 (d, 2H), 3.80-3.81 (d, 1H), 3.45-3.51 (m, 1H), 2.40 (s, 3H) 1.78-1.82 (m, 2H), 1.62-1.71 (m, 2H), 1.48-1.58 (m, 1H), 1.30-1.33 (m, 1H), 1.15-1.21 (m, 2H), 0.85-1.00 (m, 2H), 0.85-0.90 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: CC1(C)[C@H]2[C@@H]1CN[C@@H]2C#N.[CH3:11][O:12][C:13]([C@H:15]1[NH:20][CH2:19][C@H:18]2[C@@H:16]1[C:17]2([CH3:22])[CH3:21])=[O:14]>>[CH3:11][O:12][C:13]([CH:15]1[NH:20][CH2:19][CH:18]2[CH:16]1[C:17]2([CH3:22])[CH3:21])=[O:14]
Reactant: COC(=O)[C@H]1NC[C@H]2[C@@H]1C2(C)C
Agent: CC1(C)[C@@H]2[C@@H](C#N)NC[C@@H]21
Product: COC(=O)C1NCC2C1C2(C)C

Procedure:
The (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile prepared according to Example 16 or 17 is converted to the corresponding substantially enantiomerically pure (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester by the procedure described in PCT International Application Publication WO 2007/075790.