Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:19](#[N:23])[CH2:20][C:21]#[N:22].C(NCC)C.O>CN(C=O)C>[NH2:23][C:19]1[O:1][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[C:20]=1[C:21]#[N:22]
Reactant: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Reactant: N#CCC#N
Solvent: CN(C)C=O
Solvent: CCNCC
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 236 g (974 mmol) 2-hydroxy-1-(4-methoxyphenyl)-2-phenylethanone and 83.66 g (1266 mmol) malononitrile in 470 ml DMF and, with cooling on an ice bath, add 86.6 ml (836.7 mmol) diethylamine. After 1 h, heat the mixture to RT and continue stirring for 4 h at RT, before adding 2.5 litre water and a few seed crystals. After 30 min, decant the supernatant water and replace with 1.25 litre of fresh water. Stir the suspension thoroughly and again decant the supernatant water. Take up the sticky crystalline residue in ethyl acetate and then concentrate under vacuum almost completely. Stir the residue with 730 ml diisopropyl ether and leave the suspension to stand overnight at RT. Then filter off the solid matter with suction and dry under vacuum. 211.5 g (57.6% of theor.) of the title compound is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.BrCC1CCCCO1.[O:21]=[C:22]1[C:30]2([C:34]3[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:33]=3[O:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1CC1C=CC=CN=1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:7]1[C:6]2[CH:11]=[CH:12][C:3]([CH2:2][N:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4([C:34]5[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:33]=5[O:32][CH2:31]4)[C:22]3=[O:21])=[CH:4][C:5]=2[O:10][CH2:9][CH2:8]1
Reactant: ClCc1ccc2c(c1)OCCO2
Reactant: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccc3c(c2)OCCO3)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-(chloromethyl)-2,3-dihydrobenzo[b][1,4]dioxine (Capilla, A. S. et al., Tetrahedron (2001), 57:8297) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile was obtained (54%) as a colorless solid: mp 181-183° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.29-7.16 (m, 1H), 7.15-6.97 (m, 3H), 6.89-6.75 (m, 5H), 5.04 (d, J=9.2 Hz, 1H), 4.94 (d, J=15.3 Hz, 1H), 4.80-4.67 (m, 2H), 4.25-4.19 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.2, 160.8, 143.8, 143.3, 142.2, 134.7, 131.3, 129.5, 128.5, 125.8, 124.4, 123.8, 123.7, 120.5, 118.5, 117.8, 116.3, 113.8, 113.3, 109.8, 80.2, 64.3 (2C), 57.8, 43.8.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+]([C:17]1[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=1)([O-])=O.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][C:17]3[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(Sc2nc3ccc(Cl)cc3[nH]2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Aldehyde intermediate preparation: 5-Chloro-2-mercaptobenzimidazole (1.5 g, 8.12 mmol) dissolved in 10 ml of anhydrous tetrahydrofuran is added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.325 g, 8.12 mmol) in anhydrous tetrahydrofuran (20 ml) at 10° C. over a 15 minute period. The reaction mixture is stirred for 2 hours at room temperature. Then 5-nitro-2-furaldehyde (1.146 g, 8.12 mmol) dissolved in 20 ml of anhydrous tetrahydrofuran is added dropwise over a 15 minute period and the reaction mixture is stirred at room temperature for an additional 16 hour period. The reaction mixture is then poured into 300 ml of water and extracted twice with 150 ml of ethyl acetate. The combined organic extracts are dried over MgSO4 and concentrated under reduced pressure. The residue is purified on a silica gel column (120 g) eluted with a mixture of cyclohexane and ethyl acetate (80/20, v/v) to yield 1.9 g of 5-(6-chloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde. Yield=88%. Analytical LC/MS (method B): retention time=3.40 min., m/z=278.95/1Cl (positive ion mode).