Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:25])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:26](O)(=O)CCCCCCCCC#CC#CCCCCCCCCCCCC.C(O)(=O)CCCCCCCCC#CC#CCCCCCCCCCC.C(O)(=O)CCCCCCCCC#CC#CCCCCCCCCCCCC>C(O)C>[C:1]([O:25][CH3:26])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Solvent: CCO
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC

Procedure:
Alcoholic Monomer Solution of TDA/PDA: 10,12-Tricosadiynoic acid (TDA, 6 gm GFS Chemicals) and 10,12-pentacosadiynoic acid (PDA, 0.9 gm GFS Chemicals) were dissolved in 60 ml ethanol (Fisher). The solution was slightly warmed and stirred. The solution (TDA/PDA) was filtered (Whatman No. 1) to remove residual polymer. Dye colorant could be added to the alcoholic monomer solution as an indicator. Standard organic solvent based dyes were added at 2 drops per ml.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CS(C)=O>[C:12](/[C:11](/[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:14]\[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:19][CH:20]=1)#[N:13]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCCCOc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Compound 1 (200 mg) was dissolved in dimethyl sulfoxide, and anhydrous potassium carbonate was added to the resultant solution, followed by stirring at room temperature for one hour. Thereafter, ethyl 7-bromoheptanoate (169 mg) was added to the resultant mixture, and the mixture was stirred. The potassium carbonate was separated through filtration, and the resultant filtrate was poured into ice water. Hydrochloric acid was added to the resultant mixture so as to adjust the pH to 3, and then the mixture was subjected to extraction with chloroform twice. The resultant chloroform layer was washed with brine, and then dried over anhydrous sodium sulfate. The sodium sulfate was separated through filtration, and the resultant filtrate was concentrated to dryness under reduced pressure, followed by recrystallization, to thereby produce the target product (223 mg, yield: 72%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([B-](F)(F)F)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[K+].Br[C:16]1[CH:17]=[C:18]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:19]([Cl:22])=[N:20][CH:21]=1.C(N(CC)CC)C.O>CCO>[Cl:22][C:19]1[N:20]=[CH:21][C:16]([C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)=[CH:17][C:18]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29]
Reactant: F[B-](F)(F)c1ccc2ncsc2c1
Reactant: COCCOCOc1cc(Br)cnc1Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCCOCOc1cc(-c2ccc3ncsc3c2)cnc1Cl
Reaction time: 1 h
Yield: 10.3 %

Procedure:
A 50 mL Schlenk flask was charged with potassium benzo[d]thiazol-6-yltrifluoroborate (0.1929 g, 0.800 mmol), Pd(dppf)C12-DCM adduct (0.0469 g, 0.0641 mmol) and a stirbar. The flask was evacuated to <1 mm Hg and refilled with nitrogen. A degassed solution of 5-bromo-2-chloro-3-((2-methoxyethoxy)methoxy)pyridine (0.1900 g, 0.641 mmol) in 5 mL 1% aqueous EtOH was added, followed by triethylamine (0.262 ml, 1.92 mmol). The flask was fitted with a cold finger, and was heated using a 110° C. oil bath for 12 h. The solution was cooled, and water (10 mL) was added. The mixture was vigorously stirred for 1 h, and poured onto a glass frit. The oily residue was washed with water (2×10 mL), and then dissolved in MeOH (30 mL). The brownish solution was stirred for 30 minutes, and then filtered through a 0.22 μm PTFE membrane. The filtrate was concentrated in vacuo. The sample was purified