Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1([F:21])[CH2:17][CH:16]([C:18](Cl)=[O:19])[CH2:15]1>O1CCCC1.Cl.[Cu](I)I>[F:13][C:14]1([F:21])[CH2:17][CH:16]([C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[O:19])[CH2:15]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=C(Cl)C1CC(F)(F)C1
Agent: I[Cu]I
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C2CC(F)(F)C2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 16 %

Procedure:
In a 3-neck flask at −30° C. containing ethyl 4-iodobenzoate (600 mg, 2.17 mmol) in anhydrous tetrahydrofuran (6.00 mL) was added isopropylmagnesium chloride lithium chloride complex (1.84 mL, 2.39 mmol) dropwise and then stirred at the same temperature for another 40 min. Copper iodide (124 mg, 0.650 mmol) was then added quickly in one portion. The mixture was brought to −15° C. for 20 min. to ensure the solid has dissolved. The reaction is then brought back to −40° C. Crude 3,3-difluorocyclobutanecarbonyl chloride (470 mg, 1.50 mmol pure) was then added and the reaction was then warmed to 0° C. over 1 h and then stirred at room temperature for 18 h. The mixture was then diluted with 1 N HCl and extracted three times with ethyl acetate. The combined organic layers were then washed with brine and then dried over sodium sulfate, filtered, and concentrated to provide 680 mg of crude oil. Purification by silica gel flash chromatography (0-10% ethyl acetate in heptane) afforded impure ethyl 4-(3,3-difluorocyclobutanecarbonyl)benzoate (130 mg, approximately 0.24 mmol pure) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=9.0 Hz, 2H), 7.18 (d, J=9.2 Hz, 2H), 4.39 (q, J=7.4 Hz, 2H), 3.34-3.15 (m, 1H), 3.12-2.78 (m, 4H), 1.40 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:4]=2[N:3]=1>N.CO>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(F)c(F)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(F)c(F)cc32)[C@H](O)[C@@H]1O

Procedure:
Compound 64 (0.894 g, 2 mmole) was treated with 20 mL of NH3 /MeOH in a pressure bottle at room temperature for 3 hr. The reaction mixture was evaporated and coevaporated with MeOH to give a solid. This was recrystallized from MeOH to give 0.573 g (3 crops, 89%) of 65 as a crystalline compound. MP~215° C. (dec.); MS m/e 320.0385 (20%, M+ =320.0375); 1H NMR (DMSO-d6): d 8.34 (dd, 1,7-H, 3JF-H =11.5 Hz, 4JF-H =7.5 Hz), 7.77 (dd, 1, 4-H, 3JF-H =11.0 Hz, JF-H =7.5 Hz), 5.88 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.50 (d, 1, 2'-OH, J2-2-OH =6.5 Hz), 5.45 (t, 1, 5'-OH, J5'-5'OH =4.5 Hz), 5.30 (d, 1, 3'-OH, J3'-3'OH=4.5 Hz), 4.40 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.14 (m, 1, 3'-H, J3'-4' =1.5 Hz), 4.01 (m, 1, 4'-H), 3.72 (m, 2, 5'-H, J5'-4' =2.5 Hz, J5'-5" =12.0 Hz); 13C NMR (DMSO-d6): d 148.53, 148.42, 148.37, 148.26, 145.88, 145.76, 145.72, 145.60 (C5 and C6, 1 JF-C =241 Hz, 2JF-C =16 Hz ), 140.84 (C2), 137.16, 137.04 (C3a, 3JF-C =11 Hz), 128.55, 128.42 (C7a, 3JF-C =12 Hz), 106.77, 106.54 (C4, 2JF-C =20 Hz), 102.12, 101.84 (C7, 2JF-C =25 Hz), 89.10 (C1'), 86.39 (C4'), 71.55 (C2'), 69.81 (C3'), 6.12 (C5').
Reaction SMILES: CN(C)C=O.[Na].[C:7]([O:10][CH2:11][C:12]1[CH2:19][S:18][CH:17]2[N:14]([C:15](=[O:21])[CH:16]2[NH2:20])[C:13]=1[C:22]([OH:24])=[O:23])(=[O:9])[CH3:8].Cl[CH2:26][O:27][C:28](=[O:31])[CH2:29][CH3:30]>C(OCC)(=O)C>[C:28]([O:27][CH2:26][O:23][C:22]([C:13]1[N:14]2[CH:17]([S:18][CH2:19][C:12]=1[CH2:11][O:10][C:7](=[O:9])[CH3:8])[CH:16]([NH2:20])[C:15]2=[O:21])=[O:24])(=[O:31])[CH2:29][CH3:30]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CCC(=O)OCCl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)OCOC(=O)C1=C(COC(C)=O)CSC2C(N)C(=O)N12
Reaction time: 3 h