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][CH2:28][CH2:29][CH:30]([OH:52])[CH2:31][O:32]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O.O>[CH2:11]([O:27][CH2:28][CH2:29][CH:30]([O:52][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:31][OH:32])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCOCCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCCC(CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a suspension of 6.17 g of 50% sodium hydride (washed with hexanes) in 245 ml of dry dimethylformamide was added 19.45 g of benzyl bromide at 0° C. A solution of 56.65 g of 4-(hexadecyloxy)-1-(triphenylmethoxy)-2-butanol in 60 ml of dimethylformamide was added dropwise with stirring at 0° C. under argon. The mixture was stirred overnight at room temperature, then poured into 1000 ml of iced water and extracted with petroleum ether. The organic phase was dried, the solvent removed and the residue dissolved in a mixture of 235 ml of methanol and 125 ml of tetrahydrofuran. A 500 mg portion of p-toluene sulfonic acid was added, the mixture was allowed to stand overnight and then the solvent was removed. The residue was dissolved in petroleum ether, washed with saturated aqueous sodium bicarbonate, dried and the solvent removed giving an oil. This oil was again subjected to treatment with p-toluenesulfonic acid in the solvent system described above, again giving an oil which was purified by HPLC, giving 23 g of the desired compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[C:14](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH3:14][N:10]1[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=2[C:7](=[O:12])[O:8][C:9]1=[O:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 6-methyl-1H-3,1-benzoxazine-2,4-dione (2 g), anhydrous potassium carbonate (0.64 g), dimethylformamide (10 ml) and methyl iodide (0.9 ml) was stirred at room temperature for 24 hours. More methyl iodide (0.9 ml) was added and stirring continued for a further 18 hours. More potassium carbonate (1 g) and methyl iodide (0.8 ml) were added and stirring continued for a further 23 hours. The mixture was poured on to a mixture of ice and water. The resulting precipitate was washed with water and dried to give the novel compound 1,6-dimethyl-1H-3,1-benzoxazine-2,4-dione, m.p. 165°-170°.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[H][H].Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1.Cl>C1COCC1.C(OCC)(=O)C>[N+:33]([C:30]1[CH:31]=[CH:32][C:27]([CH:2]([C:1]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[N:28][CH:29]=1)([O-:35])=[O:34]
Reactant: [H][H]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
A solution of dibenzyl malonate (2.84 g, 10 mmol) in THF (10 ml) was gradually dropped to sodium hydride (800 mg, 20 mmol: 60%) in THF (20 ml) under a nitrogen atmosphere at room temperature. After cessation of evolution of hydrogen, thereto was gradually added 2-chloro-5-nitropyridine (1.59 g, 10 mmol) in THF (10 ml). The mixture was stirred for 24 hours at room temperature, and then neutralized with 1N hydrochloric acid. The resulted precipitate was dissolved by adding ethyl acetate (200 ml) thereto. The aqueous layer was separated and the organic layer was washed with saturated brine (30 mL), followed by concentration in vacuo. The residue was washed with hexane (50 mL×2) and dried to give the object compound (8) as an orange solid (3.29 g, yield 81%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:11][CH3:12])=[N:4][C:5]([CH3:10])=[CH:6][C:7]=1[S:8][CH3:9].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23].O>O1CCCC1>[CH3:12][S:11][C:3]1[C:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])=[C:7]([S:8][CH3:9])[CH:6]=[C:5]([CH3:10])[N:4]=1
Reactant: CSc1cc(C)nc(SC)c1N
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CCl
Reaction time: 10 h
Yield: 75 %

Procedure:
Part A. A solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (0.38 g,1.88 mmol) and triethylamine (0.30 mL, 2.07 mmol) in tetrahydrofuran (8 mL)was cooled to 0° C., and treated with a solution of chloroacetyl chloride (0.18 mL, 2.26 mmol) in tetrahydrofuran (4 mL). After being stirred for 10 hours, the mixture was poured into water (100 mL), and thiswas extracted with ethyl acetate (2×100 mL). The extracts were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The resulting solid was recrystallized to purity from ether, mp 190°-192° C., to afford N-[2,4-bis(methylthio)-6-methyl-pyridin-3-yl]-2-chloroacetamide (0.39 g, 1.41 mmol, 75%). 1H NMR (CDCl3): δ 7.69 (1H, br s); 6.68 (1H, s); 4.26 (2H, s); 2.53 (3H, s); 2.51 (3H, s); 2.43 (3H, s). Mass spectrum (NH3 -CI/DDIP): m/z 279 (42%); 278 (17%); 277 (100%); 227 (4%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([NH:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](O)=[O:22])=[O:18])=[CH:11]2>>[CH2:24]([CH:20]([NH:19][C:17]([C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:7])=[CH:16][CH:15]=2)=[O:18])[C:21]([N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1)=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: OC1CCNC1
Product: O=C(NC(Cc1ccccc1)C(=O)N1CCC(O)C1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Racemic3-pyrrolidinol (2.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3phenyl-propionic acid (1 mmol) were coupled according to procedure A (0-25° C. reaction temperature, washing first with acid then base), and the product purified by column chromatography on silica gel eluted with 0.5-16% ethanol in dichloromethane to give a colorless foam: Yield 260 mg, 63%; HPLC (60/40) 100%, 3.86 minutes; PBMS 412/414 (MH+, 100%);
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[F:33][C:34]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44](O)=O)=[N:41][NH:42][CH:43]=1)=[O:37].[Cl:52][C:53]1[C:58]([Cl:59])=[CH:57][C:56]([NH2:60])=[C:55]([NH2:61])[CH:54]=1>>[Cl:52][C:53]1[C:58]([Cl:59])=[CH:57][C:56]2[NH:60][C:44]([C:40]3[C:39]([NH:38][C:36](=[O:37])[C:35]4[C:34]([F:33])=[CH:50][CH:49]=[CH:48][C:47]=4[F:51])=[CH:43][NH:42][N:41]=3)=[N:61][C:55]=2[CH:54]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(Cl)c(Cl)cc2[nH]1)c1c(F)cccc1F

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), however using 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D) and 4,5-dichloro-1,2-phenylene diamine to give N-[3-(5,6-dichloro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide (29 mg) as a beige solid. (LC/MS: Rt 3.53, [M+H]+ 408.02).
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].P([O-])(O)(O)=O.[K+]>CS(C)=O>[F:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: [F-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
Anhydrous potassium fluoride (5.5 g, 93 mmol) was suspended in anhydrous dimethylsulfoxide (200 ml) and the solvent reduced to half its volume by distillation under an atmosphere of nitrogen. The resulting suspension was cooled to room temperature and 4-chloro-3-nitropyridine (14 g, 88 mmol) was added. The reaction mixture was stirred at 120° C. for three hours under an atmosphere of nitrogen, cooled and then poured into a saturated aqueous solution of potassium dihydrogen phosphate. The resulting mixture was extracted with ethyl acetate. The organic phase was washed three times with water and then brine before being dried over anhydrous magnesium sulphate. The solvent was removed in vacuo to yield as an oil, 4-fluoro-3-nitropyridine (6.5 g), (δ(CDCl3) 7.32 (1H, 4 lines), 7.86 (1H, t, J=5 Hz) and 8.29 (1H, d, J=9 Hz), represented by the structural formula: ##STR21##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]#[CH:18])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:19][CH2:20][C:21]([NH:24][S:25]([C:28]1[CH:29]=[N:30][CH:31]=[C:32](Br)[CH:33]=1)(=[O:27])=[O:26])([CH3:23])[CH3:22]>>[OH:19][CH2:20][C:21]([NH:24][S:25]([C:28]1[CH:29]=[N:30][CH:31]=[C:32]([C:18]#[C:17][C:16]2[CH:15]=[N:14][N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)[CH:33]=1)(=[O:27])=[O:26])([CH3:23])[CH3:22]
