Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([OH:24])=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Cl)=[CH:42][CH:41]=1>CN(C=O)C.CCOCC>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][N:12]([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([O:24][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([O:39][CH3:38])=[CH:41][CH:42]=2)=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(C(C(=O)O)c2ccccc2Cl)C[C@@H]1c1ccccc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(COC(=O)C(c2ccccc2Cl)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of crude 2-(R/S)-(3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidin-1-yl)-(2-chlorophenyl)acetic acid (from EXAMPLE 10, Step A), 338 mg (1.0 mmol) of cesium carbonate and 0.14 mL (1.0 mmol) of 4-(methoxy)benzyl chloride in 3 mL of DMF was stirred at rt for 22 h. The reaction mixture was diluted with 100 mL of ether and washed with 100 mL of 1.0 N NaHCO3. The layers were separated and the aqueous phase was extracted with 100 mL of ether. The combined organic phases were dried over MgSO4 and concentrated. Flash chromatography using 9:1 v/v hexanes/EtOAc as the eluant afforded 377 mg (63%, two steps) of the title compound: RF: 0.68 (4:1 v/v hexanes/EtOAc). For the pair of diastereomers: 1H NMR (300 MHz) δ 0.0, 0.01, 0.02,0.04 (4s, 6H), 0.86,0.88 (2s, 9H), 2.42 (m, 1H), 2.67 (m, 1H), 2.84-3.10 (m, 4H), 3.57-3.62 (m, 2H), 3.83 (s, 31), 4.80, 4.81 (2s, 1H), 5.10 (ABq, J=12.1, 2H), 6.83-6.87 (m, 2H), 7.20-7.41 (m, 10H), 7.73 (m, 1H).
Reaction SMILES: [Br:1][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]([C@H:17]3[CH2:29][CH2:28][O:27][C@H:18]3[CH2:19]O2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[NH2:30]C1C(C(OC)=O)=C2C(C3CCOC=3C=N2)=CC=1.BrC1C=C(F)C=CC=1S(Cl)(=O)=O>>[Br:1][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]([C:17]3[CH2:29][CH2:28][O:27][C:18]=3[CH:19]=[N:30]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c3c(cnc12)OCC3
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@@H]1OCC[C@H]21
Agent: O=S(=O)(Cl)c1ccc(F)cc1Br
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c3c(cnc12)OCC3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from methyl 7-amino-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylate (Intermediate 23) and 2-bromo-4-fluorobenzenesulfonyl chloride and stirring at room temperature for 3 days.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(Cl)(Cl)=O>CCOCC>[CH2:10]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[NH2:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: CCCC[C@H](N)C(=O)O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCCC[C@H](N)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
According to the general procedure outlined in J. Med Chem. 1986, Vol. 30, p. 3575, 15.0 g norleucine (Nle) was mixed with 200 mL benzyl alcohol and cooled to 0° C. Thionyl chloride (25 ml) was added dropwise over 15 min. and the mixture was slowly heated to 90° C. with a fierce evolution of SO2 occurring at about 50° C. After 2 h at 90° C. the mixture was cooled to 0° C. and 25 mL more thionyl chloride was added. The mixture was then heated again at 90° C. for 2 h, cooled, diluted with 1.6 L ether and stored overnight at 0° C. The crystals which formed were filtered, washed with ether and dried to give 23.1 g of a damp solid which was recrystallized from 1:10 ethanol-ether, using 23 mL ethanol. The filtered and dried solid weighed 17.1 g, TLC Rf 0.25 in System C (the spotted plate was exposed to ammonia vapor and dried prior to elution).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]C[CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][C:22]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]([CH:14]([CH3:18])[CH3:15])[CH3:17])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@H](N(C)C(C)C)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 52A for the product of Example 1E and substituting the product of Example 2A for pyrimidine-5-boronic acid. MS: (M+H)+=366.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.C(Cl)(OCC1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=O>CCOCC>[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=1)([O:5][CH2:1][CH:4]1[C:43]2[C:44](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:45]2[C:50]1=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)c1ccc(OC[C@@H]2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
To the above (S)-4-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxybenzoic acid was added CH2Cl2 (10 mL) and TFA (10 mL). The mixture was stirred at room temp for 1 hr Et2O was added to the mixture and resulting solid was collected. The solid was dissolved in water (100 mL), dioxane (50 mL) and NaHCO3 (4.4 g). Fmoc-Cl (3.34 g, 12.9 mmol) was added to the solution, and the resulting mixture was stirred for 20 hr at room temp. The mixture was washed with Et2O (×2) and aqueous layer was separated. The layer was acidified by the addition of 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with water, brine, dried over MgSO4 and evaporated in vacuo to afford 5.36 g (91%) (S)-4-(1-Fmoc-2-pyrrolidinyl)methoxybenzoic acid as a viscous oil, which was crystallized on standing.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15]([NH2:17])=[NH:16].[C:20]([O-])(=[O:22])[CH3:21].C(Cl)(=O)C>O1CCCC1.C(O)(=O)C>[ClH:1].[C:20]([O:12][CH:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][NH:16][C:15](=[NH:17])[C:14]([Cl:19])([Cl:18])[Cl:13])(=[O:22])[CH3:21]
Reactant: CC(=O)[O-]
Reactant: OC(CCl)COc1ccccc1
Reactant: N=C(N)C(Cl)(Cl)Cl
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OC(CNC(=N)C(Cl)(Cl)Cl)COc1ccccc1
Product: Cl

