Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:30]=CC2NC(C3C(=O)N(CCC(C)C)C4C(C=3O)=CC=CN=4)=NS(=O)(=O)C=2[CH:3]=1.[OH:31][C:32]1[C:41]2[C:36](=[N:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[C:34](=[O:47])[C:33]=1[C:48]1[NH:53][C:52]2[CH:54]=[CH:55][C:56]([NH:58][S:59]([N:62]3[CH2:66]CC(NC(=O)OC(C)(C)C)[CH2:63]3)(=[O:61])=[O:60])=[CH:57][C:51]=2[S:50](=[O:76])(=[O:75])[N:49]=1.C(N(CC)CC)C>ClCCl>[OH:31][C:32]1[C:41]2[C:36](=[N:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH2:42][CH2:43][CH:44]([CH3:45])[CH3:46])[C:34](=[O:47])[C:33]=1[C:48]1[NH:53][C:52]2[CH:54]=[CH:55][C:56]([NH:58][S:59]([N:62]3[CH2:66][CH2:30][CH2:2][CH2:3][CH2:63]3)(=[O:61])=[O:60])=[CH:57][C:51]=2[S:50](=[O:75])(=[O:76])[N:49]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)N4CCC(NC(=O)OC(C)(C)C)C4)ccc3N2)c(O)c2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)N4CCCCC4)ccc3N2)c(O)c2cccnc21
Yield: 371.9 %

Procedure:
A mixture of the product of Example 205 (2 mg, 0.1 ml), the product of Example 451A (17 mg, 0.1 mmol) and triethylamine (0.1 mL) in dichloromethane (2 mL) was stirred for 18 hours at 25° C., diluted with dichloromethane (25 mL) and washed with 1 N HCl and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/10 mM ammonium acetate in water over 8 minutes (10 minutes run time) at a flow rate of 40 mL/min to provide the title compound (10 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.62 Hz, 6 H) 1.43 (s, 6 H) 1.57 (m, 2 H) 1.69 (m, 1 H) 3.14 (s, 4 H) 4.49 (m, 2 H) 7.51 (m, 1 H) 7.53 (s, 1 H) 7.60 (d, J=2.21 Hz, 1 H) 7.72 (d, J=8.82 Hz, 1 H) 8.56 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.78, 1.84 Hz, 1 H) 10.47 (s, 1 H) 14.06 (s, 1 H) 15.05 (s, 1 H). MS (ESI−) m/z 573 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:27])[C:24](Cl)=[O:25].C(=O)(O)[O-].[Na+]>CCOCC>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[C:24](=[O:25])[C:23]2=[O:27])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(NC2CCN(Cc3ccccc3)CC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc2c(c1)N(C1CCN(Cc3ccccc3)CC1)C(=O)C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
1-Benzyl-4-(3-methoxyphenyl)aminopiperidine (1.88 g) synthesized in accordance with the method of Referential Example 1 of JP-B 40-6347 was dissolved in ether (38 ml). Into the resultant solution was added dropwise oxalyl chlori de (1.62 g) over 30 min at room temperature followed by heating under reflux for 3.5 hr. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. Into a suspension of aluminum chloride (5.9 g) in methylene chloride (20 ml) was added dropwise a solution of the resulting residue in methylene chloride (100 ml) at 0° C. over 30 min. After the completion of the addition, the resultant mixture was stirred at room temperature for additional 1.5 hr. After the completion of the reaction, the reaction solution was poured into ice and neutralized by adding an aqueous solution of sodium bicarbonate thereto. The resulting precipitate was filtered off and the filtrate was extracted with methylene chloride. After removing the solvent, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give 1-(1-benzylpiperidin-4-yl)-6-methoxyindoline-2,3-dione (1.63 g) (yield: 73%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-])=O)[C:4]=2[O:3]1.[H][H].S([O-])([O-])(=O)=O.[Mg+2]>[Ni].O1CCCC1>[NH2:11][C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC1Cc2cccc([N+](=O)[O-])c2O1
Agent: [Ni]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC1Cc2cccc(N)c2O1

