Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.CC([O:40]C([C@H](O)[C@@H](O)C(OC(C)C)=O)=O)C>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:15]([CH:16]1[O:40][CH:17]1[CH:31]([C:30]1[CH:33]=[CH:34][C:27]([C:26]([F:35])([F:36])[F:25])=[CH:28][CH:29]=1)[OH:32])([CH3:19])([CH3:18])[CH3:14]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: C#CC(C)(C)C
Reactant: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C1OC1C(O)c1ccc(C(F)(F)F)cc1
Yield: 85 %

Procedure:
The product was prepared by General procedure T using 50 mg (0.28 mmol) Cy2BH, 35 μL (0.28 mmol) 3,3-dimethyl-1-butyne, 0.39 mL (0.78 mmol, 2.0 M in hexanes) Et2Zn, 2.4 mg (0.01 mmol) (−)-MIB, 34 μL (0.25 mmol) p-trifluoromethylbenzaldehyde, 50 μL (0.05 mmol, 1.0 M in hexanes) Ti(OiPr)4, and 10.6 μL (0.05 mmol) (+)-DIPT. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound in 85% yield (58 mg, 0.21 mmol). threo-diastereomer: Colorless solid. m.p.: 76-79° C.; [α]D20=−10.0 (c=0.27, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.90 (s, 10H), 2.89 (d, 1H, J=2.2 Hz), 3.03 (dd, 1H, J=5.5, 2.2 Hz), 4.58 (d, 1H, J=5.4 Hz), 7.53 (d, 2H, J=8.1 Hz), and 7.64 (d, 2H, J=8.1 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 25.7, 30.6, 59.0, 65.3, 73.6, 125.54, 125.58, 125.59, and 126.3 ppm; IR (film): 3411, 3028, 2969, 2927, 2871, 2367, 2332, 1622, 1477, 1460, 1420, 1365, 1331, and 1241 cm−1; HRMS-CI m/z 255.1192 [(M−F)+; calcd for C14H17F2O2: 255.1197]. erythro-diastereomer: Colorless solid. m.p.: 74-75° C.; [α]D20=−32.0 (c=0.10, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.83 (s, 9H), 2.30 (br s, 1H), 2.93 (d, 1H, J=2.0 Hz), 3.03 (t, 1H, J=2.6 Hz), 4.90 (d, 1H, J=2.2 Hz), 7.48 (d, 2H, J=8.0 Hz), and 7.60 (d, 2H, J=8.0 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 25.7, 31.6, 57.9, 62.8, 75.6, 125.50, 125.51, 125.53, and 126.6 ppm; IR (film): 3350, 3037, 2955, 2868, 1661, 1620, 1477, 1463, 1414, 1365, and 1327 cm−1; HRMS-CI m/z 255.1192 [(M−F)+; calcd for C14H17F2O2: 255.1197].
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:34]([CH3:35])[C:26]=4[CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1cccc(C(=O)Cl)c1C
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c1C
Yield: 13.4 %

Procedure:
As described for Example 9, 0.628 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.506 g (3.0 mmol) of 2,3-dimethylbenzoyl chloride in dichloromethane. The product is recrystallized from hexane-dichloromethane to give 0.12 g of crystals, m.p. 138°-142° C. Anal. Calc'd for C30 H26N2O2 : C,80.7; H,5.9; N,6.3. Found: C,80.0; H,5.9; N,6.1.
Reaction SMILES: [Na].O=[C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH:5]=O.Cl.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[NH:24][C:25]([NH2:27])=[NH:26]>C(O)(C)C.C1(C)C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[NH:24][C:25]1[N:27]=[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:26]=1
Reactant: O=CCC(=O)c1cccnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C

