Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][C:7]3[CH:11]=[CH:10][S:9][C:8]=3[C:2]1=2.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[I-].[K+]>CS(C)=O>[CH2:12]([C:6]1([CH2:7][CH2:8][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:2]2[S:1][CH:5]=[CH:4][C:3]1=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: c1cc2c(s1)-c1sccc1C2
Reactant: CCCCCCBr
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCC1(CCCCCC)c2ccsc2-c2sccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4H-Cyclopenta[2,1-b:3,4-b′]dithiophene (CDT) (1.63 g, 9.14 mmol) in dimethyl sulfoxide (50 mL) was added hexyl bromide (3.1 g, 18.9 mmol) and a catalytic amount of potassium iodide (50 mg). The mixture was purged with argon for 10 minutes followed by the slow addition of solid potassium hydroxide (2 g). The now dark green mixture was stirred in the dark at room temperature for 72 hours. The mixture was then poured into de-ionized water (150 mL) and the organic phase extracted with diethyl ether (4×100 mL). The organic phases were collected and washed with brine (100 mL) and a saturated ammonium chloride solution (100 mL). The organic phase was dried over magnesium sulphate, filtered, and concentrated to give the crude product as yellow oil. Purification via flash chromatography with hexanes (monitored at 254 nm, collected at 320 nm) and drying under high vacuum for 48 hours gave pure product as colorless oil. Yield 2.8 g (88%). 1H NMR (500 MHz, CDCl3): δ=7.15 (d, 2H, 3JH-H=5 Hz), 6.94 (d, 2H, 3JH-H=5 Hz), 1.84 (m, 4H, C—CH2), 1.19 (m, 12H, alkyl-CH2), 0.95 (m, 4H, alkyl-CH2), 0.82 (m, 6H, alkyl-CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[NH:1][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18])=[O:8]
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccccc1
Yield: 92.4 %

Procedure:
Methyl 3-aminothiophene-2-carboxylate (3.14 g, 20 mmol) was dissolved in pyridine (10 mL) at room temperature. The flask was sealed with a septum and a nitrogen inlet. The solution was treated slowly with a benzenesulfonyl chloride (2.5 mL, 19.5 mmol). The reaction was followed by thin layer chromatography. The reaction was diluted with ethyl acetate and washing with 2N HCl. The organic layer was washed with saturated, aqueous sodium chloride solution and dried over sodium sulfate. The solution was decanted and evaporated under reduced pressure to give 3-benzenesulfonylaminothiophene-2-carboxylic acid methyl ester (5.36 g, 90%), which was used without further purification.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:14]Cl>C1(C)C=CC=CC=1.O>[Cl:14][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: ClCl
Reactant: CC(=O)CC(=O)Nc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C(Cl)C(=O)Nc1ccccc1
Temperature: 6 °C
Yield: 63.9 %

Procedure:
A suspension of 177 g (1.0 mole) of acetoacetanilide in 1440 ml of toluene and 167 ml of water, in a chlorinator (2000 ml 3-neck flask), was cooled to approximately 6° C. and chlorine gas was added at about the rate of 1.5 g/minute, while maintaining the temperature at 6° C. until 82.6 g (1.16 moles) of chlorine had been added (about 56 minutes). The resultant mixture was stirred for an additional 36 minutes and then heated to 70° C. for 15 minutes. The mixture was then cooled and the product was precipitated. The precipitate was filtered from the toluene/aqueous HCl mixture to give 134.8 g (63.9%) of α-chloroacetoacetanilide, mp 132°-134° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Cl)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][O:15][CH2:16][CH:17]([NH2:19])[CH3:18].CS(C)=O>O>[CH3:14][O:15][CH2:16][CH:17]([N:19]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1)[CH3:18]
Reactant: COCC(C)N
Reactant: O=[N+]([O-])c1cc(CCl)n(CCBr)n1
Solvent: O
Solvent: CS(C)=O
Product: COCC(C)N1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 120 °C
Yield: 67.5 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 1-(2-bromoethyl)-5-(chloromethyl)-3-nitro-1H-pyrazole 296c (1.0 g, 3.7 mmol), 1-methoxypropan-2-amine (1.0 g, 11.2 mmol), and DMSO (6 mL). The mixture was heated at 120° C. under microwave irradiation for 1.0 h. It was the cooled to room temperature and diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (60/1 to 1/1) to afford 300a (600 mg, 68%) as a yellow solid. MS-ESI: [M+H]+ 241.0
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2C(=O)C(C)(C)C3C(=CC([N+]([O-])=O)=CC=3)C2=O)[C:6]([N+:26]([O-:28])=[O:27])=[CH:5][C:4]=1[C:29]1[NH:30][C:31]2[C:32]([N:39]=1)=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2.O.NN>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:26]([O-:28])=[O:27])=[CH:5][C:4]=1[C:29]1[NH:30][C:31]2[C:32]([N:39]=1)=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2
Reactant: COc1ccc2[nH]c(-c3cc([N+](=O)[O-])c(N4C(=O)c5cc([N+](=O)[O-])ccc5C(C)(C)C4=O)cc3OC)nc2n1
Agent: NN
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2[nH]c(-c3cc([N+](=O)[O-])c(N)cc3OC)nc2n1

