Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:17][C:16]=3[O:15][CH2:14][C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[CH:8][C:7]=2[O:6]1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH:5]([CH2:4][CH:3]=[O:2])[O:6][C:7]4[CH:8]=[C:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH:10]=[CH:11][C:12]=4[C:13]=3[CH2:14][O:15][C:16]=2[CH:17]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)CC1Oc2cc(O[Si](C)(C)C(C)(C)C)ccc2C2=C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(CC=O)C1=C2COc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: -78 °C
Reaction time: 6 h

Procedure:
At −78° C., to a solution of [2,8-Bis-(tert-butyl-dimethyl-silyloxy)-5,11-dihydro-chromeno[4,3-c]chromen-5-yl]-acetic acid methyl ester, the compound prepared as in Example 96 (120 mg, 0.21 mmol) in toluene (2 mL) was added DIBAL (0.28 mL, 1.5 M in toluene, 2 eq.) at −78° C. and stirred for 6 hours at −78° C. The reaction mixture was then quenched at −78° C. with chilled MeOH. HPLC purification of the residue yielded the title compound as a thick oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH2:15]([C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH3:16]>>[CH2:15]([C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:24]=2)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)[CH3:16]
Reactant: CCC1(c2cccc(O)c2)CCOCC1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: CCC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1
Yield: 63 %

Procedure:
Using a similar procedure to that described in Example 14, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-ethyl-4-(3-hydroxyphenyl)tetrahydropyran to give 4-ethyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 63% yield, m.p. 139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C@@H:7]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[C@@H:8]([NH:10][CH:11]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH3:9])=[CH:4][CH:3]=1.[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.CCOCC.[Cu]I>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C@@H:7]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[C@@H:8]([NH:10][CH:11]([C:17]2[CH:22]=[CH:21][C:20]([N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)=[CH:19][CH:18]=2)[C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: C[C@H](NC(c1ccc(Br)cc1)C(C)(C)C#N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: C[C@H](NC(c1ccc(-n2cncn2)cc1)C(C)(C)C#N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Temperature: 195 °C

Procedure:
To a solution of 22.5 mg (0.043 mmol) of 3-(1(S)-(4-chlorobenzyl)-2(S)-((1-(4-bromophenyl)-2-cyano-2-methylpropyl)amino)propyl)benzonitrile in 0.5 mL of N-methyl-pyrrolidone, 12 mg (0.173 mmol) of 1,2,4-triazole, 2.3 mg of CuI and 24 mg of K2CO3 were added. The mixture was heated in a microwave reactor at 195° C. for 4 hr. The reaction was diluted with ether, washed with water, brine, dried and concentrated. The residue was purified by prep TLC using 50% EtOAc-hexane to isolate the title compound.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:10]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:11](=[O:30])[CH2:12][C:13]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:16]=2[S:15](=[O:29])(=[O:28])[N:14]=1)=O.[O-]CC.[Na+]>C(O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:10]2[C@@H:6]3[C@@H:5]([CH2:9][CH2:8][CH2:7]3)[C:3]([OH:2])=[C:12]([C:13]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:16]=4[S:15](=[O:28])(=[O:29])[N:14]=3)[C:11]2=[O:30])=[CH:33][CH:34]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 60 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
(1R,2S)-2-{(4-Fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid methyl ester (117 mg, 0.21 mmol) was dissolved in ethanol (10 mL). A 21% w/w solution of sodium ethoxide in ethanol (0.17 mL, 0.46 mmol) was added and the mixture was stirred at 60° C. for 4 h. The reaction was allowed to cool to 25° C. and quenched with 1.0 M aqueous hydrochloric acid solution (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 0-5% methanol in dichloromethane) to afford the desired product, (4aR,7aS)-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (80 mg, 0.15 mmol, 71%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.46-1.61 (4H, m), 1.95-2.12 (2H, m), 3.07 (3H, s), 3.85 (1H, bs), 4.48 (1H, bs), 4.91 (1H, d, J=14.8 Hz), 7.16 (2H, t, J=8.4 Hz), 7.40 (2H, bs), 7.50-7.61 (3H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C23H23FN4O6S2 534.58, found 535.1 [M+H+]. e.e. =98% [HPLC-analysis: Chiralpak AS-RH 4.6×250 mm, 5 micron at 25° C., 0.7 mL/min, 310 nm, t1=14.89 min, t2=22.20 min (major)]. αD=−40.76 (c=0.92, dichloromethane/methanol 1:1). Anal. calcd for C23H23FN4O6S2 0.3H2O 0.3 EtOAc 0.2 Et2O: C, 51.66; H, 4.86; N, 9.64, found C, 51.64; H, 4.90; N, 9.56.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([C:19]1[CH:20]=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[N:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:32]([C:38]1[S:42][C:41]([C:43](Cl)=[O:44])=[CH:40][CH:39]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>O>[CH2:32]([C:38]1[S:42][C:41]([C:43]([O:31][C:28]2[CH:27]=[CH:26][C:25]([C:22]3[N:23]=[CH:24][C:19]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][N:21]=3)=[CH:30][CH:29]=2)=[O:44])=[CH:40][CH:39]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCc1ccc(C(=O)Cl)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc(CCCCCC)s3)cc2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.1 %