Procedure:
Under inert atmosphere, 5 g of sodium salt of the β-oxo-3-pyridinepropanal, with HPLC purity of 99% (A %) and salt content of 25% (residue by calcination), and 8 mL hydrochloric acid in isopropanol in 50 mL toluene is suspended. 3.7 g (2-methyl-5-nitrophenyl)guanidine is added, and the mixture is stirred at room temperature for an hour. The mixture is refluxed for 18 hours, removing the water with a Dean Stark apparatus. Once completed the conversion, the suspension is cooled to 10° C., and the precipitate is filtrated; this is crushed in warm water, yielding, upon filtration and drying, 2.5 g of product with HPLC purity of 96% (A %), identified through GC-MS.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][C:26](=[N:30][OH:31])[C:27]([OH:29])=O)=[CH:17]1.ON1C(=O)CCC1=O.Cl.[NH2:41][C@H:42]([C:47]([O:49][CH3:50])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45]>O1CCOCC1.C(OCC)(=O)C.C(N(CC)CC)C>[OH:31][N:30]=[C:26]([CH2:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][CH:17]=1)[C:27]([NH:41][C@H:42]([C:47]([O:49][CH3:50])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:29]
Reactant: O=C(O)C(Cc1c[nH]c2ccccc12)=NO
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)C(Cc1c[nH]c2ccccc12)=NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
8.68 g of dicyclohexylcarbodiimide was added to 200 ml of a solution of 8.73 g of 3-(3-indolyl)-2-hydroxyiminopropionic acid and 4.83 g of N-hydroxysuccinimide in anhydrous dioxane, with ice-cooling. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to remove the insoluble materials, to obtain a brown solution. Separately, 5.6 ml of triethylamine was added to 70 ml of a suspension of 7.27 g of methyl L-leucinate hydrochloride in anhydrous dioxane. The mixture was stirred at room temperature for 2 hours. Thereto was added the above brown solution. The mixture was stirred for 16 hours. The reaction mixture was diluted with 700 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid, an aqueous solution saturated with sodium chloride and an aqueous solution saturated with sodium hydrogen carbonate in this order, then dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent, to obtain 13.81 g of methyl N-[2-hydroxyimino-3-(3-indolyl)propionyl]-L-leucinate as a brown oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][CH:11]=2)=[C:4]([CH3:18])[N:3]=1.[C-:19]#[N:20].[K+].O>CN(C=O)C.CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:19]#[N:20])=[CH:12][CH:11]=2)=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1nc(N)nc(O)c1Sc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N)nc(O)c1Sc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step (ii) (8.7 g) and KCN (8.28 g) in DMF (20 ml) and DMSO (20 ml) was stirred at rt for 2 h then 50° C. for 2 h. Water (150 ml) was added and stirred for 30 min. The solid obtained was filtered off and added to MeOH (150 ml), heated to reflux for 5 min then hot filtered and allowed to cool to rt. The precipitate was filtered and dried under high vacuum at 45° C., to give the subtitle compound as a brown solid, 2.3 g.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[S:9][CH:8]=[C:7]([CH:10]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][C:12]#[N:13])[CH:6]=1)C.C1COCC1.Cl>O>[CH:4]([C:5]1[S:9][CH:8]=[C:7]([CH:10]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][C:12]#[N:13])[CH:6]=1)=[O:3]
Reactant: CCOC(OCC)c1cc(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4csc(C=O)c4)c3)ncnc21
Temperature: 25 °C

Procedure:
A solution of 3-[5-(diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (70 mg, 0.0001 mol) in THF (1 mL, 0.01 mol) was treated with 1 M HCl in water (400 μL). The reaction was stirred at room temperature. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-formyl-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile as a semisolid residue (60 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 9.96 (s, 1H), 8.89 (s, 1H), 8.44 (m, 2H), 7.46 (1H), 5.73 (s, 2H), 4.15 (m, 1H), 3.73-3.43 (m, 3H), 1.35 (m, 1H), 1.01 (m, 2H), 0.03 (s, 9H); MS(ES): 479 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:23]1([CH3:35])[CH:28]=[CH:27][C:26]([S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:33]([NH:32][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:35])=[CH:24][CH:25]=3)(=[O:31])=[O:30])=[O:34])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)cc1
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9, 1.2 g, 4.0 mmol) in dichloromethane (15 mL) was added p-toluenesulfonyl isocyanate (805 mg, 4.0 mmol). The resulting mixture was stirred at room temperature for 3 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (20:1) to afford 1.10 g (56%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.85 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.4 Hz), 7.16 (2H, d, J=8.4 Hz), 6.91 (1H, s), 6.12 (1H, br. s), 3.55-3.46 (2H, m), 2.85 (2H, t, J=6.3 Hz), 2.74-2.64 (5H, m), 2.42 (3H, s), 2.41 (3H, s), 1.21 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[O:6][CH2:5][CH2:4][O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>C1COCC1>[CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH2:10][NH2:11])[CH:12]=[CH:13][CH:14]=2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2cccc(C#N)c2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(c2cccc(CN)c2)OCCO1
Reaction time: 1.5 h
Yield: 59.5 %