Procedure:
One half gram of 2-[2-methoxy-5-nitro-4-(4,4-dimethyl-7-nitro-2H,4H-isoquinolin-1,3-dione-2-yl)-phenyl]-5-methoxy-imidazo[4,5-b]pyridine is suspended in 10 ml of isopropanol, mixed with 0.5 ml of 80% hydrazine hydrate, and refluxed for 1.75 hours with stirring. The reaction mixture is concentrated by evaporation, the residue is triturated with 50 ml of ice water, and the product precipitated is purified by chromatography on silica gel [eluant: methylene chloride/ethanol (100:0 to 100:2)].
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:42][C:43]1[C:44]([NH:61][CH:62]2[CH2:67][CH2:66][N:65]([CH2:68][CH2:69][C:70]#[N:71])[CH2:64][CH2:63]2)=[C:45]2[CH:51]=[CH:50][N:49]([S:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)(=[O:54])=[O:53])[C:46]2=[N:47][CH:48]=1>CN(C=O)C>[C:55]1([S:52]([N:49]2[C:46]3=[N:47][CH:48]=[C:43]([NH:42][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH3:8])[C:44]([NH:61][CH:62]4[CH2:63][CH2:64][N:65]([CH2:68][CH2:69][C:70]#[N:71])[CH2:66][CH2:67]4)=[C:45]3[CH:51]=[CH:50]2)(=[O:53])=[O:54])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CCC(C)CC(=O)O
Reactant: N#CCCN1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)CC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
Racemic 3-methylpentanoic acid (0.180 ml, 1.4 mmol), HATU (0.53 g, 1.4 mmol), and diisopropylethylamine (0.46 ml, 2.7 mmol), were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (0.54 g, 1.3 mmol, prepared as described in Example 118) in DMF (20 ml) at 25° C. The reaction mixture was stirred for 4 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (100 ml) and EtOAc (2×200 ml). The organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 8% CH3OH in CH2Cl2) afforded 3-methyl-pentanoic acid {1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-amide (0.706 g, 110%) as an off-white solid. LCMS (Method G, ESI): RT=0.73 min, m+H=523.4. This material was used in the next step below without further characterization.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[O:32][CH3:33])=[O:11])=CC=1)([O-])=O.[H][H]>CO.O1CCCC1.[Pd]>[O:23]([CH2:22][C:21]([NH:20][C@@H:19]1[C:18](=[O:31])[N:17]2[C:12]([C:10]([OH:11])=[O:9])=[C:13]([O:32][CH3:33])[CH2:14][S:15][C@H:16]12)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 1 h