Procedure:
15 ml of pyridine was added to 0.80 g (2.36×10-3 mol) of 4-(5-dodecyl-2-pyrimidinyl)phenol, followed by cooling on an iced water bath. To the mixture, 0.54 g (2.36×10-3 mol) of 5-hexylthiophene-2-carboxylic chloride was added, followed by stirring for 5 hours at room temperature. After the reaction, the reaction mixture was poured into 100 ml of water and acidified with conc. hydrochloric acid, followed by three times of extraction with 50 ml of isopropyl ether. The organic layer was washed with water repeatedly until the washing liquid reacted neutrality, followed by drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography with the use of a hexane/ethyl acetate =10/1 mixture solvent and recrystallized from ethanol to obtain 0.38 g of a pure product (yield: 30.2%). ##STR29##
Reaction SMILES: [CH2:1]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])[CH:2]([CH3:4])[CH3:3].Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20]>>[Cl:20][CH2:19][CH2:18][CH2:17][CH2:16][C:5]1([CH2:1][CH:2]([CH3:4])[CH3:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14]
Reactant: CC(C)CC1C(=O)Nc2ccccc21
Reactant: ClCCCCBr
Product: CC(C)CC1(CCCCCl)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process E starting from 3-isobutyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chlorobutane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([CH3:24])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])=[C:4]2[N:3]=1.[OH-].[NH4+:26]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:26])[N:5]2[N:9]=[C:10]([CH3:24])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[C:14]=3[CH3:23])=[C:4]2[N:3]=1
Reactant: Cc1nn2c(Cl)cc(Cl)nc2c1Cc1cccc(C(F)(F)F)c1C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nn2c(N)cc(Cl)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 20 °C
Reaction time: 30 h

Procedure:
To a suspension of 5,7-dichloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidine (374 mg, 1.0 mmol), prepared as described in Example 1 step c, and 30% ammonium hydroxide solution (584 mg, 5.0 mmol) in 1,4-dioxane (5 mL) stirred at 20° C. for 30 hours. Reaction mixture was concentrated in vacuo. The residue was dissolved with ethyl acetate (50 mL) and 5 NaHCO3 solution (10 mL). Organic layer was separated, washed with brine (5 mL) and dried. Crude product was purified on silica gel column chromatography (methanol and DCM, 0-10%). Fractions were collected and concentrated to afford the titled product, which was in next step. (331 mg, 93%); LC/MS: MS (ES+) m/e 355 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:18][C:19]([NH2:21])=[S:20].II>C(O)(C)C.CCOC(C)=O>[NH2:21][C:19]1[S:20][CH:2]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=2)[N:18]=1
Reactant: CC(=O)c1ccc(NC(=O)OCC(C)C)cc1
Reactant: NC(N)=S
Agent: II
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)Nc1ccc(-c2csc(N)n2)cc1
Yield: 51 %