in one injection using a 30×100 mm Waters Xterra Prep C18 OBD column (A=water; B=2% TFE in ACN; 100 Å pore diameter, 5 μm particle size, spherical shape, PN 186001942; Gradient: 0→5 min@35 mL/min, 40% B; 5→20 min@35 mL/min, linear gradient to 70% B; 20→24.9@35 mL/min, isocratic at 70% B, 25→29.9 min@35 mL/min, step to 100% B; 30→40 min@35 mL/min, step to 40% B; 40 min end). A fraction that eluted from 14.7 to 15.9 minutes was isolated. The solvent was removed in vacuo to afford 6-(6-chloro-5-((2-methoxyethoxy)methoxy)pyridin-3-yl)benzo[d]thiazole (0.0231 g, 10.3% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.37 (s, 3H) 3.58-3.61 (m, 2H) 3.91-3.96 (m, 2H) 5.46 (s, 2H) 7.72 (dd, J=8.51, 1.86 Hz, 1H) 7.83 (d, J=2.15 Hz, 1H) 8.15 (dd, J=1.81, 0.44 Hz, 1H) 8.23 (dd, J=8.51, 0.49 Hz, 1H) 8.35 (d, J=2.05 Hz, 1H) 9.06 (br. s., 1H). 13C NMR (101 MHz, chloroform-d) δ ppm 58.97 (s, 1 C) 68.25 (s, 1 C) 71.34 (s, 1 C) 94.14 (s, 1 C) 120.47 (s, 1 C) 122.57 (s, 1 C) 124.10 (s, 1 C) 125.67 (s, 1 C) 134.15 (s, 1 C) 134.78 (s, 1 C) 136.37 (s, 1 C) 140.24 (s, 1 C) 140.68 (s, 1 C) 149.46 (s, 1 C) 153.22 (s, 1 C) 154.95 (br. s., 1 C). HPLC-MS: 2.06 min (>99%@215 nm; 99.2% @254 nm; m/z=351.1, calculated for C16H15ClN2O3S+H+=351.1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15]([C:17]([O-:19])=[O:18])[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[N+:20]([O-])=O.[CH3:23]CO>>[NH2:20][C:3]1[CH:4]=[C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15]([C:17]([O:19][CH3:23])=[O:18])[CH2:14]3)[O:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CCO
Reactant: Cc1ccc(-c2noc(C3CN(C(=O)[O-])C3)n2)cc1[N+](=O)[O-]
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Temperature: 78 °C

Procedure:
To a stirring suspension of methyl 3-(3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (30) (795 mg, 2.50 mmol) in EtOH (20 mL) was added stannous chloride dihydrate (2.3 g, 9.99 mmol). The reaction mixture was heated at 78° C. for 3 hours. Then, the reaction was cooled to room temperature and the solvent was partially concentrated. The pH was adjusted to slightly basic pH with a saturated solution of sodium bicarbonate. The resulting white suspension was filtered and washed with water and ethyl acetate. The aqueous was extracted with ethyl acetate and washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated to give methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31). 1H NMR (400 MHz, d6-DMSO) δ 7.32 (d, J=1.6 Hz, 1H), 7.12 (dd, J=1.6, 7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 5.19 (s, 2H), 4.38-4.31 (m, 2H), 4.27-4.20 (m, 1H), 4.19-4.16 (m, 2H), 3.60 (s, 3H), 2.10 (s, 3H). MS m/z 289.12 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].C(N(C(C)C)CC)(C)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(#N)C>[S:27]([N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[C:4]=2[CH:5]=[CH:6]1)([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cccc2[nH]ccc12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C#N)cccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a stirred solution of 4-Cyano indole (0.5 g, 3.5 mmol), diisopropylethylamine (1.8 mL, 10.5 mmol) in acetonitrile (5.0 mL), p-toluene sulfonyl chloride (0.8 g, 4.22 mmol) was added and the mixture was stirred at rt for 4 h. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to yield the title compound as brown colored solid (0.95 g, 90%). [1H-NMR (CDCl3, 300 MHz): δ 8.22 (d, 1H), 7.81-7.72 (m, 3H), 7.56 (d, 1H), 7.38 (t, 1H), 7.29-7.22 (m, 2H), 6.88 (d, 1H), 2.39 (s, 3H)].
