Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=[O:5].N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>>[C:23](=[O:24])([O:1][CH:2]([CH3:15])[CH2:3][C:4](=[O:5])[CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])[O:25][CH2:26][CH3:27]
Reactant: CC(O)CC(=O)C1C(C)C=CCC1(C)C
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)OC(C)CC(=O)C1C(C)C=CCC1(C)C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 3-hydroxy-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-butanone (8.0 mmol) in pyridine (1.85 g, 23.4 mmol) was treated at 0° C. with ethyl chloroformate (1.24 g, 23.4 mmol). The reaction solution was stirred at room temperature for 36 hours, treated with 5% aqueous HCl and extracted twice with ether, washed (H2O, saturated aqueous NaHCO3, then brine), dried over Na2SO4 and concentrated. The oil (2.38 g) was purified by flash-chromatography (cyclohexane/AcOEt=98:2), using SiO2 (100 g). Yield: 2.06 g (78%).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C[Si]([C:15]([F:18])([F:17])[F:16])(C)C.[F-].[Cs+]>C(COC)OC>[F:16][C:15]([F:18])([F:17])[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnccn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: O=C(c1cnccn1)C(F)(F)F

Procedure:
Pyrazine carboxylate methyl ester (7 g) was dissolved in dimethoxy ethane (monoglyme) (20 mL) and treated at room temperature with trimethylsilyltrifluoro-methane (10 mL; 1.44 eq) and caesium fluoride (0.77 g; 0.1 eq) that had been freshly dried at for 10 minutes under vacuum while being heated with a heat gun. After 18 hours at room temperature the reaction mixture was concentrated under reduced pressure at room temperature, and the residue was dissolved in tetrahydrofuran (50 mL) and acetic acid (20 mL) and treated with tert-butylammonium fluoride (50 mL; 1M THF solution) for 3 hours at room temperature. The reaction was diluted with ethyl acetate, and washed with dilute aqueous sodium bicarbonate solution (3 times), brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to an oil. Trituration of the oil with dichloromethane/hexane gave 2,2,2-trifluoro-1-(pyrazin-2-yl)ethanone (18) as a brown solid (2.9 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43](=O)[CH2:44][C:45]1([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:47][CH2:46]1)=[O:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:40][C:43]([CH2:44][C:45]2([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:52])([CH3:53])[CH3:54])[CH2:47][CH2:46]2)=[N:42][N:41]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To s solution of PPh3 (5.2 g, 20.0 mmol) in dry DCM (60 mL) was added I2 (5.1 g, 20.0 mmol). After I2 was dissolved completely, TEA (7.0 mL, 50.0 mmol) was added quickly at rt. The mixture was stirred for 15 mins. Tert-butyl 1-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclopropyl-carbamate (4.9 g, 10.0 mmol) was added and the mixture was stirred at rt for 1 hr. The solvent was concentrated. EtOAc (250 mL) was added, and the solution was filtered to remove PPh3O. The filtrate was concentrated and the residue was purified by silica gel column chromatography (0˜60% gradient elution EtOAc/petroleum ether) to afford tert-butyl 1-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)cyclopropyl-carbamate (4.1 g, 87%) as a white solid. ESI-MS (EI+, m/z): 470 [M+H]+.
Reaction SMILES: C(N1CCCC1=O)=C.[C:9]([O:14][CH2:15][CH2:16][CH2:17]CCCCCCCCC)(=[O:13])[C:10]([CH3:12])=[CH2:11].N(C(C)(C)C#N)=NC(C)(C)C#N>O>[C:9]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)OCCCCCCCCCCCC
Agent: C=CN1CCCC1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: *CC(*)C
Solvent: O
Product: C=CCOC(=O)C(=C)C