Procedure:
A mixture of 81 g of 1B, 400 ml of tetrahydrofuran (THF) and 3 g of activated Raney nickel catalyst was shaken under 35 p.s.i.g. hydrogen pressure at room temperature for 4 hours. The resulting mixture was treated with 20 g of magnesium sulfate, filtered and the solvent was evaporated from the filtrate, to give 7-amino-2,3-dihydro-2-methylbenzofuran (1C), as an amber syrup.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14].CS([C:26]1[N:31]=[CH:30][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][N:27]=1)(=O)=O.O>C1COCC1>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:26]2[N:27]=[CH:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][N:31]=2)[CH2:18][CH2:17]1)(=[O:15])=[O:14]
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
NaH 60% (0.0217 mol) was added portionwise at room temperature to a solution of 1-(2-naphtalenesulfonyl)-piperazine (0.011 mol) in THF (50 ml) under N2 flow. The mixture was stirred at room temperature for 1 hour, then cooled to 0° C. A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ester (0.014 mol) in THF (30 ml) was added quickly. The mixture was stirred at room temperature for 2 hours, poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was taken up in diethyl ether. The precipitate was filtered off and dried, yielding 3.92 g (84%) of 2-[4-(2-naphthalenylsulfonyl)-1-piperazinyl]- 5-pyrimidinecarboxylic acid, ethyl ester (interm. 8), melting point>260° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:14][C:15]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][C:18](=[O:25])[NH:19]2>>[Cl:24][C:23]1[C:15]([CH3:14])=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:25])[C:17]2=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: COc1ccc(C=O)cc1C(C)C
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)c(C)c32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 4-methyl-5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(3-isopropyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C[Si](C)(C)[C:13]1[S:14][CH:15]=[CH:16][N:17]=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C[Si](C)(C)c1nccs1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1nccs1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
4-fluorobenzoyl chloride (3 mL, 25.4 mmol) was added to 2-(trimethylsilyl)thiazole (2 mL, 12.7 mmol) in dichloromethane (70 mL). The reaction mixture was stirred over night at rt. Dichloromethane was evaporated under reduced pressure, and the crude product purified on a normal phase silica-gel column with 0-40% ethyl acetate in hexane to afford the title compound as white amorphous solid (2.050 g, 77% yield); MS (M+H)+ 208.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2.Cl[C:35]([O:37][CH3:38])=[O:36]>N1C(C)=CC(C)=CC=1C>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][O:33][C:35]([O:37][CH3:38])=[O:36])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: COC(=O)Cl
Reactant: Cc1cc(O)c(C(=O)CCc2ccc3occc3c2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)OC[C@H]1O[C@@H](Oc2cc(C)cc(O)c2C(=O)CCc2ccc3occc3c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 23 h
Yield: 81.1 %

Procedure:
To a solution of 3-(5-benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (10 g) in 2,4,6-collidine (100 ml) is added dropwise methyl chloroformate (10.31 g) at 0° C., and the mixture is stirred at 0° C. for 23 hours. The reaction mixture is poured into ice-10% hydrochloric acid (300 ml--300 ml), and the mixture is extracted with ethyl acetate (350 ml). The organic layer is washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated sodium chloride solution, dried, and concentrated under reduced pressure. The residue (11.96 g) is dissolved in tetrahydrofuran (200 ml), and thereto is added t-butyl amine (20 ml), and the mixture is stirred at room temperature for four hours. The reaction mixture is poured into ice-10% hydrochloric acid (150 ml--150 ml), and extracted with ethyl acetate (250 ml). The organic layer is washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated sodium chloride solution, dried, and concentrated under reduced pressure. The reside is recrystallized twice from water-diethyl ether-diisopropyl ether to give 3-(5-benzo[b]furanyl)-2'-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (9.14 g).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([C:11]([NH:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:9][CH:8]=1>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]2[S:16][C:17]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:18][CH:19]=2)=[O:12])=[CH:20][CH:21]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(NCc1cccs1)c1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Reaction time: 5 h
Yield: 62.8 %

Procedure:
Chlorosulfonic acid (20.1 mL, 198 mmol) in CH2Cl2 (80 mL) was added dropwise to a solution of the above compound (1a) (10 g, 40 mmol) in CH2Cl2 (500 mL) at −80° C. The mixture was allowed to reach room temperature in 5 h. The reaction mixture was poured on ice and quickly extracted with CH2Cl2. The organic layer was dried over MgSO4 and the solvent was evaporated to dryness which afforded 8.8 g (63%) of desired sulfonyl chloride (1b); mp 133-35° C., 1H NMR DMSO-d6) δ 9.21 (t, J=6.4 Hz, 1H), 7.87 (d, J=8.67 Hz, 2H), 7.53 (d, J=8.67 Hz, 2H), 6.91 (d, J=3.39 Hz, 1H), 6.77 (d, J=3.39 Hz, 1H), 4.53 (d, J=3.77 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[O:11]=[C:12]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:11]=[C:12]1[CH2:18][CH2:17][N:16]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH2:15][CH2:14][N:13]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C1CCNCCN1Cc1ccccc1
Product: Nc1ccc(N2CCC(=O)N(Cc3ccccc3)CC2)nc1

