Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1.NN>O1CCCC1.CO>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2cccc(F)c2)sc1Cl
Reaction time: 24 h

Procedure:
To a 250 mL round-bottomed flask was added 5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (7.8 g, 14.91 mmol) and hydrazine (14.50 ml, 298 mmol) in tetrahydrofuran (THF) (75 ml) and methanol (75 mL). After 24 h at RT, the precipitate was filtered, the filtrate was concentrated. The crude product was purified on a silica gel column [CHCl3/MeOH/NH4OH, 90:9:1] to give the title compound as a white solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]([F:40])([F:39])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[N:29][C:28]([C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)=[N:27]2)=[CH:22][CH:21]=1>O1CCCC1.O>[F:40][C:18]([F:17])([F:39])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[N:29][C:28]([C:31]3[CH:38]=[CH:37][C:34](/[CH:35]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:33][CH:32]=3)=[N:27]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
To an oven-dried 2 L three-necked round bottomed flask equipped with a stirring bar was added sodium hydride (60% oil immersion, 7.20 g, 180 mmol) as a solid that was pre-weighed into a 25-mL vial. This was diluted with anhydrous tetrahydrofuran (1 L) under nitrogen, and the solution was stirred in an ice bath. Ethyl 2-(diethoxyphosphoryl)acetate (30.0 mL, 151 mmol) was added dropwise in portions over 20 minutes, and the reaction was stirred at 0° C. for an additional 2 hours. 4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (50.0. g, 150 mmol) was added in solid portions over 20 minutes, and the reaction turned orange. After stirring for 30 minutes, the ice bath was removed and the reaction was warmed to room temperature over 1 hour. The reaction was quenched with slow addition of saturated aqueous ammonium chloride (500 mL) and allowed to stand at room temperature overnight. The biphasic reaction mixture was diluted with water and extracted with 1:1 ethyl acetate/hexanes (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound as an orange solid (61.4 g, 100%): mp 135-137° C.; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.22 (d, J=8.4 Hz, 2H), 7.85-7.77 (m, 2H), 7.73 (d, J=16.0 Hz, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 6.51 (d, J=16.0 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 404 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:49])[NH:34][CH2:35][CH2:36][CH2:37][C@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39][NH2:40])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([NH:40][CH2:39][C@@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][CH2:36][CH2:35][NH:34][C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:49])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)C[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.1 g (0.263 mmol) of (3S)-6-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]hexanoic acid (Bioorg. Med. Chem. Lett. (1998) 8:1477-1482) and 0.108 g (0.342 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.066 g (0.342 mmol) of EDC and 0.011 g (0.079 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[C:5]([CH3:10])[CH:4]=[N:3]1.ClC(N(C)C)=C(C)C.[NH:19]1[C:27]2[C:22](=[C:23]([C:28]3[CH:29]=[C:30]([NH2:37])[C:31]4[CH:32]=[N:33][NH:34][C:35]=4[CH:36]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C(N(CC)CC)C>C(Cl)Cl>[NH:19]1[C:27]2[C:22](=[C:23]([C:28]3[CH:36]=[C:35]4[C:31]([CH:32]=[N:33][NH:34]4)=[C:30]([NH:37][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[CH3:10])=[O:8])[CH:29]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: Cc1cnn(C)c1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnn(C)c1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 20 °C
Reaction time: 18 h
Yield: 16.1 %

Procedure:
A solution of 1,4-dimethyl-1H-pyrazole-5-carboxylic acid (21 mg) in dry DCM (10 ml) was treated with 1-chloro-N,N,2-trimethyl-1-propen-1-amine (0.02 ml) and allowed to stir at 20° C. for 10 min when a solution of 6-(1H-indol-4-yl)-1H-indazol-4-amine (25 mg) and triethylamine (0.028 ml) in DCM (5 ml) was added and the mixture stirred at 20° C. for 18 h. The mixture was poured onto an aminopropyl SPE cartridge (1 g) and allowed to stand for 2 h, then the mixture was eluted with methanol (5 ml) and blown to dryness under a stream of nitrogen and purified by mass directed preparative HPLC (Method A) to give the title compound (6 mg) as a white solid.
Reaction SMILES: [CH2:1]1[O:19][C:4]2([CH2:9][CH2:8][C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)=[CH:6][CH2:5]2)[O:3][CH2:2]1.[H][H]>O1CCCC1.CO.[Pd]>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:19][CH2:1]1
Reactant: [H][H]
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Yield: 100141.7 %

