Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:5])C=O.[N-]=[N+]=[N-].[Na+].N([C:13]1[CH:14]=[C:15]([CH:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:20]C)[CH:16]=[CH:17][CH:18]=1)=[N+]=[N-].C(O)(C)C>O>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH:19]([C:15]1[CH:14]=[CH:13][CH:18]=[CH:17][CH:16]=1)[CH2:20][CH2:5][NH2:2]
Reactant: CN(C)C=O
Reactant: CCC(Oc1ccccc1OC)c1cccc(N=[N+]=[N-])c1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccccc1OC(CCN)c1ccccc1
Temperature: 95 °C

Procedure:
A solution of 2.6 g. of sodium azide in 10 ml. of water was placed in a 100 ml. three-neck, round-bottom flask equipped with stirrer, condenser and thermometer. A second solution containing 2.76 g. of 3-chloro-1-(o-methoxyphenoxy)propylbenzene (as provided by the procedure of Example 2) in 30 ml. of dimethylformamide was added to the sodium azide solution, and the resulting mixture heated at 95° C. overnight. The reaction mixture was cooled, diluted with water and extracted three times with ether. The ether extracts were combined, the combined extracts were washed five times with water followed by a saturated aqueous sodium chloride wash, and were then dried. Evaporation of the ether in vacuo yielded a colorless liquid comprising 3-azido-1-(o-methoxyphenoxy)propylbenzene. Forty-one grams of this latter compound were dissolved in 350 ml. of isopropanol. The resulting solution was placed in a 1 l. round-bottom flask equipped with magnetic stirrer condenser and drying tube. Fifteen and two-tenths grams of 96% sodium borohydride in the solid form were added to the azide solution. The resulting mixture was heating to refluxing temperature overnight and then cooled. The alcohol was evaporated therefrom in vacuo. About 1.5 l. of water were added, and the resulting aqueous mixture acidified cautiously with 2 N aqueous hydrochloric acid. 3-(o-methoxyphenoxy)-3-phenylpropylamine produced in the above reaction was soluble in the aqueous acidic layer as the hydrochloride salt. The acidic aqueous layer was extracted three times with ether, and the ether extracts saved to recover unreacted starting material. The acidic layer was then made basic with 5 N aqueous sodium hydroxide. The primary amine, being insoluble in base, separated and was extracted into ether. The ether layer was separated, and the aqueous alkaline layer extracted twice more with ether. The ether extracts were combined, and the combined layers washed with a saturated aqueous sodium chloride solution. Evaporation of the ether in vacuo yielded about 17 g. of 3-(o-methoxyphenoxy)-3-phenylpropylamine which was converted to the oxalate sale by the procedure of Example 1. 3-(o-methoxyphenoxy)-3-phenylpropylamine oxalate thus prepared melted at 118°-121° C. after recrystallization from an ethyl acetate-cyclohexane solvent mixture. The oxalate salt was converted to the hydrochloride salt by forming the free base in ether solution and then saturating the ether solution with gaseous hydrogen chloride. The hydrochloride salt melted at 77°-8° C. Analysis calc.: C, 65.91; H, 6.86; N, 4.77; Cl, 12.07; Found: C, 65.13; H, 7.12; N, 4.61; Cl, 12.21.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:15]([O-])=O.[C:18](OC(=O)C)(=[O:20])[CH3:19]>[Pd].CCOC(C)=O>[C:18]([NH:15][C:3]1[CH:4]=[C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:20])[CH3:19]
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(C(=O)CCC(=O)O)ccc1C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
10% Pd/C (100 g) was added to a solution of 4-(4-methyl-3-nitrophenyl)-4-oxobutanoic acid (73) (3.40 kg, 14.3 mol) and EtOAc (20 L) in 40 L Parr reactor. Acetic anhydride (2.40 L, 25.4 mol) was added. The mixture was stirred under about 5 bar H2 atmosphere overnight. The reaction was concentrated under reduced pressure. To the resulting grey solid was added EtOH (14 L) and H2SO4 (˜35 mL). The mixture was stirred in the 40 L Parr vessel under about 5 bar H2 pressure overnight at rt. The reaction mixture was poured into 2 N aqueous NaOH (35 L), stirred overnight at rt, and then filtered through of Celite® rinsing with water. The filtrate and washings were combined and concentrated under reduced pressure to remove EtOH. The aqueous residue was washed with tert-butyl methyl ether (7 L). The aqueous layer was acidified with 2 N aq. HCl. The precipitate was collected by filtration rinsing with water (2×14 L) and dried to afford 4-(3-acetamido-4-methylphenyl)-4-oxobutanoic acid (74) (2.70 kg, 76% yield). 1H NMR (300 MHz, DMSO): δ 12.03 (s, 1H), 9.25 (s, 1H), 7.50 (s, 1H), 7.30 (d, J=7.6 Hz, 2H), 6.88 (d, J=7.6 Hz, 2H), 2.56 (m, 2H), 2.28 (m, 2H), 2.16 (s, 3H), 2.04 (s, 3H), 1.74 (m, 2H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](C(CC)=O)[CH3:11]>>[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH2:10][CH3:11]
Reactant: CCC(=O)CC
Reactant: O=C(O)c1ccccc1
Product: CCC(=O)c1ccccc1