Procedure:
A solution of 9.3 g. (0.05 mole) of 1-chloro-2-hydroxy-3-phenoxypropane in 100 ml. of tetrahydrofuran is mixed with a solution of 8.1 g. (0.05 mole) of trichloroacetamidine, also in tetrahydrofuran. The mixture is heated at reflux for 3 hours, and concentrated to an oil, which is taken up in benzene and washed well with water. The benzene layer is dried over magnesium sulfate, filtered, and treated with excess ethanolic hydrogen chloride to provide the crude hydroxy amidine hydrochloride. This is dissolved in glacial acetic acid and converted to the acetate by treatment with 3.5 g. (0.04 mole) of acetyl chloride at room temperature for 3 days. The reaction mixture is evaporated, treated with benzene, evaporated to dryness, and the process repeated once more with benzene, twice with toluene and twice with petroleum ether. There is afforded N-(2-acetoxy-3-phenoxypropyl) trichloroacetamidine hydrochloride, m.p. 70° to 77° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH2:7])(=O)[CH3:2].[C]=O.[CH:10]([CH2:12][C:13]([OH:15])=[O:14])=[CH2:11]>O>[CH2:1]([O:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:10].[CH2:7]([O:14][C:13](=[O:15])[CH2:12][CH:10]=[CH2:11])[CH:6]=[CH2:5]
Reactant: C=CCOC(C)=O
Reactant: C=CCC(=O)O
Agent: [C]=O
Solvent: O
Product: C=CCOC(=O)CC=C
Product: C=CCOCC=C

Procedure:
A 1 liter shaking autoclave made of stainless steel was charged with 1 mol (100 grams) of allyl acetate, 0.5 gram RhCl3 . 3 H2O, 1 gram Ni(CO)4 and 18 grams of water, the autoclave was pressurized with 145 atm/g carbon monoxide and the mixture heated at 138° - 140°C. After a time of reaction of 7 hours the reaction was interrupted and the mixture analyzed. 98 grams of reaction mixture were obtained containing about 15 % of vinyl acetic acid. Diallyl ether and vinyl acetic acid allyl ester were not formed. Besides acetic acid the mixture further contained the unreacted allyl acetate, small amounts of allyl alcohol, a little propionaldehyde and high boiling constituents.
Reaction SMILES: C(NC(C)C)(C)C.C([N:10]([CH2:21][CH3:22])[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19])C.C(C[CH2:26][N:27]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]1)#N.O>O1CCCC1>[OH:32][C@@H:29]1[CH2:30][CH2:31][N:27]([CH2:26][CH2:22][C:21]2[NH:10][C:11](=[O:20])[C:12]3[C:13]([CH:19]=2)=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)[CH2:28]1
Reactant: N#CCCN1CC[C@@H](O)C1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cccc2c(=O)[nH]c(CCN3CC[C@@H](O)C3)cc12
Temperature: -78 °C
Yield: 22.9 %