Procedure:
4-(1H-3-indolyl)-3-cyclohexenone ethylene ketal (66.6 g, 0.26 mmol) is dissolved in 500 mL of tetrahydrofuran and 100 mL of methanol, 1.0 g 5% palladium on carbon is added and the mixture is placed under 60 pounds per square inch (psi) of hydrogen. After 2 hours the reaction is filtered and concentrated to give the product as a tan solid (67.0 g). An analytical sample is recrystallized from methanol; mp 163°-5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][CH2:43][OH:44])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.S(=O)(=O)(O)[O-].[K+]>CS(C)=O.ClCCl.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][CH:43]=[O:44])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCO)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC=O)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4.29 g of 2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-ethanol (from example 25e) in 6.0 ml of dimethylsulfoxide and 30 ml of dichloromethane at 0° C. are added 4.80 ml of triethylamine and 3.60 g of pyridine sulfur trioxide complex. The reaction mixture is allowed to stir for an additional 3 hours at this temperature and then allowed to warm to room temperature, diluted with water and acidified by the addition of 1N potassium bisulfate solution and subsequently extracted with diethyl ether. The organic phases are dried, concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.21 (EtOAc-heptane 1:1); Rt=4.82.
Reaction SMILES: [NH3:1].C(=O)=O.CC(C)=O.Cl[C:10]1[C:11]2[N:12]([C:16]([CH:29]3[CH2:32][CH2:31][CH2:30]3)=[N:17][C:18]=2[C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)[CH:13]=[CH:14][N:15]=1>N.CC(O)C>[CH:29]1([C:16]2[N:12]3[CH:13]=[CH:14][N:15]=[C:10]([NH2:1])[C:11]3=[C:18]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[N:17]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: N
Reactant: Clc1nccn2c(C3CCC3)nc(-c3ccc4cccnc4c3)c12
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4cccnc4c3)c12
Temperature: 110 °C

Procedure:
Gaseous NH3 was condensed into a cooled (dry ice/acetone) solution of 7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-quinoline (203.2 mg, 0.607 mmol) in 2M NH3/iPrOH (6 mL) in a pressure tube until the volume was doubled, then the tube was sealed and heated to 110° C. (bath temp.) for 19 h. The ammonia was evaporated, the crude material was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 1:1 (1-6)→2% MeOH in CH2Cl2 (7-27)→4% MeOH in CH2Cl2 (28-37)→5% MeOH in CH2Cl2 (38-53)→7% MeOH in CH2Cl2 (54-67)], yielding the title compound as a yellow solid, >98% pure by HPLC, mp. 94-96° C.; 1H NMR (CDCl3, 400 MHz) δ 2.00-2.10 (m, 1H), 2.12-2.25 (m, 1H), 2.47-2.57 (m, 2H), 2.61-2.73 (m, 2H), 3.85 (quint, J=8.4 Hz, 1H), 5.23 (brs, 2H), 7.10 (d, J=4.4 Hz, 1H), 7.16 (d, J=4.4 Hz, 1H), 7.44 (dd, J=4.2, 8.2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.36 (s, 1H), 8.95-9.00 (m, 1H); MS (ES+): m/z 316.2 (30) [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:11][C:10]([C:6]1[CH:5]=[CH:4][C:3]([O:8][CH3:9])=[C:2]([Cl:1])[CH:7]=1)=[O:12]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)cc1Cl
Yield: 96.2 %