Procedure:
A solution of 250 mg (0.5 mmol) of 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 2 ml of methanol/tetrahydrofurane, 1:1, is added to a mixture of 5% palladium/charcoal in 2 ml of the same solvent, which mixture has been prehydrogenated for one hour under atmospheric pressure, and the reaction mixture is hydrogenated for 3 hours at room temperature and under atmospheric pressure. After this time, about 90% of the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is taken up in 10 ml of methylene chloride and extracted with twice 10 ml of 5% strength aqueous sodium bicarbonate solution. The combined bicarbonate extracts are neutralised at 0° C with dilute hydrochloric acid and extracted with 3 times 10 ml of methylene chloride. The organic phase is dried over sodium sulphate and freed from the solvent in vacuo. After crystallisation from chloroform/pentane, the residue gives 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid of melting point 173°-174° C.
Reaction SMILES: C(OC(=O)C[CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])(C)(C)C.[CH3:17]O>C1COCC1>[CH:13]([CH:12]1[CH2:17][O:11][C:9](=[O:10])[CH2:8]1)([CH3:14])[CH3:15]
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Reactant: CO
Solvent: C1CCOC1
Product: CC(C)C1COC(=O)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A solution of 2-isobutyl-succinic acid-4-t-butyl ester (8.0 g, 34.7 mmol) in 100 mL of THF is cooled to 0° C. under Ar and borane dimethyl sulphide complex (2.6 g, 34.7 mmol) is added. The reaction mixture is stirred at 0° C. for 10 minutes, and at room temperature overnight. The solution is cooled to 0° C. and 100 mL of MeOH is added. The solvents are evaporated, and the remaining oil is dried under hi-vacuum for 2 hours. The oil remaining is taken up in 100 mL of THF, and a catalytic amount of p-toluene sulfonic acid is added. The solution is warmed to reflux overnight. After being cooled to room temperature, the solvent is evaporated, and the oil is taken up in Et2O (100 mL). The Et2O solution is extracted with 2.0N Na2CO3 (2×50 mL) followed by 100 mL of brine and dried over MgSO4. Evaporation of Et2O followed by medium pressure chromatography (MPLC) of the remaining oil in 20% EtOAc/Hexanes gives 4.4 g (89% yield) of 4-isopropyl-dihydro-furan-2-one as an oil. NMR (H1, 400 MHz, CDCl3) δ 0.9 (6H, m); δ 1.3 (2H, dd); δ 1.5 (1H, m); δ 2.1 (1H, m); δ 2.6 (2H, m); δ 3.6 (1H, m); δ 4.4 (1 H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[N+:12]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[NH2:12]
Reactant: Cc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C(F)(F)F)c1N

Procedure:
A suspension of 50 g (0.24 mol) 1-methyl-2-nitro-3-trifluoromethyl-benzene and 4.4 g 10% Pd/C in 300 mL MeOH was hydrogenated at RT and 3000 hPa hydrogen pressure until the theoretical amount of hydrogen had been taken up. The catalyst was filtered off, washed with MeOH and the filtrate was evaporated down. The crude product was further reacted without purification.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:22]=[N:21][C:9]2[O:10][C:11]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=3[NH:13][C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4].[CH3:23]I>CN(C)C=O>[N+:3]([C:6]1[CH:22]=[N:21][C:9]2[O:10][C:11]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=3[N:13]([CH3:23])[C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4]
Reactant: CI
Reactant: Cc1ccc2c(c1)Oc1ncc([N+](=O)[O-])cc1C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)Oc1ncc([N+](=O)[O-])cc1C(=O)N2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (0.73 g, 0.015 mol of a 50% dispersion in mineral oil) in dimethylformamide (75 ml) under argon was added in one portion 3-Nitro-9-methylpyrido[2,3-b][1,5]benzoxazepin-5(6H)-one (3.75 g, 0.014 mol). Methyl iodide (1.3 ml. 0.021 mol) was added, and the resulting solution was stirred overnight at room temperature. The mixture was diluted with ice Water, and the precipitated product was collected and washed with water and pet ether. The crude product was recrystallized from ethyl acetate to give 3.14 g (79% of theory) of the product as a pale yellow solid. m.p. 197°-198° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:12])[C:6]([CH2:10][CH3:11])=[C:7]([CH3:9])[N:8]=1)[CH3:2].Br[CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.[H-].[Na+]>>[CH2:1]([C:3]1[N:4]([CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)[C:5](=[O:12])[C:6]([CH2:10][CH3:11])=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)c(CC)c(=O)[nH]1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: [H-]
Agent: [Na+]
Product: CCc1c(C)nc(CC)n(CCOc2ccc(C=O)cc2)c1=O
Yield: 27.8 %