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([NH2:14])[CH3:13]>C1COCC1.CCOC(C)=O>[CH2:12]([NH:14][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:13]
Reactant: CCN
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNc1ccc(N)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 98 %

Procedure:
To a pressure tube was added 4-fluoro-3-nitroaniline (550 mg, 3.50 mmol) and a 2.0 M solution of ethylamine in THF (8 mL). The sealed tube was heated at 120° C. for 24 h. The reaction solution was cooled, diluted with EtOAc (30 mL), washed with saturated NaHCO3 (2×25 mL), dried over Na2SO4, and concentrated under reduced pressure to provide the title compound (625 mg, 98%) as a purple solid. 1H-NMR (CDCl3): δ 7.72 (1H, br s), 7.49 (1H, d), 6.96 (1H, dd), 6.74 (1H, d), 3.45 (2H, br s), 3.30 (2H, m), 1.33 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:4]2[CH:3]=1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:36]>O1CCCC1>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[N:8][N:5]4[C:6]([Cl:36])=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(Cl)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (100 mg, 0.25 mmol) in anhydrous tetrahydrofuran (5 mL) at −78° C. was added n-butyllithium (0.5 mL of 1.6 M solution in hexanes, 0.8 mmol). The resulting reaction mixture was stirred at −78° C. for 10 minutes, followed by addition of carbon tetrachloride (1 mL) and stirring at −78° C. for additional 20 minutes. The reaction was then quenched by the addition of water. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:1 ethyl acetate-hexane) to give 50 mg (45%) of N-cyclopentyl-4-[5,7-dichloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine as a yellow foam. 1H NMR (CDCl3): δ 8.53 (broad s, 1H), 8.06 (d, 1H), 7.63 (m, 2H), 7.15 (t, 2H), 7.05 (d, 1H), 6.27 (d, 1H), 5.17 (d, 1H), 4.35 (m, 1H), 2.0-2.1 (m, 2H), 1.4-1.9 (m, 6H); 19F NMR (CDCl3): δ−112.2; MS m/z 442 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]2[CH2:14][S:13][CH2:12][C:11]=2[C:15]([O:17]C)=O)=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:19](=[O:25])[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:15]([OH:17])[C:11]3[CH2:12][S:13][CH2:14][C:10]2=3)=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)N(Cc1ccc(Cl)nc1)C1=C(C(=O)OC)CSC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(O)c2c(n(Cc3ccc(Cl)nc3)c1=O)CSC2

Procedure:
To the product of Step A (6.645 g, 17.3 mol) in MeOH (60 mL) was added sodiummethoxide (5.92 mL, 25.9 mmol, 25 wt %) at rt. After 20 min the reaction was concentrated and then diluted with EtOAc and washed with aq HCl (2M) and then water providing the unpurified title compound (RE-2) which was used directly in Reference Example 3. HPLC/MS: 353.0 (M+1); Rt=2.68 min.
Reaction SMILES: [CH:1]([OH:3])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.C(N1C=CN=C1)=O.[Cl:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=2[Cl:36])=[CH:27][NH:26][CH:25]=1>O1CCCC1>[Cl:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=2[Cl:36])=[CH:27][N:26]([CH:1]=[O:3])[CH:25]=1
Reactant: O=CO
Reactant: Clc1c[nH]cc1-c1cccc(Cl)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=Cn1ccnc1
Solvent: C1CCOC1
Product: O=Cn1cc(Cl)c(-c2cccc(Cl)c2Cl)c1
Reaction time: 8 h

Procedure:
5 ml of a solution of 0.7 g of formic acid (99%) in tetrahydrofuran was added dropwise to a solution of 2.3 g of carbodiimidazole in 50 ml of tetrahydrofuran at room temperature with stirring to prepare the solution of 1-formylimidazole. A solution of 1g of 3-chloro-4-(2,3-dichlorophenyl) pyrrole in 10 ml of tetrahydrofuran was added dropwise to the solution of 1-formylimidazole. After refluxing the solution for two hours with stirring, the resulting reaction solution was left overnight and then the solvent was removed by distillation under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate and the solution was washed with water and then saturated aqueous solution of sodium chloride. After drying the solution with anhydrous magnesium sulfate, the solvent was removed by distillation to obtain 1.1 g of the desired product. The product was purified by recrystallization from ethyl acetate to obtain colorless needles of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17]([CH3:20])[CH:18]=[O:19].