Procedure:
The dimer of allyl methacrylate, which was prepared according to Example 1, was added in the amount of 3 wt.-% (based on to the entire mixture) to the mixture containing 90 wt.-% N-vinylpyrrolidone and 10 wt.-% dodecyl methacrylate. The mixture was polymerized in a polypropylene mold at 60° C. for 16 h in the presence of 0.4 wt.-% azobisisobutyronitrile. The resulting gel contained, after swelling with water, 76 wt.-% water at G=0.048 MPa. The soluble extractable portion was 2%.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:20][O-:21].[Na+]>CO>[CH3:20][O:21][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O[C@H]1CC[C@H](Nc2ncc3ccc(F)cc3n2)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1

Procedure:
To a solution of trans-4-[(7-fluoroquinazolin-2-yl)amino]cyclohexanol (800 mg, 3.06 mmol) in MeOH (25 mL) was added sodium methoxide powder (1.65 g, 30.62 mmol) and the solution heated to reflux for 16 hours under nitrogen. The mix was cooled and the solvents evaporated. The residue was diluted with water (100 mL), brine (50 mL) and extracted with DCM (4×150 mL), and the combined organics were dried over MgSO4, filtered and stripped. The residue was purified via Biotage flash chromatography (40M) eluting with 2-6% MeOH/DCM over 1300 mL to yield the title compound as an off white solid, 830 mg, 99%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.86 (1H, s) 7.63 (1H, d, J=8.84 Hz) 7.08 (1H, d, J=6.57 Hz) 6.78 (2H, dd, J=8.72, 2.15 Hz) 4.55 (1H, d, J=4.55 Hz) 3.86 (3H, s) 3.71-3.84 (1H, m) 3.35-3.50 (1H, m) 1.76-2.02 (4H, m) 1.14-1.42 (4H, m); MS (API+) for C15H19N3O2 m/z 274.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[N:28]=[C:27]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[N:28]=3)[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)c3ccc(Cl)cc3)CC2)n1

Procedure:
Example 90 was prepared from 2-(4-chlorophenyl)propanoic acid and N{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.0 Hz), 7.75 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.34–7.27 (m, 4H), 7.22 (br s, 1H), 6.89 (d, 1H, J=7.6 Hz), 3.53 (q, 1H, J=7.2 Hz), 3.36 (m, 1H), 3.29 (m, 1H), 3.05 (d, 1H, J=11.6 Hz), 2.95 (d, 1H, J=10.4 Hz), 2.58 (m, 1H), 2.45–2.40 (m, 3H), 2.02–1.63 (m, 8H), 1.50 (d, 3H, J=7.2 Hz), 1.22 (dd, 6H, J=1.6, 6.8 Hz); ESMS m/e: 471.2 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:5])[CH3:4].[Cl:6][C:7]1[C:12](F)=[CH:11][CH:10]=[CH:9][C:8]=1[F:14].C1(C)C=CC=CC=1>[Cl-].C[N+](C)(C)C.O>[Cl:6][C:7]1[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=1[O:5][CH2:3][CH3:4]
Reactant: CCO
Reactant: Fc1cccc(F)c1Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1cccc(F)c1Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
560 g of potassium hydroxide and 23 g of tetramethylammonium chloride (TMAC) were added to a reactor having 2,000 mL of ethanol placed therein in a temperature range of 50 to 60° C., followed by stirring for 30 minutes in that temperature range. Thereafter, the solution was heated to 80° C., and 594 g of a compound (b2) was added thereto over 1 hour in a temperature range of 80 to 85° C., followed by stirring for 5 hours at 80° C. After cooling the resulting reaction mixture to 25° C., 1,000 mL of toluene and 500 mL of water were added thereto and well mixed, and the mixture was left at rest to separate into an organic layer and an aqueous layer. After collecting the resulting organic layer, 500 mL of toluene was newly added to the aqueous mixture and well mixed, and the mixture was subjected to the same operation to extract again the compound contained in the aqueous layer. The toluene solution was added to the organic layer. After washing the organic layer with water in three times, the resulting organic layer was distilled under reduced pressure to obtain 606 g of 2-chloro-1-ethoxy-3-fluorobenzene (b43). The resulting liquid was colorless and had a boiling point of 98 to 99° C./8 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][C@@H:36]([F:40])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:9][N:10]([CH2:18][CH:19]2[CH2:21][CH2:20]2)C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:41]>O1CCOCC1>[ClH:1].[ClH:41].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][C@@H:36]([F:40])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:28][CH2:29]2)=[O:23])=[CH:4][CH:3]=1
Reactant: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)[C@H](CN(CC4CC4)C(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)[C@H](CNCC4CC4)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamate (0.955 g, 1.669 mmol) was dissolved in dioxane (20 mL). The solution was treated with HCl in dioxane (10.43 mL, 41.73 mmol; 4M), and the mixture was stirred at ambient temperature for 16 hours. HPLC showed no SM remaining, so the reaction mixture was concentrated in vacuo, re-dissolved in MeOH and re-concentrated (3×). The residue was re-dissolved in MeOH (about 4.5 mL+2 mL wash) and added dropwise to stirred ether (about 190 mL). The suspension was stirred for 30 minutes then filtered and dried under nitrogen blanket to give (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (797 mg, 88%) as a solid. LC/MS (APCI+, FIA) m/z 472.2/474.2 [M+H]+
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[CH2:5][C:6]#[N:7])[CH2:2][CH3:3].[OH2:11]>>[CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[CH2:5][C:6]([NH2:7])=[O:11])[CH2:2][CH3:3]
Reactant: O
Reactant: CCCC(CC#N)CCC
Product: CCCC(CCC)CC(N)=O
Temperature: 80 °C