Procedure:
To 35 ml of dimethyl formamide is added 7.5 g of the sodium salt of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and the solution is stirred at room temperature for about 30 minutes after which 8 ml of chloromethylpropionate is added. Stirring is continued at room temperature for about 3 hours. The mixture is diluted with ethyl acetate and washed with water. The organic layer is separated and evaporated to dryness. The residue is recrystallized from ethyl acetate to give 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0 ]oct-2-ene-2-carboxylic acid propionyloxymethyl ester
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:6]=2[N:7]=1.[OH:26][CH2:27][CH2:28][NH2:29]>>[OH:26][CH2:27][CH2:28][NH:29][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:6]=2[N:7]=1
Reactant: NCCO
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCCCCCO)ncnc23)CC1
Product: O=S1CCN(c2nc(NCCO)nc3c(NCCCCCO)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-(5-hydroxypentyl-amino)-4-(1-oxidothiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 202°-204° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: [P:1]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:2]CCCCCCCCCCCCCCCCCC.[C:59]([C:63]1[C:68]([OH:69])=[C:67]([CH3:70])[C:66]([CH2:71]Cl)=[C:65]([CH3:73])[CH:64]=1)([CH3:62])([CH3:61])[CH3:60]>>[C:59]([C:63]1[CH:64]=[C:65]([CH3:73])[C:66]([CH2:71][P:1](=[O:2])([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[C:67]([CH3:70])[C:68]=1[OH:69])([CH3:62])([CH3:61])[CH3:60]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Reactant: CCCCCCCCCCCCCCCCCCOP(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCCCOP(=O)(Cc1c(C)cc(C(C)(C)C)c(O)c1C)OCCCCCCCCCCCCCCCCCC

Procedure:
21.7 Grams of trioctadecyl phosphite and 5.75 grams 6-tert.-butyl-3-chloromethyl-2,4-dimethylphenol were stirred together as a melt at 110° to 120° for 2 hours and at 120° to 125° for 7 hours. The reaction mixture was dissolved in 100 ml. of toluene and the colorless, slightly turbid solution was successively washed with 3N aqueous hydrochloric acid, water, 2N aqueous sodium carbonate solution and water until the wash waters were neutral. After drying over anhydrous sodium sulfate and filtering free of drying agent, the clear filtrate was concentrated by distillation of the solvent at reduced pressures. The residual oil was topped in the "ASCO 50" Rota-Film Molecular Still at a wall temperature of 210° to 215° and a pressure of 1 to 5 microns. After crystallization from methylethyl ketone, the desired product was obtained as while crystals melting at 70° to 72.5°. (compound 4)
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 21.6 %

