Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)OCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:23][C:24]1[CH:25]=[CH:26][C:27](F)=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:8]2([C:11]#[N:12])[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]2)=[N:28][CH:29]=1
Reactant: Fc1ccc(Br)cn1
Reactant: N#CC1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Br)cn2)CCC(=O)CC1
Temperature: 0 °C
Yield: 64.4 %

Procedure:
To 1,4-dioxaspiro[4.5]decane-8-carbonitrile (13.4 g) described in Reference Example 82 (1) was added a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (100 ml), stirred at 0° C., then a solution of 5-bromo-2-fluoropyridine (12.8 g) in tetrahydrofuran (20 ml) was added thereto, and stirred at room temperature for 1 hour. Tetrahydrofuran (20 ml) was added thereto, additionally stirred for 1 hour, then to the reaction solution was added an aqueous solution of potassium carbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. To the residue were added water (10 ml) and trifluoroacetic acid (50 ml), and stirred at room temperature for 6 hours. The reaction solution was added to an aqueous solution of potassium carbonate, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(5-bromopyridin-2-yl)-4-oxocyclohexanecarbonitrile (13.08 g) as a pale yellow solid. MS (ESI) m/z: 279, 281 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH2:32])[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:32][C:2]2[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:3]=2)[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: CC(C)(O)c1cc(N2CCOCC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(N3CCOCC3)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1

Procedure:
Using in analogous manner the procedure described in example 1e), 2-(2-chloro-6-morpholin-4-yl-pyrimidin-4-yl)-propan-2-ol (77 mg, 0.3 mmol) was reacted with 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol) to give the title compound was obtained as light yellow foam (62 mg, 49%). MS ISP (m/e): 425.2 [(M+H)+].) 1 1H NMR (CDCl3, 300 MHz): (ppm)=7.82 (s, 2H), 7.16 (d, 1H), 6.98 (dd, 1H), 6.95 (s, 1H), 6.87 (s, 1H), 6.12 (s, 1H), 4.15 (br s, 1H), 3.81 (s, 3H), 3.78 and 3.65 (2 m, 2×4H), 3.16 (s, 6H), 2.30 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[S:11]1[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[NH:13][CH2:12]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:2]([N:13]1[CH:14]([C:16]([OH:18])=[O:17])[CH2:15][S:11][CH2:12]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C(O)C1CSCN1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)C1CSCN1C(=O)c1cccnc1
Temperature: 64 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
Nicotinoyl chloride hydrochloride (534 g) is added over 1 hour at a temperature of between 30° and 52° C. to a solution of thiazolidine-4-carboxylic acid (400 g) and triethylamine (613 g) in chloroform (4,500 cc). The solution obtained is heated at a temperature of about 64° C. for 4 hours. After stirring at a temperature of about 20° C. for 16 hours, the crystals which have appeared are separated off by filtration, washed 3 times with chloroform (1,500 cc in total), then 3 times with diethyl ether (1,500 cc in total) and are dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. N-nicotinoylthiazolidine-4-carboxylic acid (403 g) is thus obtained in the form of white crystals melting at 190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([NH2:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.N1C=CN=C1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1.C(OC(=O)C)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]#[N:14])[S:11][C:7]=2[C:6]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(N)=O)nc12
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCOCC2)c2sc(C#N)nc12
Yield: 89.9 %