Procedure:
Intermediate B-26 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and hexahydro-5-oxo-4-(phenylmethyl)-1H-1,4-diazepine as starting materials. MS (M+1): 297.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][Si:10]([CH3:60])([CH3:59])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([O:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)[CH:17]=1>CC#N>[CH3:58][Si:55]([CH3:57])([CH3:56])[CH2:54][CH2:53][O:52][CH2:51][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:59])[CH3:60])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([O:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)[C:17]=1[Br:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NBS (246 mg, 1.38 mmoL) was added to a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate (Int-11b, 1022 mg, 1.38 mmoL) in CH3CN (15 mL). After stirring at room temperature for 30 min, the mixture was concentrated in vacuo. Purification by column chromatography afforded tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate (Int-11c): LCMS tR=3.59 Min (5 min run, UV254nm). Mass calculated for, M+824.3, observed m/z 825.1 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1.C([O-])(=O)C.[K+]>C(#N)C.O>[O:25]1[CH2:26][CH:27]=[C:28]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[NH:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:30]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3[nH]2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C1=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4[nH]3)cc2)CCOC1
Temperature: 25 °C

Procedure:
To a round bottomed flask was added N-(4-(3-bromopyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.5674 g, 1.488 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.938 g, 4.47 mmol), PdCl2(PPhtBu2)2 (0.093 g, 0.149 mmol), and potassium acetate (0.698 mL, 11.16 mmol) in ACN (3.72 mL) and water (1.240 mL) at 100° C. to stir. Upon completion, reaction allowed to cool to room temperature. Solvent was evaporated. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 mM, 0.1% TFA in ACN/H2O, gradient 25% to 90% over 20 min to provide N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 385.0 (M+1).
Reaction SMILES: [CH2:1]([C:8]1S(=O)(=O)[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:22](#[N:27])/[CH:23]=[CH:24]/[C:25]#[N:26]>C(Cl)(Cl)Cl>[CH2:13]([C:10]1[CH:11]=[CH:12][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:24]([C:25]#[N:26])[C:23]=1[C:22]#[N:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCC1=CC=C(CCCCCCC)S1(=O)=O
Reactant: N#C/C=C/C#N
Solvent: ClC(Cl)Cl
Product: CCCCCCCc1ccc(CCCCCCC)c(C#N)c1C#N
Yield: 0 %

Procedure:
In a typical experiment 2,5-diheptylthiophene 1,1-dioxide (2 g, 6.4×10 mole) and fumaronitrile (0.5 g, 6.4×10 mole) in chloroform (5 ml) were heated in a sealed tube to 180° for 18 H. The contents of the tube were evaporated to dryness and chromatographed over silica (toluene as eluent) to afford 3,6-diheptylphthalonitrile (0.98 g, 47%) as a yellow solid. The material was recrystallised from ethanol to afford a colourless solid, mp 44°-46° C. 1H-nmr (CDCl3) shows S 7.52 (s, 2H); 2.85 (t, 4H); 1.0-1.9 (m, 20H); 0.90 (t, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[N:15][O:16][C:17]=1[CH3:18])[CH3:9].C([O:29][C:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:31])C.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]([NH:12][C:13]1[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:36]3[CH:37]=[CH:38][C:33]([CH2:32][C:30]([OH:31])=[O:29])=[CH:34][CH:35]=3)=[CH:21][CH:20]=2)=[N:15][O:16][C:17]=1[CH3:18])=[O:26])[CH3:9]
Reactant: Cc1onc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Reactant: CCOC(=O)Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1onc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Temperature: 90 °C
Reaction time: 3 h

Procedure:
[3-(4-Bromo-phenyl)-5-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester (0.080 g, 0.16 mmol), (4-ethoxycarbonylmethylphenyl)boronic acid, pinacol ester (0.055 g, 0.19 mmol), potassium carbonate (0.055 g, 0.40 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.011 g, 0.016 mmol) were combined in 2:1 DME:H2O and degassed with N2 for 5 minutes. The reaction was stirred at 90° C. for 3 hours, until no starting material was seen by analytical LCMS. 1N Aqueous LiOH (0.5 mL) was added, and the reaction was stirred at room temperature until no ester starting material was seen by analytical LCMS. After acidic work-up, the crude material was purified by preparative HPLC to give the title compound. Mass spectometric data [M+H]=475.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[C:12]([Cl:35])=[C:13]([NH:19][C:20]4[N:25]=[C:24]([NH:26][CH:27]5[CH2:29][CH2:28]5)[C:23]5=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:22]5[N:21]=4)[CH:14]=[C:15]([C:17]#[N:18])[CH:16]=3)[CH2:7][CH2:6]2)[CH2:2]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>>[Cl:35][C:12]1[C:11]([CH:8]2[CH2:7][CH2:6][N:5]([CH:3]3[CH2:2][N:1]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:4]3)[CH2:10][CH2:9]2)=[CH:16][C:15]([C:17]#[N:18])=[CH:14][C:13]=1[NH:19][C:20]1[N:25]=[C:24]([NH:26][CH:27]2[CH2:28][CH2:29]2)[C:23]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:22]2[N:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCN(C3CNC3)CC2)c1
Product: CS(=O)(=O)N1CC(N2CCC(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CC2)C1