Procedure:
The title compound (1.42 g, 28%) was prepared from 2,5-diethyl-4-methyl-1,6-dihydro-6-pyrimidone (2.70 g, 16.26 mmol) and 4-[2-bromoethoxy]benzaldehyde (4.09 g, 17.86 mmol) in the presence of 95% NaH (508 mg, 20 mmol) as base by a similar procedure to that described in preparation 1.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C@H:15]([CH3:22])/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]>CCOC(C)=O.O=[Pt]=O>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)/C=C/[C@@H](C)C1=CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Reaction time: 15 h
Yield: 96.3 %

Procedure:
To a solution of compound 1.7a (17.5 g, 41 mmol) in EtOAc (350 mL) was added PtO2 (4.37 g), and the resulting slurry was hydrogenated in a Parr apparatus (70 psi) for 14-16 h. At this point the reaction was determined to be complete by TLC. The mixture was filtered through a small plug of Celite® and the solvent was removed under vacuum, affording compound 1.8a (17.0 g, 96.0%) as a white solid. The above product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7].CCO[CH2:17][CH3:18]>CO.C(O)(=O)C>[CH2:6]1[C:17]2[C:18](=[CH:12][CH:3]=[CH:4][CH:13]=2)[CH2:11][CH2:10][C:5]1=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=1[CH3:13]
Reactant: COc1cccc(C(=O)NN)c1C
Reactant: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(C(=O)NN=C2CCc3ccccc3C2)c1C

Procedure:
3-Methoxy-2-methyl-benzoic acid hydrazide (1.0 g) and P-tetralone (0.9 g) were mixed in 4 mL of methanol with 1 drop of acetic acid at room temperature for 10 minutes. Approximately 10 mL of ether were added and the mixture was refrigerated. Crystals of 3-methoxy-2-methyl-benzoic acid (3,4-dihydro-1H-naphthalen-2-ylidene)-hydrazide formed, which were collected by filtration (0.85 g). 1H NMR (300 MHz, CDCl3)δ(ppm): 6.8-7.3 (m, 4H), 3.75+3.8 (2 s, 3H), 3.45+3.7 (2 s, 2H), 2.85 (t, 2H), 2.4 (t, 2H), 2.27+2.25 (2 s, 3H); multiple conformers; Rf=0.56 (3:1 ethyl acetate:hexane); m.p.=138° C.; m.p. of 3-methoxy-2-methyl-benzoic acid hydrazide=113-116° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[C:18](N)(=O)[CH2:19][CH2:20]C.B(Br)(Br)Br>ClCCl>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1)[CH:19]=[CH2:18]
Reactant: CCCC(N)=O
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CCOc1cccc([C@@H]2C[C@H]2CNC(=O)CCC)c1
Reaction time: 18 h
Yield: 75 %

Procedure:
(trans)-N-[[2-(3-Hydroxyphenyl)cyclopropyl]methyl] butanamide: To a stirred solution of (trans)-N-[f2-(3-methoxyphenyl)cyclopropyl]methyl]butanamide (3.50 g, 14.2 mmol) in dichloromethane (50 mL) at -78° C. was added BBr3 (28.4 mL, 1N in CH2Cl2, 28.4 mmol) dropwise. After addition was complete, the cooling bath was removed and stirring was continued for 18 h. The solution was poured over ice/H2O (100 mL) and extracted with 2.5N NaOH. The basic extracts were combined, washed with dichloromethane, and acidified (conc. HCl). The acidic solution was extracted with dichloromethane, the organics were combined, washed with brine, dried (MgSO4), and concentrated to afford 2.49 g (75%) of the title compound: 1H NMR (300 MHz, DMSO-d6)δ0.72-0.84 (m, 5H), 1.09-1.15 (m, 1H), 1.42-1.54 (m, 2H), 1.63-1.69 (m, 1H), 2.02 (t, J=5.0 Hz, 2H), 2.99-3.11 (m, 2H), 6.39-6.50 (m, 3H), 6.98 (t, J=7.8 Hz, 1H), 7.91 (s, 1H), 9.19 (br s, 1H); IR (NaCl Film) 3300, 2964, 1642, 1585, 1542, 1466 cm-1 ; MS (isobutane--DCI) m/e 233; Analysis calc'd for C14H19NO2.0.1 H2O: C, 71.52; H, 8.23; N, 5.96; found: C, 71.53; H, 8.32; N, 5.92.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)(C)C.C([O-])([O-])=O.[K+].[K+]>CO>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 5.5 g (29 mmol) 5-trimethylsilanylethynyl-pyridin-2-ylamine and 2.0 g (14 mmol) K2CO3 in 30 mL MeOH. The product is purified by chromatography on silica gel using a hexane/ethyl acetate gradient. Yield: 2.9 g (85%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[Cl:8][C:6]1[CH:7]=[C:2]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[CH:4][N:5]=1
Reactant: C1CCNCC1
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Product: Clc1cc(N2CCCCC2)ncn1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
A mixture of 10.0 g (67.1 mmol) 4,6-dichloropyrimidine and 5.7 g (67.1 mmol) piperidine in 100 ml water is stirred at a bath temperature of 115° C. for 16 h. After cooling to RT, the precipitate is filtered off, washed with water and dried in vacuo.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br.[Br:16][CH2:17][CH2:18][CH2:19][NH2:20].C(=O)([O-])O.[Na+]>CC(C)=O.O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([NH:20][CH2:19][CH2:18][CH2:17][Br:16])(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: NCCCBr
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCCBr)cc1
Temperature: 2.5 °C
Yield: 166.7 %