Procedure:
A suspension of 3.51 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 1.78 g 1,1′-carbonyl-diimidazol in 30 ml DMF was stirred at room temperature for 18 hours. 0.8 ml Ammonium hydroxide (25% in water) was added and stirring was continued for 5 hours. Extraction with water/ethylacetate and crystallization from dichloromethane yielded 1.17 g (40%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid amide as a yellow solid; M.p.: 228–231° C.; MS (ISP): m/e=294 (M+H+). To a solution of 4.67 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid amide and 2.18 g imidazole in 95 ml pyridine were added at 0° C. 5.95 ml phosphoroxychloride. After 5 hours the cold solution was diluted with ethylacetate and extracted with water. The organic solution was dried with sodiumsulfate and the solvents were distilled off to yield 3.94 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonitrile as yellow solid; M.p.: 145–147° C.; MS (ISP): m/e=276 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[NH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[NH2:18].C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]1[C:12](=[O:14])[C:3]2=[CH:4][NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:18]1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The mixture of 4.0 g of ethyl 4-chloroquinolin-3-carboxylate, 2.04 g of 2-hydrazinopyridine and 50 ml of eutectic diphenyl ether-biphenyl is stirred at 110°-130° for 3 hours under nitrogen. After cooling to room temperature it is diluted with diethyl ether, filtered, the solids washed with diethyl ether and dissolved in 100 ml of aqueous sodium hydroxide. The solution is washed with diethyl ether and the pH thereof adjusted to 8.5 by addition of ammonium chloride. The precipitate formed is collected, washed successively with water, methanol and diethyl ether, to yield the 2-(2-pyridyl)-pyrazolo[4,3-c]quinolin-3(5H)-one showing in the IR-spectrum peaks at 887, 865, 853, 788, 780, 765, 756, 737 and 726 cm-1.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([O:7]CC)=O)=[O:2].[CH:10]1([C:13](=[N:15]O)[NH2:14])[CH2:12][CH2:11]1>CCO>[CH:10]1([C:13]2[N:15]=[C:5]([CH2:4][NH:3][CH:1]=[O:2])[O:7][N:14]=2)[CH2:12][CH2:11]1
Reactant: NC(=NO)C1CC1
Reactant: CCOC(=O)CNC=O
Solvent: CCO
Product: O=CNCc1nc(C2CC2)no1
Temperature: 25 °C

Procedure:
A solution of ethyl formylaminomethyl-carboxylate (150 mmol) and cyclopropyl carboxamide oxime (100 mmol) in 100% EtOH (100 ml) was charged with Na (200 mg) and crushed molecular sieve (4Å) (10 g). The mixture thus obtained was stirred and heated to reflux for 8 hours. The mixture was cooled to room temperature, filtered through filter aid and the fiItrate was evaporated in vacuo. The oiIy residue was partitionated into a CHCl3 phase which was dried with Na2SO4 and evaporated.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:40]([NH:42][C@H:43]([C:45](O)=[O:46])[CH3:44])=[O:41])[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:31][CH:30]=3)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[NH2:55][CH2:56][C:57]1[C:70]([O:71][CH3:72])=[CH:69][CH:68]=[C:67]2[C:58]=1[O:59][C:60]1[C:61]([CH2:77][C:78]([O:80][CH2:81][C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)=[O:79])=[C:62]([O:75][CH3:76])[CH:63]=[CH:64][C:65]=1[C:66]2([CH3:74])[CH3:73].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:76][O:75][C:62]1[CH:63]=[CH:64][C:65]2[C:66]([CH3:74])([CH3:73])[C:67]3[C:58]([O:59][C:60]=2[C:61]=1[CH2:77][C:78]([O:80][CH2:81][C:82]1[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=1)=[O:79])=[C:57]([CH2:56][NH:55][C:45](=[O:46])[C@H:43]([CH3:44])[NH:42][C:40](=[O:41])[C@H:27]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:33][CH:34]=1)[NH:26][C:24](=[O:25])[C@H:19]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[C:70]([O:71][CH3:72])=[CH:69][CH:68]=3
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)O
Reactant: COc1ccc2c(c1CN)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)NCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C

Procedure:
A solution of 0.52 g (0.8 mmol) of N-(9H-fluoren-9-ylmethoxycarbonyl)-L-isoleucyl-O-tert-butyl-L-tyrosyl-L-alanine in 20 ml of dimethylformamide was cooled to 0° and treated with 0.45 g (0.8 mmol) of benzyl 5-aminomethyl-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate trifluoroacetate and with 0.45 g (1.2 mmol) of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate. Thereafter, 0.31 g (2.4 mmol) of ethyldiisopropylamine was added, whereupon the reaction mixture obtained was warmed from 0° to room temperature within 3 hours and concentrated. The residue remaining was taken up in chloroform, whereupon the solution obtained was washed with water and dried over magnesium sulphate. After chromatography over silica gel (chloroform) 0.77 g of benzyl 3,6-dimethoxy-9,9-dimethyl-5-[(N-(9H-fluoren-9-ylmethoxycarbonyl)-L-isoleucyl-O-tert-butyl-L-tyrosyl-L-alanyl)aminomethyl]xanthene-4-acetate of m.p. 218°-220° was obtained; IR 1728, 1662, 1606, 1503, 1492 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18](OC)=[CH:17][CH:16]=1.ClC1C=CC(O)=CC=1[N+]([O-])=O>>[CH2:14]([O:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: COc1ccc(CCl)cc1
Agent: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2ccccc2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 10C substituting benzyl bromide and the product from Example 47C for 1-chloromethyl-4-methoxy-benzene and 4-chloro-3-nitro-phenol (0.72 g, 79%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]=O)[C:6]#[N:7])[CH3:2].[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].C(O)(=O)C.N1CCCCC1>ClCCl>[C:16]([C:15]([C:14](=[O:19])[CH3:13])=[CH:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:1][CH3:2])(=[O:18])[CH3:17]
Reactant: CC(=O)CC(C)=O
Reactant: CCc1cc(C#N)ccc1C=O
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCc1cc(C#N)ccc1C=C(C(C)=O)C(C)=O