[BH4-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)[S:4][C:3]=1[CH:17]([CH3:20])[CH2:18][OH:19]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(C)CO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionaldehyde (1.40 g, 4.69 mmole) in THF (20 mL), is added to NaBH4 (0.266 g, 7.04 mmole) in one portion at 0° C. The reaction is kept at 0° C. for 15 minutes and warmed up to room temperature for 2 hours. The reaction is quenched using NH4Cl(aq) (50 mL) at 0° C. The THF is removed on rota vapor, the aqueous solution is then extracted with ethyl acetate (2×50 mL). The combined organic solution is washed with brine (3×100 mL), dried over Na2SO4 and concentrated. The crude product is purified on a silica gel column, gradient eluting with 0-20% ethyl acetate in hexane and concentrated to provide the titled compound as white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.CCN(CC)CC.[Cl:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[C:39]([C:46]([NH:48][C:49]3[C:50]([OH:56])=[N:51][CH:52]=[CH:53][C:54]=3[OH:55])=O)[CH:40]=[CH:41][CH:42]=2)[N:37]=1>C(Cl)Cl>[Cl:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[C:39]([C:46]3[O:55][C:54]4[CH:53]=[CH:52][NH:51][C:50](=[O:56])[C:49]=4[N:48]=3)[CH:40]=[CH:41][CH:42]=2)[N:37]=1
Reactant: O=C(Nc1c(O)ccnc1O)c1cccc2ccc(Cl)nc12
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]ccc2oc(-c3cccc4ccc(Cl)nc34)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of triphenylphosphine (381 mg, 1.454 mmol), perchloroethane (287 mg, 1.212 mmol), and Et3N (540 μl, 3.88 mmol) in DCM (4846 μl) was stirred at RT for 1 h. The yellow solution was transferred to a flask containing solid 2-chloro-N-(2,4-dihydroxypyridin-3-yl)quinoline-8-carboxamide (153 mg, 0.485 mmol); this was stirred at RT for 1 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(2-chloroquinolin-8-yl)oxazolo[4,5-c]pyridin-4(5H)-one (181, >99% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.92 (d, J=7.04 Hz, 1H) 7.53 (t, J=6.65 Hz, 1H) 7.77 (d, J=8.61 Hz, 1H) 7.84-7.90 (m, 1H) 8.35 (dd, J=8.22, 1.37 Hz, 1H) 8.43 (dd, J=7.24, 1.37 Hz, 1H) 8.64 (d, J=8.61 Hz, 1H) 11.89 (br. s., 1H). MS (ESI, pos. ion) m/z: 298.1 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:7][N:6]([CH2:8][C@@H:9]([C:11]2[C:12]([CH3:21])=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[O:15][CH2:14]3)[OH:10])[CH2:5]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)#[N:23].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:2][CH2:3][CH:4]2[CH2:7][N:6]([CH2:8][C@H:9]([OH:10])[C:11]3[C:12]([CH3:21])=[C:13]4[C:17](=[CH:18][CH:19]=3)[C:16](=[O:20])[O:15][CH2:14]4)[CH2:5]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)#[N:23]
Reactant: Cc1c([C@@H](O)CN2CC(CN)C2)ccc2c1COC2=O
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@@H](O)CN2CC(CNS(=O)(=O)c3ccc(C#N)cc3)C2)ccc2c1COC2=O
Reaction time: 24 h

Procedure:
To a vial containing (R)-5-(2-(3-(aminomethyl)azetidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride [INTERMEDIATE 12] (0.17 g, 0.54 mmol) was added commercially available 4-cyanobenzene-1-sulfonyl chloride (0.20 g, 1.0 mmol) as a solution in DMF (500 μL) followed by diisopropylethylamine (0.16 g, 1.2 mmol). The vial was shaken for 24 hours, and then was concentrated in vacuo. The resulting residue was dissolved in DMSO (1 mL) and purified by HPLC to provide (R)-4-cyano-N-((1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)azetidin-3-yl)methyl)benzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39])[CH2:5][C:6]1[CH:11]=[C:10]([CH:12]=[CH2:13])[CH:9]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:5][C:6]1[CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=[C:10]([CH2:12][CH3:13])[CH:11]=1)[CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39]