Procedure:
A solution of cyano ketal 19 (290 mg, 1.53 mmol) in dry THF (10 mL) was cooled to 0° C. under a nitrogen atmosphere. Then a solution of 2 M lithium aluminum hydride (3 mmol) in THF was added over a 10-min period. The reaction mixture was stirred for 1.5 h and then ethyl acetate was added followed by slow addition of water to decompose the excess LAH. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by column chromatography using chloroform and methanol as an eluent to give 20 (176 mg, yield 60%). 1H NMR (CDCl3, 400 MHz) δ 1.66 (s, 3H), 3.79 (t, J=6 Hz, 2H), 3.88 (s, 2H), 4.04 (t, J=6 Hz, 2H), 7.24-7.42 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7](OC=C)=[CH:6][C:5]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])=[C:4]([F:22])[CH:3]=1.Cl[C:24]([F:29])([F:28])[C:25]([O-])=[O:26].[Na+].[CH3:31]OCCOCCOC>>[Cl:1][C:2]1[C:7]([O:26][CH:25]2[CH2:31][C:24]2([F:29])[F:28])=[CH:6][C:5]([N:11]2[C:12](=[O:21])[C:13]3[CH2:20][CH2:19][CH2:18][CH2:17][C:14]=3[C:15]2=[O:16])=[C:4]([F:22])[CH:3]=1
Reactant: C=COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COCCOCCOC
Agent: [Na+]
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CC2(F)F)c(Cl)cc1F

Procedure:
1.2 g N-[4-Chloro-2-fluoro-5-vinyloxyphenyl)-3,4,5,6-tetrahydrophthalimide was dissolved in 5 ml diethylene glycol dimethyl ether, the mixture was heated to reflux and a solution of 2.8 g sodium chlorodifluoroacetate in 5 ml diethylene glycol dimethyl ether was added slowly. The mixture was heated under reflux for 5 hours, then separated from the sodium chloride, which formed, and the solvent removed. The residue was chromatographed on silica gel using a mixture of hexane/diethyl ether=1:1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:34][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[CH:47]([C:48]2[NH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56](Br)=[CH:55][CH:54]=3)=[CH:51][N:52]=2)[CH:46]2[CH2:60][CH:43]1[CH2:44][CH2:45]2)=[O:41])([CH3:38])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([O:39][C:40]([N:42]1[CH:47]([C:48]2[NH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:22]4[CH:21]=[CH:20][C:19]([C:16]5[NH:15][C:14]([CH:13]6[CH:12]7[CH2:34][CH:9]([CH2:10][CH2:11]7)[N:8]6[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:18][CH:17]=5)=[CH:24][CH:23]=4)=[CH:55][CH:54]=3)=[CH:51][N:52]=2)[CH:46]2[CH2:60][CH:43]1[CH2:44][CH2:45]2)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5C6CCC(C6)N5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 80 °C
Yield: 6.1 %

Procedure:
To the solution of 3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (560 mg, 1.22 mmol) and 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (535 mg, 1.28 mmol) in 1,2-dimethoxyether (11 ml) and water (3.5 ml) was added sodium bicarbonate (343 mg, 4 mmol), followed by Pd(PPh3)4 (55 mg). The mixture was heated at 80° C. for 7 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/MeOH) gave 4,4′-bis-[2-(2-tert-butoxycarbonyl-2-aza-bicyclo[2.2.1]hept-3-yl)-3H-imidazol-4-yl]-biphenyl (50 mg). m/z: 677.2 (M+H)+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:33][C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([OH:29])=[O:28])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:11]=1.CN(C=O)C>C1COCC1>[Br:8][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=[O:28])[CH:23]=2)[O:33][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
NBS (125 mg, 0.702 mmol) was added to a stirred suspension of 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (215 mg, 0.645 mmol) in THF (5 mL)/DMF (1 mL). The solids dissolved and the reaction was stirred at room temperature for 30 min, then quenched with 10% Na2S2O3, and acidified with 1 N HCl. The solvent was evaporated and the material was diluted with water, filtered and dried to afford a mixture of starting material and product. The material was resubjected to the reaction conditions (80 mg of NBS in 3 mL THF/0.5 mL DMF). After 3 h, the reaction was quenched by the addition of 10% Na2S2O3, and the solution was acidified with 0.1 N HCl. The volatiles were removed and the resulting off-white precipitate was collected by filtration, rinsed with water and Et2O, and air-dried to afford the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (140 mg, 53% yield) as an off-white powder consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (1H, d, J=2.26 Hz), 8.27-8.33 (2H, m), 8.19-8.26 (2H, m), 8.05-8.12 (1H, m), 8.03 (1H, d, J=7.78 Hz), 7.68 (1H, t, J=7.78 Hz), 7.45-7.55 (2H, m). LC-MS retention time: 1.20 min; m/z (MH+): 412, 414. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][C@H:15]([OH:18])[CH2:16][CH3:17].[H-].[Na+]>C1COCC1>[F:11][C:10]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:18][C@H:15]([CH2:16][CH3:17])[CH3:14])[C:6]#[N:7]
Reactant: CC[C@H](C)O
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](C)Oc1ccc(C#N)cc1C(F)(F)F
Reaction time: 2 h
Yield: 38.3 %