Procedure:
A method according to claim 1 wherein the ketone is diethyl ketone and the carboxylic acid is benzoic acid to yield propiophenone.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:51]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:51])[C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCC(=O)N1CCOCC1

Procedure:
2-(Ethoxymethyl)-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinoline (5.1 g, 14 mmol) was treated with mCPBA (5.57 g, 24.2 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (5.14 g, 26.9 mmol) according to a modification of the method described in Part D of Example 8. The reaction was not washed with 10% aqueous sodium hydroxide prior to the addition of ammonium hydroxide. The crude product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol) and then triturated with ethyl acetate and isolated by filtration to provide 0.843 g of 2-(ethoxymethyl)-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-4-amine as off-white needles, mp 187-189° C.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([S:21][CH3:22])=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: CSc1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Yield: 52 %

Procedure:
2,3,4-Trifluorobenzoic acid and the product of Example 26, Step B, 2-fluoro-4-methylthioaniline, were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, this material was purified by dry flash column chromatography on silica (0.5% Et2O in 1:1 CH2Cl2/hexanes as eluant) to afford 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]benzoic acid as a cream solid (52%); m.p. (Et2O/hexanes) 210-220° C. 1H NMR (400 MHz, CDCl3) δ 13.70 (br s, 1 H), 9.24 (br s, 1 H), 7.81 (ddd, J=9.0, 6.1, 2.1 Hz, 1 H), 7.20 (dd, J=11.8, 1.9 Hz, 1 H), 7.03-6.99 (m, 3 H), 2.47 (s, 3 H). Anal. Calcd for C14H10F3NO2S-0.125 Et2O: C, 54.0; H, 3.5; N, 4.3. Found: C, 54.2; H, 3.3; N, 4.5.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[CH3:25][S:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:31][C:30]1[CH:32]=[CH:33][C:27]([S:26][CH3:25])=[CH:28][CH:29]=1
Reactant: CSc1ccc(N)cc1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(SC)cc3)c2cc1OC
Yield: 95.1 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 181.0 mg (1.3 mmol) of 4-(methylmercapto)-aniline to give 334.1 mg (95.2%) of the product as a yellow solid, m.p. 235-237° C., mass (electrospray, m/e): M+H 351.9, 352.9, 353.8, 354.9.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:14][CH2:15][CH2:16]Br.[OH-].[Na+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:16][CH2:15][Br:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: BrCCBr
Reactant: Oc1ccc(Cn2cccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccc(Cn2cccn2)cc1
Temperature: 0 °C
Yield: 47.3 %