Procedure:
Diisopropylamine (122 mL) was dissolved in tetrahydrofuran (400 mL), and n-butyllithiun (1.56 mol/L) (534 mL) was added dropwise to the solution under ice-cooling. The mixture was stirred under ice-cooling for 30 min, and then cooled to −78° C. A solution (150 mL) of N,N-diethyl-2,3-dimethylbenzamide (85.4 g) in tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at −78° C. for 0.5 hr. The reaction mixture was cooled to −78° C. and a solution (150 mL) of (R)-1-(2-cyanoethyl)-3-hydroxypyrrolidine (53 g) in tetrahydrofuran was added dropwise to the mixture. The reaction mixture was allowed to warm to room temperature. After the completion of the reaction, water was added to the reaction mixture and the organic layer was separated and concentrated. The residue was dissolved in chloroform and the solution was washed with saturated brine and dried over magnesium sulfate. The organic layer was extracted with 1N hydrochloric acid, and the layer was basified. The aqueous layer was extracted with chloroform and the extract was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography to give (R)-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (23.6 g).
Reaction SMILES: [OH:1][C@@:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=O.[C:21]([C:28]1NC=CN=1)(C1NC=CN=1)=[O:22].C1C[O:36][CH2:35]C1>>[CH3:35][O:36][C:21](=[O:22])[CH2:28][C:4](=[O:6])[CH2:3][C@:2]([OH:1])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)C[C@@](O)(CCc1ccccc1)c1ccccc1
Reactant: C1CCOC1
Product: COC(=O)CC(=O)C[C@@](O)(CCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The title compound was prepared using (S)-3-hydroxy-3,5-diphenyl-pentanoic acid from Example AA (0.7 g, 2.59 mmol), THF (30 mL), and carbonyl diimidazole (0.5 g, 3.08 mmol). The reaction was stirred for 6 hours at room temperature; bis [3-methoxy-3-oxopropanoato (1-)-O,O'] magnesate from Example BB (0.8 g, 3.10 mmol) was added, and the reaction was stirred for 3 days at room temperature. The reaction was concentrated and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. Purification by silica gel chromatography, eluting with EtOAc:hexane (20:80) gave the title compound. 1H NMR (CDCl3) δ 2.01 (m, 1 H), 2.11 (m, 1 H), 2.24 (m, 1 H), 2.64 (m, 1 H), 2.97 (d, 1 H), 3.28 (s, 2 H), 3.30 (d, 1 H), 3.64 (s, 3 H), 4.15 (s, 1 H), 7.03-7.42 (m, 10 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.C1(C)C=CC=CC=1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2cccnc2)cc1
Yield: 17.2 %

Procedure:
A solution of 4-bromobenzeneboronic acid (6.0 g) in absolute ethanol (15 ml) was added slowly to a stirred mixture of a solution of 3-bromopyridine (4.7 g) in toluene (30 ml), a saturated aqueous solution of sodium carbonate (10 ml) and tetrakistriphenylphosphine palladium [0] (1.0 g) under an atmosphere of argon. The mixture was then heated to reflux and stirred at reflux under an atmosphere of argon for 6 hours. The mixture was cooled and water (50 ml) added. The resulting mixture was extracted with ethyl acetate (3×30 ml). The ethyl acetate extracts were combined, and then extracted with 2M aqueous hydrochloric acid (3×20 ml). The acidic extracts were combined, cooled by the addition of ice and basified by the addition of sodium hydroxide solution (1.35 g.cm-3) to give a pH of 9. The mixture was then extracted with ethyl acetate (3×30 ml). These ethyl acetate extracts were combined, dried (MgSO4) and evaporated to afford 4-(pyrid-3-yl)bromobenzene as a colourless oil (1.2 g); NMR (CDCl3): 7.3-7.5 (3H, m), 7.6(2H, d), 7.85(1H, d of t), 8.6(1H, d of d) and 8.8(1H, d).
Reaction SMILES: Br[CH2:2]C1C=CC(F)=CC=1.Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.[O:15]=[C:16]1[NH:20][CH2:19][CH2:18][N:17]1[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24]([O-:26])=[O:25]>>[CH:14]1([CH2:13][N:20]2[CH2:19][CH2:18][N:17]([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=3)[C:24]([O:26][CH3:2])=[O:25])[C:16]2=[O:15])[CH2:12][CH2:11]1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C([O-])c1ccnc(N2CCNC2=O)c1
Reactant: BrCC1CC1
Product: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 69 %