Procedure:
While stirring, 139.2 g (1 mol) of 3-n-propyl-hexanenitrile were added. The mixture was heated to 80° C. and maintained at this temperature for 2 hours. After cooling to room-temperature, the medium was hydrolysed while stirring with 1500 g of distilled water for 1 hour. The crude product so obtained was suction-filtered and taken up, while stirring for 1 hour at room-temperature, with 1500 g of distilled water. The medium was again suction-filtered, washed and dried to constant weight in a drying-oven under vacuum.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1>O>[S:9]1[CH:10]=[CH:11][N:12]=[C:8]1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Brc1nccs1
Reactant: C1CNCCN1
Solvent: O
Product: c1csc(N2CCNCC2)n1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To piperazine (48 g) dissolved by heating at 110° C. was added dropwise 2-bromothiazole (5 ml) over 20 min. The mixture was stirred at 150° C. for 1 hr, poured into water (150 ml) and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (9.5 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])=[O:4].Br[CH2:18][C:19]1[CH:23]=[C:22]([C:24]2[S:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[O:21][N:20]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:23]=[C:22]([C:24]3[S:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[O:21][N:20]=2)[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])=[O:4]
Reactant: COC(=O)c1[nH]c(-c2ccccc2)nc1C
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(C)nc(-c2ccccc2)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 60 mg 5-Methyl-2-phenyl-3H-imidazole-4-carboxylic acid methyl ester in 1 ml DMF 95 mg caesium carbonate and 82 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added and the mixture was stirred for 2 h at 60° C. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 78 mg.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:15]([NH2:16])=[CH:14][C:13]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[CH:12][C:11]=1[NH2:21].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[NH2:21][C:11]1[C:10]([O:9][CH3:8])=[C:15]([NH:16][S:23]([CH3:22])(=[O:25])=[O:24])[CH:14]=[C:13]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[CH:12]=1
Reactant: COc1c(N)cc(C2(C)CC2)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(N)cc(C2(C)CC2)cc1NS(C)(=O)=O
Temperature: 25 °C
Yield: 50.4 %