Procedure:
885 mg (5.55 mmol) of 3-ethyl-4-formylbenzonitrile, 0.62 ml (6.11 mmol) of 2,4-pentanedione, 0.47 ml (8.33 mmol) of acetic acid and 0.11 ml (1.11 mmol) of piperidine in 40 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue (1.07 g) is reacted further without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][NH:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[CH:27][CH:26]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][N:11]3[C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH:35]=[CH:34][N:33]=[CH:32]4)=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Reactant: Brc1ccc(-n2ccnc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ccc(-n3ccnc3)cc1)C2

Procedure:
3-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-9H-pyrrolo[3,4-b]quinolin-9-one (30.6 mg, 0.1 mmol), 1-(4-bromo-phenyl)-1H-imidazole (22.3 mg, 0.1 mmol), Pd2dba3 (4.6 mg, 0.005 mmol), biphenyl-2-yl-di-tert-butyl-phosphane 3.0 mg, 0.01 mmol) and NaOtBu (14 mg, 0.14 mmol) were stirred in 1,4-dioxane (0.6 mL) at 89° C. for 17 hours. Purification by preparative TLC (5% CH3OH/CH2Cl2) yielded the title product as yellow powder.
Reaction SMILES: [CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[CH:12]([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:3])[CH3:2].[CH3:46][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH3:46])([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:2])[CH3:3]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3ccc4ccccc4c3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3ccc4ccccc4c3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 200 mg (0.34 mmol) of N-Isopropyl-N-(4-methoxy-phenyl)-2-(3-naphthalen-2-ylmethyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl) acetamide, prepared as in Example 36, in 5 mL of DMF at 0° C. is added 0.60 mL (0.60 mmol, 1.8 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and 37 μL (0.60 mmol, 1.8 equiv) of methyl iodide is added. The resulting solution is stirred 3 h at RT, warmed to 50° C. for 16 h, and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 5/2 as eluent followed by lyophilization in acetonitrile/H2O afforded 180 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.88-7.79 (m, 3H), 7.64-7.19 (m, 14H), 7.05 (m, 2H), 6.92 (dd, 1H, J=1.0, 8.1), 4.87 (m, 1H), 4.30 (s, br, 2H), 3.80 (s, 3H), 2.76 (dd, 2H, J=13.9, 23.9), 1.22 (s, 3H), 1.00 (m, 6H); low resolution MS (FAB)m/e 612 (MH+), 611 (M+), 447.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li][CH2:12]CCC.IC>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH3:12])[S:10][C:3]=12
Reactant: [Li]CCCC
Reactant: Clc1ccnc2ccsc12
Solvent: CI
Product: Cc1cc2nccc(Cl)c2s1
Yield: 81 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine (1.69 g, 10 mmole) by treatment with n-BuLi and iodomethane (2 ml, 4.56 g, 32 mmole) in a manner as previously described for example 1b to give a pale yellow, low-melting solid (1.48 g, 81%). 1H NMR (DMSO-d6): δ 8.56 (1H, d, J=5.1 Hz), 7.48 (1H, d, J=5.1 Hz), 7.38 (1H, s), 2.65 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21]Cl.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][N:8]([CH2:21][CH2:20][O:19][CH3:18])[C:7]1=[O:11]
Reactant: COc1ccccc1C=C1CCNC1=O
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN1CCC(=Cc2ccccc2OC)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The intermediate 3-(2′-methoxybenzylidene)-2-pyrrolidone (5.0 g) obtained in Example 317 was dissolved in dimethylformamide (50 ml) and sodium hydride (0.99 g) was added under ice-cooling. The mixture was stirred at room temperature for 30 min. To the reaction mixture was again added 2-methoxyethyl chloride (2.3 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hr and at 70° C. for 1 hr. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily title compound (2.8 g).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[C:8](=O)[CH2:7][C:6]2([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[O:5]1.[CH3:16]CCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:3][CH:4]1[C:8](=[CH2:16])[CH2:7][C:6]2([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[O:5]1
Reactant: CC1OC2(CCN(C)CC2)CC1=O
Reactant: CCCCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=C1CC2(CCN(C)CC2)OC1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
60% oily sodium hydride (272 mg), placed in a flask, was treated with n-hexane in an argon gas atmosphere to wash off the oil component, and the remaining hexane was distilled off under reduced pressure. Dimethyl sulfoxide (8 ml) was added to the residue, the mixture was heated at 60° to 70° C. for about one hour, the faint-green solution thus obtained was ice-cooled, and 2.43 g methyltriphenylphosphonium bromide was added. Heating the mixture at about 40° C. put the solid into solution, giving a yellowish-red solution. It was cooled to about 30° C., 590 mg 2,8-dimethyl-1-oxa-8-azaspiro[4,5]decan-3-one was added, and the mixture was stirred at room temperature for about two hours. It was then poured into 50 ml ice water, the resulting mixture was extracted with chloroform, and the extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure from the dried solution, the residue was purified by silica gel column chromatography by using, as eluent, a mixed solvent of chloroform/methanol (10:1 by volume), giving 320 mg of 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane as oil. It was dissolved in ether, and ethanolic hydrogen chloride was added to the solution, giving the corresponding hydrochloride as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted with 1-methylpiperazine to give (2S)-1-(tert-butoxycarbonyl)-2-(4-methylpiperazin-1-ylcarbonyl)pyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.7-2.05 (m, 4H), 2.1-2.25 (m, 1H), 2.32 (s, 3H), 2.35-2.5 (m, 4H), 2.6-2.7 (m, 1H), 2.8-2.9 (m, 1H), 3.3-3.7 (m, 8H), 4.15 (br s, 1H); Mass Spectrum: M+H+ 242.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][N:27]=[C:26]3[CH3:30])=[CH:21][CH:20]=2)[CH:5]=[C:6]([C:8]2([C:14]([NH2:16])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32].C(=O)(O)[O-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][N:27]=[C:26]3[CH3:30])=[CH:21][CH:20]=2)[CH:5]=[C:6]([C:8]2([C:14](=[S:32])[NH2:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(N)=O)CCOCC3)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(N)=S)CCOCC3)c2)cc1
Temperature: 40 °C