Procedure:
Following the procedure as described in Preparation 17, making variations as required to replace 1-(bromomethyl)-4-fluorobenzene with (bromomethyl)cyclopropane to react with 2-(2-oxoimidazolidin-1-yl)isonicotinate, methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate was obtained as a colorless solid in 69% yield: mp 75-77° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 7.35 (d, J=5.1 Hz, 1H), 3.94 (t, J=8.0 Hz, 2H), 3.85 (s, 3H), 3.54 (t, J=8.0 Hz, 2H), 3.06 (d, J=6.9 Hz, 2H), 0.97-0.87 (m, 1H), 0.49-0.43 (m, 2H), 0.22-0.15 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 165.8, 156.5, 153.8, 149.1, 138.4, 116.1, 111.4, 53.2, 48.2, 41.7, 41.5, 9.4, 3.6; MS (ES+) m/z 276.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.Cl[C:25]([O:27][CH3:28])=[O:26]>N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:25](=[O:26])[O:27][CH3:28].[OH:20][B:17]1[C:16]2[CH:21]=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:25](=[O:26])[O-:27])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:13]=[CH:14][C:15]=2[CH2:19][O:18]1
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Product: O=C([O-])Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.64 %
Yield: 21.28 %

Procedure:
A solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (832.5 mg, 2.5 mmol) in pyridine (20 ml) was stirred at room temperature for 30 mins. Methyl chloroformate (708.5 mg, 7.5 mmol) was then added to the mixture and it was stirred at room temperature for overnight. The solution was concentrated in vacuo and the residue was purified by prep. HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 5%-45%, 30 min) to give methyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)benzylcarbamate (208 mg, 21.28%) as a yellow solid and methyl 3-(methoxycarbonylamino)methyl)-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylcarbamate (445 mg, 39.64%) as an orange solid.
Reaction SMILES: CN(C)CCN.[CH:7]([O:10][N:11]1[C:15](=O)[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2C1=O)([CH3:9])[CH3:8].C(O)(=O)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[C:29](C(C2CCCCC2)=O)[CH:28]=1>CCO>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33][S:34]([C:37]([F:40])([F:38])[F:39])(=[O:36])=[O:35])=[C:31]([C:15]([CH:14]2[CH2:13][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:11][O:10][CH:7]([CH3:8])[CH3:9])[CH:32]=1
Reactant: CC(C)ON1C(=O)c2ccccc2C1=O
Reactant: O=C(c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F)C1CCCCC1
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)ON=C(c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F)C1CCCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-isopropoxyphthalimide (308 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(4-chloro-2-cyclohexanecarbonylphenyl)-trifluoromethanesulfonamide 29E (370 mg, 1.0 mmol), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-[4-chloro-2-(cyclohexylisopropoxyiminomethyl)phenyl]trifluoromethanesulfonamide 210 (390 mg, 91%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) (1:1 mixture of E- and Z-isomers) δ 10.59, br s, 1H; 8.11, br s, 1H; 7.61, d, J=8.8 Hz, 1H; 7.49, d, J=8.8 Hz, 1H; 7.46, d, J=2.4 Hz, 1H; 7.42, dd, J=2.4 and 8.8 Hz, 1H; 7.30, dd, J=2.4 and 8.8 Hz, 1H; 7.24, d, J=2.4 Hz, 1H; 4.49, m, 1H; 4.39, m, 1H; 2.97, m, 1H; 2.45, m, 1H; 1.97-1.71, m, 14H; 1.34-1.24, m, 18H. HRMS (M+) 426.0983.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:22][C:23]([F:33])([F:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C(#N)C.[I-].[Na+]>C(OCC)(=O)C>[F:19][C:18]([F:21])([F:20])[C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:29][C:28]4[CH:30]=[CH:31][C:25]([O:24][C:23]([F:22])([F:32])[F:33])=[CH:26][CH:27]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1cccnc1N1CCc2c(Cl)ncnc2C1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1
Temperature: 150 °C