Procedure:
To a mixture of 15 g of 4-(1-pyrazolyl)methylphenol, 32.4 g of 1,2-dibromoethane and 150 ml of water was added dropwise 30 ml of an aqueous solution of 4.1 g of sodium hydroxide while stirring under heating at reflux over 2 hours. Then, after heating at reflux under stirring for further 30 minutes, the reaction mixture was poured into 200 ml of ice water, which was extracted twice with 100 ml of diethyl ether. The organic layers were combined, washed with 5N aqueous sodium hydroxide solution, water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 11.44 g of 2-[4-(l-pyrazolyl)methylphenoxy]ethyl bromide as white crystals. Yield, 47%.
Reaction SMILES: C([O:4][C:5]1[CH:36]=[CH:35][C:8]([C:9]([O:11][CH2:12][C:13]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[O:30][CH3:31])=[CH:21][CH:20]=[C:19]3[C:14]=2[C:15]([CH3:34])=[CH:16][C:17]([CH3:33])([CH3:32])[NH:18]3)=[O:10])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:13]([CH2:12][O:11][C:9](=[O:10])[C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:36][CH:35]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([CH3:32])([CH3:33])[CH:16]=[C:15]3[CH3:34])=[C:24]([O:30][CH3:31])[CH:25]=1
Reactant: COc1cc(F)ccc1-c1ccc2c(c1COC(=O)c1ccc(OC(C)=O)cc1)C(C)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(F)ccc1-c1ccc2c(c1COC(=O)c1ccc(O)cc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
5-(4-Acetoxybenzoyloxymethyl)-6-(4-fluoro-2-methoxyphenyl)-2,2,4-trimethyl -1,2-dihydroquinoline (Compound No. 12-5, 40.9 mg, 0.0835 mmol) and potassium carbonate (24.0 mg, 0.174 mmol) were suspended in anhydrous methanol (1 mL), and the mixture was stirred at room temperature for 1.5 hours. After the unsoluble materials were filtered, the filtrate was concentrated under reduced pressure, and ethyl acetate (50 mL) and water (50 mL) were added thereto, and then separated. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was filtered with hexane to give the titled compound (28.8 mg) as a colorless solid. (Yield 78%)
Reaction SMILES: [CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([Cl:16])[C:11]=2[N+:13]([O-:15])=[O:14])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[ClH:16].[CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]=2[N+:13]([O-:15])=[O:14])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1
Reactant: C1CCNC1
Reactant: CN(C)n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)c([N+](=O)[O-])c21
Product: CN(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCC3)c([N+](=O)[O-])c21
Product: Cl
Yield: 93.2 %

Procedure:
3.3 g of 1-dimethylamino-7-chloro-6-fluoro-8-nitro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are reacted with 6 g of pyrrolidine analogously to Example 11 and, after acidification to pH 1 with 10% strength hydrochloric acid, 3.4 g of 1-dimethylamino-6-fluoro-8-nitro-7-(1-pyrrolidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are isolated. After recrystallization from glycol monomethyl ether, the crystals have a melting point of 266°-268° C., with decomposition.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22]([O:24]C)=[O:23])[CH:9]=1)(=[O:3])[CH3:2].C1(N2CCNCC2)C=CC=CC=1.ClCCl>CS(C)=O>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22]([OH:24])=[O:23])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(=O)Nc1cc(NCCNC(C)=O)nc(-c2ccccc2)n1
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)NCCNc1cc(NC(=O)C(=O)O)nc(-c2ccccc2)n1
Reaction time: 16 h