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2ccc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3ccc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.6) (63 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (77 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (74 mg, 62%). MS (ISP) 482.0 [(M+H)+]; mp 185-186° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:22][N:9]1[CH2:10][CH2:11][CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)C1CCNN1C(=O)OC(C)(C)C
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of di-tert-butylpyrazolidine-1,5-dicarboxylate (7 g, 25.7 mmol) dissolved in 1,2-dichloroethane (DCE) (80 mL) were added HCHO (2.224 g, 69.4 mmol), sodium triacetoxyborohydride (14.71 g, 69.4 mmol), and acetic acid (8 mL). The reaction was stirred at rt for appropriate time. The solvent was then removed and the residue was diluted with DCM and saturated NaHCO3 (150 mL). The aqueous layer was extracted with DCM. The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel column chromatography to afford 4 g (13.97 mmol, 54.3% yield) of bis(1,1-dimethylethyl) 2-methyl-1,5-pyrazolidinedicarboxylate as a pale yellow oil. LC-MS (ES) m/e 287.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CO.[OH-].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
4-(2-Propenyloxy)benzoic acid was synthesized by Apfel's method (Apfel et al, Anal. Chem., 1985, 57, 651-658). A 1 L three-neck round-bottom flask was equipped with a condenser, 150 mL additional funnel, heating bath, and magnetic stirrer. 90 g (0.65 mol) of 4-hydroxybenzoic acid and 400 mL of methanol were added at 25° C. and stirred. After the acid was dissolved, 105 g (1.9 mol) of potassium hydroxide in 125 mL of distilled water was added dropwise. The reaction mixture was heated to reflux, and 90 g (0.74 mol) of allyl bromide was then added over a 2 hour period. The reaction mixture was allowed to reflux for 8 hours. As the reaction proceeded, potassium bromide precipitated. From this mixture, 250 mL of methanol was removed by evaporation. The remainder of the reaction mixture was cooled to 25° C. and then added to 2.5 L of distilled water. Hexane (250 mL) was added to extract organic impurities. After discarding the organic phase, the aqueous phase was heated to 40° C. and neutralized with 300 mL of 20% HCl. The crude product precipitated during the neutralization, was subsequently collected by filtration and purified by recrystallization from ethanol. Yield: 46 g (40.2%), mp 165° C.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6])[CH3:3].O[CH:17]([C:20]1[CH:36]=[C:35]2[N:23]([CH2:24][C:25]3[C:26]2=[N:27][C:28]2[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22](=[O:37])[C:21]=1[CH3:38])[CH2:18][CH3:19]>>[CH3:38][C:21]1[C:22](=[O:37])[N:23]2[C:35](=[CH:36][C:20]=1[CH:17]([O:13][C:12](=[O:14])[CH:8]([NH:7][C:5]([O:4][C:2]([CH3:3])([CH3:1])[CH3:15])=[O:6])[CH:9]([CH3:11])[CH3:10])[CH2:18][CH3:19])[C:26]1=[N:27][C:28]3[C:33]([CH:34]=[C:25]1[CH2:24]2)=[CH:32][CH:31]=[CH:30][CH:29]=3
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Product: CCC(OC(=O)C(NC(=O)OC(C)(C)C)C(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 3A except using N-[(1,1-dimethylethoxy)carbonyl]-L-valine and (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one. 1H NMR (CDCl3) d 8.34 (s, 1H), 8.22 (m, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.80 (m, 1H), 7.62 (m, 1H), 7.34 (two s, 1H), 5.94 (m, 1H), 5.26 (s, 2H), 5.04 (two br d, J=9.3 Hz, 1H), 4.36 (two d, J=4.5 Hz, 1H), 2.36 (s, 3H), 2.4-2.2 (m, 1H), 2.1-1.8 (m, 2H), 1.44 and 1.38 (two s, 9H), 1.00 (overlapping t and d, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[CH3:15][C:14]1[C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:18]=[CH:17][C:6]=3[N:7]=2)=[C:11]([NH2:16])[NH:12][N:13]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Reactant: C1CCNC1