Procedure:
A mixture of 30 grams (210 millimoles) of orthochloroanisole and 19.8 grams (252 millimoles) of acetyl chloride was dissolved in 400 milliliters of methylene chloride, and then 33.6 grams (252 millimoles) of anhydrous aluminum chloride was gradually added thereto while cooling with ice and stirring. The resulting mixture was further stirred for 3 hours while cooling with ice. The reaction mixture was allowed to stand to room temperature and stirred for 2 hours at room temperature. Then the reaction mixture was added to 1,200 milliliters of 5% hydrochloric acid, which was then allowed to separate into aqueous and organic layers. The organic layer thus obtained was washed with a 5% aqueous solution of sodium carbonate and dried over anhydrous sodium sulfate and, thereafter, the methylene chloride was distilled away under reduced pressure. Thus, as a product, 37.4 grams (202 millimoles) of 3-chloro-4-methoxyacetophenone was obtained (yield, 97%).
Reaction SMILES: [N+:1]([O:4][C@@H:5]([CH2:41][O:42][N+:43]([O-:45])=[O:44])[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:32]=[N:33][NH:34][N:35]=3)=[CH:21][CH:20]=2)[C:16]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:15][C:14]=1[Cl:40])=[O:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+:50].[K+]>CC(O)C>[N+:1]([O:4][C@@H:5]([CH2:41][O:42][N+:43]([O-:45])=[O:44])[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:32]=[N:33][N-:34][N:35]=3)=[CH:21][CH:20]=2)[C:16]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:15][C:14]=1[Cl:40])=[O:10])([O-:3])=[O:2].[K+:50]
Reactant: CCCCc1nc(Cl)c(COC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCCCc1nc(Cl)c(COC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of (2-butyl-4-chloro-1-{[2′-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)methyl (5R)-5,6-bis(nitrooxy)hexanoate (349.3 mg, 0.543 mmol) and potassium carbonate (922.7 mg, 6.68 mmol) was added 2-propanol (25 mL). After 30 minutes, the reaction mixture was filtered and concentrated in vacuo. More washings of the residual solids were performed with ethyl acetate, and the product was precipitated with hexanes. Repeating the cycle twice and drying of the solid in vacuo afforded the title compound as a white solid. 1H NMR (500 MHz, CD3CN) δ 7.62 (dd, J=1.3, 7.3 Hz, 1H), 7.39 (dt, J=1.6, 7.4 Hz, 1H), 7.36 (dt, J=1.6, 7.3 Hz, 1H), 7.31 (dd, J=1.7, 7.4 Hz, 1H), 7.14 (d, J=8.2 Hz, 2H), 6.83 (d, J=8.2 Hz, 2H), 5.27 (dq, J=2.6, 6.4 Hz, 1H), 5.13 (s, 2H), 4.96 (s, 2H), 4.76 (dd, J=2.6, 12.9 Hz, 1H), 4.51 (dd, J=6.1, 12.9 Hz, 1H), 2.54 (t, J=7.7 Hz, 2H), 2.05 (dt, J=1.8, 7.1 Hz, 2H), 1.48-1.68 (m, 6H), 1.30 (pent, J=7.5 Hz, 2H), 0.85 (t, J=7.3 Hz, 3H). LCMS: m/e 643.2 (M+H).
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[S:18][C:19]([CH2:22]C)=[CH:20][CH:21]=2)O)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:17]1[S:18][C:19]([CH3:22])=[CH:20][CH:21]=1
Reactant: CCc1ccc(C(O)c2cccc(Br)c2)s1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(Cc2cccc(Br)c2)s1
Reaction time: 2 h