Procedure:
To a well of a 96 well microtitre plate were added methyl [(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetate (30 μl of a 0.3M solution in anhydrous DMSO) and 4-phenylpiperazine (30 μl of a 1.5M solution). This solution was left to shake on a plate shaker for 16 hrs. After this time 800 μl of dichloromethane were added, then 100 mg of PS-NCO. The plate was sealed, then mixed for 48 hrs. The slurry was filtered and the solvents removed in vacuo, to furnish the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:22]4[CH:24]=[C:25]([NH:28][C:29](=[O:37])[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:36])[CH:26]=[CH:27][C:21]=4[CH2:20][CH2:19][C:18]=3[C:17]([C:38]([NH2:40])=[O:39])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:21]2[CH2:20][CH2:19][C:18]3[C:17]([C:38]([NH2:40])=[O:39])=[N:16][N:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[C:23]=3[C:22]=2[CH:24]=1)=[O:37]
Reactant: NC(=O)c1nn(-c2ccc(OCc3ccccc3)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nn(-c2ccc(O)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 84 h
Yield: 101.2 %

Procedure:
The final product from Example 259 (7.5 g, 0.014 mol) was dissolved of TFA (120 mL) and the dark brown solution was stirred at room temperature for 84 h. Solvent was removed and the residue was taken up with 200 mL of water. The solid was collected and air-dried to give 6.5 g of product as a pale white solid (83% yield); 1HNMR (DMSO, 400 MHz) δ: 10.29 (s, 1H), 9.84 (s, 1H), 7.24-7.51 (m, 11 H), 6.87 (d, 2H), 2.90 (m, 4H); Anal. Calcd. for C25H19ClN4O3+1.0 H2O: C, 62.96; H, 4.44; N, 11.75. Found: C, 62.92; H, 4.28; N, 11.76.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][O-:13].[Na+].O>CO>[CH3:12][O:13][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A roundbottom flask was charged with a solution of 6-chloro-2-methyl-3-nitropyridine (12.0 g, 69.36 mmol) in methanol (100 ml). Sodium methanolate (5.6 g, 103.70 mmol) was added and the resulting solution was stirred at room temperature for 24 hours. The mixture was poured into 100 ml of water and the solids that formed were collected by filtration to afford the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[N:13]([C@@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=4)[CH2:22]3)[CH2:16][C@H:15]2[OH:36])[C:12]2[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:11]=2[N:10]=1.C(N(C(C)C)CC)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][C:9]1[N:13]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C@H:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=4)[CH2:22]3)[CH2:16][CH:15]2[O:36][S:52]([CH3:51])(=[O:54])=[O:53])[C:12]2[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:11]=2[N:10]=1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@@H]1CCN(C[C@H]2Cc3ccc(NC(=O)C(C)C)cc3C2)C[C@H]1O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)nc(C)n2C1CCN(C[C@@H]2Cc3ccc(NC(=O)C(C)C)cc3C2)CC1OS(C)(=O)=O
Reaction time: 1 h

Procedure:
A solution of N-{(S)-2-[(3R,4R)-4-(2,5-Dimethyl-benzoimidazol-1-yl)-3-hydroxy-piperidin-1-ylmethyl]-indan-5-yl}-isobutyramide; compound with trifluoro-acetic acid (235 mg; 0.51 mmol) and diisopropylethylamine (122 mL; 0.7 mmol) in CH2Cl2 was treated with methanesulfonyl chloride (47 mL; 0.6 mmol). The reaction mixture was stirred for 1 h and then poured into saturated NaHCO3. The aqueous phase was extracted three times with CH2Cl2 and the combined organic layers were dried over Na2SO4. Filtration and removal of volatiles under reduced pressure gave a brown solid from which the methanesulfonic acid 4-(2,5-dimethyl-benzoimidazol-1-yl)-1-((R)-5-isobutyrylamino-indan-2-ylmethyl)-piperidin-3-yl ester was isolated by flash chromatography (0-10% CH3OH in EtOAc) as a waxy solid (171 mg; 62%)
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[H][H]>CO.[Pt]>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:1][C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)[CH2:15][CH2:14]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CN1CCNCC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Temperature: 80 °C
Yield: 69.4 %