Solvent: CCO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CN3CCCC3)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine (20 mg) in ethanol (1 mL) was added excess pyrrolidine. The reaction mixture was stirred at room temperature overnight. The solvent was then removed by evaporation and the residue was purified by flash column chromatography eluting with CHCl3:MeOH=9:1 to yield 2.7 mg of the title compound as a cream coloured solid. MS (m/z, ES+): 314.1 (M+1, 45%), 243.0 (M-C4H8N, 100%).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:3][CH2:2]1.C(O[C:9](=[O:26])[CH2:10][N:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.O1[CH2:31][CH2:30][CH2:29]C1>>[CH:1]1([C:9]([CH:29]2[CH2:30][CH2:31]2)([OH:26])[CH2:10][N:11]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: Cl[Mg]C1CC1
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Product: OC(CN(Cc1ccccc1)Cc1ccccc1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
To 20 ml of a 0.5 M (0.010 mol) solution of cyclopropylmagnesium chloride in tetrahydrofuran was a solution of 1.00 g (0.004 mol) dibenzylamino-acetic acid ethyl ester in 10 ml tetrahydrofuran and the mixture was allowed to stir at room temperature for 18 h. The reaction mixture was partitioned between 10% aqueous ammonium chloride and ethyl acetate the phases were separated and the organic phase was purified by chromatography on silca gel with heptane:ethyl acetate=9:1 to 4:1 to yield 0.29 g (26% Th) of the title compound as light yellow oil. MS (ISP) (M+H+)=322.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=1)=[O:20].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:14]2[CH2:15][CH2:16][CH2:11][CH2:12][CH2:13]2)[CH:22]=1)=[O:20]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(Cl)c1
Reactant: C1CCNCC1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(N3CCCCC3)c2)c1)c1ccnc(N2CCCCC2)c1
Yield: 96 %

Procedure:
Using an analogous procedure to that described in Example 21, N-[2-chloro-5-(2-chloropyrid-4-ylcarbonylamino)phenyl]-2-chloropyridine-4-carboxamide was reacted with piperidine to give the title compound in 96% yield; NMR Spectrum: (DMSOd6) 1.6 (m, 12H), 3.58 (m, 8H), 7.01 (m, 2H), 7.24 (d, 2H), 7.54 (d, 1H), 7.73 (d, 1H), 8.02 (s, 1H), 8.13 (m, 2H), 10.09 (br s, 1H), 10.44 (br s, 1H); Mass Spectrum: M+H+ 519.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][C@@H:19]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:20][OH:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:18][C@@H:19]([CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[CH:20]=[O:21])([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CO)CC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](C=O)CC1CCCCC1
Reaction time: 0.17 h

Procedure:
1.5 ml (21.1 mmol) of dimethyl sulfoxide were added dropwise over a period of 2 minutes to a solution of 1.0 ml (11.5 mmol) of oxalyl chloride in 20 ml of methylene chloride at -78° C. The mixture was allowed to stand for 10 minutes, after which a solution of 2.54 g (9.32 mmol) of (S)-2-t-butyldimethylsilyloxy-3-cyclohexylpropyl alcohol [prepared as described in step (iii) above] in 12 ml of methylene chloride was added dropwise over a period of 5 minutes. The resulting mixture was then stirred for 20 minutes at the same temperature, after which 6.5 ml (46.6 mmol) of triethylamine were added. The mixture was then allowed to stand for 7 minutes, and the cooling bath was removed. After a further 10 minutes, the reaction was stopped by adding an aqueous solution of ammonium chloride. The reaction mixture was then extracted with diethyl ether. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure, to give 2.55 g (a quantitative yield) of the title aldehyde compound as a colorless oil.