Procedure:
To a stirred solution of N-acetylsulfanilyl chloride (57.15 g, 0.244 mol) in acetone (500 mL) and H2O (187.5 mL) at 0° C. was added 3-bromopropylamine hydrobromide (25.0 g, 0.114 mol). When a clear solution was obtained, a solution of sodium hydrogencarbonate (44.15 g, 0.526 mol) in H2O (550 mL) was added dropwise, maintaining the internal temperature at 0-5° C. When the addition was completed, the reaction mixture was heated at 50° C. for 5 h, then cooled to room temperature and poured into ice H2O with stirring. After stirring at 5° C. for 4 h, the suspension was filtered and the filter cake was washed with H2O and dried in vacuo to give 34.6 g (90%). An additional reaction was performed to give an additional 63.7 g of similar material.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[CH:4]=[N:3][C:2]([N:38]6[CH2:42][CH2:41][CH2:40][CH2:39]6)=[CH:7][N:6]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: C1CCNC1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CCCC5)cn3)C4)n[nH]c2c1
Yield: 21.2 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80 mg, 154 μmol) and pyrrolidine (22 mg, 308 μmol) using the method of Example 32. The crude material was purified by HPLC Method D to afford (18 mg, 19%) of the title compound as off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Cl[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[N:38]1[CH:39]=[CH:40][CH:41]=[N:42][C:37]=1[O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: Clc1ncccn1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(Oc3ncccn3)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 2-chloro-pyrimidine
Reaction SMILES: C([Li])CCC.[CH:6]([C:9]1[C:10]([CH:17]([CH3:19])[CH3:18])=[C:11]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH:13]=1)([CH3:8])[CH3:7].S(C1C=CC(C)=CC=1)(O[CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])(=O)=O.O>O1CCCC1>[CH3:27][N:26]([CH2:25][CH2:24][C:13]1[CH2:12][C:11]([CH:14]([CH3:16])[CH3:15])=[C:10]([CH:17]([CH3:19])[CH3:18])[C:9]=1[CH:6]([CH3:8])[CH3:7])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C)cc1
Reactant: CC(C)C1=CCC(C(C)C)=C1C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C1=C(C(C)C)C(C(C)C)=C(CCN(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a dry 500 mL three-necked flask with a magnetic stirrer, a solution of 62.5 mL of n-butyllithium (1.6 M in n-hexane; 100 mmol) was added under a dry nitrogen atmosphere to a solution of 19.2 g (100 mmol) of triisopropyl-cyclopentadiene in 250 mL of tetrahydrofuran at -60° C. After heating to room temperature (in approximately one hour) stirring continued for a further two hours. After cooling to -60° C., a solution of dimethylaminoethyl tosylate (105 mmol) prepared in situ was added over a period of 5 minutes. The reaction mixture was heated to room temperature, followed by overnight stirring. After addition of water, the product was extracted with petroleum ether (40-60° C.). The combined organic layer was dried with sodium sulphate, and evaporated under reduced pressure. The conversion was greater than 95%. The yield of product after distillation (based on triisopropyl-cyclopentadiene) was approximately 55%.