Procedure:
1,3-Dibromobenzene (25 g) and a solution of a Grignard reagent prepared using metal magnesium in ether (50 ml) were added to a solution of 5-ethylthiophene-2-carboxyaldehyde (5.0 g) in tetrahydrofuran (50 ml) at 0° C., and the mixture was stirred for one hour. The reaction mixture was poured into ice-cooled water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (3-bromophenyl) (5-ethyl-2-thienyl)methanol (5.57 g). Borontrifluoride diethyl ether complex (1.57 ml) and triethylsilane (3.83 ml) were added to a solution of (3-bromophenyl) (5-ethyl-2-thienyl)methanol in acetonitrile (20 ml) at −40° C., and the mixture was stirred for two hours. Aqueous solution of saturated potassium carbonate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-(3-bromobenzyl)-5-methylthiophene (3.77 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]=[C:7](S(C)(=O)=O)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][O:11][C:9]=2[N:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.O>CC(O)C>[CH3:1][S:2]([C:5]1[N:6]=[C:7]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][O:11][C:9]=2[N:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1nc(S(C)(=O)=O)c2c(-c3ccccc3)coc2n1
Reactant: NCc1ccccn1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1nc(NCc2ccccn2)c2c(-c3ccccc3)coc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 29.2 %

Procedure:
A mixture of 2,4-bis-methylsulfonyl-5-phenyl-furo[2,3-d]pyrimidine (54 mg, 0.153 mmol), triethylamine (17 mg, 0.168 mmol) and 2-(aminomethyl)pyridine (18 mg, 0.168 mmol) in propan-2-ol (5 ml) was warmed to obtain a solution and stirred at ambient temperature for 2.5 hr. Water (50 ml) was then added and the mixture was extracted with dichloromethane (3×30 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude (2-methanesulfonyl-5-phenyl-furo[2,3d]pyrimidin-4-yl)-pyridin-2-ylmethylamine which was purified by flash chromatography (silica) eluting with 40′-60° C. petroleum ether followed by ethyl acetate to give a white solid (17 mg), m.pt. 171-173° C.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=O.[CH2:13]([C:15]1([CH2:44][CH3:45])[C:18](=[O:19])[N:17]([C:20]([NH:22][CH:23]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH2:24][CH2:25][CH3:26])=[O:21])[CH:16]1[O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=O)=[CH:37][CH:36]=1)[CH3:14].CN(C)CCN.C1C=CC=CC=1>C(Cl)Cl>[CH3:1][N:3]([CH3:4])[CH2:7][CH2:6][NH:5][C:39]([C:38]1[CH:42]=[CH:43][C:35]([O:34][CH:16]2[C:15]([CH2:44][CH3:45])([CH2:13][CH3:14])[C:18](=[O:19])[N:17]2[C:20]([NH:22][CH:23]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH2:24][CH2:25][CH3:26])=[O:21])=[CH:36][CH:37]=1)=[O:41]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)O)cc1)c1ccc(C)cc1
Agent: CN(C)CCN
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)NCCN(C)C)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.104 g carbonyldiimidazole in 2 ml methylene chloride is added a solution of 0.227 g of [S-(R*,S*)]-4-((3,3-diethyl-1-((-1-(4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)-oxy)benzoic acid in 3 ml methylene chloride. The mixture is stirred at ambient temperature for 30 minutes at which time 0.100 g of N,N-dimethylethylenediamine is added. After stirring overnight at room temperature the reaction mixture is poured into benzene (50 ml) and washed with water. The organic layer is separated, dried through sodium sulfate and concentrated in vacuo. Silica gel chromatography using 5% methanol in methylene chloride yields 0.160 g of 2-[4-[[[2-(dimethylamino)-ethyl]amino]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide. (Compound 73).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1.[F:16][C:17]([F:32])([F:31])[C:18]([C:20]1[S:24][C:23]([CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)=[O:19]>>[CH3:1][CH:2]1[N:7]([C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:23]2[S:24][C:20]([C:18](=[O:19])[C:17]([F:31])([F:32])[F:16])=[CH:21][CH:22]=2)[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1
Reactant: CC1CN(c2ccc(C#N)cn2)CCN1
Reactant: O=C(O)CCCc1ccc(C(=O)C(F)(F)F)s1
Product: CC1CN(c2ccc(C#N)cn2)CCN1C(=O)CCCc1ccc(C(=O)C(F)(F)F)s1
Yield: 16 %