Procedure:
Triethylamine (521 mL, 3.74 mmol) was added to a solution of 2-methoxy-5-(1-methyl-cyclopropyl)-benzene-1,3-diamine (718 mg, 3.74 mmol) in methylene chloride at −10° C. Methanesulfonyl chloride (290 μL, 3.74 mmol) was then added dropwise over a 10 min period and the resultant solution was allowed to slowly warm to rt over 2 h. The mixture was quenched with saturated aqueous NaHCO3 and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% ammonium hydroxide/35% ethyl acetate in hexanes to 1% ammonium hydroxide/50% ethyl acetate in hexanes) provided a red solid which was triturated with a diethyl ether/hexanes (1:1) to yield Compound 1 (510 mg, 51%) as a pale brown solid: mp 144–146° C. ESI MS (m/z 271, M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH:9]C(OC(C)(C)C)=O)=[C:6]([F:17])[C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[F:26][C:27]([F:40])([F:39])[C:28]1[CH:38]=[CH:37][C:31]([C:32]([N:34]=[C:35]=[O:36])=O)=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:22])[CH3:23])=[C:6]([F:17])[C:7]=1[N:8]1[C:35](=[O:36])[NH:34][C:32]([C:31]2[CH:37]=[CH:38][C:28]([C:27]([F:40])([F:39])[F:26])=[CH:29][CH:30]=2)=[N:9]1
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)cc3)[nH]c2=O)c1F
Yield: 73.5 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate (Intermediate-57, 0.050 g, 0.13 mmol), 4-(trifluoromethyl)benzoyl isocyanate (Intermediate-59, 0.060 g, 0.26 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.045 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.12 (s, 9H), 4.30 (d, J=4.4 Hz, 2H), 7.41 (t, J=8 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.2 Hz, 2H), 8.17 (t, J=5.8 Hz, 1H), 12.9 (br s, 1H); MS (m/z): 471.10 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([O:13][CH3:14])=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9].[H-].[Na+].I[CH3:18]>O1CCCC1>[CH3:12][O:11][C:6]1[CH:5]=[C:4]([O:13][CH3:14])[C:3]([CH2:2][O:1][CH3:18])=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: COc1cc(OC)c(CO)cc1C#N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc(C#N)c(OC)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
To a solution of 5-hydroxymethyl-2,4-dimethoxy-benzonitrile (218 mg, 1.128 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. were sequentially added sodium hydride (34.2 mg, 1.354 mmol) and iodomethane (140 μL, 2.256 mmol). The icebath was removed after 5 min and the reaction mixture was stirred at room temperature under argon for 12 h. Water was added and the product was extracted with methylene chloride (2×15 mL). The organic layers were washed with brine (1×2 mL) and dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40% ethyl acetate in hexanes yielded 2,4-dimethoxy-5-methoxymethyl-benzonitrile as a white solid (221 mg, 95%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1Cl
Reaction time: 1 h

Procedure:
Ethyl 4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxylate (Aldrich, 10.0 g, 35.1 mmol) and phosphorus oxychloride (100 mL, 1.07 mol) were refluxed for 2 hours. After cooling the mixture was poured onto ice (1.0 L) and stirred for 1 hour. The mixture was extracted twice with dichloromethane (500 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-40% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.40 (t, J=7.12 Hz, 3H), 4.46 (q, J=7.12 Hz, 2H), 8.14 (d, J=8.82 Hz, 1H), 8.54 (s, 1H), 8.62 (d, J=8.82 Hz, 1H), 9.30 (s, 1H). MS (ESI) m/z 303.95 (M+H)+.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[Na].[H-].[Na+].[CH3:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>CN(C)C=O>[CH3:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:24]=1[C:25]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)=[O:26]
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)n2c3ccccc3n3c(=O)c4ccccc4nc23)c(C)c1
Temperature: 0 °C