Reactant: C=Cc1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)C(=O)OC)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)C(=O)OC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(trifluoromethyl)-5-vinylbenzyl]carbamate (14 mg, 0.025 mmol) (Example 44) and Pd/C (5 mg) in THF (1 mL) and MeOH (500 μL) was placed under hydrogen. The reaction was stirred at room temperature under hydrogen for two hours. The reaction was then diluted with hexanes (25 mL), loaded on a silica gel column, and purified with 20% EtOAc/hexanes to afford methyl[3-ethyl-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.31 (25% EtOAc/hexanes). LCMS=568.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.72 (broad singlet, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 7.07 (d, J=8.0Hz, 1H), 7.01 (dd, J=2.0 Hz, 8.5, 1H), 7.01 (broad singlet, 1H), 6.86 (d, J=2.5 Hz, 1H), 6.59 (d, J=8.5 Hz, 1H), 4.44 (broad singlet, 2H), 4.11 (broad singlet, 2H), 3.39 (s, 3H), 3.24 (s, 3H), 2.73 (m, 1H), 2.25 (q, J=7.5 Hz, 2H), 1.15 (d, J=7.0 Hz, 6H), 0.92 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[C:24]([O:26]C)[C:23]([O:28]C)=[C:22]([O:30]C)[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[C:24]([OH:26])[C:23]([OH:28])=[C:22]([OH:30])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2cc3c(cc2Nc2ccccc2)C(=O)NC3=O)cc(OC)c1OC
Agent: BrB(Br)Br
Product: O=C1NC(=O)c2cc(Nc3cc(O)c(O)c(O)c3)c(Nc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 78 mg (0.18 mmol) of 4-anilino-5-(3,4,5-trimethoxy-anilino)-phthalimide (Example 27) in 4 ml ofdichloromethane, a solution of 314 μl (3.24 mmol) boron tribromide is added dropwise at RT. The reaction mixture is stirred for 4 hours at RT, is then cooled to 0° and quenched with 5 ml of water, and the phases are separated. The water phase is extracted three times with ethyl acetate. The organic phases are combined and washed twice with water, dried over magnesium surf ate and concentrated by evaporation. Excluding light, the evaporation residue is chromatographed with ethylacetate/dichloromethane 4:1 on a silica gel column (precoated with 0.4 g of sodium ascorbate per g silica gel) that is cooled with ice-water (double jacket), the product fractions are combined and concentrated by evaporation yielding the title compound in the form of dark red crystals, m.p. 152° C. (decomp.), FAB-MS: 378 [M+ +H].
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:13]=1[N:14]1[CH2:43][CH2:42][C:17]([CH3:44])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([F:41])[CH:27]=[CH:28][C:29]=2[CH2:30][O:31][CH2:32]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:44])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([F:41])[CH:27]=[CH:28][C:29]=2[CH2:30][O:31][CH2:32]3)[CH2:42][CH2:43]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1cc(F)ccc1COC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCCc1cc(F)ccc1COC3
Yield: 67.8 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-{16-fluoro-4,25-dimethyl-11,24-dioxa-1,5,7,8-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetate (36 mg, 0.059 mmol) and NaOH (0.295 mL, 0.295 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then filtered and purified by preparative HPLC to obtain (2S)-2-(tert-butoxy)-2-{16-fluoro-4,25-dimethyl-11,24-dioxa-1,5,7,8-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetic acid (23.3 mg, 0.040 mmol, 67.8% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.37-7.29 (m, 1H), 7.04 (d, J=9.9 Hz, 1H), 6.95 (t, J=8.3 Hz, 1H), 6.49 (s, 1H), 5.59 (s, 1H), 4.72-4.66 (m, 1H), 4.65-4.57 (m, 3H), 4.45 (t, J=11.7 Hz, 1H), 3.58-3.30 (m, 4H), 2.84-2.75 (m, 1H), 2.66 (d, J=12.8 Hz, 2H), 2.50 (br. s., 3H), 1.93-1.88 (m, 1H), 1.83 (d, J=13.9 Hz, 1H), 1.70-1.49 (m, 8H), 1.19 (s, 3H), 1.14 (s, 9H). LCMS (M+1)=583.7.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH:5]([C:20]#[C:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:23]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1.[OH-].[Na+].Cl>CO.O>[C:28]([C:24]1[CH:23]=[C:22]([C:21]#[C:20][CH:5]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:7]=2)[CH2:4][C:3]([OH:32])=[O:2])[CH:27]=[CH:26][CH:25]=1)([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CC(C#Cc1cccc(C(=O)OC)c1)c1ccc(OC)c(OC2CCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(C#CC(CC(=O)O)c2ccc(OC)c(OC3CCCC3)c2)c1
Reaction time: 24 h
Yield: 14.8 %

Procedure:
To a solution of (+/-)-methyl-3-(3-carbomethoxyphenyl)ethynyl-3-(3-cyclopentyloxy-4-methoxyphenyl)propionate (0.14 g, 0.32 mmol) in 5:2 methanol/water was added NaOH (0.01 g, 0.32 mmol). After 24 h, 3N HCl was added, the methanol was evaporated and the aqueous residue was extracted twice with CH2Cl2 and was evaporated. Purification by flash chromatography (silica gel, 5% CH3OH/CHCl3) provided the title compound as a yellow oil (0.02 g, 13%). Anal (C25H26O6 ·0.25H20) calcd: C, 70.32; H, 6.26. found: C, 70A6; H, 6.45.