Procedure:
Prepared from (3-amino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G49) (160 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (115 mg, 0.5 mmol) according to the general procedure K. Obtained as a white solid (53 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]([C:23]([NH2:25])=[O:24])[CH2:17]2>C(Cl)Cl>[C:8]([N:19]1[C:20]2[C:16](=[CH:15][C:14]([O:13][CH3:12])=[CH:22][CH:21]=2)[CH2:17][CH:18]1[C:23]([NH2:25])=[O:24])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CC(C(N)=O)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CC(C(N)=O)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
Triethylamine (0.0106 mole) then acetyl chloride (0.0106 mole) were added to a solution of intermediate (21) (0.0032 mole) in DCM (40 ml) cooled in an ice bath under argon. The mixture was allowed to slowly warm to room temperature and stir overnight. The mixture was cooled in an ice bath and ice cold water (30 ml) was added. After stirring for 10 minutes, the mixture was filtered, and the solid was allowed to dry overnight. The residue was suspended in 50 ml water. The suspension was allowed to stir for 30 minutes, filtered, and dried overnight, yielding 0.40 g of 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carboxamide (intermediate 22, mp. 196-197° C.).
Reaction SMILES: [CH3:1][C@@:2]1([OH:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].[C:19]([OH:22])(=O)[CH3:20]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:3]([O:18][C@:2]1([CH3:1])[C@H:6]([O:7][C:6](=[O:7])[CH3:5])[C@@H:5]([CH2:8][O:9][C:19](=[O:22])[CH3:20])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])(=[O:4])[CH3:2]
Reactant: CC(=O)O
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(OC(C)=O)[C@@H]1OC(C)=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
The preparation of Compound 55 is illustrated in Scheme 5, above. To a solution of 2′-C-methyluridine (1 g) in pyridine (40 ml) were added acetic acid (3 ml) and DMAP. The mixture was stirred at 50° C. during 3 hours, followed by two days at room temperature. Then, the mixture was concentrated and co-evaporated with toluene and the residue purified by silica gel chromatography eluting with 0→10% methanol in dichloromethane to yield 2′,3′,5′-Tri-O-acetyl-2′-C-methyluridine (93%). MS (ESI, EI+) m/z=385.2 (MH+).
Reaction SMILES: I[C@H:2]1[C@H:19]([CH3:20])[C@@:18]2([CH3:21])[C:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])=[CH:4][C:3]1=[O:23].C(=O)([O-])[O-].[Li+].[Li+].O>CN(C)C=O>[CH3:20][C:19]1[C@@:18]2([CH3:21])[C:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])=[CH:4][C:3](=[O:23])[CH:2]=1
Reactant: C[C@H]1[C@H](I)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]12C
Reaction time: 1.5 h

Procedure:
2.13 g (5 mmol) of 2β-iodo-1α-methylandrost-4-ene-3,17-dione of example 1 is introduced in a suspension of 0.73 g (10 mmol) of lithium carbonate in 10 ml of dimethylformamide preheated to 130° C. and stirred for 1.5 hours at this temperature. After cooling, the reaction solution is added to 30 ml of water, extracted with ethyl acetate and after drying on sodium sulfate, concentrated by evaporation. The crude product is chromatographed on silica gel with ethyl acetate/hexane as mobile solvent. After recrystallization from ethyl acetate, 1.1 g of 1-methylandrosta-1,4-diene-3,17-dione (74% of theory) of melting point 169° C. is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][CH:28]([CH2:30][C@H:31]([OH:35])[C:32](O)=[O:33])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][N:19]([C:32](=[O:33])[C@@H:31]([OH:35])[CH2:30][CH:28]([CH3:29])[CH3:27])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Reactant: CC(C)C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@@H](O)CC(C)C)CC1
Reaction time: 3 h
Yield: 49.1 %

Procedure:
(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-piperidin-4-yl-amine (Ic) (0.89 g, 2.54 mmol) was dissolved in DMF (17 mL) and treated with N,N-diisopropyletbylamine (1.77 mL, 10.17 mmol), L-2-hydroxyisocaproic acid (0.34 g, 2.54 mmol), and HBTU (0.96 g, 2.54 mmol). The reaction was stirred for 3 hours, then diluted with EtOAc (200 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 4% MeOH/CH2Cl2 to give 0.58 g (49%) of the desired product.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[CH2:7]([O:9][SiH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH3:8]>CC1C=CC(C)=CC=1>[N:4]([CH2:1][CH2:2][CH2:3][Si:10]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:9][CH2:7][CH3:8])=[C:5]=[O:6]
Reactant: C=CCN=C=O
Reactant: CCO[SiH](OCC)OCC
Solvent: Cc1ccc(C)cc1
Product: CCO[Si](CCCN=C=O)(OCC)OCC
Yield: 71.8 %