Procedure:
To a stirred solution of 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]-phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (Example 5) in THF (10 ml) was added phosphorus pentasulfide (236 mg, 0.53 mmol) and sodium bicarbonate (176 mg, 2.1 mmol). The resulting mixture was heated at 40° C. for 4 hr. The mixture was concentrated in vacuo. To the residue was added water (100 ml) and the mixture was extracted with dichloromethane (2×100 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified on column chromatography (LiChropprep --NH2) and then by p-TLC eluting with dichloromethane-methanol (10:1) to afford 38 mg of the titled compound as white solids.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[NH2:15])=[CH:10][C:9]=1[NH:17][C:18](=[O:36])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29](C=O)=[CH:28][C:27]=1[O:34][CH3:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:7])([CH3:6])[CH3:5]>N1C=CC=CC=1.O>[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[NH2:15])=[CH:10][C:9]=1[NH:17][C:18](=[O:36])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29](=[N:2][OH:3])[CH2:28][C:27]=1[O:34][CH3:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:5])([CH3:7])[CH3:6]
Reactant: NO
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)C1=C(OC)CC(=NO)C=C1
Reaction time: 0.33 h

Procedure:
137 mg (1.97 mmol) of hydroxylamine hydrochloride were added to a solution of 398 mg (0.879 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(4-formyl-2-methoxyphenyl)octanamide (prepared as described in Example 110) in 5 ml of pyridine, and the resulting mixture was stirred for 20 minutes. At the end of this time, the reaction mixture was diluted with water, and the diluted aqueous mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. In order to remove the pyridine remaining in the residue, it was dissolved in toluene and the solvent was azeotropically distilled off. Repetition of this procedure gave 414 mg (a quantitative yield) of the title compound as a foam-like substance.