Procedure:
A solution of 1.1 g (5.9 mmol) of 4-fluoro-3-trifluoromethylbenzonitrile and 485 mg (6.5 mmol) of (S)-(+)-2-butanol in 10 mL of THF at −10° C. was treated with 235 mg (5.9 mmol) of sodium hydride. The resulting mixture was stirred at cold for 2 h, then quenched with 10 mL of H2O. The quenched solution was extracted with 30 mL of Et2O, dried over MgSO4 and concentrated. Chromatography on a Biotage 40M cartridge using 4:1 v/v hexanes/Ethyl acetate as the eluant afforded 550 mg of the title compound: 1H NMR δ 0.99 (t, J=7.6, 3H), 1.35 (d, J=6.2, 3H), 1.58-1.83 (m, 2H), 4.51 (septet, 1H), 7.04 (d, J=8.7, 1H), 7.75 (d, J=8.7, 1H), 7.85 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][CH2:15][CH2:16][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]3)=[O:28])[N:23]=2)[CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:54][OH:55]>CN(C)C=O>[NH3:23].[CH:8]1([CH2:14][CH2:15][CH2:16][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]3)=[O:28])[N:23]=2)[CH2:18][C:19]([NH:54][OH:55])=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CN(C)C1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)CC1
Reactant: NO
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)CC1
Product: N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 8.1 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[4-(dimethylamino)-1-piperidinyl]carbonyl}-1,2,4-oxadiazol-5yl) hexanoic acid trifluoroacetate (Preparation 26) (702 mg, 1.31 mmol) and N-methylmorpholine (159 μl, 1.45 mmol) in N,N-dimethylformamide (15 ml) was cooled to 0° C. and then treated with dropwise with isobutyl chloroformate (188 μl, 1.45 mmol). The resulting solution was stirred at 0° C. under a nitrogen atmosphere for 45 minutes. Hydroxylamine hydrochloride (274 mg, 3.94 mmol) was then added followed by further N-methylmorpholine (433 μl, 3.94 mmol) and the mixture was stirred for 18 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium carbonate. The pH of the solution was adjusted to 9 by dropwise addition of acetic acid and the product was then extracted with ethyl acetate (×2). The combined organic phases were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:0.88 ammonia (90:10:1) then dichloromethane:methanol:0.88 ammonia (80:20:2) to afford the title compound as an oil (23 mg)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[N:18]=[CH:19][C:20]2[NH:21][C:22]3[C:27]([C:28]=2[C:29]=1[CH2:30][O:31][CH3:32])=[C:26]([CH2:33][C:34]1C=[CH:38][C:37](Cl)=[CH:36][CH:35]=1)[CH:25]=[CH:24][CH:23]=3)=[O:16])[CH3:13].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.Cl[CH2:58][Cl:59]>>[CH2:12]([O:14][C:15]([C:17]1[N:18]=[CH:19][C:20]2[N:21]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[C:22]3[C:27]([C:28]=2[C:29]=1[CH2:30][O:31][CH3:32])=[C:26]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:58]=1[Cl:59])[CH:25]=[CH:24][CH:23]=3)=[O:16])[CH3:13]
Reactant: ClCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c2c1COC
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc2c(c1COC)c1c(Cc3ccccc3Cl)cccc1n2S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.25 h

Procedure:
0.744 g (0.0039 mol) of p-toluenesulfochloride is added under ice cooling to a solution of 1.2 g (0.0029 mol) of 5-(4-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, 0.16 g (0.0013 mol) of dimethylaminopyridine and 0.54 ml (0.0039 mol) of triethylamine in 120 ml of dichloromethane. The reaction mixture is stirred for another 15 minutes under ice cooling and then for 2 hours at room temperature. Then it is diluted with dichloromethane, washed with water, dried and concentrated by evaporation. The evaporation residue is crystallized under trituration with ether. The yield is 1.36 g (82% of theory) of 5-(2-chlorobenzyl)-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid ethyl ester, melting point 140°-142° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:26][CH:23]([CH3:25])[CH3:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCOc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)N
Product: CC(C)NCCCCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
As described in Example 19, 1-benzyloxy-4-(6-bromohexyloxy)benzene was reacted with isopropylamine at 100° (12 hours; 500 psi) to give 1-benzyloxy-4-[6-(1-methylethyl)aminohexyloxy]benzene. The crude oil was crystallized from pentane yielding the purified product, mp 47°-49°.