Procedure:
In analogy to Example 6, a reaction mixture consisting of 640 g of p-xylene, 680 g (8.17 mol) of allyl isocyanate and 1250 g (7.6 mol) of triethoxysilane was reacted at from 76° to 92° C. over the course of 150 minutes. Working up by distillation gave 1350 g of 3-isocyanatopropyltriethoxysilane in addition to the trimer.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[O:3][SiH:4]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[O:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[C:17]([O:20]CC=C)(=[O:19])[CH3:18].C>[Ru]>[CH3:8][Si:6]([CH3:7])([CH3:9])[O:5][Si:4]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])([O:3][Si:2]([CH3:16])([CH3:15])[CH3:1])[O:20][C:17](=[O:19])[CH3:18]
Reactant: C=CCOC(C)=O
Reactant: C[Si](C)(C)O[SiH](O[Si](C)(C)C)O[Si](C)(C)C
Agent: [Ru]
Product: CC(=O)O[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 105 °C

Procedure:
A mixture containing 296 g of tris-(trimethylsiloxy)silane, 110 g of allyl acetate and 2.4 g of ruthenium supported on activated charcoal (5 percent by weight of ruthenium and 95 percent by weight of activated charcoal), in which the 2.4 g refers to the total wieght of the charcoal and the ruthenium, are heated to boiling under reflux (approx. 105° C.) for 4 hours. The tris-(trimethylsiloxy)-acetoxysilane yield is quantitative.
Reaction SMILES: [C:1]([C:6]1[CH:41]=[C:40]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH:39]=[CH:38][C:7]=1[O:8][CH:9]([CH2:34][CH2:35][CH2:36][CH3:37])[C:10]([NH:12][C:13]1[C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:21][C:16]2[NH:17]C(=O)[O:19][C:15]=2[CH:14]=1)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].C1(C)C(C)=CC=CC=1.[OH-].[Ca+2].[OH-]>C(O)CO>[NH2:17][C:16]1[CH:21]=[C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[C:13]([NH:12][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:38]=[CH:39][C:40]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])=[CH:41][C:6]=2[C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:14][C:15]=1[OH:19]
Reactant: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc2oc(=O)[nH]c2cc1Oc1ccc(C(C)(C)C)cc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: OCCO
Solvent: Cc1ccccc1C
Product: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(O)c(N)cc1Oc1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
In a 250-ml flask inert with nitrogen, place 11.3 g (0.018 m) of 6-{2-(2,4-di-t-pentylphenoxy)hexanoyl}amino-5-(4-t-butylphenoxy)-benzoxazol-2-one (2, Y=4-t-butylphenoxy and R′=1-(2,4-di-t-pentylphenoxy)pentyl), 120 ml of xylene, 12 ml of ethylene glycol, and 8.0 g of calcium hydroxide. Heat under reflux collecting approximately 7 ml of water-ethylene glycol and 20 ml of xylene in a Dean-Stark trap. Detach the trap and heat under reflux for 5 hrs. Cool to 80° C. and add 100 ml of toluene, 100 ml of hot water, 25 ml of acetic acid, and 2 g sodium hydrosulfite. Stir the mixture at 60°-65° C. for 15 min and filter through a Celite pad to remove interlayer insolubles. Separate toluene-xylene solution, wash with 100 ml of hot water +12 ml of acetic acid +2 g sodium hydrosulfite and 100 ml of hot water twice, and concentrate under a reduced pressure to a thick oil. Dissolve the oil in 200 ml of heptane, add seed crystals, and stand at room temperature over night. Cool in an ice-water bath for 1 hr, collect solid, wash with heptane, and dry in a vacuum oven to give 9.2 g (85%) of 2-amino-5-{2-(2,4-di-t-pentylphenoxy)hexanoyl}amino-4-(4-t-butylphenoxy)-phenol (Formula I; Y=4-t-butylphenoxy and R′=1-(2,4-di-t-pentylphenoxy)pentyl).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C[O-].[Na+].[C:10]([CH2:18][C:19]#[N:20])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:20][C:19]1[N:3]([C:4]([NH2:6])=[O:5])[N:2]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=1
Reactant: NNC(N)=O
Reactant: N#CCC(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)n1nc(-c2ccccc2)cc1N
Reaction time: 0.17 h
Yield: 51.3 %