Procedure:
In a 5 ml microwave vial was combined 4-chloro-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.113 g, 0.000356 mol), 4-(trifluoromethoxy)aniline (0.0964 mL, 0.000711 mol), acetonitrile (2 mL, 0.04 mol), and sodium iodide (0.00533 g, 0.0000356 mol). The mixture was heated at at 150° C. for 10 minutes and reduced in vacuo. The remaining solid was taken up in ethyl acetate (10 mL) and washed with saturated sodium bicarbonate (2×10 mL) and water (1×10 mL). The organic layer was dried over magnesium sulfate and reduced in vacuo to yield an off white solid. The mixture was purified by flash chromatography using an ethyl acetate:hexanes (0-50%) gradient to yield the desired product as an off white solid (0.105 g).
Reaction SMILES: Br[C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[CH3:19][N:20]1CCCC1=O.[C-]#N.[Na+]>O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:3]2[C:2]([C:19]#[N:20])=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)=[N:4]2)=[C:12]([F:18])[CH:13]=1
Reactant: Fc1cc(Cl)ccc1-n1nc2c(c1Br)CCCC2
Reactant: CN1CCCC1=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1c2c(nn1-c1ccc(Cl)cc1F)CCCC2

Procedure:
4.7 Parts of 3-bromo-2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole [from Example 1-d] was combined with 1.5 parts of cuprous cyanide in 60 parts of N-methylpyrrolidinone and heated to 190° for 2 hours. After cooling to 30°, the reaction mixture was digested in a solution of 15 parts of sodium cyanide in 150 parts of water at 65°-70° for 2 hours, then extracted with 250 parts of toluene four times. The combined toluene extracts were washed with 500 parts of water 4 times, followed by 100 parts saturated aqueous sodium chloride. After drying with anhydrous sodium sulfate, the solution was evaporated at 50° and 50 mm. Hg to yield 4.4 parts of a brown oil. After crystallization from methylcyclohexane, 1.1 parts of 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole-3-carbonitrile melting at 83°-84° were isolated.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][C:12]=1[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O.O1CCCC1.CO>[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Lithium hydroxide (3.38 g, 0.14 mol, 3 eq) in water (50 mL) was added to a stirred solution of benzyl 2-benzyloxy-5-formylbenzoate (16.13 g, 0.046 mol, 1 eq) in a mixture of tetrahydrofuran (200 mL) and methanol (50 mL). The solution was stirred overnight, acidified to pH 1 with 10% HCl, and the organic solvents removed in vacuo. The aqueous solution was extracted with ethyl acetate (200 mL), and the organic solution washed with brine (200 mL), then extracted with saturated aqueous sodium bicarbonate (3×200 mL). The basic solution was washed with ethyl acetate (200 mL), then acidified to pH 1 with 10% HCl and back extracted with ethyl acetate (3×200 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give a pale yellow powder (10.83 g, 89%). 1H NMR (CDCl3) δ9.94 (s, 1H, O═C—H), 5.37 (s, 2H, CH2Ph).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:10][N:11](C)C)[CH:5]=[CH:6][CH:7]=1.O.[NH2:22]N.C(OCC)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][NH:11][N:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CN(C)C=C(C(=O)c1cccc(Br)c1)c1ccncc1
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: Brc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Reaction time: 4 h
Yield: 99.9 %

Procedure:
8 g (0.024 mol) of 1-(3-bromophenyl)-3-(dimethylamino)-2-pyridin-4-ylprop-2-en-1-one were dissolved in 20 ml of ethanol and 3 mL (0.06 mol) of hydrazine hydrate were added. The solution was refluxed under stirring for 4 hours. The title compound was collected by filtration. The filtrate was evaporated, the residue taken up with dichloromethane and washed with water. The organic layer, dried over Na2SO4, was evaporated to dryness and triturated with diethylether affording a second crop of the title compound (7.2 g overall; 100% yield).