Procedure:
The title compound was prepared from 2-((3-(1-(azetidin-3-yl)piperidin-4-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 318) and methanesulfonyl chloride using a method analogous to that used to prepare Example 319 HPLC Rt 3.020 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[S:7][C:8]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[O:15])=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.O[Li].O>CO.O>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[S:7][C:8]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:15])=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1
Reactant: COC(=O)CCCCNC(=O)c1sc2ccc(OC)cc2c1OC(C)C
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc2sc(C(=O)NCCCCC(=O)O)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 85 %

Procedure:
Methyl 5-[[5-methoxy-3-(1-methylethoxy)benzo[b]thien-2-yl]carbonyl]aminovalerate (250 mg, 0.66 mmol) and 83 mg of LiOH-H2O in a mixture of 5 mL of methanol and 2 mL of water are stirred at room temperature for 7 hours. The reaction mixture is partitioned between ethyl acetate and aqueous HCl. The organic layer is washed with water, then brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethyl acetate:hexane gives 205 mg of product (85%); mp 135°-137° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:14]=[N:15][OH:16])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1.C1C(=O)N([Cl:24])C(=O)C1>CN(C=O)C>[F:1][C:2]1[C:3]([C:14]([Cl:24])=[N:15][OH:16])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: CC1(C)OB(O)c2cc(F)c(C=NO)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2cc(F)c(C(Cl)=NO)cc21
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of the crude compound 6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (205 mg, 0.92 mmol) in DMF (4.0 mL) at rt was added NCS (147 mg, 1.1 mmol). The reaction mixture was stirred at 45° C. for 3 h. The mixture was cooled to rt, poured into ice-water and extracted with DCM (60 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude compound 6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride as colorless oil. It was used in next step without further purification.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[CH2:25][CH2:24][C@@:18]3([NH:22]C(=O)[O:20][CH2:19]3)[CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[OH-].[Li+].O>O1CCOCC1>[NH2:22][C@:18]1([CH2:19][OH:20])[CH2:24][CH2:25][C@@H:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=2)[CH2:17]1
Reactant: CCCCCCCCOc1ccc([C@@H]2CC[C@]3(COC(=O)N3)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCOc1ccc([C@@H]2CC[C@](N)(CO)C2)cc1
Yield: 58.4 %

Procedure:
A solution of (5R,7R)-7-(4-octyloxy-phenyl)-3-oxa-1-aza-spiro[4.4]nonan-2-one (61.0 mg, 0.177 mmol) in dioxane (3.0 mL) was treated with lithium hydroxide, hydrate (100 mg, 2.38 mmol) and water (1.0 mL). The mixture was heated to reflux for about 10 hours. The reaction was concentrated, treated with water (10 mL) and extracted twice with ether (10 mL). The ether extracts were dried over Na2SO4, filtered and concentrated. The residue was treated with 2 M HCl (2.0 mL) to yield a white solid which was collected and dried to yield 33.0 mg (52%) of [(1R,3R)-1-Amino-3-(4-octyloxy-phenyl)-cyclopentyl]-methanol; hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:6]([O:8][CH2:9][C:10]([N:19](C(OC(OC(=O)CNC(=O)C)C)=O)[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][CH3:12])=[O:7].[OH2:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:6]([O:8][CH2:9][C:10]([NH:19][CH2:20][C:9]([O:8][CH2:6][C:5]1[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[CH:3][CH:4]=1)=[O:41])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:11][CH3:12])=[O:7]
Reactant: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(c1ccccc1)N(C)C(=O)OC(C)OC(=O)CNC(C)=O
Reactant: O
Product: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(NCC(=O)OCc1ccc(OC)cc1)c1ccccc1

Procedure:
20 ml water is added to the mixture. The product is extracted with ethyl acetate (3 times 50 mL) then the organic phase is washed successively with water and a saturated solution of sodium chloride (10 mL). The organic phases are dried over Na2SO4, filtered then concentrated to dryness in order to produce a brown oil. The oil is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate: 3/7) in order to produce 200 mg of the expected product (S) 2-{[1-(2-acetylamino-acetoxy)-ethoxycarbonyl]-methyl-amino}-2-phenyl-n-butyl 3,4,5-trimethoxy-benzoate in the form of a brown solid (yield=7%).