Procedure:
To a solution of the product of the preceding section (a) (19 g, 80.75 mmol) in isopropanol (120 mL) was added thiourea (24.6 g, 323 mmol) and iodine (20.5 g, 161.5 mmol). The resulting mixture was heated at reflux for 7 h, then diluted with EtOAc, washed serially with H2O and saturated aqueous NaHCO3. The resulting solution was then treated with 4N aqueous HCl and Et2O and stirred vigorously. The precipitate was filtered and washed with Et2O. The collected solid was then treated with saturated aqueous NaHCO3 and extracted serially with EtOAc and CH2Cl2. The combined organic extracts were washed with H2O and brine, then dried (MgSO4) and concentrated under reduced pressure to yield 2-methylpropyl N-{4-(2-amino-4-thiazolyl)-phenyl}carbamate (12 g, 51% yield) as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ9.63 (s, 1H), 7.70 (d, 2H, J=8.9 Hz), 7.46 (d, 2H, J=8.7 Hz), 6.99 (s, 2H), 6.84 (s, 1H), 3.88 (d, 2H, J=6.9 Hz), 1.95 (m, 1H), 0.99 (d, 6H, J=6.9 Hz); MS (FAB) m/z 292 (MH)+. This product was used as such in the next reaction (section (c)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[OH-:28].[K+]>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]([NH2:8])=[O:28]
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1C(N)=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
To a solution of 5-chloro-2-[8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl]benzonitrile (55.0 mg, 0.138 mmol) in tert-butyl alcohol (1.5 mL) was added potassium hydroxide (30.9 mg, 0.551 mmol). The reaction mixture was stirred at 80° C. for 15 min. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-60% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from methanol to give the title compound as a colorless powder (24.6 mg, 0.0872 mmol, 43%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:11][C:12]([Cl:16])([Cl:15])[CH2:13]O.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[C:1]([O:10][CH2:13][C:12]([Cl:16])([Cl:15])[Cl:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C(O)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: O=C(OCC(Cl)(Cl)Cl)c1ccccc1O
Temperature: 100 °C
Yield: 59.2 %

Procedure:
--A mixture of salicylic acid (90 g), 2,2,2-trichloroethanoI (270 g) and concentrated sulphuric acid (50 g) was stirred and heated at 100° C. for 4 hours. The mixture was diluted with chloroform (800 ml) and extracted with water (2×500 ml). After further extraction with saturated aqueous sodium bicarbonate solution (1000 ml), the organic layer was washed with water (2×500 ml) and dried (Mg SO4). The chloroform and excess trichloroethanol was removed in vacuo (65° C./20 mmHg) and the product was distilled (110°-112° C./0.5 mmHg) to give 2,2,2-trichloroethyl salicylate (104 g, 59% ) as a clear liquid which solidified on cooling.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][O:14][C:15](Cl)=[O:16]>>[CH3:13][O:14][C:15]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)Cl
Agent: [K]
Product: COC(=O)N1C(=O)c2ccccc2C1=O

Procedure:
A suspension comprising 25 millimoles of potassium phthalimide and 20 ml of methylchloroformate is refluxed for a period of approximately 31/2 hours. Upon completion of refluxing, the reaction mediuim is cooled, filtered, with insolubles being removed continuously by treatment with hot acteone until only potassium chloride remains. The desired product m.p. 184° - 184.5°C., is obtained from the acetone.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:7][CH:8]([CH2:21][CH:22]=[CH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:3]([O:5][CH3:6])=[O:4]>C(O)C.[Pd]>[CH3:1][C:2]([CH3:30])([CH2:7][CH:8]([CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)CC(CC=Cc1cccnc1)CCCCO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(C)(C)CC(CCCCO[Si](C)(C)C(C)(C)C)CCCc1cccnc1
Reaction time: 7.5 h