Procedure:
To a stirred solution of 6.0 g of semicarbazide hydrochloride in 100 ml of ethyl alcohol is added 2.8 g of sodium methoxide at room temperature. The reaction mixture is stirred for 10 minutes and 7.0 g of benzoylacetonitrile added. The reaction mixture is heated at reflux for 1 hour, cooled and concentrated in vacuo to a yellow solid. The yellow solid is suspended in water, filtered and dried. The dried solid is suspended in 100 ml of ethyl alcohol and 10 ml of triethylamine followed by heating at reflux for 1 hour. The reaction mixture is cooled and the volatiles removed in vacuo to a residue which is suspended in water, filtered, washed with water and dried to give 5.0 g of the desired product as a solid, m.p. 255° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(C(C)(C)C)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-tert-butyl-phenylboronic acid to give [1-(4-tert-butyl-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 357(MH+).
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[S:29]1[CH:33]=[C:32]([CH:34]=[O:35])[N:31]=[CH:30]1>C1(C)C=CC=CC=1.ClCCl>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[CH:34]([C:32]1[N:31]=[CH:30][S:29][CH:33]=1)[OH:35]
Reactant: O=Cc1cscn1
Reactant: CN(C)CCc1sc2ccccc2c1Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(C)CCc1sc2ccccc2c1C(O)c1cscn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 89.7 %

Procedure:
To a cooled (−78° C.) solution of [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (200 mg, 0.7 mmol) in anhydrous toluene (8 mL), TMEDA (110 uL, 0.7 mmol) was added followed by nBuLi (0.47 mL, 0.75 mmol, 1.6M in hexanes). The mixture was stirred for 40 min at −78° C. and a solution of thiazole-4-carbaldehyde (0.32 g, 2.8 mmol) in dichloromethane (1 mL) was added. The mixture was stirred for 16 hrs during which the temperature reached room temperature. The reaction was quenched with water, the resulting mixture was basified by the addition of NH4OH and extracted with EtOAc. The combined organic layers were concentrated and subjected to mass triggered preparative HPLC to afford [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-thiazol-4-yl-methanol (Compound 14-1) (200 mg). MH+=318.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CNC(=O)c1cccc(OCc2ccc(Cl)cc2C(=O)O)c1
Agent: Cl
Product: CNC(=O)c1cccc(OCc2ccc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-({3-[(methylamino)carbonyl]phenoxy}methyl)benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 1):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][C:13]=1[CH3:19].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:10])[CH:4]([S:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[C:13]([CH3:19])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1cc(S)ccc1F
Reactant: CCCCC(Br)C(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(Sc1ccc(F)c(C)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 46 h
Yield: 91.7 %

Procedure:
To a solution of 2-bromo-hexanoic acid methyl ester (0.500 g, 2.404 mmol) and 4-fluoro-3-methyl-benzenethiol (0.340 g, 2.404 mmol) in 20 mL of dichloromethane, was added triethylamine (3.3 mL, 12.020 mmol). After stirring at room temperature under N2 for 46 h, the reaction mixture was diluted with dichloromethane and washed with 1N HCl and brine. The organic layer dried over anhydrous Na2SO4. After removing the solvent under reduced pressure, the product was isolated by Flash chromatography (silica gel) eluting with 0-20% ethyl acetate/hexanes to give the title compound as colorless oil (0.596 g, 92% yield). LC-MS: tR=11.2 min; m/z 271 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:19]([CH3:21])[CH3:20]>CN(C)C=O.O>[I:1][C:2]1[N:3]([CH:19]([CH3:21])[CH3:20])[N:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(C)I
Reactant: CCOC(=O)c1c[nH]nc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(C(C)C)c1I
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
To a solution of ethyl 3-iodopyrazole-4-carboxylate (1.58 g, 5.94 mmol, Truong; et al. Bioorg. Med. Chem. Lett., 19, 4920 (2009)) in 20 mL N,N-dimethylformamide was added cesium carbonate (3.87 g, 11.9 mmol) and 2-iodopropane (0.89 mL, 8.90 mmol). The mixture was stirred 2 hours at 60° C. and then cooled to ambient temperature. The reaction mixture was diluted with 150 mL water and extracted with 2×100 mL diethyl ether. The combined organics were washed with 50 mL brine, dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by flash chromatography (7-60% ethyl acetate/heptane gradient, 50 g silica) to yield 340 mg of ethyl 5-iodo-1-isopropyl-1H-pyrazole-4-carboxylate as a clear oil which crystallized on standing and 740 mg of ethyl 3-iodo-1-isopropyl-1H-pyrazole-4-carboxylate as a clear oil.