Procedure:
A suspension of 4-formyl-benzoic acid (10.0 g, 67 mmol) in methanol (100 ml) is treated sequentially with 1-methylpiperazine (7.3 g, 73 mmol) and platinum (5%) on sulfided carbon (1 g). The resulting suspension is then heated at 80° C. and is subjected to a pressure of 5 bar of hydrogen for a period of 20 hrs until the hydrogen uptake is complete. The reaction mixture is cooled to room temperature and filtrated over a pad of Celite. Water (20 ml) is used to rinse the reactor and dissolve the fraction of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid that crystallizes on the walls during the cooling of the reaction mixture. The resulting aqueous solution is filtrated over the pad of Celite employed previously. The combined filtrates are concentrated in vacuo and crystallized in EtOH/H2O 9:1 v/v to give 10.9 g (70%) of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[CH:5]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17](B(O)O)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[NH:12][CH:13]=[CH:14]3)[CH:5]=1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(-c2ccc3[nH]ccc3c2)c1
Reaction time: 12 h
Yield: 24.5 %

Procedure:
2-Chloroisonicotinic acid methyl ester (1.22 g, 7.11 mmol), 1H-indole-5-boronic acid (1.15 g, 7.13 mmol), 2M-aqueous sodium carbonate solution (10 mL, 20 mmol) and tetrakis(triphenylphosphine)palladium (0.41 g, 0.35 mmol) were dissolved in toluene (140 mL), and stirred for 12 h under reflux. After completion of the reaction, ethyl acetate (200 mL) was added, and washed with aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by column chromatography to give the title compound (440 mg, 1.74 mmol, 25% Yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[CH3:1][O:2][C:3]([C:5]1([C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3cc(OC)c(OC)cc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a mixture of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (17.1 g, 70.5 mmol), as prepared in the previous step, and 4-chloro-6,7-dimethoxyquinazoline (15.0 g, 67.0 mmol) (Oakwood Products, Inc.) immersed in a −78° C. bath was added 1.08 M LiHMDS/THF (71 mL, 77 mmol) in ˜20 mL portions under argon via syringe along the sides of the flask (to allow cooling of the hindered base before reaction with the ester). Following completion of LiHMDS/THF addition, the reaction was allowed to sit in the −78° C. bath for 2-3 min before removing the cold bath and allowing the mixture to stir with gradual warming to rt. After 18 h stirring at rt, and an additional 2 d sitting at rt, the mixture was quenched with 0.5 M NaH2PO4 (150 mL) and extracted with DCM (1×150 mL and 1×100 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to provide the crude title compound as a translucent yellow oil that was used in the next step without further purification (33 g, “114%” crude yield). A small sample was purified by flash chromatography (1:1 hex/EtOAc) for characterization. 1H-NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H), 3.76-3.67 (m, 2H), 3.62-3.49 (m, 2H), 3.61 (s, 3H), 2.50-2.36 (br s, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 431.2, found 432.2 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](/[F:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([OH:14])=[O:13].[CH2:16]([N:19]1[CH2:23][C:22](=[O:24])[N:21]([CH2:25]O)[C:20]1=[O:27])[C:17]#[CH:18]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](/[F:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:14][CH2:25][N:21]1[C:22](=[O:24])[CH2:23][N:19]([CH2:16][C:17]#[CH:18])[C:20]1=[O:27])=[O:13]
Reactant: COC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: C#CCN1CC(=O)N(CO)C1=O
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C(/F)C(=O)OC)C2(C)C)C1=O

Procedure:
Using the procedure of Step B of Example 43, (1R,cis,E) 2,2-dimethyl-3-(2-fluoro-3-oxo-3-methoxy-1-propenyl)-cyclopropane carboxylic acid and [3-(2-propyn-1-yl)-2,5-dioxo-1-imidazolidinyl]-methanol were reacted to obtain [3-(2-propyn-1-yl)-2,5-dioxo-1-imidazolidinyl]-methyl (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-methoxy-1-propenyl]-cyclopropanecarboxylate with a specific rotation of [α]D20 =+3.5°±2° (c=0.5% in chloroform).