Procedure:
To a solution of 1.83 g of methyl 2,2-dimethyl-4-[3-(3-pyridyl)-2-propenyl]-8-(t-butyldimethylsiloxy)-octanoate in 50 mL ethanol is added 0.18 g of 10% palladium on carbon. The mixture is hydrogenated at 3 atmospheres pressure in a Parr apparatus for 7.5 hours. The catalyst is filtered off and washed with ethanol. The solvent is evaporated to give methyl 2,2-dimethyl-4-[3-(3-pyridyl)-propyl]-8-(t-butyldimethylsiloxy)-octanoate as an oil; NMR (CDCl3): delta 3.58 (s,3H), 3.55 (t,2H), 2.57 (t,2H), 1.13 (s,6H).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Ca+2]>C(O)C>[N:20]1([C:13]2[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=[CH:2][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1N1CCCCC1
Yield: 91.2 %

Procedure:
Proceeding as in example 2, with 0.035 mole (10.4 g) of 2,4'-dichloro-5-nitro-benzophenone and 0.07 mole (6 g) of piperidine and 0.035 mole (5 g) of calcium carbonate mixed in ethanol, 11 g (Yield: 97%) of the expected product are obtained after recrystallization in ethanol. M.P.=141° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:13][O:14][CH:15]([O:19][CH3:20])N(C)C>>[CH3:13][O:14][CH:15]([O:19][CH3:20])[N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:8][CH2:9]1
Reactant: COC(OC)N(C)C
Reactant: c1cn(CC2CCNCC2)cn1
Product: COC(OC)N1CCC(Cn2ccnc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[(1H-imidazol-1-yl)methyl]-piperidine (5 g, 0.03M) and dimethylformamide dimethylacetal (40 ml) was heated at 100° C. for 8 hrs. Removal of the excess of dimethylformamide dimethylacetal gave 4-[(imidazol-1-yl)methyl]-1-piperidine carboxaldehyde dimethylacetal (6.33 g) which was dissolved in methylene chloride (25 ml) and added to the mixture of 6-aminopenicillanic acid (5.15 g, 0.024M) and diisopropylethylamine (3.14 ml) in methylene chloride (90 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr and room temperature for 3 hrs. The solvent was then removed and water (80 ml) was added. After being washed with ethylacetate, the aqueous solution, acidified to pH 3, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-imidazol-1-yl-methyl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-6 -oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (5.2 g, 55% yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:32](Cl)=[CH:33][CH:34]=[N:35][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([SH:51])=[CH:47][CH:46]=1>CN(C=O)C.CCOC(C)=O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:32]([S:51][C:48]4[CH:49]=[CH:50][C:45]([O:44][CH3:43])=[CH:46][CH:47]=4)=[CH:33][CH:34]=[N:35][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCN(c2ccc(-c3ccc4c(c3)c3c(Cl)ccnc3n4S(=O)(=O)c3ccccc3)cc2)CC1
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2ccnc3c2c2cc(-c4ccc(N5CCN(C)CC5)cc4)ccc2n3S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a suspension of 9-Benzenesulfonyl-4-chloro-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-9H-pyrido[2,3-b]indole (Building block A) (60 mg) in DMF (1.2 mL), under Argon, K2CO3 (56 mg, 3.5 equiv.) and 4-methoxythiophenol (0.029 mL, 2 equiv.) were added. After stirring for 0.5 h at r.t., the reaction mixture was diluted with AcOEt (20 mL), washed with sat. aqueous NH4Cl (20 mL) and brine (20 mL) The organic layer was dried over MgSO4, filtered and evaporated to dryness. The trituration procedure afforded the desired compound in 72% yield as a beige solid. 1H-NMR (300 MHz, CDCl3) δ=8.55 (d, J=8.8 Hz, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.21 (d, J=5.4 Hz, 1H), 8.18-8.09 (m, 2H), 7.77 (dd, J=8.8, 1.9 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.57-7.48 (m, 3H), 7.45-7.35 (m, 2H), 7.04 (d, J=7.8 Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 6.53 (d, J=5.5 Hz, 1H), 3.88 (s, 3H), 3.47-3.33 (m, 4H), 2.90-2.74 (m, 4H), 2.51 (s, 3H). 13C-NMR (75 MHz, CDCl3) δ=161.4 (C), 150.7 (C), 150.6 (C), 147.7 (C), 146.0 (CH), 138.8 (C), 137.7 (2 CH), 137.1 (C), 136.0 (C), 134.0 (CH), 131.9 (C), 129.0 (2 CH), 128.0 (2 CH), 127.6 (2 CH), 126.5 (CH), 123.8 (C), 121.5 (CH), 118.2 (C), 116.3 (2 CH), 115.8 (2 CH), 115.1 (CH), 114.8 (CH), 114.6 (C), 55.5 (CH3), 55.1 (2 CH2), 48.8 (2 CH2), 46.2 (CH3). ESI-MS: m/z 621.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH:16]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Product: CCOC(=O)c1cnc2cn[nH]c2c1Nc1ccccc1
Reaction time: 8 h
Yield: 67 %