Procedure:
Benzimidazo[2,1-b]quinazolin-12(6H)one, 7.05 g. in 200 ml. of dry dimethylformamide was converted to the sodium derivative with sodium hydride according to the procedures described in previous examples and 2,4-dimethylbenzoyl chloride, 5.8 g. in 25 ml. of dimethylformamide were added dropwise with vigorous stirring. The reaction mixture was stirred for an additional hour and then poured into ice water. The precipitate which formed was filtered, washed with water, dried and twice recrystallized from benzene to yield 6-(2,4-dimethylbenzoyl)benzimidazo[2,1-b]quinazolin-12(6H)one as a crystalline solid melting at about 213°-214° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13](=[CH2:18])[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>[Pd].C(O)C>[CH3:18][CH:13]([C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: C=C(C(=O)OC)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 95 %

Procedure:
An aqueous slurry of palladium on carbon (50 mg) was added to a solution of methyl 2-[3,5-bis(trifluoromethyl)phenyl]-2-propenoate (Description 2, 1.0 g, 3.4 mmol) in ethanol (40 mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 1 hour. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (0.97 g, 95%). 1H NMR (360 MHz, CDCl3) δ 1.57 (3H, d, J 7.2 Hz), 3.71 (3H, s), 3.86 (1H, q, J 7.2 Hz), 7.76 (2H, s) and 7.79 (1H, s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[N:31]2.C(N(C(C)C)C(C)C)C>CC#N>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:27][C:28]5[CH:29]=[C:30]6[C:35](=[CH:36][CH:37]=5)[N:34]=[CH:33][CH:32]=[N:31]6)[CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccc2nccnc2c1
Reactant: CC(C)(C)c1ccc(-c2nc3cccc(N4CCNCC4)c3o2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(-c2nc3cccc(N4CCN(Cc5ccc6nccnc6c5)CC4)c3o2)cc1
Temperature: 95 °C
Yield: 69.4 %

Procedure:
To a suspension of 2-(4-tert-butylphenyl)-7-piperazin-1-yl-1,3-benzooxazole 23.5 mg, 0.070 mmol) and 6-bromomethylquinoxaline (17.2 mg, 0.077 mmol) in CH3CN (anh., 10 mL) was added ethyldiisopropylamine (0.015 mL, 0.084 mmol). The mixture was heated in a 95° C. bath overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was adsorbed onto silica gel. Silica gel chromatography using a gradient of 25% EtOAc/hexane to 50% EtOAc/hexane then 100% EtOAc afforded the title compound (23.2 mg) as an ivory powder. MS (ESI) m/z 478 [M+H]+; HPLC Method C, r.t.=10.9 min (98.9% @210-370 nm; 97.4% @ 236 nm).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH2:8][C:7]2=1.[N+:23]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)([O-:25])=[O:24].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[N+:23]([O-:25])=[O:24])[C:12]1[CH2:11][CH2:10][CH:9]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH2:8][C:7]2=1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)NC1CCc2c(c3cc(Cl)ccc3n2Cc2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
Suspend sodium hydride (60%, 120 mg, 3 mmol) in anhydrous DMF (2.5 mL) under nitrogen and cool in an ice bath. Slowly add N-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (prepare essentially as described in Preparation 4)(727 mg, 2.5 mmol) dissolved in DMF (8 mL). After 10 min remove ice bath and allow the reaction to warm to ambient temperature over 1 h. Add DMF (25 mL) and cool in a dry ice/acetone bath. Add dropwise a solution of 2-nitrobenzylbromide (648 mg, 3 mmol) in DMF (2.5 mL). Stir for 18 h, allowing to warm to ambient temperature. Pour into water and extract with ethyl acetate/diethyl ether (100 mL/50 mL). Separate and wash the aqueous portion with ethyl acetate (50 mL). Combine organics and wash with 1N hydrochloric acid (2×100 mL), brine (2×100 mL), dry (MgSO4), and concentrate in vacuo to obtain a yellow solid. Purify by flash chromatography eluting with dichloromethane and then a gradient up to 10% ethyl acetate/dichlorometbane to obtain 833 mg (79%) of a yellow solid.