Procedure:
This compound was synthesized from 6-(3-methylpiperazin-1-yl)nicotinonitrile and 4-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)butanoic acid as described for example 37 step 3 (40 mg, yield 16%). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 8.45-8.44 (m, 1H), 7.98-7.96 (m, 1H), 7.82-7.79 (dd, J=9.1 Hz, 2.4 Hz, 1H), 7.20-7.19 (d, J=4.0 Hz, 1H), 6.89-6.87 (d, J=9.1 Hz, 1H), 4.45 (m, 1H), 4.20-4.14 (m, 2H), 3.98 (m, 1H), 3.39-3.34 (dd, J=13.4 Hz, 4.0 Hz, 1H), 3.27 (m, 1H), 3.17-3.11 (m, 1H), 2.99 (m, 1H), 2.89 (m, 1H), 2.46-2.36 (m, 2H), 2.01-1.94 (m, 2H), 1.11-1.09 (d, J=6.7 Hz, 3H). MS (ESI) m/z: Calculated for C21H21F3N4O2S: 450.13. found: 449.2 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([C:38]#[N:39])=[C:13]([C:27]3[CH:32]=[CH:31][N+:30]([O-:33])=[C:29]([NH:34][C:35](=[O:37])[CH3:36])[CH:28]=3)[S:14][C:15]=2[C:16]2[N:20]=[CH:19][N:18](C3CCCCO3)[N:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([C:38]#[N:39])=[C:13]([C:27]3[CH:32]=[CH:31][N+:30]([O-:33])=[C:29]([NH:34][C:35](=[O:37])[CH3:36])[CH:28]=3)[S:14][C:15]=2[C:16]2[NH:20][CH:19]=[N:18][N:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(S(=O)(=O)c3ccc(Cl)cc3)c2C#N)cc[n+]1[O-]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(-c2sc(-c3nnc[nH]3)c(S(=O)(=O)c3ccc(Cl)cc3)c2C#N)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.2 %

Procedure:
N-(4-{4-[(4-chlorophenyl)sulfonyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}-1-oxidopyridin-2-yl)acetamide (0.0742 g, 0.127 mmol) was dissolved in trifluoroacetic acid (4.00 mL, 51.9 mmol). The mixture was stirred at room temperature for 4 hrs, solvent was evaporated and the residue was purified by HPLC to yield a solid product (0.0421 g, yield 66.3%) LCMS: (AA) ES+ 501, 503. 1H NMR (300 MHz, MeOD) δ: 8.90 (s, 1H), 8.60 (s, 1H), 8.43 (d, 1H), 8.35 (d, 2H), 7.67 (d, 2H), 7.59 (d, 1H), 2.28 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][O:25][CH2:26][C@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH3:24][O:25][CH2:26][C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:22][C:16]1([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: COC[C@H]1CCCN1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: COC[C@H]1CCCN1CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 59.4 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 1.575 mmol), (R)-2-(methoxymethyl)pyrrolidine (347 mg, 4.21 mmol), absolute ethanol (20 ml), activated 3 Å molecular sieves (500 mg), titanium (IV) isopropoxide (2.33 ml, 7.88 mmol) and STAB (2.84 g, 13.4 mmol) were reacted in accordance with the general procedure D. The isolated waxy solid was purified by column chromatography on silica eluting with DCM:MeOH:NH3 95:14:1 to give the title compound as a viscous pale yellow oil (390 mg, 59%). 1H NMR (400 MHz, CDCl3) δ7.18 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.85-3.69 (m, 2H), 3.59 (td, 1H), 3.45 (td, 1H), 3.27 (s, 3H), 3.10 (dd, 1H), 3.02 (dd, 1H), 2.94 (d, 1H), 2.63 (t, 2H), 2.58-2.45 (m, 6H), 2.39 (m, 1H), 2.21 (m, 1H), 2.07-1.67 (m, 11H), 1.57-1.33 (m, 3H).