Procedure:
Ethyl 7-chloro-1H-pyrazolo[4,3-b]-pyridine-6-carboxylate (370 mg, 1.6 mmol) was dissolved in aniline (3 ml) and stirred overnight. The resulting mixture was triturated with 60°-80° petrol, and the precipitated solid was collected and dissolved in aqueous ethanol. The solution was adjusted to pH 8 with saturated sodium hydrogen carbonate solution, and the precipitated solid was collected to give the title compound (310 mg, 67%) m.p. 164°-165° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Reactant: CCNCC
Solvent: CS(C)=O
Product: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N,N-diethylamine (3.60 ml, 34.7 mmol) in DMSO (20 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.78 g, 77%).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.[I:22][Si](C)(C)C.II>C(Cl)Cl>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([I:22])[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)I
Reactant: O=C1CCCc2c(F)cccc2N1
Agent: CN(C)CCN(C)C
Agent: II
Solvent: ClCCl
Product: O=C1Nc2cccc(F)c2CCC1I
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.5 %

Procedure:
6-Fluoro-1,3,4,5-tetrahydro-1-benzazepin-2-one (25 g, 140 mmol) was charged to a 100-mL three neck flask with a dropping funnel and an overhead stirrer. DCM (250 ml) is added and the reaction is cooled to 0° C. TMEDA (29.5 ml, 195 mmol) is added, followed by drop wise addition of iodotrimethylsilane (26.6 ml, 195 mmol). The mixture was stirred for 45 minutes. Iodine (49.6 g, 195 mmol) is added in 5 portions and the mixture is stirred for another 1.5 h. The reaction was quenched with 250 mL Na2SO3 (aqueous solution). The solids were dissolved in dichloromethane and the layers separated. The organic layer is washed with water, dried over Na2SO4, and concentrated to give 6-fluoro-3-iodo-1,3,4,5-tetrahydro-1-benzazepin-2-one (42.5 g) as a brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([C:4]1[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCCOc1ccc(C(C)=O)cc1OC
Reactant: O=[N+]([O-])O
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 4-(4-acetyl-2-methoxyphenoxy)butyrate (10 g) was added to cold 70% nitric acid (140 cm3) and the resulting orange solution was stirred for 2 h and then poured into a beaker containing ice-water (1 dm3). The slurry warmed with stirring overnight to give a yellow solid which was collected and recrystallised from methanol to give methyl 4-(4-acetyl-2-methoxy-5-nitrophenoxy)butyrate as a pale yellow solid (8.5 g). 1H NMR (CDCl3) δ 2.21 (2H, m, J=6.6 Hz, CCH2C), 2.50 (3H, s, MeCO), 2.57 (2H, t, J=7.1 Hz, CH2CO), 3.7 (3H, s, OMe), 3.99 (3H, s, OMe), 4.16 (2H, t, J=6.2 Hz, CH2O), 6.75 (1H, s, aromatic) and 7.62 (1H, s, aromatic).